DE2024062B2 - PROCESS FOR SEPARATION AND RECOVERY OF L-LYSINE - Google Patents

Description

The invention relates to the separation of the racemic form of d-lysine and 1-lysine into the individual Components (d-lysine and 1-lysine) using 5-oxo-2-pyrrolidinecarboxylic acid or its ammonium salt as an optical separation agent.

The naturally occurring form of lysine is 1-lysine, which is optically active. With chemical synthesis obtained lysine does not have this property, however, since it is available as an equimolar mixture of d-lysine and 1-lysine is present. 1-Lysine is used for many purposes, for example as feed, as entrophes Agent or medicine, as it has physiological activity.

It is easy to manufacture d, 1-lysine industrially, but its physiological activity is only half that large as that of 1-lysine. The d-form of lysine has no such p'r "logical activity as many other α-amino acids. As a result of the present invention, it is considered industrially possible to Obtain 1-lysine by chemical synthesis. The invention provides a simple and effective method Separate d, l-lysine into the individual components d-lysine and J-lysine.

So far it has been suggested for the purpose of splitting before d, l-lysine into d-lysine and 1-lysine, Use 5 optical resolution agents which are themselves optically active acids. Following this method will d, l-lysine reacted with an optical resolution agent, and this reaction yields diasteroisomers, which have different solubilities, and

ίο then 1-lysine is due to the different Solubility by filtration, centrifugation or the like. Obtained. This is one of the most typical methods at the optical separation.

In the optical separation of d, l-lysine, however, various known optical ones were found Dissolution mu'el with optical activity, such as camphoric acid, Di-benzoyl-d-tartaric acid, glutamic acid with optical activity and l, l-methylene-bis- (5-oxo-2-pyrrolidinecarboxylic acid) with optical activity on an industrial scale to be unsatisfactory. When camphoric acid was used as an optical separation agent, it was found necessary to Carry out recrystallization steps and repeat these several times to obtain pure 1-lysine, because of the small difference between the solubility of the 1-lysine salt to be obtained and d-lysine salt. Therefore, 1-lysine was recovered in low yield at best. Besides, there was such Camphoric acid was expensive and difficult to obtain on an industrial scale. In the case of dibenzoyl-d-tartaric acid the obtained d-lysine salt had a lower degree of solubility than the others Salts, so that this salt was obtained first and it was difficult to separate the 1-lysine from the reaction mixtures. Glutamic acid with optical activity has been a preferred resolving agent to date. That however, solvents used in this process had to be carefully chosen to be good Achieving result, and particularly careful handling was required in this method because of the moisture absorption by the lysine glutamic acid salt. When 1,1-methylenebis (5-oxo-2-pyrrolidinecarboxylic acid) was used, it was found necessary to recrystallize several times to obtain 1-lysine with high purity, since this agent has poor separation ability.

It was found that 5-oxo-2-pyrrolidinecarboxylic acid with optical activity and its ammonium salt have excellent properties for optical Separation of d, l-lysine into d-lysine and 1-lysine.

The object of the present invention is achieved in the following way:

a) A solution of a mixture is prepared, the d- and 1-lysine and the d-isomer of 5-oxo-2-pyrrolidinecarboxylic acid or its ammonium salt or the 1-isomer of 5-oxo-2-pyrrolidinecarboxylic acid or the ammonium salt thereof, of these compounds the d-isomer or its ammonium salt reacts with d-lysine to form an insoluble product, while the reaction product reacts with 1-lysine remains soluble and the 1-isomer or its Ammonium salt reacts with d-lysine to form a soluble product, while the reaction product with 1-lysine remains insoluble, whereupon one (b) the insoluble reaction product obtained from the soluble reaction product obtained according to ar

known methods and (c) 1-lysine by 0.7 to 1.0 mol, per mole of d, l-lysine. The solvents too per se known methods either by amount is not critically limited, but will the soluble or insoluble reaction - usually about 270 to 1500 percent by weight, product containing 1-lysine wins. preferably 410 to 610 percent by weight, based on

In the present invention, the optical 5 on the weight of the d, l-lysine, are used. To the

Resolving agents such as the d- and I-isomers to accelerate crystallization of the optical isomer salt

5-Oxo-2-pyrrolidinecarboxylic acid (PCA) and its amines, it is preferred to use a precipitating agent such as

monium salts, commercially available. For example I-lysine / 1-PCA salt and d-lysine / d-PCA salt, to be

these remedies are easy to turn from glutamic acid with. When 1-PCA or its ammonium salt is used as

synthesized optical activity. io separation agent used is 1-lysine / l-PCA-

The optical resolution reaction according to the invention salt useful. When d-PCA or its ammonium manure is carried out in a solvent. salt is used as the resolving agent, water and organic solvents with affinity for d-lysine / d-PCA salt are useful. Such an outwater as low molecular weight aliphatic alcohols precipitant is added to the solution obtained by reaction and low molecular weight aliphatic ketones. The amount of the appropriate solvent to be added. For example, methanol, precipitant is normally 0.1 to 1.0 Ge-ÄtbanoJ, propanol, isopropanol, acetone, methyl percent by weight, preferably 0.3 to 0.5 weight ethyl ketone and mixtures thereof are the preferred percent by weight des d, l-lysine. In order to obtain solvents and aqueous solutions of this organ- a crystalline salt in a higher yield ratio to small solvents with a content of 2 to 20, the addition of an unlimited amount of water - 20 percent by volume of water are even more preferred. soluble organic solvent to the solution. Aqueous methanol at a level of 2 to 4 may be preferred, which has a very low ability, 20 volume percent, is the most preferred to dissolve the crystalline product of the optical isomer salt solvent in the practice of the process. Methanol, ethanol and acetone are according to the invention. ₂₅ typical such solvents.

The reaction temperature is not limited critically. In the present invention, it is preferable to use the reaction usually at 20 to the same solvent as in the precipitation 70 ⁰ C, preferably at about 50 ⁰ C, with stirring reaction. If especially an aqueous one, carried out. Lysine (d-, 1-lysine) reacts with PCA with low molecular weight alkanol or an aqueous, low optical activity to form a solution of the 30 molecular weight alkyl ketone or a mixture for this reaction mixture. The 1,1-form or the d, d-form, is used for the reaction, this is an optical isomer salt, gradually falling solvent continuously also for the Ausaus, if the solution to about 5 to 40 ^c ' C, precipitation stage used, even without the addition of a preferably holds about room temperature. organic solvent.

In the case of the optical resolution according to the invention. In the present invention, the expression 1-lysine reacts when 1-PCA or "d, 1-lysine" or "lysine" is used not only a racemic ammonium salt thereof with 1-PCA to form Mixture or compound of d-lysine and I-lysine / 1-PCA salt with low solubility in water, 1-lysine, but can also be a composition and d-lysine reacts with 1-PCA to form, which is derived from d -Lysine and 1-lysine and in which a d-lysine / 1-PCA with a very substantial water 40 of the two components is present in excess, solubility. On the other hand, when d-PCA or its resulting insoluble low ammonium salt product is used, I-lysine reacts with moisture absorption from the resulting d-PCA to form 1-lysine / d-PCA salt with soluble product after any conventional substantial solubility in water, and d-lysine method, such as by filtration, centrifugation and the like, reacts with d-PCA to form d-lysine / d-PCA 45 separated. In this way you will be 1-lysine and with very little water solubility. There is ad-lysine separated from each other,
large difference in solubility between the 1-lysine is obtained by the conventional chemical Tren-1,1 form and the d, l form on the one hand and the I, d form. Especially if 1-PCA as optical and the d, d-form on the other hand. There are also separating agents used, 1-lysine is obtained according to the invention a noticeable difference 50 by decomposition of this insoluble salt, the crystallization between the 1,1-form and the and d-lysine is obtained by decomposition of its soluble l, d- Form on the one hand and the l, d-form and the d, d-Forni salt obtained. The decomposition of the 1-lysine salt, on the other hand. The difference in crystallinity is normally made by treatment with a cation is considered to be more important than the difference in ion exchange resin. Both cation exchangers with regard to the degree of solubility. In fact it is 55 Resins like anion exchange resins are difficult to use, a 1-lysine / d-PCA salt or a d-lysine / bar. When a cation exchange resin is used, 1-PCA salt is used to crystallize. On the other hand, it is easy to treat the aqueous solution of 1-lysine salt with an I-lysine / 1-PCA salt or d-lysine / d-PCA salt to give the resin. The resin will crystallize after. Therefore, according to the invention absorbing 1-lysine washed with water, and 1-lysine and d-lysine slightly apart from each other from a 6 ° then the 1-lysine is obtained by treating the resin composition which contains 1-lysine and d-lysine, obtained with aqueous ammonia. On the other hand, separately, by adding the resulting insoluble, 1-PCA is recovered from the filtrate through the resin. Product from the resulting soluble product. If an anion exchange resin is used, separate. Optical isomer salts are obtained in high, the aqueous solution of I-lysine salt with the yield, and these have a high optical 65 resin treated and filtered. I-lysine is made from purity. Recovered filtrate. On the other hand, 1-PCA is through

The amount of PCA to be added with optical treatment of the resin with an acid such as hydrochloric acid

Activity is about 0.5 to 1.0 moles, preferably sulfuric acid and recovered. After the same

D-lysine and d-PCA from the insoluble salt or 1-lysine and d-PCA from the method obtained soluble salt.

1-Lysine obtained from d, J-lysine by the method of the present invention has a high level optical purity and as such is used for various purposes. When a higher optical purity of 1-lysine is desired, it is preferred to post-purify the compound using the following steps:

1. Synthesis of I-lysine monohydrochloride to not to include any water of crystallization. 1-Lysine is treated with hydrochloric acid in the presence of Reacted water to form an aqueous solution of 1-lysine monohydrochloride. The water is converted from the aqueous solution to form a solid by heating, preferably under reduced pressure Pressure, removed. The solid is then further heated and dried. In this way 1-LysinilihydiOchlorid is obtained without crystallization water.

2. Treatment with hydrous alcohol. 1-Lysine monohydrochloride without water of crystallization is used in an alcohol, preferably methanol or ethanol, with a content of 5 to 50 percent by weight Water, preferably 10 to 30 percent by weight water, dissolved at 60 to 70 ° C. d, l-lysine monohydrochloride, possibly also in the I-lysine monohydrochloride remains because of its low solubility in such a solvent back in solid state. The 1-lysine monohydrochloride should not contain any water of crystallization because an essential difference between the solubility of 1-L.ysine monohydrochloride and the solubility of d, 1-lysine monohydrochloride for this solvent consists if the salt does not have water of crystallization contains. At this stage, the 1-form is rapidly dissolved in the solvent, while the d, l-form just solves pretty slowly.

3. Obtaining 1-lysine monohydrochloride. After dissolving the 1-form, it is filtered through Removal of solvents obtained from the filtrate and drying. 1-lysine monohydrochloride is then cleaned afterwards.

The invention is further illustrated by the following examples.

45

example 1

a) 14.60 g (0.1 mol) of 1-lysine and 12.90 g (0.1 mol) of 1-PCA were dissolved in 10 ml of water, and the viscous liquid thus obtained was washed with isopropanol. The wall of the kettle containing the liquid contents was rubbed and kept in a refrigerator at 5 ³ C for 1 week. The liquid was poured onto a plate and formed into a film. The film-like material was kept at 20 ° C. for 2 weeks, and a crystal structure was obtained. The crystals were taken up in methanol containing 5% by weight of water and recrystallized, and the resulting crystals had a melting point of 213 C and a specific rotation [*]? = -6.80 ° (C = 5, H ₂ O) and was obtained in a yield of 95 ⁿ / ₀ . By elemental analysis of this compound, it was confirmed that these crystals were a salt composed of one molecule of lysine and one molecule of PCA.

b) 14.60 g (0.10MoI) d, I-lysine (d- / l- = 1/1) and 12.90 g (0.10 mol) of I-PCA were added to 110 ml of methanol with a content of 5 percent by volume of water Room temperature dissolved with stirring, and 0.05 g of the salt of 1-PCA and 1-lysine was added to the Solution added. This solution was kept at room temperature with stirring for 22 hours. the Crystals that precipitated out were separated from the solution and washed with methanol. After this Drying gave 12.70 g of the salt of 1-PCA and 1-lysine.

The salt was dissolved in 100 ml of water, and the solution thus obtained was passed through a strongly acidic cation exchange resin (H ⁺ type). The resin was then washed with water until the water passing through the resin was neutral. The solution that had passed through the resin was mixed with the water that was used to wash the resin. 5.95 g of 1-PCA was recovered from the mixed solution by concentrating and drying. This 1-PCA recovered in this way did not contain any racemization product.

Lysine absorbed in the resin was dissolved in aqueous ammonia to separate it from the resin. After the ammonia was removed from the solution thus obtained, the solution was treated with hydrochloric acid H-- converted to a pH of 6.0. After concentrating From this solution, the precipitated crystals were dried at 70 to 80 ° C., and 8.40 g were obtained 1-lysine monohydrochloride. The yield was 92.0%, expressed as I-lysine monohydrochloride. The specific rotation of this salt ([x] c °) was + 19.1 "(C = 5.0, 6 N · HCl). Therefore, the purity of this salt was 90.3%.

On the other hand, the filtrate for removing the 1-lysine salt and 1-PCA was mixed with the solutions used for washing the salt of 1-lysine and 1-PCA. This mixed solution was treated using the same method as for the salt of I-lysine and 1-PCA to give 9.60 g of d-lysine monohydrochloride. The yield, expressed as the hydrochloride, was 106%. The specific rotation of this salt (hJo °) was -16.6 ° (C = 5.0. 6 H • HCl), and its optical purity was 7S.6 ". _O. This Salt contained 89.5 percent by weight d-lysine monohydrochloride.

6.90 g of 1-PCA was recovered from the filtral. The total recovery at 1-PCA was 99.6%.

Example 2

7.30 g (0.05 mol) d, l-lysine (d- / I- = 1/1) and 6.45 g (0.05 mol) I-PCA were dissolved in 32 ml of methanol containing 7 percent by volume of water at room temperature dissolved with stirring, and 0.03 g of 1-PCA · l-lysine salt was added to the solution. To After stirring for 22 hours, 6.53 g of the crystals of 1-PCA · l-lysine salt were obtained. Using a similar method as in Example Ib, 4.30 g of 1-lysine hydrochloride were obtained. The yield was 94.3% in terms of I-lysine monohydrochloride. The specific The rotation of this salt ([\] o °) was +18.5 ' (C = 5.0, 6 N · HCl), and its optical purity was 87.7%.

Example 3

5.84 g (0.04 mol) d, I-lysine (d- / l- = 1/1) and 2.58 g 1-PCA was dissolved in 35 ml of methanol containing 5 percent by volume of water, and 0.01 g 1-PCA · l-lysine salt was added to the solution at room temperature. After stirring for 15 hours

7 8

Room temperature one received 2.31 g! -PCA · 1-lysine ammonium salt containing, with the formation of an equal

Salt was added by filtering the precipitated crystals and forming a solution. This solution was at

Dry. This salt was concentrated under reduced pressure ⁰ C for a similar 4O until their

Method treated as in Example Ib, the weight being 32.0 g. After mixing 103 ml

Received 2.30 g of 1-lysine monohydrochloride. The yield 5 methanol with the solution thus obtained were

was 42.0%. The specific rotation of this salt 0.05 g of 1-PCA · 1-lysine in the form of fine crystals

([«]?) Was + 19.4 ° (C - 5.0, 6 N · HCl), and that was added to the mixed solution, and it was

optical purity of this salt was 92.0%. ^{Maintained at 20 °} C. with stirring for 22 hours.

Be 'D i e 1 4 By a treatment similar to Example 5

" ¹⁰ , 6.84 g of l-lysine monohydrochloride were obtained

7.30 g (0.05 mol) of d, l-lysine (d- / l- = 1/1) and 6.45 g yield was 75.0 and the optical purity

(0.05 mol) 1-PCA was in 28 ml methanol at 93.0%.

a content of 20 percent by volume of water dissolved, _R. -17

and 0.02 g of 1-PCA · 1-lysine salt were added to the solution Example /

added at room temperature. After 22 hours 15 l \ fi g (0.1 mol) of d, 1-lysine (d- / l- = 1/1) became

Stirring at room temperature was obtained by 30 ml of an aqueous solution containing

Filtering the precipitated crystals and drying 14.6 g (0.1 mol) of I-PCA ammonium salt added,

same 2.06 g of 1-PCA · 1-lysine salt. After a This solution was under reduced pressure at

Similar to a method as in Example 2, 1.36 g of 40 ^° C. were concentrated until it was 33.0 g. After

Obtained 1-lysine monohydrochloride. The yield - mixing 73 ml of methanol with the so concentrated

The ratio was 29.8%, expressed as I-lysine-trated solution, 0.05 g of 1-PCA · I-lysine was in the

monohydrochloride. The specific rotation of this form fine crystals to the mixed solution

Salt {[*}%) was 4 20.1 ° (C = 5.0, 6 N · HCl), added, and this solution was taken for 20 hours

and its optical purity was 95.2%. Stirring kept at room temperature.

... ² 5 Using a method similar to Example 5

Example 5 gave 8.48 g of l-lysine monohydrochloride. the

14.06 g (0.1 mol) of d, l-lysine (d- / l- = 1/1) resulted in the yield was 93.0% and the optical purity

30 ml of an aqueous solution with a content of 90.5%.

14.6 g (0.1 mol) of 1-PCA ammonium salt added in order to increase the amount of 18

to obtain a uniform solution. This solution 3 °

was removed under reduced pressure at 40 ⁰ C concen- 14.6 g (0.1 MoI) of 1-PCA and 14.6 g (0.1 mole) d, l-lysine

trated until their weight was 35.2 g. 103 m! Methanol (d- / l- = 1/1) were mixed together. That

to the resulting solution thus concentrated, mixture was dissolved in methanol containing

added to a transparent and uniform 7 percent by volume of water with the formation of a uniform

Solution. 0.05 g of 35-shaped solution were dissolved with stirring. Were stirring

1-PCA · 1-lysine salt was added to the solution, and the 0.05 g of 1-PCA · 1-lysine salt in the form of fine crystals

Mixture was added to the solution at room temperature for 22 hours, and it was left at for 20 hours

touched. 12.5 g of 1-PCA · 1-lysine salt were obtained through continuous stirring at room temperature.

Filter the resulting crystals twice by a method similar to Example 5

Washing with 30 ml of methanol and drying. 7.30 g of 1-lysine monohydrochloride were obtained. That

The salt was dissolved in 80 ml of water, and the yield ratio was 80.0% and the optical one

The solution obtained was 93.0% pure by a strongly acidic.

Cation exchange resin sent with aqueous ice 0 ie I 9
Ammonia was treated as described above.

After recovery of the aqueous 1-PCA-ammonium 45, 14.6 g (0.1 mol) of d, I-lysine (d- / l- = 1/1) became

saline solution, the lysine absorbed in the resin became 30 ml of an aqueous solution containing

in aqueous ammonia with a content of 12.70 g (0.1 mol) 1-PCA with the formation of an equal

7 weight percent ammonia dissolved added to it from the shaped solution. This solution was

Separate resin. concentrated under reduced pressure at 40 ^° C.,

The 1-lysine-containing solution thus obtained became 5 <> until their weight was 35.2 g. 103 ml of methanol

concentrated and neutral with hydrochloric acid - were added to the solution so concentrated,

and then again to form a solid to obtain a transparent solution. The so

concentrated. resulting solution was stirred for 22 hours

It was kept at room temperature by drying the solid.

70 to 8O ⁰ C 8.3 g of l-lysine monohydrochloride. The 55 By a similar treatment as in Example 1 b

Yield was 91.0%. 8.3 g of l-lysine monohydrochloride were obtained ^{and the optical purity was obtained.} the

was 92.0%. The yield was 91.0% and the optical purity

On the other hand, from the filtrate, it became d-lysine / 92.0%.

1-PCA salt contained by the same treatment as Example 10

9.95 g of d-lysine monohydrochloride obtained as above. ^6o

The yield was 109.0% and the optical purity 14.6 g (0.1 mol) of d, l-lysine (d- / l- = 1/1) became

i.e. 76.6%. 30 ml of an aqueous solution containing

In addition, 1-PCA, which is the optical solution, 14.6 g (0.1 mol) of 1-PCA ammonium salt was added, and

was separating agent, in a yield of 99.6%, this solution was at 40 ⁰ C under diminishing

recovered. . ⁶ 5 pressure concentrated until its weight was 35.2 g.

B e 1 s ρ 1 e 1 6 _The resulting solution was mixed with 103 ml of methanol

14.6 g (0.1 mol) of d, l-lysine (d- / l- = 1/1) became to form a transparent and uniform

an aqueous solution mixing 10.9 g (0.075 mol) of 1-PCA solution, and then this solution became

Stirred for 22 hours at room temperature. Treatment similar to Example 5 gave 8.3 g of l-lysine monohydrochloride. The yield was 91.0% and the optical purity was 92.0%.

Example 11

l-Lysine monohydrochloride without water of crystallization was obtained by heating l-lysine monohydrochloride for 5 hours at 80 ^° C. The optical purity was 84.1%. 15 g of the salt thus obtained were added to 300 ml of ethanol containing 20 percent by volume of water.

The mixture was ^{heated to 70 °} C. and kept at this temperature for 15 minutes. The insoluble solid was removed by filtration, and 20 ml of ethanol was added to the filtrate. After maintaining at 15 ° C. for 3 hours, the precipitated crystals were collected by filtration and dried. 11.5 g of 1-lysine monohydro chloride were obtained. Its optical purity was 98.9% and the yield 91.2%.

Example 12

Using the same method as in Example Y , l-lysine monohydrochloride was obtained without a crystal! tion water and with an optical purity of 74.1%. 2.7 g of the salt became 25 ml of methano

ίο with a content of 20 percent by volume Wassei added, then heated to 60 ° C. for 20 minutes. The insoluble salt was removed by filtration and 5 ml of methanol were added to the filtrate after being kept at 15 ° C for 3 hours the precipitated crystals were separated by filtration and dried. I-lysine monohydrochloride was obtained with an optical purity of 98.1% and in a yield of 86%.

t * -

Claims (5)

Patent claims: 1. Process for the separation and recovery of 1-lysine from a d- and 1-lysine containing Mixture, characterized in that (a) a solution of d- and 1-lysine containing mixture and the d-isomer of 5-oxo-2-pyrrolidinecarboxylic acid or of its Ammonium salt or the 1-iomer of 5-oxo-2-pyrrolidinecarboxylic acid or from its ammonium salt, the d-isomer or its ammonium salt reacts with d-lysine to form an insoluble product, while the Reaction product with 1-lysine remains soluble and the 1-isomer or its ammonium salt with d-Lysine reacts to form a soluble product, while the reaction product reacts with 1-lysine remains insoluble, (b) the insoluble reaction product obtained from the soluble one obtained The reaction product is separated off by methods known per se and (c) 1-lysine is also added to known methods from the 1-lysine-containing reaction product wins. 2. The method according to claim 1, characterized in that there is used as a solvent for the preparation the solution is water, an aqueous, low molecular weight alkanol and / or an aqueous, low molecular weight Ketone used. 3. The method according to claim 1 and 2, characterized in that one is used to precipitate the Crystals of an aqueous low molecular weight alkanol, aqueous low molecular weight ketone or mixtures of these used, which contain about 2 to 20 percent by volume water. 4. The method according to claim 1 to 3, characterized in that one for the precipitation of the Crystals and the same solvent used to make the solution. 5. The method according to claim 1 to 4, characterized in that one is used as the precipitating agent uses the same compound that is the insoluble product.