DE1061329B - Process for the resolution of racemic threo-1- (p-nitrophenyl) -2-aminopropane-1,3-diol - Google Patents

Description

GERMAN

REGISTRATION DATE: JUNE 4, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: 1 6 JULY 1 9 5 9

The cleavage of racemic threo-1- (p-nitrophenyl) -2-amino-propane-1,3-diol (In the following this compound is racem. Aminodiol or the optically active Form called active aminodiol) by means of optically active acids of various types is already in the literature described several times. So it is already known, as optically active acid, tartaric acid or a diacyltartaric acid to be used, in an amount of 1 mole of diacid per mole of amine to be cleaved. Here become both optically active forms - those in the racem. Aminodiol are included - forming a acid salt converted into the salt form. The salts of the two optical isomers are then fractionated using Crystallization separated from each other.

It is also known to use a monobasic acid as the optically active acid, which is in an amount of 1 mole of optically active acid is used per mole of racemic aminodiol to be cleaved. Furthermore, one has an acid has already been used as the optically active acid to separate the phenylaminopropanediol, which, like glutamic acid, only salt with one optically active form of the base to be cleaved able to form. In this case, however, if a satisfactory yield is to be achieved, the optically active one must Acid in considerable excess, i.e. H. in the case of glutamic acid, 1 mole of glutamic acid per mole of racemic acid Aminodiol.

It has also been suggested to use phenylamino propanediols split into the optically active components by means of optically active tartraniles (chemical Zentralblatt, 1957, p. 5363). This creates a mixed diamide of tartaric acid, which is due to the different solubilities to split into the two optical isomers and afterwards by boiling with saponify dilute hydrochloric acid. The optically active Tartranil used for the cleavage is also used here saponified so that it cannot be used again. Apart from that, the whole split is proceeding very inconvenient.

It has been found that the racemic threol- (p-nitrophenyl) -2-aminopropane-1,3-diol can surprisingly easily be separated into the optically active components if the racemic aminodiol is only ^{1 to} ₂ mol of the hemiamide an optically active diacyltartaric acid, with a salt being formed only between the one optically active aminodiol and the optically active acid, which salt can easily be separated from the other aminodiol antipode.

The term half-amide of a diacyltartaric acid should not only refer to the half-amides that are unsubstituted on the nitrogen atom, but also include those whose nitrogen atom has one or two alkyl and / or aralkyl substituents wearing.

This procedure differs in this advantageous procedure

for the decomposition of racemic

threo-1 - (p-nitrophenyl) -2-amino-

propane-1,3-diol

Applicant:

CHINOIN Gyogyszer es Vegyeszeti

Termekek Gyara r. t.,

Budapest

Representative:

Dr. GW Lotterhos and Dr.-Ing. HW Lotterhos,
Patent attorneys, Frankfurt / M., Lichtensteinstr. 3

Claimed priority:
Hungary from January 28, 1958

Rezsö König and Dr. Zoltan Földi, Budapest,
have been named as inventors

of the previously known that the cleaving acid, which is only able to form salts which crystallize well with one optical modification of the two stereoisomers, only ^{needs to be used in an amount of about 1 to} ₂ mol of acid per mol of racemic aminodiol; the resulting salts, e.g. B. from the half-amide of diacyltartaric acid and the levorotatory aminodiol, crystallize well, so that they separate out during the salt formation from the reaction mixture in very good, sometimes almost theoretical yield and consequently have an excellent degree of purity.

Most of the acids used according to the invention are hardly soluble in water. You can therefore do without Regaining difficulties.

Since these acids are not described in the literature, methods for their preparation are given below specified.

According to an advantageous embodiment of the method of the invention, 1 mole of an optical active diacyltartaric acid half-amide with 2 moles of the racemic aminodiol base and the equivalent amount an inorganic acid, expediently hydrochloric acid, and the salt between the optically active aminodiol and the optically active acid of

909 577 / 4'5

separated the salt between the aminodiol antipode and the inorganic acid.

Another embodiment is that one mole of the optically active diacyltartaric acid half-amide in Form of a metal salt - including the unsubstituted or substituted ammonium group is considered such a metal - with 2 moles of the racemic Aminodiol - in the form of a neutral salt - converts and the salts formed of the two antipodes of the aminodiol separates from each other.

A halamide is expediently used as the optically active acid the diaroyltartaric acid, preferably a tartaric acid used with substituted or unsubstituted Benzoyl groups is acylated. These acids are usually rather poorly soluble in water and can therefore can be recovered practically quantitatively after the end of the cleavage process. It is It is also possible to use a hemiamide of a diacyl-d-tartaric acid as the optically active acid, which acts as acyl groups Residues of a low molecular weight fatty acid, e.g. B. acetic acid contains.

Suitable optically active acids also include the diacyl-tartaramic acids, e.g. B. from d-tartaric acid produced dibenzoyl-tartaramic acid, likewise diacyl-tartaramic acids, in which the nitrogen atom is replaced by two lower alkyl groups, e.g. B. methyl groups, is substituted, such as dibenzoyl-N-dimethyl-tataramic acid.

The following describes the preparation of some of the acids to be used in accordance with the present invention :

Dibenzoyl-d-tartaric acid half-amide

50 g of dibenzoyl - d - tartaric anhydride, melting point 194 ° C., are concentrated to a mixture of 40 ecm. Ammonia and 250 ecm of water are added, heated and nitrided. Then you put the cooled filtrate with cooling with about 30 ecm conc. Hydrochloric acid to a pn value of 1, an oil separating out which, after inoculation and stirring, can be converted into needle-like crystals. The crystals are suctioned off and washed with water. After drying, 42.4 g of a product are obtained which ^{melts at 187 °} C. (decomposition). The acidimetric titration gives an equivalent weight of 354 (calculated for dibenzoyl-d-tartaric acid half-amide: 357). It can be from 50 ° / ₀ methanol recrystallization. The specific rotation capacity in acetone solution is [α] 1 ° = -138 ° to -144 °.

Dimethyl half-amide of dibenzoyl-d-tartaric acid

5.1 g of dibenzoyl-d-tartaric acid anhydride is dissolved in a 17.5 ° / _o aqueous solution of 8 cc of dimethylamine under mild heating and then the filtered, cooled solution with about 3.5 cc conc. Hydrochloric acid adjusted to pH 1. Any oily product which precipitates out crystallizes on seeding and stirring. The crystals are separated, washed with water and recrystallized to 4.5 times amount of 50 ° / _o by weight of the alcohol from 4-. The product is obtained in hexagonal prisms; it melts at 150 ° C (decomposition). The yield is 85 to 91 ° / ₀ of theory. The acidimetric titration gives an equivalent weight of 383 (compared to 385 according to theory). The specific rotation in alcohol is [α] f? = -76 °.

Diacetyl-d-tartaric acid half-amide

2.16 g of diacetyl-d-tartaric anhydride are added to a mixture of 2 ecm of 11 n-ammonia and 3 ecm of water while cooling with ice and stirring. The solution obtained is left to ^{stand for about x} / ₄ hours at normal temperature, then acidified with about 1 ecm of conc. Hydrochloric acid, after standing in ice water for about an hour separates the crystals and washes them carefully with water. 1.85 g of a product which melts at 196 ° C. with decomposition are obtained. The specific rotatory power is [a] ² S = -28 ° in alcohol and [a] ² O ⁰ = -36 ° in acetone.

The cleavage process according to the invention is illustrated below with the aid of a few examples ίο be:

example 1

2.12 g (1 centimole) of racemic threo-1- (p-nitrophenyl) -2-aminopropane-1,3-diol are stirred with 10 ecm of water and with 5 ecm of n-HCl and then with 1.8 g (0.502 centimoles) of dibenzoyl-d-tartaric acid half-amide were added. An oily deposit forms temporarily, which changes into the crystalline form after further stirring. The reaction mixture shows a pn-value of 5. After 2 hours of stirring ¹ hour _J2 cooled in ice water, then the crystals are filtered, washed with water and dried. 2.7 g of the salt between the levorotatory aminodiol and the dibenzoyl-d-tartaric acid half-amide, which melts at about 128 to 129 ° C. in this degree of purity, are obtained. Its specific ability to rotate is [a] i ° = -84 ° in alcohol.

The 2.7 g of the salt obtained are heated to about 50 ° C. with 5 ecm of water and 10 ecm of n-HCl, a suspension being obtained which is thoroughly ground, then cooled in ice water and the crystals are separated off after about an hour , washes with water and dries. One gets 1.76 g (0.492 Centimol) back of Dibenzoyld-Wcinsäurehalbamids that melts without further purification at 188 ⁰ C (decomposition). The filtrate obtained during the isolation of the recovered dibenzoyl-d-tartaric acid half-amide is combined with the washing water and concentrated with about 2 ecm. Ammonia added. After inoculation, crystals separate out which, after cooling for about 2 hours in ice, are separated off, washed with water and dried. This gives 0.88 g (0.414 centimoles) of levorotatory l- (p-nitrophenyl) -2-amino-propane-1,3-diol, which melts in this degree of purity at 161 to 162 ° C and has a specific rotation capacity in n- HCl of [a] ² S = -26 °.

The mother liquor obtained after the separation of the salt between the dibenzoyl-d-tartaric acid half-amide and the levorotatory aminodiol and the corresponding washing water are concentrated with 2 ecm. Ammonia made alkaline, whereby crystallization begins. After standing in ice water, the crystals are filtered off, washed with water and dried. 0.95 g (0.448 centimoles) of dextrorotatory l- (p-nitrophenyl) -2-aminopropane-1,3-diol, which melts at 161 to 162 ° C. in this degree of purity, are obtained. The specific rotation in n-HCl is [α] f = + 22 °.

The filtrates of the optically active bases can be treated or extracted with solvents further amounts of the optically active bases can be isolated.

Example 2

1.06 g (0.5 centimole) of racemic threo-aminodiol are in a mixture of 5 ecm of water and 2.5 ecm Dissolved n-HCl at about 60 ° C. and the solution 0.96 g (0.25 centimoles) of dibenzoyl-d-tartaric acid-dimethyl-half-amide added, which for the most part goes into solution. When rubbing the wall of the vessel with the glass rod crystal deposition begins in the warmth.

The reaction mixture is then left for about 1 hour

Stand in ice water with stirring, filter off the crystals, wash them with water and dry them. 1.5 g (0.25 centimoles) of the salt between dibenzoyld-tartaric acid-dimethyl-hemiamide and the levorotatory aminodiol are obtained. This salt melts at 161 ° C (decomposition). The specific rotation in alcohol is [a] l ° = -74 °.

The salt obtained is in a mixture of 2.5 ecm Water and 5 ecm n-H Cl heated to about 60 ° C, then left to stand in ice water. The crystals are filtered off, washed with water and dried. The isolated The product is the dibenzoyld-tartaric acid-dimethyl-half-amide used for splitting, which is recovered in theoretical yield. After separating off the dibenzoyl-d-tartaric acid-dimethyl-hemiamide The filtrate obtained is combined with the washing water and 1 ecm conc. Ammonia added. The left turning Aminodiol begins to crystallize out immediately. After cooling in ice water and standing for a while, be the crystals separated, washed with ice water and dried. 0.45 g (0.213 centimoles) of the levorotatory are obtained Aminodiol, which in this degree of purity melts at 162 ° C and shows a specific rotatory power of -26 ° in n-H Cl.

From the mother liquor and the washing waters of the salt between dibenzoyl-d-tartaric acid-dimethyl-hemiamide and levorotatory aminodiol are converted into an alkaline reaction by adding ammonia the manner already indicated 0.45 g (0.213 centimoles) of the dextrorotatory aminodiol obtained in this Melts at 163 ° C and has a specific rotation capacity of + 24 ° in η-hydrochloric acid.

Example 3

2.12 grams (1 centimole) of racemic threo-aminodiol and 1.17 grams (0.506 centimoles) of diacetyl-d-tartaric acid half-amide are dissolved in 10 ecm hot methyl alcohol. After cooling, crystallization occurs. After removing the Methyl alcohol in vacuo and after the residue has been dried at 60 ° C. in vacuo, it is pulverized and rubbed with 6 ecm of water, then cooled in ice water and filtered after about a quarter of an hour. the Crystals are washed three times with 1 ecm each and then twice with 0.5 ecm each of ice water. The dried one The product (levorotatory aminodiol) weighs 0.99 g (0.467 centimoles) in this state. For the purpose of eventual further cleaning it is rubbed well with 1 ecm of ice water, placed on a suction filter, washed four times with 0.5 ecm of ice water each time and then dried. You get 0.78 g of the levorotatory aminodiol, which melts at 161 ° C in this degree of purity. It shows a specific one Rotational power of -28 ° in n-HCl.

The diacetyl-d-tartaric acid half-amide forms a well with the dextrorotatory aminodiol in methyl alcohol crystallizing salt. This melts at 179 ° C (decomposition). The specific rotation capacity of this Product is -4 ° in water. This salt dissolves in about five times the amount of ice water.

The levorotatory aminodiol forms diacetyl-d-tartaric acid half-amide with an equivalent amount in methyl alcohol Solution not a sparingly soluble salt.

The conditions in the cleavage reaction can be in various respects, e.g. B. choice of solvent, the temperature, the concentration, can be varied.

Claims (5)

PATENT CLAIMS 1. A process for the resolution of racemic threol- (p-nitrophenyl) -2-amino-propane-l, 3-diol into its optically active isomers, characterized in that the racemic aminodiol with about ¹ Z ₂ mol of a hemiamide is an optically active one Diacyltartaric acid is reacted and the salt of one optically active antipode of the aminodiol which is deposited is separated off with the optically active acid. 2. The method according to claim 1, characterized in that 1 mol of an optically active diacyltartaric acid half-amide with 2 moles of the racemic aminodiol base and the equivalent amount of an inorganic one Acid, advantageously hydrochloric acid, reacted and that from the one optically active component of the Aminodiol and the optically active acid, precipitating salt from the salt of the other optically active antipodes is separated with the inorganic acid. 3. Process according to Claims 1 and 2, characterized in that an optically active acid is used Half-amide of diaroyltartaric acid, preferably that with a substituted or unsubstituted benzoyl group acylated tartaric acid. 4. Process according to Claims 1 and 2, characterized in that an optically active acid is used Half-amide of a diacyl-d-tartaric acid is used, the acyl group of which is of a low molecular weight Fatty acid, e.g. B. acetic acid residue is formed. 5. Process according to Claims 1 to 4, characterized in that the optically active acid is used such diacyltartaramic acid used in which the nitrogen atom with two alkyl groups of lower Carbon number, e.g. B. is substituted with methyl groups. Considered publications:
U.S. Patent No. 2,742,500. © 909 577/416 7.