DE1236510B - Process for the preparation of acylaminotetramic acids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07d

German class: 12p -2

Number: 1236 510

File number: M 5 1853 IV d / 12 ρ

Filing date: February 17, 1962

Open date: March 16, 1967

The acylaminotetramic acids are so far only by treating 2 moles of acylglycine ester with Sodium has been produced. However, the yields in these processes are very unsatisfactory.

The invention relates to a process for the preparation of 3-acylaminotetramic acids of the general formula

Process for the production of
Acylaminotetramic acids

H
Ri - NH - C -

O = C

C = O

Applicant:

E. Merck Aktiengesellschaft,
Darmstadt, Frankfurter Str. 250

Ri - NH - C

C-OH

in the Ri lower acyl groups, R-2 a hydrogen atom and R3 is a hydrogen atom, lower alkoxyalkyl or lower dialkoxyalkyl groups or Ro and Ra together form a lower alkoxyalkylidene group and R4 represent a hydrogen atom or lower alkyl groups, which is characterized is that one mole of a compound of the general formula

I.
Ri - NH - CH

COOR5

R ₂

in which X is aliphatic acyl groups or the COOR5 radical and R5 is lower alkyl groups, with about 2 mol of a strongly basic condensing agent, optionally in the presence of an inert one.
Dr. Ulrich Schmidt, Freiburg (Breisgau);
Dipl.-Chem. Friedhelm Geiger,
Kenzingen (Bad.)

Heated solvent and, if appropriate, the reaction mixture obtained, small amounts of water clogs.

Strongly basic condensing agents that can be used are those that are customary for such condensations basic catalysts, for example alkali metal alcoholates, such as sodium methylate, sodium ethylate, Potassium methylate, potassium ethylate, potassium tert-butylate, potassium isopropylate or sodium amide, sodium hydride, finely divided alkali metal, alcoholic alkali hydroxide solutions, e.g. B. methanolic sodium hydroxide solution or ethanolic potassium hydroxide solution can be used.

The reaction according to the process can be carried out in the presence or in the absence of a solvent. If you work without a solvent, the reaction is carried out in the melt. The reaction temperatures when working in the melt are in the order of magnitude of about 80 to 150 ^° C., preferably about 100 ^° C.

If you work in the presence of a solvent, then, for example, the following solvents are used: alcohols such as methanol, ethanol, propanol, n-butanol, tert-butanol, tetrahydrofuran, Dioxane, diethylene glycol dimethyl ether, toluene, xylene. They are preferably used Solvent in which both the starting material and the basic condensing agent are soluble. The yields of the process are always best when one is more homogeneous Solution works.

709 519/539

When carrying out the reaction in the presence of a solvent can in many cases be a primary Condensation product that of the formula

Ri - NH - C

C = O

(Ri to R-i and X have the meaning given above) should correspond to, should be isolated, but this with further treatment with the named basic condensation agents - preferably in homogeneous solution -, optionally after addition of some water, can be converted into the corresponding 3-acylaminotetramic acid.

In the presence of a solvent, it is advantageous to carry out the reaction at about the boiling point of the To complete the solvent, if necessary by refluxing. So you can, for example the reactants at room temperature, possibly even with cooling, for Bring reaction and then after some time the reaction temperature up to the boiling point of the Increase the solvent used.

It has proven particularly advantageous to terminate the reaction by adding the reaction mixture add small amounts of water. The procedure here is roughly such that the mixture of the starting ester is added and the basic condensation agent, after briefly boiling under the reflux condenser, some water added and heated for a short time. The amount of water added is approximately in of the order of 1 to 5 mol, based on the ester used.

In most cases the reaction has ended when the boiling point of the solvent is reached. In isolated cases it is advisable to cook ^{for about 1 to} _{4 hours.}

The reaction products are worked up, for. B. by evaporating the reaction mixture up to dryness, taking up the residue in water and neutralizing the aqueous solution with mineral acid. If the acylaminotetramic acids obtained are sparingly soluble in water, they crystallize directly from the solution after neutralization and can be filtered off. Otherwise shakes the aqueous solution with a suitable organic solvent, such as chloroform, from. the End products can then be obtained from the combined extracts by evaporating the solvent will.

The following esters, for example, can be used as starting material for the implementation according to the method: N - («- Acetyl-a-acetaminoacetyl) - amino - methyl acetate, N - ( η - acetyl - H - acetamino - acetyl) - amino - ethyl acetate, Ν- (α-Acetyl-ra-acetamino-acetyl ) -amino-acetic acids - butyl ester, N - (a - alkoxycarbonyl - a - acetaminoacetyl) -amino-acetic acid methyl ester, N - («- alkoxycarbonyl-a-acetamino-acetylj-amino-acetic acid ethyl ester , N - {a - alkoxycarbonyl - a - acetamino - acetyl) amino acetic acid n-butyl ester, N-methyl-N- (a-acetyl - α - acetamino - acetyl) - amino - acetic acid methyl ester, N - methyl - N - (a - acetyl - α - acetamino - acetyl) -amino - acetic acid ethyl ester, N - methyl - N - (a - acetyl-α - acetamino - acetyl) - amino - acetic acid - η - butyl ester, N-methyl-N- ( a-alkoxycarbonyl-a-acetamino-acetyl) -amino - acetic acid methyl ester, N - methyl - N - (a - alkoxy-carbonyl-a-acetamino-acety ^ -amino-acetic acid ethyl ester, N - methyl - N - (α - alkoxyca rbon yl - α - acetamino-acetyl) -amino-acetic acid-n-butyl ester.

The starting compounds are in contrast to those used in the previously known syntheses Raw materials are relatively easily available. For example, one can use the α-acetamino-α-acetylacetylamino compounds win by reacting diketene with amino acid esters, nitrosating, reducing and acetylating. All of these mentioned implementations run in good yield. Starting compounds in which X is an alkoxycarbonyl group means are accessible from malonic acid ester chloride and amino acid esters with the following Nitrosation, reduction and acylation. These reactions also proceed in good yield. For the The above-mentioned production process of the compounds used as starting material is described in No protection claimed within the scope of the invention.

In the literature (R. N. L a c e y, Journal of the Chemical Society [London], 1954, pp. 850 to 853) Corresponding condensations with starting compounds have already been described, which instead of the Acyl - NH group contain a hydrogen atom. In these reactions, however, the radical X, which is acetyl, is retained. It was therefore surprising that in the presence of an acylaniino group, the radical X under the conditions of the process Implementation is removed practically quantitatively.

After the implementation according to the process, the tetramic acid derivatives are obtained in yields of 70 to lOO'Vo of theory.

After the implementation according to the process, for example 1 - methyl - 3 - acetylamino - 5 - diethoxymethyltetramic acid, 1 - methyl - 3 - acetylamino - 5 - ethoxymethylene -. tetramic acid, 3 - acetylamino - 5 - ethoxymethylene tetramic acid and l-methyl-3-acetylaminotetramic acid can be obtained.

The tetramic acid derivatives which can be prepared according to the process are valuable intermediate products for preparation of physiologically active compounds. Some of the substances themselves also have interesting ones pharmacological properties. In the form of their salts, especially their alkali and ammonium salts, the new compounds are readily soluble in water.

example 1

9.0 g (0.025 mol) of a- (diethoxymethyl) -N-methyl-N-ia'-acetyl-a'-acetamino-acetyO-amino-acetic acid ethyl ester are dissolved in 50 ml of methanol and, with stirring, form a solution of 0.055 mol of sodium methylate dropped into 20 ml of methanol. The mixture is refluxed for a further 20 minutes and then evaporated to dryness on a rotary evaporator. The solid sodium enolate comes in little Dissolved water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is filtered and the filtrate evaporated. 4.7 g (69% of theory) are obtained

1 - methyl - 3 - acetamino - 5 - diethoxymethyl - tetramic acid; Mp. 119 to 120 ^: C (from ether or petroleum ether).

Example 2

8.2 g (0.025 mol) of a- (ethoxymethylene) -N-methyl-N-ia'-methoxycarbonyl-a'-acetamino-acetyD-aminoacetic acid ethyl ester 12.5 ml of a 2 normal alcoholic sodium ethylate solution are added and heated to reflux. After 2 minutes, 25.5 ml of 2-normal alcoholic sodium ethylate solution are added and 2.5 ml of water were added and the mixture was refluxed for 15 minutes. The mixture is then on Rotary evaporator evaporated, the remaining sodium salt dissolved in a little water and with Washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and with chloroform shaken out. The chloroform solution is filtered and the filtrate is evaporated. You get 4.4 g of 1 - methyl - 3 - acetamino - 5 - ethoxymethylenetetramic acid (78.6% of theory) with a melting point of 225 to 226 C (acetone).

Example 3

18.1 g (0.05 mol) of a-diethoxymethyl-N - («'- methoxycarbonyl-rz'-acetamino-acetyb-ammo-acetic acid- ethyl esters are mixed with 50 ml of a 2 normal alcoholic sodium ethylate solution with the exclusion of moisture (= 0.1 mol) are added and the mixture is heated under reflux. After 2 minutes, a further 51 ml of 2-normal alcoholic sodium ethylate solution are added and 5 ml of water are added. The reaction mixture is refluxed for a further 15 minutes and then the ethanol is distilled off on a rotary evaporator. The solid residue is in as possible dissolved a little water and extracted with chloroform. The aqueous layer is now diluted with Hydrochloric acid acidified and the tetramic acid extracted with chloroform. The chloroformic Solution is filtered and then evaporated. The solid residue is recrystallized from acetone. 9.2 g of 3-acetamino-5-ethoxymethylenetetramic acid (86.8% of theory) with a melting point of 230 ° C. are obtained (Decomposition).

Example 4

45

27.4 g (0.1 mol) of N-methyl-N- (a-methoxycarbonyl- «-acetamino-acetyU-amino-acetic acid ethyl ester dissolved in 100 ml of methanol and, with stirring and with exclusion of moisture, to a solution of 0.21 mol of sodium methylate was added dropwise to 50 ml of methanol. The mixture is refluxed for a further 5 minutes heated and then the methanol is distilled off on a rotary evaporator. The solid residue is dissolved in as little water as possible, extracted with chloroform and the aqueous layer acidified with concentrated hydrochloric acid. The excreted l-methyl-3-acetaminotetramic acid is filtered off and recrystallized from water or from acetone; M.p. 206 to 207C; Yield 14.6g = 85% of theory.

Example 5

25.8 g (0.1 mol) of N-methyl-N- (a-acetyI-a-acetaminoacetyl) -amino-acetic acid ethyl ester are dissolved in 80 ml of methanol and added dropwise with stirring to a solution of 0.21 mol of sodium methylate in 50 ml of methanol. The mixture is refluxed for a further 10 minutes and then the methanol is distilled off on a rotary evaporator. The remaining solid sodium salt is dissolved in as little water as possible and washed with chloroform. The aqueous layer is acidified with concentrated hydrochloric acid and the precipitated 1-methyl-3-acetaminotetramic acid is filtered off with suction. Yield: 13.1 g = 77.1% of theory; M.p. 206-207 ^; C (water).

Example 6

9.4 g (0.025MoI) of α- diethoxymethyl-N-methyl-N-ia'-methoxycarbonyl-a'-acetammo-acetyli-aminoacetic acid ethyl ester are mixed with 12.5 ml of 2 normal alcoholic sodium ethylate solution and heated under reflux. After 2 minutes, a further 25.5 ml of 2-normal alcoholic sodium ethylate solution and 2.5 ml of water are added and the mixture is refluxed for a further 15 minutes. The ethanol is then distilled off on a rotary evaporator, the residue is dissolved in a little water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the tetramic acid is extracted with chloroform. The chloroform solution is filtered and the filtrate is evaporated to dryness. The remaining oil solidifies after a short time. 5.9 g (86.7% of theory) of 1-methyl-S-acetamino-S-diethoxymethyl-tetramic acid with a melting point of 119 to 120 ° C. (ether or petroleum ether) are obtained.

Example 7

6.5 g (0.025 mol) of N- (a-acetylamino-a-methoxycarbonyl-acetyl) -glycine ethyl ester are refluxed with 50 ml of normal alcoholic sodium ethylate solution. After 2 minutes, 55 ml of 1.0 normal alcoholic sodium ethylate solution and 5 ml of water are added and the mixture is refluxed for a further 15 minutes. The mixture is evaporated on a rotary evaporator, the residue is taken up in a little water and washed with chloroform. The aqueous layer is acidified with concentrated hydrochloric acid and the precipitated 3-acetylamino-tetramic acid is filtered off. Yield 3.2 g (82 ⁰ O of theory). After recrystallization from water, the product melts with decomposition at 256 to 257 ^: C and gives a blue enol reaction with aqueous iron (III) chloride.

Example 8

3 g of N-trt'-acetamino-a'-methoxycarbonyl-acetyl) -a-ethoxymethylamino-acetic acid ethyl ester are left to stand overnight at room temperature in 12 ml of normal absolute ethanolic sodium ethylate solution under nitrogen. A solution of 0.8 ml of glacial acetic acid in 30 ml of absolute ethanol is added dropwise to the 'solid crystal slurry while stirring under nitrogen, and everything goes into solution. After dilution with 20 ml of water, the solution is allowed to run over a strongly acidic cation exchanger (counterion H "*") to release the strongly acidic hydroxypyrrolone and the eluate is evaporated to dryness under reduced pressure. Yield 1.8 g of 5-ethoxymethyl - 3 - acetaminotetramic acid as pale yellowish crystals, which uncharacteristically ^{decompose between 180 and 190:} C with puffing after sintering from 160C; are sparingly soluble in solvents such as ether, chloroform, ethyl acetate, easily soluble in alcohol, water and dimethylformamide.

Claims (1)

Claim: Process for the preparation of acylaminotetramic acids of the general formula R ₁ - NH H -C- C = O / R, R4 IO 15th Ri - NH - C = C - OH / R ₂ C: Alkoxyalkyl or lower dialkoxyalkyl groups or R-2 and R3 together form a lower alkoxyalkylidene group and R4 represent a hydrogen atom or lower alkyl groups, thereby characterized in that one mole of a compound of the general formula X
Ri - NH - CH O = C COOR ₅
/ R2 R ₃ R ₄ "N ' in the Ri lower acyl groups, R2 a water atom and R3 is a hydrogen atom, lower in X is aliphatic acyl groups or the COORä radical and R5 is lower alkyl groups, with about 2 moles of a strongly basic condensing agent, optionally in the presence an inert solvent, heated and optionally the resulting reaction mixture adds small amounts of water.