DE2024062C3 - Process for the separation and recovery of L lysine - Google Patents

Description

known methods and (c) I-lysine after 0.7 to 1.0 mol. per mole of d.I-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 the I-lysine wins. preferably 410 to 610 weight percent based 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 l-isomers from crystallization of the optical isomer salt to accelerate 5-oxo-2-pyrrolidinecarboxylic acid (PCA) and their amnigen. it is preferred to use a precipitating agent such as monium salts, commercially available. For example I-lysine i-PCA salt and d-lysine d-PCA salt. to be used easily turn this remedy from glutamic acid with. When l-PCA or its ammonium salt as synthesized optical activity. io disintegrating agent used is 1-lysine / l-PCA-Die optical separation reaction according to the Errin salt useful. If d-PCA or their ammonium dung is carried out in a solvent. salt is used as a separating agent Water and organic solvents with affinity for d-lysine d-PCA salt can be used. Such an outwater as low molecular weight aliphatic alcohol precipitant becomes that obtained by reaction and low molecular weight aliphatic ketones, 15 'are added to the solution The amount of the to be added suitable solvents. For example, are methanol. Precipitant is usually 0.1 to 1.0 ge \ ethanol, propanol, isopropanol. Acetone, methyl weight percent. preferably 0.3 to 0.5 weight ethyl ketone and mixtures thereof the preferred percent. based on the weight of the d, l-lysine. Around Solvents, and aqueous solutions of these orga- a crystalline salt in a higher yield ratio niche solvent with a content of 2 to 20 can be added an unlimited amount of water-20 Volume percent water is 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. JO volume percent is most preferred the crystalline product of the optical isomer salt Dissolve solvents when performing the procedure. Are methanol, ethanol and acetone laugh of the invention. 25 typical such solvents.

The reaction temperature is not critically limited. It is preferred in the present invention. However, the reaction will normally take place at 20 to the same solvent as in the precipitation 70 "C, preferably at about 50C. to use with stirring reaction. If, in particular, a watery, i carried out. Lysine (d-, I-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 thereof Reaction mixture. The 1.1-form or the d, d-form, used for the implementation, becomes this which are an optical isomer salt, (all gradually solvent continuously also for the if you use the solution to about 5 to 40 "C, precipitation stage, even without adding one preferably held at about room temperature. organic solvent.

In Optical Separation According to the Invention 35 In the present invention, the expression is

When using l-PCA or "d, l-lysine" or "lysine", I-lysine does not just react as a racemic one

its ammonium salt with l-PCA to form a mixture or a compound of d-lysine and

1-lysine / l-PCA salt with low solubility in water, I-lysine, but can a-.ich ei.ie composition

and d-lysine reacts with l-PCA to form its which consists of d-lysine and I-lysine and in one

d-lysine / 1-PCA is present in excess with a very substantial amount of water of the two components,

solubility. On the other hand, when d-PCA or its The resulting insoluble product with less

Ammonium salt is used, I-lysine reacts with moisture absorption is from the resulting

d-PCA to form 1-lysine / d-PCA salt with soluble product according to any conventional one

substantial solubility in water, and d-lysine method, such as by filtration, centrifugation, etc.,

reacts with d-PCA to form d-lysine / d-PCA 45 separated. In this way, I-lysine and

with very low water solubility. There is ad-lysine separated from each other.

large difference in solubility between the I-lysine is due to Tren-1,1 conventional chemical form and the d, l-shape on the one hand and the l, d-shape on the one hand. Especially when l-PCA as an optical one and the d, d-form on the other hand. Also there is disintegrating agent used is I-Lysine according to the invention a noticeable difference of 5 ° obtained by decomposition of this insoluble salt, the crystallization between the 1,1-form and the and d-lysine is praiseworthy by the decomposition of its l, d-form on the one hand and the l, d-form and d, d-form salt obtained. The decomposition of the 1-lysine salt on the other hand. The difference in crystalline is usually done by treating with a cation is seen as more important than the difference in ion exchange resin. Both cation exchangers 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 Crystallize I-PCA salt. On the other hand, it will be easy to use the aqueous solution of 1-lysine salt a 1-lysine / l-PCA salt or d-lysine / d-PCA salt to the resin. The resin is after crystallize. Therefore, according to the invention, absorbing I-lysine are washed with water, and I-lysine and d-lysine slightly apart from one another 60 then becomes the I-lysine by treating the resin Composition containing I-lysine and d-lysine obtained with aqueous ammonia. on the other hand separately, by adding the resulting insoluble, l-PCA is recovered from the filtrate through the resin. Product of the resulting soluble product If an anion exchange resin is used, separates. Optical isomer salts are obtained in higher quantities. The aqueous solution of 1-lysine salt with the Yield, and these possess a high optical 65 resin treated and filtered. I-lysine is made from the Purity. Recovered filtrate. On the other hand, 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

Method are d-LvMii and d-PCA from. the insoluble SaI / or 1-lysine and d-PCA obtained from the soluble salt.

From d, 1-lysine by the process of \ succumbing ^(rlindung obtained I-lysine has a high optical pure salvation and we 'J as such \ arious / wake \ he \\ ends. If a higher optical Reinheii I-lysine desired it is preferred to post-purify the compound using the following steps:

1. Synthesis of l-lysine monohydrochloride. so as not to include crisis water. 1-lysine is with hydrochloric acid in the presence \ on W ater reacted to form an aqueous solution of l-lysine monohydrochloride. The water is from the aqueous solution with the formation of an I csistoffes by heating, preferably with verminder.em Pressure, removed. The solid is then heated and dried. This is how l-lysine monohydrochloride is obtained without crystallization water.

2. Treatment with hydrous alcohol. 1-lysine monohydrochloride without crystallization ** 'water 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. dJ-lysine monohydrochloride. which is possibly also contained in the l-lysine monohydrochloride. remains v \ egcn his low solubility in such a solvent returns in the solid state. The l-lysine monohydrochloride should not contain water of crystallization, as there is an essential difference between solubility of l-lysine monohydrochloride and the solubility of d.l-L.ysine monohydrochloride for these solvents exists when the salt does not contain any water of crystallization. At this stage, the 1-form becomes fast dissolved in the solvent while the .l-form just solves pretty slowly.

3. ^weight: inung of L-lysine monohydrochloride. After the 1-form has dissolved, it is obtained by filtering, removing solvents from the filtrate and drying. The l-lysine monohydrochloride is then purified.

The invention is further illustrated by the following examples.

example 1

a) 14.60 g (0.1 mol) of I-lysine and 12.90 g (0.1 mol) of I-PCA were dissolved in 1/2 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 ° 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 [λ]? , -6.80 ° (C = 5, H ₂ O) and was obtained in a yield of 95%. By L-Icmcnlaranalyse this compound was confirmed as (i, these crystals were a salt consisting of one molecule of lysine and one molecule I ¹ CA.

h) 14.60g (OJOMoI) d, I-lysine (d- / l- 1/1) and 12.9Og (OJO mol) of I-PCA were dissolved in 110 ml of methanol with i'ineni Gehair of 5 Volumpro / .i: nl water with Room temperature dissolved with stirring, and 0.05 g of the salt of! -PCA and 1-lysine were 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 Drying gave 12,70 g of the sal / cs of 1-PCA and 1-lysine.

The salt was dissolved in 100 ml of water, and so on

The solution obtained was replaced by a strongly acidic Cation exchange resin (H type) passed. The resin was then washed with whitener until it was through the resin going water was neutral. The solution that passed through the resin was mixed with the water used to wash the resin would. 5.95g of I-PCA were obtained by concentrating and drying recovered from the mixed solution. This I-PCA finally recovered in this way no racemization product.

Lvsin absorbed in the resin was dissolved in aqueous ammonia to remove it. to separate from the resin. After the ammonia had been removed from the solution thus obtained, the solution was reacted with hydrochloric acid to a pH of 6.0. Before this solution was concentrated, the precipitated crystals were dried at 70 to 80 ° C., and 8.4 oy l-lysine monohydrochloride was obtained. The howl was 92.0 °. expressed as l-lysine monohydrochloride. The specific rotation of this * salt ([λ]?) Was: 19.1 (C 5.0, 6 N · HCl). Therefore, the purity of this salt was 90.3 ⁰ Z ₀ .

On the other hand, the filtrate for removing the I-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 1-lysine and 1-PCA to give 9.60 g of d-lysine monohydrochloride. The / uisbeute, expressed as the hydrochloride, was 106 ° / _0th The specific rotation of this salt ([O ") was -16.6 (C = 5.0.6 H · HCl) and its optical purity was / 8.6%. This salt contained 89.5% by weight of d-lysine monohydrochloride.
6.90 g of 1-PCA was recovered from the filtrate. The total recovery of 1-PCA was 99.6%.

Example 2

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

Example 3

5.84 g (0.04 mol) of d, l-lysine (d- / l- = 1/1) and 2.58 g of 1-PCA were dissolved in 35 ml of methanol with a concentration of of 5 percent by volume of water, and 0.01 g of 1-PCA · I-lysine silica were dissolved at room temperature Solution added. After stirring for 15 hours

At room temperature, 2.31 g of 1-PCA I-lysine ammonium salt were obtained, 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 after a similar 40 ^{0 C until you}

Method treated as in Example 1b, 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 I-PCA · I-lysine in the form of fine crystals

([• v]?) 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.

. ■ ι λ By a treatment similar to Example 5

B e ι s ρ ι e I 4 _{10 crme} | _{t one 6 84 g of} l-lysine monohydrochloride. the

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

(0.05MoI) I-PCA were in 28 ml of methanol at 93.0%.

dissolved in a volume of 20 percent by volume of water, _R. . . _

and 0.02 g of I-PCA · I-lysine salt were added to the solution ^p

added at room temperature. After 22 hours, 14.6 g (0.1 mol) of d, l-lysine (d- / l-1/1) became to

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 I-PCA · I-lysine salt. After a This solution was under reduced pressure at

Method similar to that in Example 2, 1.36 g of 40 ^° C. were concentrated until it was 33.0 g. After

Obtained 1-lysine monohydrochloride. The yield ao 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 (M?) Was [ 20.1 ° (C 5.0, 6 N · HCl). added, and this solution was taking 20 hours

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

. ^a 5 Nac! a similar method as in example 5

* Example 5 obtained 8.48 g of l-lysine monohydrochloride. the

14.06 g (0.1 mol) of d, l-lysine (d- / l- 1/1) were obtained. The yield was 93.0% and the optical purity

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

t: 14.6 g (0.1 mol) of i-rCA oil salt added to B <*: = η j _e l 8

[to gain a uniform solution. This solution 3o ^r -

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

trated until their weight was 35.2 g. 103 ml of methanol (d- / l ---- 1/1) were mixed together. The

j were added to the so concentrated resulting solution 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

j 1-PCA · I-lysine salt was added to the solution, and the 0.05 g of 1-PCA · I-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 I-PCA · I-lysine salt were obtained with 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. The

! 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.

j cation exchange resin sent with aqueous Example 9
Ammonia was treated as described above.

After the aqueous 1-PCA-ammonium was obtained, 14.6 g (0.1 mol) of d, l-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) of I-PCA with the formation of a «.r equal-

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

Separate resin. concentrated under reduced pressure at 40 ⁰ C.

The I-lysine-containing solution thus obtained became 5 ° until its 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 an elite solid in order 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 80 ° C 8.3 g of l-lysine monohydrochloride. The 55 By a similar treatment as in Example 1 b

The yield was 91.0% and the optical purity was found to be 8.3 g of 1-lysine monohydrochloride. 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 B - i s ρ i e 1 10

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

The yield was 109.0%, and the optical purity 14.6 g (0.1 mol) of d, t-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

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

recovered. . . 65 pressure concentrated until its weight was 35.2 g.

^els P ■ ^e The resulting solution was with 103 ml of methanol

14.6 g (0.1 mol) d, I-L> sin (d- / l- - 1/1) became to form a transparent and uniform

an aqueous solution, the iO.9 g (0.075 Mo!) S-PCA solution mixed ?, and then this solution

Stirred for 22 hours at room temperature. A treatment similar to that in Example 5 gave 8.3 g of l-lysine monohydrochloride. The yield was 91.0% and the optical purity 92.0 ° / _0th

B e i s ρ i e 1 11

l-Ly5, yn monohydrochloride without water of crystallization was obtained by heating l-lysine monohydrochloride to 80 ° C. for 5 hours. The optical purity was 84.1%. ⁵ 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 l-lysine monohydrochloride were obtained. Its optical purity was 98.9% and the yield was 91.2%.

Example 12

Using the same method as in Example 1, l-lysine monohydrochloride was obtained without crystals tion water and with an optical purity of 74.1% · 2.7 g of the salt were 25 ml of Mcthano

ίο added at a content of 20 volume percent wat, then 20 minutes at 60 ⁰ C heated The insoluble salt was removed by filtration and 5 ml of methanol was added to the filtrate After holding 3 hours at 15 ° C, the precipitated crystals were collected by Filtration separated and dried. I-Lysi.i monohydrochloride was obtained with an optical purity of 98.1% and in a yield of 86%.

Claims (5)

drive. d.l-lysine in the individual components claims: to burn d-lysine and I-lysine. So far, for the purpose of splitting 1. Proposals for the separation and recovery of d.l-lysine into d-lysine and 1-lysine are proposed, \ on! -lysine and 5 optical separation agents containing d- and 1-lysine, which themselves Mixture, characterized. are optically active acids. Following this method will that one (a) a solution of the d- and 1-lysine d.l-Ly> in with an optical separation means containing mixture and the d-isomer of the reacted, and this L'msetzung provides diasteroiso-5-O. \ o-2-pvrrolidincarbonsäure or \ on its mers which have different solubilities, and The ammonium salt or the I-Iomer of 5-oxo-io is then 1-lysine due to the different 2-p> rrolidinecarboxylic acid or its ammo-solubility by filtration, centrifugation or the like. nium salt produces, the d-isomer or obtained. This is one of the most popular methods at its ammonium salt with d-lysine with formation of the optical resolution. of an insoluble product reacts, while the optical separation of d, 1-lysine Reaction product with 1-lysine remains soluble and 15 however various known optical ones have been found the! isomer or its ammonium salt with a solvent with optical activity, such as camphor d-lysine to form a soluble product acid, di-ben / vl-d-tartaric acid. Glutamic acid with reacts while the reaction product has optical activity, and l, l-methylene-bis- (5-oxo- 1-Lysm remains insoluble, (b) the resulting insoluble 2-pyiTolidip.carboxylic acid) with optical activity in Reaction product from the obtained soluble industrial scale to be unsatisfactory. Reaction product according to known Me- If camphoric acid as an optical separation agent methods and (c) 1-lysine was also used after, it turned out to be necessary known methods from the! -lysine contained- to carry out recrystallization stages and these tend reaction product wins. repeat several times to get pure 1-lysine, 2. The method according to claim! as a result, because of the small difference between draws that as a solvent for the her- the solubility of the l-lysine salt to be obtained and Position of the solution Water, an aqueous, low-d-lysine salt. Hence, 1-lysine was using at best molecular alkanol and / or an aqueous, low-low yield obtained. Besides, there was such molecular ketone used. Camphoric acid was expensive, and it was difficult to indus- 3. The method according to claim 1 and 2, thereby obtaining 30 striellem scale. In the case of Dige, that the d-lysine salt obtained was used to precipitate the benzoyl-d-tartaric acid Crystals an aqueous low molecular weight alkanol, a lower degree of solubility than the others Aqueous low molecular weight ketone or mixtures of salts, so that this salt was obtained first and it was difficult of this, which was about 2 to 20 volume percent, was used to water off the 1-lysine from the reaction mixtures contain. 35 separate. Was glutamic acid with optical activity 4. The method according to claim 1 to 3, characterized to this day a preferred separation agent. The characterized in that one had to use the solvent used in this process for the precipitation Crystals and for the preparation of the solution, however, are carefully selected to be a good one same solution center! used. Achieving a result, and it was a special one 5. The method according to claim 1 to 4, characterized by 40 careful treatment required in this method, that ma.1 as a precipitating agent Hch because of the moisture absorption by the the same compound used as the insoluble lysine glutamic acid salt. When 1,1-methylene-bisliche Product is. (5-oxo-2-pyrrolidinecarboxylic acid) was used, it proved necessary to recrystallize several times 45 sizing to obtain 1-lysine with high purity, as this agent has a poor ability to separate owns. The invention relates to the resolution of the racemi- It has been found that S-oxo-l-pyrrolidincarbonschen Form of d-lysine and 1-lysine into the individual acid with optical activity and their ammonium components (d-lysine and 1-lysine) using 50 salt excellent properties for an optical of 5-oxo-2-pyrrolidinecarboxylic acid or its Am separation of d, l-lysine into d-lysine and 1-lysine monium salt as an optical resolution agent. own. The naturally occurring form of lysine is The object of the present invention is in 1-lysine, which is optically active. With chemical synthesis solved in the following way: However, the lysine obtained does not have this property, 55 a) A solution of a mixture is prepared, since it is an equimolar mixture of d-lysine and the d- and 1-lysine as well as the d-isomer of the 5-oxo 1-lysine is present. For many purposes 1-lysine is converted to 2 »pyrrolidinecarboxylic acid or its ammonium salt applies, for example as feed, as entrophes or the 1-isomer of 5-oxo-2-pyrrolidinecarboxylic acid Means or as a drug, as it contains physiological or their ammonium salt, of these Owns activity. . 60 compounds the d-isomer or its ammonium It is easy to industrially manufacture d, l-lysine, salt with d-lysine to form an insoluble one but its physiological activity is only half as reacting with the product, while the reaction product is with large as that of 1-lysine. The d-form of lysine 1-lysine remains soluble and the 1-isomer or its does not have such a physiological activity as many ammonium salts with d-lysine to form a other x-amino acids. As a result, the present 65 soluble product reacts during the reaction invention it is to be regarded as industrially possible, product with I-Lsyin remains insoluble, what one on Obtain 1-lysine by chemical synthesis. The (b) the obtained insoluble reaction product of The invention provides a simple and effective method of using the soluble reaction product obtained