DE2727528A1 - (n)-cyano-alkenyl-amino-acetic acid derivs, - intermediates for amino-acetamido beta lactam antibiotics - Google Patents

Abstract

Glycine derivs. of formula (I) are new. In the formula, R is residue of a natural or synthetic alpha-amino acid; R1 is H, opt. substd. alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl; R2 is H or opt. substd. alkyl; and Z is base residue, esp. Na or K. (I) are made by reacting RCH(NH2)COOZ with R1C(NH2)=C(R2)CN. Prodn. of beta-lactams of formula (IV), (Y is -S-C(CH3)2.CH(R3) or -U-CH2.C(CH2T)=CR4-. R3 AND R4 = opt. esterified carboxy; the ester gp. being any used conventionally in penicillins and cephalosporins, esp. silyl ester gps. T is H, alkylcarbonyloxy, OH, pyridinium, aminopyridinium, carbamoyloxy, N3, CN, thiocarbamoylthio, opt. substd. phenylthio or HetS-. Het = 5- or 6-membered heterocycle. U = O, S or CH3), comprises reacting the corresp. 6 (or 7)amino cpd. (V) with a mixed anhydride of (I), then removal of the N-protecting gp. (IV) are known antibiotics; specifically the method is used to make ampicillin. (I) are easily prepd. in good yield and form stable mixed anhydrides at relatively high temps. Subsequent hydrolytic removal of the N-protecting gp. is carried out without side-reactions.

Description

N- (1-Cyanalken-2-yl) 9OC-aminoacetic acids, whose origin

position process and process for the production of ß-lactam antibiotics The present invention relates to new N- (1-Cyanalken-2-yl) -lL-aminoacetic acids, a process for their production and their use as intermediates.

The new compounds can be expressed by Formula I. represent, in which R denotes the radical of a naturally occurring or synthetically produced dL-amino acid, R1 denotes hydrogen, an optionally substituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl radical, R2 denotes hydrogen or optionally substituted alkyl and Z denotes a base residue.

R preferably denotes hydrogen or an optionally substituted one Alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl or heterocyclyl radical.

Particularly preferred radicals R are: phenyl; by one to three substituents from the series alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, halogen, hydroxy substituted phenyl; Cyclohexadienyl; Cyclohexenyl; Thienyl; Furyl.

Examples of R include: p-methylphenyl, p-chlorophenyl, p-hydroxyphenyl, 1,4-cyclohexandien-1-yl, thienyl- (2), furyl- (2).

R1 preferably denotes hydrogen or alkyl with 1-4 carbon atoms, in particular Methyl and R2 preferably represent hydrogen.

Z preferably represents the metal radical of an alkali or alkaline earth metal hydroxide.

Examples of the compounds of the formula I according to the invention are called: N- (1-cyanopropen-2-yl) -α-aminophenylacetic acid, N- <1-cyano-buten-2-yl) - £ -aminophenylacetic acid, N- (1-cyano-styr-2-yl) -; -amino-p-hydroxyphenylacetic acid, N- (1-cyano-buten-2-yl) -d -α-amino-p-hydroxyphenylacetic acid, N- (1-cyano-styr-2-yl ) -α-amino-p-hydroxyphenylacetic acid, as well as the alkali, especially sodium and potassium salts of these compounds.

A particularly important intermediate is sodium N- (1-Cyan-proper2-yl) - I5-aminophenyl acetate.

To prepare the compounds of the formula I according to the invention, Oc-aminocarboxylic acids of the formula II are used in which R and Z have the meaning given above, preferably in the form of their sodium or potassium salts, with aminonitriles of the formula III in the presence of a solvent which is inert under the reaction conditions at temperatures between about +200 and about + 1200C and isolates the reaction product of the formula I.

The α-amino acids and their salts are known or can obtained by known processes for the synthesis of amino acids (amination of α-halogen fatty acids, Gabriel synthesis, Strecker synthesis, malonic ester synthesis, Aldehyde condensations; s.a. L.F. Fieser, M. Fieser, Organic Chemistry, Verlag Chemie, Weinheim, 1965, pp. 1275-1283). Examples of dL-amino acids which can be used according to the invention are: cL-aminophenylacetic acid, d-amino-p-hydroxyphenylacetic acid, aL-amino-p-chlorophenylacetic acid, & -Amino-p-methylphenylacetic acid, k-amino- (1, 4 -cyc lohexadien- 1 -yl) -es setic acid, The starting materials of the formula III are also known or can be prepared by methods known from the literature.

An example is ß-amino-crotonitrile, the alkaline Condensation of acetonitrile can be produced 9. Practical chemistry J 39, 230 (1889); FR-P 1,377,891; U.S. Patent 2,307,643.

When carrying out the process according to the invention, one uses pro Moles of amino acid, which is preferably used in the form of a salt, about 1 to about 1.1 moles of aminonitrile.

Suitable diluents are those organic solvents which are inert under the reaction conditions, i.e. no cause for side reactions give. Such solvents are ethers such as diethyl ether, tetrahydrofuran or dioxane, Alcohols such as methanol, ethanol, i-propanol, chlorinated hydrocarbons such as methylene chloride, Chloroform or carbon tetrachloride and dimethylformamide or dimethyl sulfoxide, whereby this list can only have an exemplary character.

Solvent mixtures, of which mixtures are also suitable, are also suitable Methanol and i-propanol are particularly suitable.

The reaction of II with III takes place at temperatures between approximately + 200C up to about + 1200C, preferably in a temperature range from about + 550C to about + 650C carried out.

The reaction time depends on the reactants, the diluent and the reaction temperature. In most cases it is about 2 to about 8 Hours. The reaction product is then isolated and purified in a manner known per se Way.

The described process for the preparation of compounds according to Formula I is generally applicable to protect the amino function of an aminocarboxylic acid, which is to be further implemented while retaining the amino function.

The N- (1-cyanoalken-2-yl) radical meets the requirements to a high degree which are placed on an amino protecting group.

So it can be introduced in a simple manner and with good yields, is inert under the conditions of peptide synthesis and can be easily and without Eliminate side reactions again.

It can be described as extremely surprising that »L-aminocarboxylic acids or their salts react very smoothly with aminonitriles under such simple conditions convert to N-protected aminocarboxylic acids of type I that these compounds with other carboxylic acids form remarkably stable anhydrides and that the hydrolytic Cleavage of the N-protective group takes place without side reactions.

In general, it is to be regarded as surprising that enaminonitriles suitable as N-protecting group in the formation of the peptide bond.

The N- (1-cyanoalken-2-yl) protective group is a particularly interesting form of use accordingly also peptide-like synthesis found in one of the present invention Compounds like the ß-lactam antibiotics.

The invention thus also relates to a process for the preparation of compounds of the formula IV in which R has the meaning given above and Y is the group stands, in which R3, R4 can stand for a free or esterified carboxyl group, where as ester groups all in the penicillin or. Ester groups known from cephalosporin chemistry come into consideration (especially the silyl ester group), T for hydrogen, alkyl-CO-O-, hydroxy, pyridinium, aminopyrodinium, carbamoyloxy, azido, cyano, thiacarbamoylthio, the optionally substituted group -S-phenyl, or the group -S-Het denotes in which Het stands for an optionally substituted heterocyclic 5- or 6-membered ring, and U stands for oxygen, sulfur or the CH2 group, which is characterized in that a mixed anhydride from a l- Amhnrostonibre of the general Fo = II and another carboxylic acid, the formation of this mixed anhydride by reacting the z -amino carboxylic acid of the general formula I or its salts with a corresponding derivative of the other carboxylic acid in a hydroxyl group-free organic solvent at temperatures between -300C and + 300C and takes place in the presence of a tertiary organic nitrogen base, with compounds of the general formula V in which Y has the meaning given above, and the N-protected reaction product obtained is hydrolyzed to split off the protective group in a pH range from about 0.5 to about 3.5, preferably 0.8 to 1.5 .

As examples of ß-lactam antibiotics according to the invention Processes which can be advantageously prepared include: .t-aminobenzylpenicillin (Short name: ampicillin), α-amino-p-hydroxybenzylpenicillin (short name: Amoxycillin) cl α-amino-p-methylbenzylpenicillin, al -amino-p-chlorobenzylpenicillin, 6- (2-Amino-2- (1,4-cyclohexadien-1-yl) -acetamido) -penicillanic acid (short name: Epicillin), 7- (d - aminophenylacetamido) -3-methyl-ceph-3-em-4-carboxylic acid, 7- (dL-amino-phenylacetamido) -3-acetoxy-methyl-ceph-3-em-4- carboxylic acid (Short name: cephaloglycine), 7- (-aminophenylacetamido) -3 - ((1-methyltetrazol-5-yl) -thiomethyl) -ceph-3-em-4-carboxylic acid, 7- (JL-Amino-phenylacetamido) -3 - ((2-methyl-13 # 4-thiadiazol-5 yl) -thiomethyl) -ceph-3-em-4-carboxylic acid as well as the sodium salts and the mono- and di- (trimethylsilyl) derivatives of these compounds.

It is known (US Pat. No. 3,316,247) that penicillins as described in of the side chain in the AL position carry an amino group, such as α gL-aminobenzylpenicillin, manufactured by 6-aminopenicillanic acid with a mixed anhydride from a chlorocarbonic acid ester and an α-aminocarboxylic acid protected on the amino group converts and then cleaves off the protective group again by simple hydrolysis.

The protection of the amino group is through condensation the JL-aminocarboxylic acid with a ß-dicarbonyl compound (ß-diketone, ß-keto acid ester) achieved.

However, this method has a number of disadvantages.

So it is common according to the current state of the art that in the production the water of reaction formed is removed from the N-protected aminocarboxylic acid, in order to obtain good yields and qualities, e.g. through azeotropic distillation.

Furthermore, the preparation of the mixed anhydride must be carried out after this Procedure must necessarily be done at -400C.

The reaction temperature must not rise above -300C and you must ensure good cooling.

In addition, such solutions must contain mixed anhydrides despite holding the temperature can be worked up very quickly, as the stability of these compounds is very low.

The method according to the invention has a number of advantages.

How to get the N-protected aminocarboxylic acid (in the form of its salts) in great purity and very good yields in a simple reaction by using the Aminocarboxylic acid (in the form of its salts) in an organic solvent with a Enaminonitrile is heated, with ammonia escaping as a gas.

It is also of great advantage that the mixed anhydride is produced from an N-protected sL-aminocarboxylic acid and a derivative of another carboxylic acid in the case of enaminonitrile Protection group is far more stable than the comparable anhydride with a B-dicarbonyl protective group, which has the advantage that the reaction can be carried out at higher temperatures and the mixed anhydride can hold in solution for a long time without decomposition.

If ß-aminocrotonitrile and D - (-) - pC-aminophenylacetic acid in the form of the sodium salt are used as starting materials, the course of the reaction can be represented by the following equation: If ethyl chloroformate is used as the other carboxylic acid component for the production of the mixed anhydride and 6-aminopenicillanic acid in the form of the sodium salt as a further starting material, the further course of the reaction can be represented by the following formula: The compounds of the formula V used as starting materials are already known or can be obtained by known methods (cf., for example, EH Flynn, Cephalosporins and Penicillins, Academic Press, New York and London, 1972).

Their use in the process according to the invention takes place in generally in the form of their esters and salts or other reactive forms.

The general manufacture of mixed anhydrides from N-protected Aminocarboxylic acids and from corresponding derivatives of carboxylic acids, e.g. chlorocarbonic acid esters is also known, e.g., U.S. Patent 3,325,379.

The implementation of such analogous mixed anhydrides with compounds of the general formula V is also known per se and is, for example, in U.S. Patent 3,316,247. In general one proceeds in such a way that one the solution of the mixed anhydride directly to a solution of the compounds of Formula V adds the N-protected penicillin or cephalosporin derivative obtained subjected to hydrolysis in a manner known per se to remove the protective group and then the free amino group-containing penicillin or

Cephalosporin isolated in a manner known per se.

Example 1 a) 43.25 g (0.25 mol) of D - (-) - α-aminophenylacetic acid sodium salt and 22.5 g (0.275 mol) of B-aminocrotonitrile are in 187.5 ml of methanol for 4 hours stirred under reflux. At the beginning a clear solution is formed, after 20 to 30 Minutes begin to form crystals of sodium N- (1-cyanopropen-2-yl) -D - (-) - aminophenyl acetate to deposit aminophenyl acetate. After 4 hours, isopropanol is added (200 ml) and let cool. The collected precipitate is 2 x with about 40 ml isopropanol washed and dried at 500C.

Yield: 53.5 g (90% of theory) sodium N- (1-cyanopropen-2-yl) -D- (-) - d: -aminophenyl acetate m.p .: 2910 (decomposition) [#] 20: -183 (C = 1; methanol) 578 b) 450 ml of acetone are cooled to + 10 °; there are 25.3 g (0.23 mol) of ethyl chloroformate, 0.53 ml of 3-dimethylaminopropanol-1 and 53 g (0.22 mol) of sodium N- (1-cyanopropen-2-yl) -D- (-) - -aminophenyl acetate added with stirring and then another 30 minutes stirred at this temperature. The colorless suspension obtained contains the resulting mixed anhydride in solution and sodium chloride as a solid.

c) In the meantime, at 0-5 ° C in 150 ml of water from 50 g (0.23 mol) 6-aminopenicillanic acid (6-APS) and 118 ml of 2N sodium hydroxide solution, a 6-APS sodium salt solution with a pH of 7.8 and pour this into 210 ml of acetone at -15 ° permit.

In this clear yellow solution you can now at -250 with stirring pour in mixed anhydride.

In the course of 20 minutes, the temperature now rises to -100. the Reaction solution is now largely at room temperature under reduced pressure freed of acetone. The light yellow concentrate obtained in this way becomes after it with 0 ° has been covered with 570 ml of isobutyl acetate, at 0-5 ° C with conc. hydrochloric acid adjusted to a pH of 0.5 to 1.5. Then you separate the lighter one Isobutyl acetate phase and washes it with a little water.

The combined aqueous phases are now at 0-5 ° with 2N sodium hydroxide solution adjusted with stirring to a pH of 4.4 within 20 minutes, including about 120 ml of sodium hydroxide solution are required. This creates a white crystalline one Precipitation. After stirring for a further 30 minutes, the crystal slurry is left for 10-20 hours stand at + 5 °.

The crystals collected on a filter are mixed with a little acetone and water each washed 2 times and dried at 450. 76.2 g of D - (-) - -aminobenzylpenicillin trihydrate are obtained (82.2% of theory, based on 6-APS) with an ampicillin content of 86.5%.

Example 2 a) Sodium N- (1-Cyanpropen-2-yl) -D - (-). (-Aminophenyl acetate is prepared according to Example 1a).

b) 180 ml of acetonitrile are cooled to +100; it will be 18.5 g (0.17 mol) ethyl chloroformate, 0.2 ml of 3-dimethylaminopropenol- (1) and 36.9 g (0.155 mol) of sodium N- (1-cyanopropen-2-yl) -D - (-) - £ -aminophenyl acetate with stirring added and then stirred for a further 30 minutes at this temperature.

c) In the meantime, from 40 g (0.147 mol) of 7-aminocephalosporanic acid (7-ACS) in 170 ml of acetonitrile at 0- + 50C by adding 70.4 ml (0.29 mol) of bis (trimethylsilyl) - acetamide silylated 7-ACS produced.

It becomes a suspension of the mixed in one serving at -250 Allowed anhydride to flow in. The flask is rinsed with 20 ml of acetonitrile.

The mixture is stirred for 1.5 hours at 0-5 ° C.

Then 200 ml of methanol and 40 ml of water are added at OOC. A pH of 1.5 is then set with dilute hydrochloric acid while stirring, which should remain constant for 30 minutes. Otherwise it has to be readjusted with dilute hydrochloric acid will.

Now 5 g of activated charcoal are added and the solution is filtered.

In the case of OOC, it is now made with triethylamine within 30 minutes a pH of 4.5.

At pH = 2.5 the precipitation of gel-like cephaloglycine begins, that soon crystallized.

After stirring for 2 hours and if necessary readjusting the pH the resulting crystal slurry is sucked off and first with acetonitrile, which is 24% Contains methanol and 12% water and then washed with a little pure acetonitrile.

The white crystals are dried over phosphorus pentoxide i.V. 200C.

46.6 g (78% of theory, based on 7-ACS) of cephaloglycine are obtained.

Claims (10)

Claims Compounds of Formula (I) in which R is the radical of a naturally occurring or synthetically produced amino acid, R1 is hydrogen, an optionally substituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl radical, R2 is hydrogen or optionally substituted alkyl and Z is a base radical designated. 2. Compounds according to claim 1, in which R is hydrogen or a optionally substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, Aryl, aralkyl or heterocyclyl radical. 3. Compounds according to claim 1, in which R is phenyl, by a up to three substituents from the series alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, Halogen, hydroxy-substituted phenyl, cyclohexadienyl, cyclohexenyl, thienyl or Called Furyl. 4. Compounds according to claims 1 to 3, in which R1 is hydrogen or alkyl with 1-4 carbon atoms. 5. Compounds according to claims 1 to 4, in which R2 is hydrogen designated. 6. Compounds according to claims 1 to 5, in which Z is for the Metal residue of an alkali or alkaline earth metal hydroxide, in particular potassium or Sodium stands. 7. Sodium N- (1-cyanopropen-2-yl-) ε-aminophenyl acetate. 8. Process for the preparation of compounds of the formula (I) in which R denotes the radical of a naturally occurring or synthetically produced .í -amino acid, R1 denotes hydrogen, an optionally substituted alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl radical, R2 denotes hydrogen or optionally substituted alkyl and Z denotes a base residue, characterized in that compounds of the formula (II) in which R and Z have the meaning given above, preferably in the form of their sodium or potassium salts, with aminonitriles of the formula (III) in the presence of a solvent which is inert under the reaction conditions at temperatures between about +200 and about + 1200C and the reaction product of the formula (I) is isolated. 9. Process for the preparation of compounds of the formula (IV) in which R has the meaning given above and Y is the group in which R3 and R4 can stand for a free or esterified carboxyl group, with all ester groups known in penicillin or cephalosporin chemistry (especially the silyl ester group), T for hydrogen, alkyl-CO-0-, hydroxy -, pyridinium, aminopyrodinium, carbamoyloxy, azido, cyano, thiacarbamoylthio, the optionally substituted group -S-phenyl, or the group -S-Het, in which Het stands for an optionally substituted heterocyclic 5- or 6-membered ring, and U stands for oxygen, sulfur or the CH2 group, by reacting a mixed anhydride of an aminocarboxylic acid of the general formula (I) and another carboxylic acid, the formation of this mixed anhydride by reaction of the aminocarboxylic acid of the general formula (I) or its Salts with a corresponding derivative of the other carboxylic acid in a hydroxyl-free organic solvent at temperatures between -30 ° and +300 and in the presence of a tertiary organic nitrogen base, with compounds of the general formula (V) in which Y has the meaning given above, is obtained by hydrolyzing the N-protected reaction product obtained in order to split off the protective group in a pH range from about 0.5 to about 3.5, preferably 0.8 to 1.5, and the compound of formula (IV) is isolated. 10. Process for the preparation of ampicillin according to claim 9, characterized in that the mixed anhydride of the formula with or reacts its carboxylic acid salt, splits off the protective group and isolates ampicillin.