DE960011C - Process for the production of DL- or D- or L-threo-1- (p-nitrophenyl) -2-dichloroacetamidopropanediol- (1,3) - Google Patents

Description

ISSUED JULY 13, 1961

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In recent times, chloramphenicol has gained considerable interest due to its therapeutically valuable properties. The compound has already been produced synthetically in several ways, using as a starting material because of the structural similarity in particular the ß (p-nitrophenyl) -serine or the jS-phenylserine or an ester thereof. For example, threo- / S- (p-nitrophenyl) -N-dichloroacetyl-O-acetylserine ethyl ester has been reduced with lithium aluminum hydride to give O-acetylchloramphenicol Furthermore, chloramphenicol was produced by reducing 5- (p-nitrophenyl) -a-dichloromethyl-oxazoline ^ -carboxylic acid esters using lithium aluminum hydride and subsequent hydrolytic cleavage of the oxazoline ring.

In the case of the non-acylated ß- (p-nitrophenyl) serine ethyl ester, however, only the erythro form, but not the threo form, could be reduced to the corresponding serinol with lithium aluminum hydride. The yields from most of these processes are not particularly good.

It has now been found that dl- or D- or L-threo-i- (p-nitrophenyl) -2-diehlQracetamidopropanediol- (i, 3) from dl- or D- or L-threo-ß- (p-nitrophenyl) -N-dichloroacetylserine esters can be obtained with good yield if this is reacted with hydrazine,

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allows nitrous acid to act on the hydrazide formed and then the reaction product with complex metal hydrides.

As a starting material in the process according to the invention, it is expedient to use the esters of dl-, D- or. L-threo - ^ - (p-nitrophenyl) -N-dichloroacetylserine with aliphatic alcohols such as methyl, ethyl, propyl, isopropyl, butyl, amyl alcohol and the like

ίο The reaction can also with the appropriate Serine esters of aromatic or aromatic alcohols or phenols are carried out.

The conversion of the / 3- (p-nitrophenyl) -N-dichloroacetylserine ester used as starting material The corresponding hydrazides are expediently carried out in inert solvents, such as, for example lower aliphatic alcohols, benzyl alcohol, dibutyl ether, dioxane, tetrahydrofuran and others. The hydrazine is expediently used in the form of its hydrate. The implementation can take place at room temperature or only moderately higher temperatures can be carried out.

It is particularly advantageous in terms of preparation that the hydrazides are sparingly soluble and from the reaction mixture fail; they can be converted into the azide without further purification.

The reaction of the hydrazides with nitrous acid takes place in a manner known per se, expediently with good cooling, the nitrous acid being set free from its salts during the reaction will.

Even for the subsequent reduction, it is not necessary to isolate the azide in pure form, rather one can convert the azide formed into organic

Absorb solvents, e.g. B. in ether or in mixtures of ether, and ethyl acetate and these Then add the solution of the reducing agent to the solutions.

Complex metal hydrides are used as reducing agents, such as lithium aluminum hydride, Magnesium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride and the like. The use of the water-resistant complex boron hydrides, especially des Sodium borohydrides, since with their help the azide is also reduced in organic water-containing solvents can be.

After the reduction mixture has been worked up, the process product is recrystallized obtained from water or from dichloroethane in pure form and good yield.

example 1

93 g of DL-threo-ß-ip-nitrophenylJ-N-dichloroacetylserine ethyl ester are dissolved in 320 ecm of anhydrous ethanol with heating. After adding 19 ecm of 85 ^O / _O igein hydrazine hydrate, the reaction mixture is left to stand for 12 hours at room temperature and the hydrazide which has separated out is then filtered off with suction.

Yield 73 g, melting point 218 ^° C. (corrected).

^I 7> 5 S DL-threo- _J ö- (p ^ -nitrophenyl) -N-dichloroacetylserine hydrazide are dissolved in 100 ecm 2 η-sulfuric acid with stirring and cooling (-3 to 0 ⁰ C) with a solution of 4, 5 g of sodium nitrite in 10 ecm of water are slowly added. The azide separates out in voluminous form. It is extracted from the reaction mixture using a mixture of ether and ethyl acetate (1: 1). This ether-ethyl acetate solution of the azide is finally washed with water and filtered to remove excess acid.

For the reduction of the azide whose Essigester ether solution is added dropwise under strong cooling (about -15 ⁰ C) and treated with a solution of 5 g 7o ° / ₀ sodium borohydride in 50 cc of water within half an hour stirring. After adding 50 ecm of methanol, stirring is continued for a further hour. The alkaline-aqueous layer is then separated off and extracted again with ethyl acetate. The combined ethyl acetate-ether extracts are now washed with 50 ecm n / 2-sulfuric acid and then with water. After evaporation of the solvent, 11 g of crude chloramphenicol remain. After this residue has been boiled with water and the aqueous solution has been treated with activated charcoal, the pure DL-chloramphenicol crystallizes out (possibly after concentration). Yield 7.7 g, melting point 152 ^° C. (corrected).

Example 2

93 g of DL-threo- | S- (p-nitrophenyl) -N-dichloroacetylserine ethyl ester are, as described in Example 1, converted into the DL-threo / 5- (p-nitrophenyl) -N-dichloroacetylserin azide and not the azide the specified mixture of ether and ethyl acetate, but only shaken out with ether. After the essential azide solution, which contains about 20 g of azide, has been thoroughly dried with anhydrous sodium sulfate, a solution of 4 g of lithium aluminum hydride in 500 ecm of anhydrous ether is added dropwise with stirring and good cooling. After stirring for a further 2 hours, 20 ecm of water are added to the reaction mixture. The residue is then separated off from the ether by suction and extracted three times for half an hour each time under reflux with boiling ethyl acetate. The combined ethyl acetate extracts are then shaken through with η-hydrochloric acid or η-sulfuric acid, then washed neutral with n / 2 soda solution and finally with water. The resin that remains after the ethyl acetate solution has been concentrated is taken up in boiling water. This solution is treated hot with activated charcoal, concentrated in vacuo to half and clarified again with activated charcoal. After further concentration to 50 cc of the DL-chloramphenicol crystallized from pure, mp 152 ⁰ C (uncorrected).

Example 3

5.4 g L (+) - threo- / 5- (p-nitrophenyl) -N-dichloroacetylserine hydrazide 40 ecm in sulfuric acid are added and a layer of 100 ecm ethyl acetate is added. Then, within half an hour, it becomes saturated drop by drop with good cooling aqueous solution of 1.3 g of sodium nitrite was added. The ethyl acetate layer is separated and still washed once with water.

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For the reduction of the azide formed is allowed to at -10 to -14 ⁰ C a solution of 1.0 g 8o, _^0/0 sodium borohydride in 25 cc of methanol over 10 minutes flow to and stirred for a further 30 minutes. The reaction mixture is then extracted with water. Finally, the ethyl acetate layer is treated twice with 5% sodium carbonate solution and with 0.5 N sulfuric acid. After concentrating the ethyl acetate solution, 4.5 g of a product with a syrupy consistency remain, which is dissolved in hot 1,2-dichloroethane. After standing for a while, the optically active chloramphenicol crystallizes out. Yield: 1.10 g, melting point 148-149 ⁰ C (capillary), oc ² S = + 20 ° (5 ° / _o solution in absolute ethanol).

The preparation of the hydrazide is carried out from the l (+) -ihxeo-SS (p-nitrophenyl) -N-dichloracetylserinäthylester ( "■ ff = +21.5 ⁰ Ui 2 ° / _o solution in methanol) according to the Example 1 specified regulation.

Claims (2)

Patent claims: 1. Process for the preparation of dl- or D- or L-threo-i- (p-nitrophenyl) -2-dichloroacetamidopropanediol- (i, 3) from dl- or D- or L-threo- ^ - (p- Nitrophenyl) -N-dichloroacetylserine esters, characterized in that they are reacted with hydrazine, nitrous acid is allowed to act on the hydrazide formed and the reaction product is reduced with complex metal hydrides. 2. The method according to claim 1, characterized in that that sodium borohydride is used as the complex metal hydride. © 109 615/11 7.