DE1920413C3 - Process for the optical cleavage of DL-lysine - Google Patents

Description

L-Lysine is an essential amino acid that is unlike D-Lysine for medicinal purposes as well is important for nutritional purposes.

In US-PS 29 34 561 a method for Cleavage of DL-lysine and thus described for the recovery of valuable L-lysine, which consists of To separate lysine into its enantiomers with the help of the optically active butane-2-sulfonic acid. The US PS 25 56 907 describes a process for the cleavage of DL-lysine using optically active glutamic acid or the ammonium salt of this acid.

From »Chem. Reviews ", 63 (1963), pages 297-309 a procedure known as selective crystallization is known, according to which racemic mixtures are resolved by selective crystallization. A prediction of whether or not a resolution of a given racemic modification is feasible, is generally not possible, so that every pair of optical isomers experimentally for one such Possibility needs to be investigated. So far it is only possible to have a limited number of connections to split into the enantiomers by selective crystallization, although there is no general rule which a prediction of the applicability of this cleavage method, not even in the case of compounds that differ greatly in terms of their chemical structure are similar. A prerequisite for the applicability of this cleavage method seems to be that the Solubility of the optical isomers is lower than that of the racemic modification, however It should be pointed out that a split is not always possible even if this requirement is met, as for example with DL-aspartic acid (cf. "Nature", 194 [1962], page 768).

JA-PS 68 03 601 describes the selective crystallization of DL-lysine (3,5-dinitrobenzoate). However, the yield from this process is quite low. In addition, the optical purity of the optically active lysine salt obtained is not particularly good as a Coprecipitation of the undesired antipode occurs during the selective crystallization, so that the optically active lysine salt obtained must be further purified. These disadvantages of the known method shows the comparative example below.

The object of the invention is therefore to create an economical method for the optical splitting of DL-lysine in its enantiomers, which does not have the above-described shortcomings of the known Procedure.

It has been found that by reacting DL-lysine with p-aminobenzenesulfonic acid, a salt obtained that many for selective crystallization has suitable favorable properties The racemic modification of lysine (p-aminobenzene sulfonate) is namely more soluble than the two enantiomers thereof. In a saturated solution of the racemic modifiers tion, the respective enantiomer is no longer dissolved. The supersaturated solution of an enantiomer is itself

ίο stable after the selective crystallization of the other enantiomer. Immediate crystallization occurs of each of the enantiomers. Even an enantiomer, for example D- or L-lysine \ p-aminobenzene sulfonate), can be selected from a supersaturated Solution of the racemic modification or from a supersaturated solution which contains the racemic modification and one of the enantiomers, can be crystallized out. This possibility of splitting into the enantiomes ren with the help of the p-aminobenzene sulfonate of DL-lysine In addition, it is also extremely surprising because it was not possible to obtain DL-lysine in the form of the following To split salts: hydrochloride, sulfate, nitrate, phosphate, Acetate, propionate, succinate, p-nitrobenzoate, benzenesul fonate, p-toluenesulfonate, o- or m-aminobenzene sulfo- nat, p-chlorobenzenesulfonate or m-nitrobenzenesulfonate. The fact that a separation is possible with the salt mentioned is therefore surprising and represent considerable technical progress.

The method according to the invention for the optical cleavage of DL-lysine by selective crystallization of a DL-lysine salt from a supersaturated solution of this salt in an inert solvent Adding crystals of one of the enantiomeric salts to

.15 the solution before and / or after reaching the State of supersaturation, letting it crystallize out, separating the crystals and converting them to optical active lysine or an acid addition salt thereof is characterized in that the optical cleavage with DL-lysine (p-aminobenzene sulfonate).

This procedure allows the implementation of the Cleavage of DL-lysine in much higher yield and in a much smoother way compared to the process known from JA-PS 68 03 601. the Splitting efficiency of DL-lysine (p-aminobenzenesulfonate) is about 1.6-2.1 times higher than that of DL-lysine (3,5-dinitrobenzoate) according to the aforementioned JA-PS. In addition, can according to the invention an optically active lysine salt in one obtained high purity, for example 98 to 100% amounts to. If, on the other hand, DL-lysine (3,5-dinitrobenzoate) is cleaved, coprecipitation takes place unwanted antipodes during the selective crystallization, so that the obtained optically active Lysine salt must be further purified. Another advantage that can be achieved according to the invention is that L-lysine (p-aminobenzenesulfonate), which is separated during the decomposition, can be easily racemized by a simple method, for example

ho by heating in the presence of water. One In contrast, racemization of DL-lysine (3,5-dinitrobenzoate) is achieved by heating in an inert Solvent not possible. To use D-lysine (3,5-dinitrobenzoate) as the starting material for the selective

'' To be able to use the crystallization process again, the lysine salt must be converted to another suitable salt, such as D-lysine hydrochloride, whereupon the racemization of the hydrochloride and then the

Conversion of the resulting racemate to its 3,5-dinitrobenzoate then follows called JA-PS known processes uneconomical. In one embodiment of the invention, a small amount of crystals of one of the enantiomers of the supersaturated solution added as seed crystals, and the mixture is stirred to allow the selective crystallization of the enantiomer with which was vaccinated to effect. Alternatively, a small amount of one of the enantiomers becomes in a hot solution the racemic modification resolved to give this enantiomer over the other in solution to make it dominant. The solution is then cooled, whereupon spontaneous crystallization of the enantiomer which has been added occurs. It is also possible to combine these processes with one another by dissolving a subset of the crystals of one of the enantiomers in the hot solution of the racemic modification and the remaining subset for seeding the over-saturated solution in which one of the enantiomers predominates over the other, is used. In this case, the amount of seed crystals can be reduced to a minimum. the supersaturated solution can be made from a solution of DL-lysine (p-aminobenzene sulfonate) in a suitable Solvent by using conventional procedures including cooling, concentration, addition suitable solvents or a combination of these procedures. The most practical way of preparing the supersaturated solution is to To cool a hot solution saturated with DL-lysine (p-aminobenzene sulfonate), since the solubility of this Salt increases with increasing temperature. The preferred proportion of the seed crystals to be added can be about 0.1% by weight of the solution, while the better cleavage results, depending larger the amount of seed crystals is In order to bring about a smooth optical cleavage, the seeding of the solution preferred. The temperature at which the crystallization is carried out is not critical in the process according to the invention, but it is preferred to work at around room temperature. The crystallization is carried out by passing the solution too stimulated a smoother course. Any inert solvent which DL-lysine (p-aminobenzene sulfonate) can dissolve and from which the compound is used as Able to crystallize conglomerate is suitable for the process of selective crystallization. Water, aqueous solvents, for example mixtures of water with alkanols with up to 6 Carbon atoms or a ketone with up to 6

table

"5

Carbon atoms are suitable for this purpose. As the solvent, water is the most suitable from an economic point of view.

After isolation of one enantiomer, the mother liquor, in which the other enantiomer predominates over the crystallized component, again for optical splitting for the other Enantiomers are used for this purpose, the mother liquor is concentrated to the original Restore concentration of the enantiomorphic mixture. Alternatively, an amount of the racemic modification, which is preferably the amount of the previously separated enantiomer is the same, are dissolved in the mother liquor. The procedure carried out in the previous treatment is repeated to separate the other enantiomer. In this way, the treatment cycle can be arbitrary are often repeated, the resulting racemic modification successively and completely in D- and

L-lysine (p-aminobenzene sulfonate) is cleaved. Further can in a preferred embodiment in the after the recovery of crystals of the desired Enantiomeric mother liquor additionally obtained under racemic modification at elevated temperature

Formation of a new supersaturated solution is dissolved and a small amount of the other enantiomer is excreted and recovered. That way Crystals obtained may sometimes vary depending on the state of the supersaturated solution as well as the extent

, o the crystallization should not be optically pure. The raw ones However, crystals are easy to purify because the solubility of the racemic modification is higher than that of each enantiomer, and since the enantiomer is in the saturated solution of the racemic

Modification does not resolve. Crystals with a 100% optical purity can be obtained in this way be that raw crystals are placed in a sufficient amount of a solvent, the Raw crystals are dissolved and the enantiome-

re lets crystallize and separated from the solution. For crystallization of the optically active enantiomer the solution can be used, for example, for cooling, concentration or the addition of a solvent or a combination of these procedural measures

apply men. Furthermore, any of the inert solvents described above can be used for this purpose can be used.

Melting point, specific rotation and solubility of DL-, L- and D-lysine (p-aminobenzenesulfonate) are

listed in the table below.

Lysine (p-aminobenzene sulfonate)

F. (Decomposition) Specific rotation,
(C = 2,! N-HCI)

solubility
(g / 100g water)

25 ° C

45 ° C

DL

Optically active lysine (p-aminobenzene sulfonate) thus obtained can be easily racemized by heating the aqueous solution of the enantiomer. To perform the racemization smooth, it is necessary, but not more than 210 ⁰ C to heat the solution to about 13O ⁰ C. The preferred racemization temperature

239 ⁰ C 0 66.1 90.6 251 ° C + 11.65 ° 42.7 63.1 251-C -11.65 ° 42.7 63.1

is around 140 to 190 ° C. The preferred amount of water to be used is about 0.33 bis 6s ten times the amount of the enantiomer, a larger one The amount of water slows down the rate of racemization.

The racemization can also be carried out

if a subset of the enantiomer is not in the Solution dissolves because such an insoluble portion of the enantiomer can gradually be dissolved and subjected to racemization as the Conversion of the dissolved subset d: s enantiomers into the racemic modification takes place The so obtained racemic modification can be recovered from the solution in a conventional manner and again can be used as starting material. Therefore, DL-Lysine-ip-aminobenzenesulfonat) in the desired Optically active enantiomers are converted by alternating the cleavage and the racemization of the invention can be combined.

Enantiomers of free lysine can be obtained from optically active lysine (p-aminobenzene sulfonate) without racemization by treatment with acid or acid Ion exchange resin and release of the resulting optically active lysines can be obtained. DL-lysine (paminobenzene sulfonate) is a new compound that by neutralizing DL-lysine with p-aminobenzenesulfonic acid in a solvent can.

Practical embodiments of the invention are illustrated in the following examples

example 1

16.5 g DL-lysine (p-aminobenzene sulfonate) are in 20 ml of water are dissolved by heating and cooled to 25 ° C. 1 g of L-lysine (p-aminobenzene sulfonate) is used added to the solution as seed crystals The mixture is stirred for 12 minutes at the same temperature, and the resulting crystals are collected by filtration. The crystals are washed with 60 percent by volume methanol and dried, whereby 2.7 g L-lysine (p-aminobenzene sulfonate) can be obtained.

[«] $ + 11.65 ° (C = 2, IN-HCl) optical purity = 100%

Example 2

42.0 g DL-lysine (p-aminobenzenesulfonate) and 2.5 g L-lysine (p-aminobenzene sulfonate) are dissolved in 50 ml of water by heating and cooled to 25 ° C. 0.2 g of L-lysine (p-aminobenzene sulfonate) are added to the solution as seed crystals. The mix turns 25 Stirred for minutes at the same temperature, and the resulting crystals are collected by filtration. The crystals are produced in the same way as in Example 1 washed and dried to obtain 7.0 g of L-lysine (p-aminobenzenesulfonate).

[et] 2? + 11.50 ° (C = 2.1 N-HCl) optical purity = 98.7%

Example 3

38.5 g DL-lysine (p-aminobenzenesulfonate) and 2.5 g D-lysine (p-aminobenzene sulfonate) are dissolved in 50 ml of water by heating to 70 ° C. The solution will be cooled to 25 "C. 50 mg of D-lysine (p-aminobenzene sulfonate) are added to the solution as seed crystals. The mixture is stirred for 65 minutes at the same temperature, and the resulting crystals are collected by filtration. The crystals are washed in the same manner as in Example 1 and dried to obtain 5.9 g of D-Lysm (p-aminobenzene sulfonate).

[et] f -11.45 ^C (C = 2.1 N-HCl),. optical purity = 983%

5.7 g are added to the mother liquor obtained after isolating D-lysine (p-aminobenzene sulfonate) DL-lysine (p-aminobenzene sulfonate) is added and the mixture is warmed until completely dissolved

ίο The solution is cooled to 25 ° C with 50 mg L-lysine (p-aminobenzene sulfonate) inoculated and then stirred at the same temperature for 65 minutes resulting crystals are treated in the same way as in Example 1, whereby 5.6 g of L-lysine- (p-aminoben-

■ 5 zolsulfonat) can be obtained.

C = 2.1 N-HCI) optical purity = 100%

To be carried out in L-lysine hydrochloride

3.20 g of the crystals in 2.5 ml of water by heating dissolved 2.5 ml of 6N hydrochloric acid are added dropwise added to this solution, whereby p-aminobenzenesulfonic acid is released as a precipitate. The solution is left in the refrigerator overnight, then the p-aminobenzenesulfonic acid is filtered off Fütrat water is added until the total amount is 40 ml. The solution is passed through a column with Given 20 ml of a strongly acidic cation exchange resin in the H + form. The column is with 50 ml Washed 1 N hydrochloric acid and water. Then it is eluted with 1N aqueous ammonia. The eluate is concentrated to remove the ammonia. The concentrated solution is adjusted to pH 4.5 with 1N hydrochloric acid. The solution is then concentrated to dryness and the residue thus obtained is washed with ethanol, whereby 1.69 g L-lysine hydrochloride can be obtained.

= 2.5 N-HCI)

Example 4

15.4 g DL-lysine (p-aminobenzenesulfonate) and 1.0 g L-lysine- (p-aminobenzene sulfonate) are in 20 ml Was ser dissolved by E ^r warming and cooled to 25 ° C. The solution is stirred for 45 minutes at the same temperature without seeding. The obtained crystals are collected by filtration, whereby 2.0 g of L-lysine (p-aminobenzene sulfonate) are obtained.

so Γλ-1 »ι hi» tr _ τ ι κι ufh

optical purity = 96.1%

Example 5

5.0 g of DL-lysine (p-aminobenzene sulfonate) and 0.2 g of D-lysine (p-aminobenzene sulfonate) are heated in 50 ml of 60 percent by volume aqueous ethanol dissolved and cooled to 25 ° C. 50 mg D-lysine- (p-

(io aminobenzolsulfonat) are added to the solution as seed crystals. The mixture is 4.5 hours at the left to stand at the same temperature, and the resulting crystals are collected by filtration, thereby obtaining 0.43 g of D-lysine (p-aminobenzene sulfonate)

ds be.

[«] F-ll, 6 ° (C = 2.1 N-HCl) optical purity = 99.6%

Example 6

7.50 g DL-lysine (p-aminobenzenesulfonate) and 0.40 g L-lysine (p-aminobenzene sulfonate) are dissolved in 20 ml of 50 percent by volume aqueous acetone with warming dissolved and cooled to 25 ° C.

0.10 g of L-lysine (p-aminobenzene sulfonate) are added to the solution as seed crystals. The mixture is stirred for 25 minutes at the same temperature and the resulting crystals are collected by filtration to give 1.24 g of L-lysine p-aminobenzenesulfonate _v) can be obtained.

[«]? + 10.3 ° (C = 2.1 N-HCI)
optical purity = 88.4%

Example 7

To 20 ml of the aqueous solution saturated with DL-lysine (p-aminobenzoisulfonate) at 25 ° C and 3.9 ml 10.0 g of L-lysine (p-aminobenzene sulfonate) with an optical purity of 74.2% are added to water. The The mixture is heated until it is completely dissolved. After cooling to 25 ° C, solution 2 Stirred for hours. The resulting crystals are collected by filtration and with a small amount Washed 60% aqueous methanol and dried to obtain 7.4 g of L-lysine (p-aminobenzene sulfonate) will.

[λ] J ⁰ + 11.65 ° (C = 2.1 N-HCl)
optical purity = 100%
Example 8

10.0 g of D-lysine (p-aminobenzene sulfonate) with an optical purity of 80.7% are mixed with 32 ml 60 percent by volume aqueous methanol is added and the mixture is heated to 50 ° C. to remove a portion of the crystals dissolve. The mixture is then stirred for 1 hour at 25 ° C. The crystals are collected by filtration, washed with a small amount of 60 percent by volume aqueous methanol and dried, 8.0 g of D-lysine (p-aminobenzene sulfonate) are obtained. The optical purity of the crystals is 100%.

Example 9

10.0 g of L-lysine (p-aminobenzene sulfonate) with an optical purity of 78.9% are added to 22.2 ml 50 percent by volume aqueous methanol is added and the mixture is stirred at 25 ° C. for 3 hours. the Crystals are collected by filtration with a small amount of 50 percent by volume aqueous Washed s methanol and dried, 7.8 g of L-lysine (p-aminobenzene sulfonate) being obtained. the optical purity of the crystals is 100%.

Attempts at racemization

ίο a) 30.0 g of L-lysine (p-aminobenzene sulfonate) will be 10 ml of distilled water were added. The part of the The mixture containing crystals which have not dissolved is heated to 145 ° C in a closed place for 20 hours Tube heated. After filtration of the reaction mixture

Is mixture the residue is washed with ethanol. 29.0 g of DL-lysine (p-aminobenzoisulfonate) are obtained.
F. 237 ° C (decomposition)

O] S ⁵ O ₁ O ⁰ (C = 4 in H ₂ O)

The degree of racemization is 100%.

b) 25.0 g of L-Lysip (p-aminobenzene sulfonate) are added to 10 ml of distilled water. The mixture is heated to 145 ° C for 6 hours, creating a solution with a specific rotation of

[«] 5, ⁵ H-3, r (C = 4inH ₂ O)

is obtained.

The extent of racemization of the optical enantiomer in the solution is 48%. 8.2 ml of water are added to the solution. The solution is stirred vigorously for a further hour at 25 ° C. and then the crystals are filtered off. The filtrate is concentrated to dryness, the residue thus obtained is washed with ethanol, 11.9 g of DL-lysine (p-aminobenzene sulfonate) being obtained.
F. 238 ° C (decomposition)

[ _Ä ] ^? _o ⁵ 0.0 ° (C = 4in water)

Comparative example

The results of Examples 1 and 2 of the JA-PS

68 03 601 and Examples 1 to 3 according to the invention are compared below in a table to the technical achievable according to the invention To show progress.

Used DL-lysine salt

Japanese patent publication 68 03 601

Example 1 Example 2

DL-lysine- (3.5-dinitro-

benzoate) monohydrate

Present invention

Example 1 Example 2 Example 3 DL-lysine (p-aminobenzene sulfonate)

Amount, g, of dissolved DL-lysine salt 36.0 144.0 16.5 42.0 38.5

Amount, g, of dissolved optically active lysine salt 0 0 0 2 ^ 2.5

Volume, ml of a solvent used (water) 100 400 20 50 50

Amount, g of the seed crystals 0.7 1.0 1.0 0.2 0.05

Yield, g of an optically active lysine salt 43 183 2.7 7.0 53

Optical purity,% 95.0 90.1 100.0 98.7 983

A 4.02 16.03 1.70 4.21 3.25

B 4.02 4.01 8.50 8.42 6.50

C 1.56 1.56 3.80 3.85 2 £ 8

Remarks:

A: The amount of cleavage (g) of an optically active lysine salt = yield (g) of an optically active lysine salt χ optical purity (%

- [amount (g) of the seed crystals + amount (g) of the dissolved optically active lysine salt}

B: Cleavage efficiency (g / 100 ml) of the lysine salt = A χ 100 / volume (ml) of the solvent used. C: splitting efficiency (g / 100 ml) of free lysine = B χ [molecular weight of free lysine / molecular weight de;

Lysine salt}

From the above results it can be seen that the method of the present invention is the cleavage of DL-lysine in a much higher yield and in a much smoother way possible. Furthermore According to the invention, an optically active lysine salt is obtained in a significantly higher purity.

Claims (1)

Claim: Process for the optical cleavage of DL-lysine by selective crystallization of a DL-lysine salt from a supersaturated solution of this salt in an inert solvent by adding Crystals of one of the enantiomeric salts to the solution before and / or after reaching the State of supersaturation, letting it crystallize out, separating the crystals and converting them to optical active lysine or an acid addition salt thereof, characterized in that the performs optical cleavage with DL-lysine (p-aminobenzene sulfonate)