KR830000025B1 - Chemical Degradation of Racemic Mandelic Acid - Google Patents

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Chemical Degradation of Racemic Mandelic Acid

The present invention relates to the chemical decomposition of racemic mandelic acid and in particular to the preparation of D (-)-mandelic acid.

In addition to optically active mandelic acid derivatives, which are generally used for racemic degradation of amines, D (-)-mandelic acid is an important intermediate product for preparing semisynthetic cephalosporins.

It is known to decompose DL mandelic acid into optically opposite materials. It is prepared via diastereomeric salts formed from optionally active compounds, in particular optically active amines.

Cinquinine, Cynquinidine, Phenylethylamine, Ephedrine, Strycnin and Morphine have been described above as decomposition products of DL-mandelic acid in the “Table of Solubilizers and Optical Degradation”, (S.H. Wilen, 1972, Notre Dame, Indiana).

When decomposing DL-mandelic acid with cinnaquinine while using an animal amount in water, the diaskeomer salt begins to crystallize by injecting at a defined high temperature. Substantially recrystallization is needed to optically increase the purity. Yield yields about 80% of diasceromer bodies, which are cleaved to yield (+)-mandelic acid. (A. Mackenzie J. Chem. Soc. 75, (1899) 966).

Decomposition of DL-mandelic acid into (+)-phenylethylamine using an equimolar amount of solvent in water requires several recrystallizations to optically increase the purity. A diastereomer of about 86% yield is obtained, which breaks down the crystal salt to (-)-mandelic acid. (A.W. Ingersoll et al., J. Amer. Soc. 55, (1933) 411).

The yield can be increased by completely completing the operation with a large amount of solvent.

Decomposition of DL-mandelic acid to (-)-ephedrine using an equimolar amount of solvent in ethanol yields a diastereomer with a maximum yield of 85%. Decomposition of the crystal salt yields (-)-mandelic acid. It is necessary to recrystallize the diastereomer several times in order to increase the optical purity of mandelic acid. Yields from the rest of the operations are indeterminate but will be around 70%. (R. Roger, J. chem. Soc. 1935, 1544).

Degradation by morphine, strycnin, and cquinquinine has been described but incomplete, and because of its high toxicity, we do not recommend practical use.

Publications on racemic degradation of DL-mandelic acid are increasingly common for the degradation of optically active polymers by chromatographic or ion exchange effects, but not by phenylalanine.

(G. Blaschke, Chem. Ber. 107, (1974), 237).

Suitable thinners were treated with optically active amines but in most cases the degradation was incomplete and has not been done on a technical scale.

In practice, optically active amines used for racemic decomposition of Mandel are very expensive and relatively high in molecular weight and therefore require large amounts.

It is therefore an object of the present invention to provide a low cost disintegrant that has a versatile low molecular weight and high efficiency for use in racemic decomposition of DL-mandelic acid.

It is well-known that a racemate is decomposed | disassembled by fractional determination of the diaskere owner salt. Immediately hydrolyzing the salt used for the fractionation crystallization, using a reactant having the properties of an acidic group separates the desired left and right symmetry from the optically active side compound. It is unpredictable which compound separates particularly well. (G.L. Eliel, Stereochemie der kohlenstoff ver bindungen.Weienheim 1966, pg. 60 sg.)

DL-mandelic acid is reacted with D (-)-2-aminobutanol- (1) in a mixture of water, aliphatic alcohols and ketones or in a single solvent to separate the diastereo salt crystallized from the mother liquor and contained in the crystal product and mother liquor. The preferred diastereomer salts can be separated into acids or bases by known methods to produce optically active acids and D (-)-2-aminobutanol, respectively.

Decomposition of the racemate with L (+)-tartaric acid readily yields D (-)-2-aminobutanol- (1) from racemic 2-aninobutanol- (1). German Patent 1 234 206

The D (-)-2-aminobutanol- (1) is rapidly racemized and can be easily purified by distillation without expensive addition. 2-aminobutanol- (1) also has a low molecular weight and dissolves very well in the solvent used for racemic decomposition. After completion of the decomposition, the used amine is recovered in a conventional manner and recycled to the reaction process.

The optically active form of 2-aminobutanol- (1) was used early as a reactant when degrading racemates.

Technically (eg tables of solubilizers and optical degradation), polymer bases (particularly secondary or tertiary nitrogen atoms) were suitable for the racemic decomposition of mandelic acid.

In this case, upon completion of the reaction according to the invention, a pure optically active mandelate with a total yield of about 90% is obtained regardless of the solvent used.

With appropriate concentrations, the pair can be precipitated with a high optical purity diastereomeric salt suitable for the following operations.

When D (-)-2-aminobutanol- (1) is used, the (-) and (-)-salts are crystallized from ketones such as water, lower alcohols and acetone. Conditions for sufficient purity and yield of about 90% are determined by varying the fender. The reaction is carried out at room temperature (the mixture is heated by exothermic reaction) and shaken from the beginning to mix. It is not necessary to add the corresponding crystals to speed up the settling.

In a series of experiments with varying solvents and solvent mixtures and different compositions and concentrations, it can be seen that the yield and optical purity of the diastereomer salts vary according to the concentration change. The most preferred concentration of the suitable solvent is determined by experiment. Water, which is used as a diluent for alkanols, generally reduces the yield but has little effect on the diastereomeric purity of the salt.

Optically active aminobutanol in a portion of 0.5 to 1.0 equivalent is used for the racemic decomposition of DL-mandelic acid. This amount is preferred because the yield is best when the amount of aminobutanol mandelic acid is equal.

=-80.3°가 다이아스테레오머염의 가장 높은 광학적 편차로 측정된다. 산을 분해하면 적어도 -79.0°의 일정한 편차를 염이 적어도 96.5%의 광학적 순도를 갖는 광학적으로 활성인 D(-)-만델산으로 된다. (

=-152.3°)The product obtained in the above experiment is washed with 5-20 ml of ethanol to purify the crystal salt. Re-decision several times

= -80.3 ° is determined as the highest optical deviation of the diastereomer salt. Decomposition of the acid results in a constant deviation of at least -79.0 °, with the salt being optically active D (-)-mandelic acid having an optical purity of at least 96.5%. (

= -152.3 °)

To calculate the optical purity of mandelic acid, it was compared with the highest deviation in the literature.

=-157.5°(물, C =3.2) (R.Roger, J. Chem, Soc. 1935, 1544)

= -157.5 ° (water, C = 3.2) (R. Roger, J. Chem, Soc. 1935, 1544)

=-157.3°(물, C -1.4) (Schwab et al., z. Physiol. Chem. 215, (1933), 121)

= -157.3 ° (water, C -1.4) (Schwab et al., Z. Physiol. Chem. 215, (1933), 121)

Salts of D (-)-mandelic acid with D (-)-2-aminobutanol- (1) not yet known in the literature have the following references. Melting point = 130-131 ° C (ethanol)

=-80.3° (C=2, H₂O)

= -80.3 ° (C = 2, H ₂ O)

H-NMRD ₂ O: (Na-TMS) 0.90 (+, 3); 1.55 (m, 2); 2.9-3.9 (m, 3); 4.83 (S, 5); 4.98 (S, 1); 7.45 (m, 5)

Elemental Analysis of C ₁₂ H ₁₉ NO ₄

Calc .: C 59.7%; H 7.9%; N 5.8%

Found: C 59.8%; H 7.7%; N% .8%

The invention is illustrated by the following examples.

Example 1

60.8 g of DL-mandelic acid (0.4 mole) is dissolved in 140 ml of ethanol (95% by volume) with stirring in a 300 ml Elenmeyer flask. Add 35.6 g of D (-)-2-aminobutanol- (1) (0.4 mole) to mix the solution and then add a small amount of D (-)-2-aminobutanol D-(-)-mandelate. After determining the solution, leave it overnight. The precipitate was strongly suction filtered, absorbed into 45 ml of ethanol, heated to melting point for a short time, cooled and filtered again. The residue is washed with 1.5 ml of ethanol (95% capacity) and dried at 50 ° C. in a drier.

=-79.3°의 일정한 편차를 갖는 무색의 D(-)-2-아미노부탄올 D-(-)-만델레이트가 43.8g 얻어진다. 사용한 DL-만델산을 기준으로 한 수득률은 90.8%이다.Melting point is 130 to 131 캜

43.8 g of a colorless D (-)-2-aminobutanol D-(-)-mandelate having a constant deviation of = -79.3 ° are obtained. The yield is 90.8% based on the DL-mandelic acid used.

=-155.2°(98.6%의 광학적 순도)의 이정한 편차를 갖는 25.8g의 D(-)-만델산이 얻어진다. 수득률은 95,0%이며 DL-만델산을 기준으로한 총수득률은 84.9%이다.To liberate mandelic acid, 43.0 g of D (-)-2-aminobutanol D-(-)-mandelate is dissolved in 150 ml of water and 16 ml of hydrochloric acid (37% by weight) is added to pH 0.8. Extract with 360 ml of diethyl ether (1 × 120 ml, 4 × 60 ml). The organic extract is combined with sodium sulfate, dried and evaporated to dryness in vacuo. After drying, melting point is 133 °

25.8 g of D (-)-mandelic acid are obtained with a deviation of = -155.2 ° (optical purity of 98.6%). The yield is 95,0% and the total yield based on DL-mandelic acid is 84.9%.

The racemate is digested with aminobutanol to separate L (+)-mandelic acid from the precipitated product, and the same treatment with hydrochloric acid without separation of (-) and (+)-salts is followed by extraction with diethyl ether.

=-130.4°(=82.8%의 광학적 수도)의 일정한 편차를 갖는 26.5g의 L(+)-만델산이 얻어진다. DL-만델산을 기준으로 산출한 수득률은 87.2%이며 이는 소량의 디에틸에테르로부터 분별 결정하여 L(+)-만델산의 광학적 순도를 수득률의 차변까지 증가시킬 수 있다.When dry

26.5 g of L (+)-mandelic acid are obtained with a constant deviation of = -130.4 ° (optical capital of = 82.8%). The yield calculated on the basis of DL-mandelic acid is 87.2%, which can be fractionally determined from a small amount of diethyl ether to increase the optical purity of L (+)-mandelic acid to the debit of yield.

(-)-2-aminobutanol-(1) is separated by an anion exchanger, for example, distilled in vacuo and purified, and then used again.

The following examples are carried out in a similar manner and only vary the molar ratio of mandelic acid / aminobutanol or the amount and composition of the solvent. 0.1 moles each time, with a deviation of ± 0.5 °.

Claims (1)

In the chemical decomposition of racemic mandelic acid and in particular in the process for producing D (-)-mandelic acid, DL-mandelic acid is dissolved in D (-)-2-aminobutanol-(1) and water, lower aliphatic alcohols and ketones. Optically active, characterized in that it is reacted in a selected solvent or a mixture of these solvents, and the diastereomeric salts crystallized in the mother liquor are separated, and then the diastereomer salts contained in the crystalline product and the mother liquor are separated by an acid or a base. Process for preparing phosphoric acid and D (-)-2-aminobutanol (1).