DE1961180A1 - Process for the optical separation of a mixture of L- and D-alpha-amino-epsilon-caprolactam - Google Patents

Description

Process for the optical separation of a mixture of L- and Da-amino- ξ -caprolactam

The invention relates to a method for the optical resolution of mixtures of La-amino- £ -caprolactara and Da-amino f-caprolactam. In particular, the invention relates to a new process for the optical separation of mixtures of L- and Da-amino- ^ f-caprolactam using derivatives of L- or D-glutamic acid of the general formula below

HOOC-7 CH-NH-CO-

QH ₂
Ή / ι

OOOH. where R is a hydrogen atom or a nitro group (-NOp) represents as a dissolving or separating agent.

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α-Amino-5-caprolactam can be selected from ε-caprolactam or

Intermediates thereof,. Which in large quantities and in are available at a lower cost than raw materials for synthetic fibers or threads, e.g. poly- £ - caprolactam (nylon β). aside from that this substance can be very easily hydrolyzed to form lysine. Hence, currently on this substance as an intermediate product with economic advantages for the synthesis of lysine directed considerable interest. Since the compound is normally in racemic

Form, i.e. in the form of a mixture of

the racemicβ equal parts of the D-form and L-form must be ^ a-amino-£ caprolactam or the racemic lysine can be resolved to obtain optically active lysine which is suitable for medical uses or as a tonic for human or animal diets.

Processes for the optical resolution or separation of racemic lysine or of mixtures of D- and L-lysine can largely be enzymatic or chemical. Working methods are classified. With regard to this procedure, numerous specific methods have so far been proposed, but none of them proved to be correspondingly advantageous for the optical separation of mixtures of D- and L-lysine. and up to now no way of working in large-scale technology has been adopted. Whenever procedures for the large-scale production of lysine by means of a synthetic intermediate, product of racemic α-amino- L- caprolactam became known, the importance of these procedures, which involved the dissolution of racemic α-amino- ^ - caprolactam or mixtures of L- and D-ct-amino-f-caprolactam with

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a high performance could be very formidable too.

The Geigy process (US Pat. No. 3,275,619) and the Stamicarbon NV process (Belgian Pat. No. 696 185) are already in the art of optical separation or resolution of mixtures of L- and D-oc-amino- ^ caprolactam known. In the former method, L-pyrrolidonecarboxylic acid is used as the separating agent and ethanol or methanol as the dissolving agent for the separation, while in the latter method the same separating agent but mixtures of water and a water-immiscible organic solvent are used as the solvent for the separation . However, L-pyrrolidone carboxylic acid is expensive because it is synthesized with considerable difficulty. Moreover, when this compound is used as a separating agent, the salt formed therefrom with L- or Da-amino-f-caprolactam cannot easily be separated from the above-mentioned solvent. As a result, not only is it difficult to obtain the salt mentioned, but inevitably the production of L-pyrrolidonecarboxylic acid by decomposition of the salt is also low. V. ^r further hen a solvent mixture consisting of water and the operation of the Belgian patent is used with a 696,183 V / ater-immiscible organic solvent according to the effectiveness of optical resolution or separation is relatively low. The process must be repeated to increase the optical purity of the resulting L- or Da-amino-B-caprolactam to a satisfactory level. This disadvantageously complicates this process.

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In view of the above, work and investigations were carried out for the purpose of determination of satisfactory release agents for mixtures of L- and D-a-amino-C-caprolactam, wherein it was found that derivatives of L- or D-glutamic acid of the following formula:

HOOC-rCH-NH-CO- ^ V-R

CH ₅

CH ₂

COOH

in which R is a hydrogen atom or a nitro group ( means to serve as an excellent release agent.

According to the invention, mixtures of L- and D-oc-amino-E-caprolactam into the optical isomers thereof can be decomposed with very high efficiency by mixing these mixtures with the aforementioned derivatives of D- or L-glutamic acid in a homogeneous treated liquid medium, which is at least 90 VoI- ^ o of at least one solvent from the group of water, aliphatic alcohols with 1 to 4 carbon atoms, Contains acetone and ethylene glycol.

The expression "Kischungen von L- and D-a-araino- £ -caprolactam "is not restricted in the sense that that the racemic compound consists of equal proportions of L- and D-α-amino - ^ - caprolactam, but includes

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Mixtures containing more than equal proportions of each of the optical isomers thereof. In the following, for convenience, these mixtures are referred to as "D, L-NH ₂ -CL mixture", the L optical isomer thereof as ¹¹ L-IiH ₂ -CL "and the D optical isomer thereof as" D-NH ₂ -CL " designated.

Examples of the derivatives of glutamic acid which _{are useful as an optical separation or resolution agent of D, L-NH 2} -CL mixtures according to the invention include:

N-benzoyl-L-glutamic acid N-Benzoyl-D-glutamic acid, N-p -nitrobenzoyl-L-glutamic acid

N-p-nitrobenzoyl-D-glutamic acid.

Among the compounds listed above N-p-nitrobenzoyl-L-glutamic acid and N-p-nitrobenzoyl-D-glutamic acid particularly preferred.

Any of the group of water, aliphatic alcohols with 1 to 4 carbon atoms, Acetone and ethylene glycol can be used, the preferred solvents of which are water, Methanol, ethanol, or their mixtures at beÜJä> .lgen. Desired conditions are. More than one of the solvents listed above can be used if desired can be used as a mixed solvent and, moreover, any homogeneous liquid medium with a Held by at least 90 vol- # by at least one, of the above solvents can be used as solvents. For example, with

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Water-miscible organic solvents, e.g. methyl ~ ethyl ketone, methyl isobutyl ketone, amyl alcohol, hexyl alcohol, propyleiiglycöl, glycerine, Dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or the like. in a crowd from below 10 Vol-9d with any solvent, consisting of water, the aforementioned aliphatic alcohols, acetone and ethylene glycol or with mixtures of more than one of the solvents mentioned and such mixtures can be used for the desired decomposition or separation will. While hydrophobic organic solvents, for example benzene, toluene, o-, m- and p-xylene, Ethylbenzöl, kerosene, ethyl ether, petroleum ether or the like. cannot be used for mixing with water alone can, however, they can be used as a solvent mixture. with any of the aliphatic Alcohols, acetone or ethylene glycol or mixtures thereof are used in an amount of less than 10% by volume. These mixed solvents can also include water within a range at which a homogeneous Solution is formed.

"Thus any solvent mixture can be used as a separating

• or decomposition solvents according to the invention applied if it is a homogeneous liquid medium (or solution) with a content of at least 90% by volume from at least one member of the group of water, aliphatic alcohols having 1 to 4 carbon atoms, acetone and ethylene glycol.

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Thus, according to the invention, D, L-IIH ₂ -CL hybrids can be produced in a simple manner and with high yields in L-NH ₂ -CL and / or D-NH ₂ -CL of high purity by treating D, L-NH ₂ -CL mixtures in the homogeneous liquid media with a content of at least 90 V0I.-S6 of at least one solvent from the group of water, aliphatic alcohols with 1 to 4 carbon atoms, acetone and ethylene glycol with one of the derivatives of L- or D-glutamic acid the formula below

HOOC • CH • NH

CH ₀ 0

1 c -CH ₂ COOH

wherein R represents a hydrogen atom or a nitro group, are optically separated, whereby a sparingly soluble salt, consisting of L- or D-NH ₂ -CL and the derivative of an optically active glutamic acid, precipitates, the sparingly soluble salt from the liquid medium, the contains a readily soluble salt of L- or D-NH ₂ -CL and the glutamic acid derivative, separated by any acceptable practical procedure, and thereafter the poorly soluble salt and / or the readily soluble salt can be decomposed from the liquid medium.

The method according to the invention is as follows explained in more detail.

According to the invention, for treating a D, L-NH ₂ -CL mixture with the said derivative of an optically active (L- or D-) glutamic acid in the said LÖ-

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solvent two solutions of the solvent, each the D, L-NHp-CL mixture or .. the glutamic acid derivative lö- - ■ sen, to be mixed; on the other hand, the mixture and the derivative can be added to the solvent and dissolved one after the other, whereby the order of addition can be chosen. It is also permissible to use a salt a D, L-NHp-CL mixture and from the derivative one optically active, i.e. an L- or D-glutamic acid which has been formed in advance, to be added to said solvent.

Suitable amounts of said derivative of an optically active glutamic acid, ie of the separating agent used, are at least 0.5 mol and preferably 0.8 to 1.3 mol per mol of the D ₁ L-NH ₂ -CL mixture used .

If the derivative of L- or D-glutamic acid is reacted as a separating or decomposing agent with the D, L-NH ₂ -CL-Miechung in the above-mentioned solvent, the major part of

(A) a salt consisting of L-NH ₂ -CL and L-glutamic acid derivative, or

(B) a salt consisting of D-NH ₂ -CL and D-glutamic acid derivative

precipitated as a poorly soluble salt and most of *

(C) a salt consisting of D-NH ₂ -CL and L-glutamic acid derivative, or

(D) a salt consisting of L-NH ₂ -CL and D-glutamic acid derivative,

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is dissolved in the solvent as a readily soluble salt. Therefore, when any of the derivatives of L-glutamic acid is used as a decomposing or separating agent, the aforesaid becomes Salt (A) and (G) formed, while when a derivative of D-glutamic acid is used, said salt (B) and (D) are formed.

The sparingly soluble and optically active ones obtained in this way Salts (A) and (B) are in the form of needle-shaped crystals and can easily be removed from the solvent after any customary measure, e.g. solids-liquid separation, "e.g. filtration, centrifugation or the like., separated will.

According to the method according to the invention, a pair of L-NHg-CL and the derivative of L-glutamic acid or a Pair of D-NHg-CL and the derivative of D-glutamic acid respectively by cleaving the salt (A), i.e. the salt of L-NHp-CL and the derivative of L-glutamic acid, or the salt (B), i.e. the salt of D-NHg-CL and the derivative of D-glutamic acid, each of which is obtained from the solvent as sparingly soluble and optically active Salt, as indicated above, can be separated by any suitable means.

Similarly, by splitting the easily soluble salt. (C) or (D), which after the recovery of the poorly soluble and optically active salt (A) or (B) remains, either in the form thus obtained or through Splitting of the same after separation from the mother liquor mentioned by further concentration and / or cooling of the

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-.10 -

Mother liquor a pair of D-NH ₂ -CL and the derivative of L-glutamic acid or a pair of LN] of D-glutamic acid can be obtained *.

L-glutamic acid or a pair of L-NH ₂ -CL and the derivative

According to the process according to the invention, L-NH ₂ -CL or D-NH ₂ -CL of sufficiently high optical purity can be obtained by the above-described separation or decomposition process alone, the purity, however, if desired ... by recrystallization of the sparingly soluble salt (A) or (B), which was separated in the above Wei-P se, is further increased in the aforesaid solvent.

According to a preferred embodiment of the invention, L-IIH _n -CL or D-NH ₂ -CL can be obtained with excellent purity and high yield using methanol, methanol-water mixtures, ethanol or ethanol-water mixtures, with the The methanol or ethanol content is at least 40 wt.%, Preferably at least 60 wt the ratio of the said separating or decomposing agent and the D, LI \ iH ₂ -CL mixture to be separated to the solvent within the range given by the following expression:

can be obtained, wherein X is a value of the number of moles in the lower Amount of component present of the L- and D-oc-amino £ caprolactam mixture or said glutamic acid derivative (where, if these equimolar amounts are present, X represents the number of moles of each individual component),

00983271816

multiplied by 424.4 (gram-moles of between formed salt), Y a fourth of the amount (ml) of the solvent (methanol, methanol-water mixture, Ethanol or ethanol-water mixture) divided by 100, and K 'is a value of the amount (g) of the salt of DjL-NHp-CL mixture and either of N-p-nitrobenzoyl-L-glutamic acid or N-p-nitrobenzoyl-D-glutamic acid, which in 100 ml of the solvent below the saturation concentration at the particular temperature used for the optical separation or decomposition according to the invention is soluble.

The embodiment described above is also preferred with regard to the mode of operation or implementation, because this makes the separation of the sparingly soluble salt (A) or (B) extremely easier.

Even better results can also be obtained with the procedure described above by regulating the ratio of the separating or decomposing _{agent and the D, L-NH 2} -CL mixture to the solvent within the range given by the expression below

(2)

specified range can be obtained, in which X, Y and K have the meaning given above.

In the practical implementation of the optical decomposition according to the invention, normally, the lower the Solubility ratio or extent (X / Y.K) of the salt of L- or D-IIHp-CL and the derivative of L- or D-glutamic acid compared to the solvent, the more so

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Solvent required and the more the amount of precipitating salt is reduced, but the optical purity of the product is improved. On the other hand, the higher the degree of solubility, the greater the amount of salt precipitated, although the optical purity of the product tends to be dimmed. Accordingly, it is preferred to appropriately determine the relative amounts of reactants and solvent in accordance with the kinds of the solvent, the separating or decomposing agent and the L- or D-NH ₂ -CL mixture to be used.

Accordingly, according to the invention, it is a suitable practice to change the quantitative proportions among, the solvent, the D, L-NH ₂ -CL mixture and the releasing agent in accordance with the above expression (1), preferably with the above expression ( 2), to be determined * if methanol, ethanol or a mixture of one of the alcohols with water is used as a solvent as described above. If in the expression (1) or (2) X / Y is lower than 2.5 K, the amount of precipitating salt becomes too small or even zero, fc. On the other hand, if X / Y is larger than 6.0 K, in particular larger is than 7.0 K, the optical purity of the product becomes unacceptably low. It is therefore preferred to use the value of X / Y. to be regulated in such a way that the value fulfills the expression (1), in particular the expression (2), and preferably the expression (3) given below:

(3)

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Using this measure, the sparingly soluble salt (A) or (B) falls in the form of needle-shaped crystals from the separation solvent after any conventional working method for fuel-liquid separation, E.g. by filtration, centrifugation, etc., can be easily separated. Especially if that Solvent contains at least 80 wt .- $ 6 methanol, the reaction mixture assumes the form of an excellent, Neten slurry, which greatly facilitates the separation process and 'a continuous mode of operation enables.

The precipitation of the sparingly soluble salt from the separating solvent can be effected at temperatures in the range from the solidification point to the boiling point of the solvent, although the preferred temperature range for practical reasons is between 20 ^° C. to the boiling point of methanol or ethanol and in particular between 2O ⁰ C and 60 ⁰ C.

The sparingly soluble salt (A) or (B) or the easily soluble salt (C) or (D) separated in this way can be resolved by any known procedure, whereby the L- or D-NHp-CL and the derivative can be obtained from L- or D-glutamic acid.

According to the preferred method of decomposition or decomposition, the sparingly soluble can Salt (A) or (.B) or the easily soluble salt (C) or (D) with (1) a hydrohalic acid in an aqueous Medium to be treated bath (2) with a cation

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Exchange resin that contains sulfonic acid groups, too be brought into contact in an aqueous medium. Using such a procedure, the Breakdown or decomposition of these salts into the L- or D-NHp-CL and into the derivatives of L- or D-glutamic acid can be effected very advantageously.

The characteristic advantages of using hydrohalic acid as indicated in (1) above, are the following:

(a) The treatment solvent can be water, the recovery of which is not necessary.

(b) The treatment temperature can be low, so that no adverse side reactions, e.g. racemation, Hydrolysis or the like. Be initiated.

(c) The separation of the hydrohalide from L- or · D-NH ₂ -CL is easy because the derivatives of L- or D-glutamic acid used as a separating agent are precipitated.

It is allowed to burn up as a solvent for the said Salt decomposition using a hydrochloric acid to use any aqueous solution containing a a hydrophilic organic solvent such as methanol, ethanol or the like to such an extent which does not interfere with the precipitation of the separating agent (the derivatives of L- or D-glutamic acid).

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Hydrochloric acid and Hydrobromic acid particularly preferred to the salt treatment medium can be added either in gaseous form or in the form of an aqueous solution. the preferred amount of such hydrohalic acid, to be used is the sum of the amount of hydrogen halide acid which is equimolar to the optically active L or E-I ^ - ^ - CL component in the salt, and the Amount of the same acid required to lower the pH of the treatment solution down to 1 is.

Although the salts can only be cleaved or separated by the use of the hydrohalic acid in an equimolar amount in the optically active L- or ^ -NHp-CL component, the resulting hydrohalogenide of L- or D-NHp-CL as well remains the derivatives of L- or D-glutamic acid as a separating agent are dissolved in the system and are therefore difficult to separate. In contrast, if more than the equimolar amount of hydrohalic acid is used to regulate the pH-V. ^r ertes the treating solution to about 1, the solubility of the release agent, that is to say * the derivatives of L- or D-glutamic acid under reduced enabling their precipitation, thereby facilitating the separation of the two components. If an even greater excess of a hydrohalic acid is used, the pH is lowered to below 1 and hydrolysis of the derivatives of L- or D-glutamic acid can take place. Moreover, since the hydrohalic acid is not normally recovered, the use of an unnecessarily large amount thereof is economically disadvantageous. Even if the salts are used for a longer period of time at high temperatures in the presence of the halogen

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Hydrogen acid are left to stand, disadvantageous side reactions, for example racemation or hydrolysis, of the optically active NHp-CL component can be initiated. Therefore, the Zersetznngs- or decomposition treatment at temperatures of not above 8O ⁰ C, preferably not above 4O ⁰ C, running to. In the treatment, the salt can first be dissolved in an aqueous medium, followed by adding hydrohalic acid and stirring, or an aqueous solution containing the hydrohalic acid can be added to the salt and stirring. The order of addition can be reversed. If the system is operated at room temperature, a treatment time of about 1 hour is sufficient. After the mechanical separation of the separating or decomposing agent which was precipitated during the decomposition of the salt, the desired hydrohalide of the optically active KI-ip-CL-I material is obtained in the form of a solution. The solution is then concentrated and suitably purified to separate the desired hydrohalide from N ^ -CL.

The decomposition process using a cat- | ion exchange resin containing sulfonic acid groups, such as indicated in (2) above, 'is represented by the following Features marked:

(a) Since the optically active salt (/ -), (B]), (C) or (D) by a cation exchange resin that contains sulfonic acid groups contains, is dismantled · and only the optically active L- or D-ITI-Ip-CL-Korr / oOriente of the two components of the named If the salt is absorbed with the resin, which cannot be eluted with aqueous media, the salt can be completely disassembled into its two components.

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Accordingly, L- or D-NHp-CL or a mineral acid salt can be used of this of high purity and almost the derivatives of L- or D-glutamic acid as a separating or decomposing agent can be obtained quantitatively separated.

(b) By filling the L or D-NHp-CL component, absorbed by the above cation exchange resin using any strongly acidic one Mineral acid, a salt of the corresponding mineral acid of L- or D-NHp-CL is also obtained. The latter can be easily converted to an optically active lysine by any known hydrolytic method will.

(c) When the L- or D-NHp-CL-form absorbed with the cation exchange resin is eluted using an aqueous solution of a volatile inorganic base, L- or D-NHp-CL can be obtained in a free form. The component that is not desired as the end product, for example D-NHp-CL, can be easily converted into a racemic D, L-NHp-CL mixture according to a known racemation procedure.

(d) Since absolutely no mineral acid or inorganic base in the recovered separating or decomposing agent is mixed in, i.e. in the derivatives of L- or D-glutamic acid, can be the release agent for repeated use of salt formation with a D, L-NHp-CL mixture be returned in the cycle.

(e) The decomposition procedure is simple.

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In the disassembly process described above using a catheter exchange resin, aqueous Media similar to those used in the previous. Hydrochloric acid processes described above may also be used, the preferred being the preferred Medium is water.

In certain cases, however, when a solvent mixture containing methanol or Xthanol is used for the production of the above-mentioned salt (A), (B), (C) or "(D) is used and the salt is advantageously used in Solution form or in not completely dried form, which - still contains residual solvent mixture, treated is to be, an aqueous solvent containing methanol or ethanol can be used.

As the cathode exchange resin containing sulfonic acid groups (-S (XH)), any known cation exchange resin containing sulfonic acid groups in the acidic form (form) can be used, the composition of the resin matrix and its degree of crosslinking being not critical Commercially available cation exchange resins of the styrene type with a content of sulfonic acid groups, which are produced on an industrial scale, are expediently used, for example resins including resins of standard type, for example "Diaion SK-1A, SK-1B, SK-11O" (products from M ₅ tshubishi Kasei Co., Japan), "Amberlite 120, 122" (products from Rohm & Haas Co., USA), "Dowex 50W" (product from Dow Chemicals, Inc.) and resins of the porous type, e.g. Diaion "PK-208", · "Amberlite 200, ΧΞ-1Ο0» or the like.

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In the treatment of said optical salts (A), (3), (C) or (D), such a cation exchange resin, v. ^r ie indicated above, can be used in the acidic form (M-Forir.). "If the resin is not in acidic form, but is in the sodium form (Na - For ..;), it should be regenerated into the acidic form by treatment with a mineral acid (eg aqueous hydrochloric acid, aqueous sulfuric acid or the like) and then thoroughly washed with water before use. The application mode of such a resin is variable depending on such factors as the manner of exposure, degree of regeneration of the resin, temperature, or the like; however, it can normally be varied in the It can be determined in a manner that the total exchange capacity of the resin used, calculated from the exchange capacity e unit volume of the resin (the latter can be determined according to a customary exchange capacity measurement: :) »exceeds the equivalent of the optically active salt to be treated.

Although the use of a large excess of the xacion exchange resin does not produce any adverse effect, this would result in an unnecessarily large amount of aqueous mineral acid or base in the elution stage of L- or D-l '/. ^ - CL and in the regeneration stage of the resin require. Malier, the suitable amount of the resin to be used is within such a range that its total exchange capacity is 1 to 10 times the equivalent amount of the salt to be treated.

V.'erji L- or D-IIH ₂ -CL at high temperatures for a longer period of time in simultaneous presence

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exposure to the acidic form of the cation exchange resin can result in adverse racemization or hydrolysis thereof. On the other hand, if the cation exchange resin treatment is carried out at excessively low temperatures, the aqueous medium may freeze. Based on such considerations, the suitable treatment temperature is not above 100 ^° C., and preferably within the range of 60 to ⁰ ° C.

The decomposition process using the ion exchange resin can either be in a fluidized bed system (fluidized system), in which the optically active salt is dissolved in an aqueous solvent and by one with. the cation exchange resin packed column is carried out or it is carried out can be run on a batch basis with the cation exchange resin added to a solution of the optically active salt and is stirred. The salt is broken down into its two components.

ΙΓε-, οη de; n method according to the invention can be based on this way D ^ -ITHp-CL mixtures in optically active L- or D-CHp-CL of high purity at high yields using a relatively inexpensive optical "racing or dismantling means and according to simple working groups disassembled

The thus decomposed L-IiHp-CL or its hydrohalide '.zaun can be easily hydrolyzed and converted into L-lysine. On the other hand, the DI ⁴ THp-CL can be racemized, further optically broken down by the process according to the invention and likewise converted into L-lysine in a similar manner.

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The method according to the invention is explained in more detail below with reference to examples, in which the optical Purity of L- or D-NHp-CL or their mixtures and the percentage of the L-form content from the degree of the specific Rotation of an aqueous 1-in hydrochloric acid solution "yclroclilorids of the above material were calculated and the yield calculated assuming was that the salt was made up of the single molar equivalent consisted of the components.

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(I) Examples of optical separation or decomposition using Mp-nitrobenzo7 ₁ rl - L-glutamic acid and

N-p-nitrobenzoyl-D-glutamic acid. example 1

(A) 1.8 g of a racemic D, L-JiH ₀ -CL-I-IiSChUJIg (optical purity: 50%) were dissolved in 25 ml of water, to which 4.0 g of Np-nitrobenzoyl-L-glutamic acid were also added

»Give and were dissolved, whereupon the mixture was stirred ^{at 0 ° C. for 2 hours.} A large amount of a crystalline, sparingly soluble salt of L- and DI ¹ TH ₂ -CL was precipitated with Np-nitrobenzoyl-L-glutaniic acid, which was separated off by filtration with suction, washed with a small amount of water and dried under reduced pressure, whereby 2.1 g of crude crystals were obtained. The crystallization yield was 36%. The product had a melting point of 186 ⁰ C and a specific rotatory power of / Jx7-q = - 0.8 (K = 3.0, water). 0.7 g of this sparingly soluble salt VRirden is decomposed with hydrochloric acid according to the procedure given in Example 23 described below; this gave 0.23 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 15% of the L-form (yield: 10.%).

(B) 1.3 g of the above obtained sparingly soluble salt was recrystallized from 12 ml of hot water to give 0.8 g of needle-shaped crystals were obtained with a melting point of 193 ⁰ C (crystallization yield of recrystallization was 62%).

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Slergrvtaranalyse; (C ^ H ^ N ^ Og) (424.40)

Calculated: $ 0.62 5.55

gei .: 50.94 5.70

/ ä / £ ² - -2, S ⁰ (X = 1.8, water)

The total amount of the crystalline product was decomposed ISIT hydrochloric acid according to the specified in the later-described Example 21, wherein 0.22 j of the hydrochloride of L-NHp-CL get v / urde. (Yield: 10>ό; Yield of dpa total sparingly soluble salt: 16 (? 5). The product had a specific rotation

OO r \

capacity of Zi ^ Q = -25 _f (K = 1.6, In-Saizäure) and

an optical purity of 1005t.

(C) The filtrate remaining after the separation of the sparingly soluble balance, ie the mother liquor from the uncrystallization and the liquid was combined, whereby an aqueous solution with a ::; Oer ~ .lt before. 4.3 g of a readily soluble salt were obtained. The oil is broken down or split up according to the procedure given in the example 32 described later, 1.58 g of the hydrochloride being obtained from a D, L-JIH ₉ -CL-Iiεchung which the D-Fora in a sledge of 66% (yield: 69%).

Example 2

', S g of an equiciolar mixture of L- and D-IC-I - CL were dissolved in 10 nl Viasser, to which 4.0 g of i'-p-xitro-benzoyl-L-glutamic acid were added and dissolved, whereupon left to stand at 4 ^° C. for 3 hours

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became. A crystalline, sparingly soluble salt precipitated out. 10 ml of water was added to the system, followed by stirring for 5 minutes and filtering. The precipitate thus separated was washed with a small amount of water and dried. The yield of the sparingly soluble salt was 2.8 g (crystallization yield: 49%) and the L-form content of the D, L-NH ₂ -CL mixture in the sparingly soluble salt was 67%. The sparingly soluble salt was then recrystallized and broken down in the manner described in Example 1, 0.32 g of the hydrochloride of L-NK ₉ CL having an optical purity of 100% (yield: -14%).

Separately, the filtrate and the washing liquids were condensed and dried together. The resulting easily soluble salt in an amount of 1.5 g was similarly treated with hydrochloric acid to be decomposed. This gave 0.43 g of the hydrochloride of the D, L-KH ₂ -CL mixture with a content of 78% of the D form. (Yield: 37%).

Example 3

1.8 g of an equimolar mixture of L- and D-NHg-CL were dissolved in 17 nl of water, including 4.0 g of N-p-nitrobenzoyl-L-glutairic acid were admitted. Using similar procedures as in Example 1 described, 3.2 g of crude crystals are one sparingly soluble salt obtained with a crystallization yield of 55%. 1 g of the crude crystals was made

for decomposition in the following example 21

treated with hydrochloric acid. Thereby 0.34 g of the hydrochloride of the DjL-NHg-CL mixture with a content of 6½% of the L-shape obtained (yield: 15%).

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T961180

On recrystallization of 2.2 g of the above. Obtained Crude crystals from 15 ml of hot water were obtained 0.92 g of needle-shaped crystals (crystallization yield : 43%). The total amount of crystalline product was similarly treated with hydrochloric acid and disassembled. This gave 0.27 g of the hydrochloride of L-NHp-CL - with a content of 95% of the L-form. (Yield: 12%).

The filtrate remaining after the separation of the crude crystals, ie the mother liquor from the recrystallization and. the liquors were combined, concentrated and dried to give 3.9 g of a readily soluble salt which was similarly decomposed. In this way, 1.1 g of a hydrochloride of the D, L-NH ₂ -CL mixture with a content of 63% of the D-form were obtained. (Yield: 4-7%).

Example 4

1.8 g of an equimolar mixture of L- and D-NHp-CL were dissolved in 19 ml of water and a solution of 4.1 g of Np-nitrobenzoyl-L-glutamic acid dissolved in 28 ml of water was added with stirring for 2 hours 3O gemisht ⁰ C, which thereby precipitates sparingly soluble salt was filtered off and dried to give 2.18 g were obtained of crude crystals. The crystallization yield was 37%. The total amount of crystals was made with a resin

decomposed according to the procedure described in Example 28 below, 0.83 g of the hydrochloride of the D, L-NH ₂ -CL mixture having a content of 88% of the L-form being obtained .

009832/1916

example 5

(A) 1.8 g of an equimolar mixture of L- and D-NHp were added dissolved in 17 ml of Vfeser, v / o to 4.0 g of X-p-KitrobeiiKoyl-D-glutamic acid were added and then appropriate procedures, as described in Example 1, were executed. This resulted in 3, A- g of a raw crystalline sparingly soluble salt with a crystallization yield received by 59%. 1.0 g of the crystals were treated with hydrochloric acid according to the following two

anse ^ ßbene way of working
spieP 2Tj. disassembled, whereby 0.39 g of the hydrochloride of the D, L-KK ₂ -CL mixture with a content of 71% of the D-form were obtained. (Yield:

(B) 2.4 g of the crude crystals obtained above were recrystallized in 17 ml of hot water, whereby 1.5 g of the needle-shaped crystals were obtained at a crystallization yield of 63%. Die The total amount of needle-shaped crystals was treated with hydrochloric acid according to that described in Example 22 below Disassembled procedure to give 0.40 g of the D-NBy-CL hydrofluoric chloride. (Yield: 17% ;.

Yield from the total amount of the poorly soluble salt: 24%). The optical purity of the D-form was 100%.

Example 6

1.0 ff an equimolar mixture of L- and D-NH ₀ -CL 1O5ml ^

were in methanol with a content of 2.3 g of N-p-nitrobenzoyl - L-glutamic acid, which was dissolved therein, introduced and dissolved with stirring. After leaving the

009832/1916

System while about 5 ole at room temperature the precipitation of needle-shaped crystals. ! laugh continued: stirring for 1 hour, the precipitated Crystals filtered off, with a small amount of methanoi washed and dried under reduced pressure, where "at 1,3 .3 of a crude crystalline poorly soluble Balances have been received. The crystallization yield was 39 / '·. Lie total amount of crude crystals was made rr.it one. Resin according to the example below disassembled working method described, whereby 0.50 g des Hydrochloride of the D, L-NHp-CL ~ mixture with a content of 95? or L-form were obtained (yield: 39/0.

The filtrate remaining after the crude crystals had been separated off and the washing liquid were combined, concentrated and dried, 2.0 c of a readily soluble calcium being separated off, which was broken down with resin according to the procedure described in Example 32. In this way, 0.77 g of the hydrochloride of the DjL- ^ Hp-CL mixture with a content of 82 *> of the ' Ώ form were obtained. (Yield: 6050).

Example 7

1.0 g of an equimolar mixture of L- and D-I7: i _o -CL were in io iri a solvent scaffold consisting of $ * ■ 'Ggw .-' / c methanol and 6 Gev .->: Yasser, solved and the solution - »rarde with another. Solution consisting of 2.3 g of Mp-Mitrobenzojrl-L-glutanic acid and 40 ml of the above-mentioned mixed solution mixture, whereupon the mixture was stirred ^{for 2 hours at 3 ° C.} In this way, 1.4 g of a crystalline heavy-

009832/1916

Soluble salt obtained with a crystallization yield of 42%, which was decomposed with resin according to the procedure described in Example 34 below and eluted with aqueous ammonia. In this way, * 0.42 g of L-NK ₂ -CL was obtained. (Yield: 42%; Yield from the L-Forci: 84%). The L-shape had an optical purity of 100%).

The filtrate and washings were concentrated and dried with- ψ each other, whereby 1.9 g of a slightly soluble salt were obtained, which was decomposed with resin by the method described in the following Example 34 operation. Thereby 0.57 g of the D, L - ^ - Ip-CL-Ziεchung with a content of 86% of the D-form were obtained. (Yield: 57%).

Example 8

1.8 3 of an equimolar mixture of L- and D-M ^ - CL were in 8 ml of a solvent mixture consisting of - 50% by weight of ethanol and 50% by weight of water, dissolved, the k solution was r. with another solution consisting of 4, o g of N-p-ITitrobenzoyl-B-glutamic acid and 20 ml mixed with the solvent mixture specified above. The procedure as in Example 6 above indicated, was followed at O = C, with 52 g of a crystalline sparingly soluble salt with a crystallization yield of 55% were obtained, 1.2 g of these crystals were treated with hydrochloric acid according to that described in Example 25 Working method disassembled, with 0.34 g of the hydrochloride D.L-K ^ -CL-l-mixture with a content of 85% of the D-form were obtained (yield 15%). The remaining 2.0 g of the crystals were in 20 ml of the above

U air ⁵ }

009832/1916

Recrystallized solvent mixture, 1.3 g of needle-shaped crystals being obtained with a crystallization yield of 65% . All of the needle-shaped crystals were broken down with a resin according to the procedure described in Example 28 "below. In this way, 0.55 g of the hydrochloride of D-KHo-CL was obtained. (Yield 2k%; Yield based on the total amount of sparingly soluble salt: 3B%) The optical purity of the D-form in the hydrochloride was 9896.

Example 9

In one with a mechanical stirrer and one

A three-necked flask equipped with a thermometer, a solution prepared by dissolving 2.3 g of Np-nitrobenzoyl-L-glutamic acid in 400 ml of ethanol was measured, and the flask was immersed in a thermostatic bath to keep the temperature at 15 ^° C to be held. Separately, 1.0 g of a ä.quimölaren mixture of L, D-NH ₂ -CL (optical purity:. £ $ 50 (dissolved in 100 ml of ethanol and likewise maintained at 15 ⁰ C. The latter solution was the former solution in The crystals thus precipitated were filtered and dried under reduced pressure to obtain 2.2 g of a crystalline sparingly soluble salt in a crystallization yield of 67 %.

The crystalline salt was treated with hydrochloric acid according to the procedure described in Example 27 below

disassembled, 0.75 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 70 % of the L-form being obtained. (Yield: 5896).

009832/1916

Example 10

0.82 g of a äquimolaTen mixture of L- and D-TIH ₂ -CL were rr in 19 l of a Lösungsmittelgeraisches, 95 Gev: - # 5 parts by weight of ethanol una Jö dissolved water and to the solution v / ere 1.9 g of Np-nitrobenzoyl-L-giutamic acid were added and dissolved with stirring. A procedure similar to that in Example 9 above was carried out at 3C ^C C, with 2.3 g of a crystalline sparingly soluble salt being obtained with a crystallization yield of 85%. 0.78 g of the hydrochloride of the D, L-NH ₂ -CL mixture having a content of 66% of the L-formin were obtained (yield: 74%).

Separately, the filtrate and the Waschflüsi £ ke _t it was concentrated and dried, and the resulting 0.44 g of a slightly soluble salt v / ere similarly broken down to give 0.17 g of the hydrochloride of DJL-NKP-CL-mixture with a content of 75% of the D-form were obtained. (Yield 16%).

Example 11

0.8 g of an equimolar mixture of L- and DI ¹ JHp-CL were dissolved in 100 ml of a solvent mixture consisting of 90% by weight of ethanol and 10% by weight of water, and the solution was mixed with another solution from 1.7 g of Np-nitrobenzoyl-L-glutamic acid, dissolved in 220 ml of the solvent mixture given above. The procedure described in Example 9 was carried out in a similar manner ^{at 30 °} _C.? where 0.8 g of a crystalline poorly soluble

BATH ORIGINAL

009832/1916.

union salt were obtained with a crystallization yield of 36 ^ -0. The salt was decomposed with resin according to the procedure described in Example 28 below mode of operation, wherein 0.37 s & s hydrochlorides of L-IH-I ₀ -CL were obtained. (Yield: 3650 The hydrochloride had an optical purity of %

Separately, the filtrate and the washing liquid; concentrated and dried and the resulting 1.7 g of a readily soluble salt was similarly decomposed, leaving 0.56 g of the hydrochloride the DjL-riHg-CL mixture with a content of 89 ^ the D-? Orrs were received. (Yield: $ 64)

Example 12

C, 9 g of an equinolar mixture of L- and D- * "M ₀ -CI, (opt is el ve. Purity: 50? S) were in 4 rl eir.es LcsuHfcv.ittol .- • er.icchcs, consisting from 80 wt. 55 i'lthanel and 2C wt. oyl-I.-cTlutainic acid in 10 ml dos vorsxendem cer.ar.nten Lösur. ^ snittolgesisches produced v.-order. v; ar, ^ cr.iccht, v.'crauf bsi r.au ^ ter.poratur left to stand v. urdo. The " - Washed using the solvent mixture given above and dried under reduced pressure. 2.1 g of the crystalline salt were obtained with a crystallization yield of 71 ~ A.

009832/1916

The total amount of the sparingly soluble salt is nil from a 30-Lösungsmi ttelgemisches consisting of 60 wt .-% ethanol and 40 wt .-% water at 7O ⁰ C uinkristal- · lisiert, whereby 0.90 g of long needle-shaped crystals with a crystallization yield from W ⁷ Sk . The crystals were separated according to the procedure given in Example 28 below, 0.45 g of the hydrochloride of L-NHp-CX being obtained (yield: 39/0. The optical purity of the L-form thereof was SOJo.

The filtrate remaining after the separation of the crude crystals, the mother liquor of the Umkr'istallisaticn and the washing liquid were combined, concentrated and dried, and the resulting 2.0 g of a readily soluble salt were broken down in a similar manner, with 0.57 g of the Hydrochloride obtained from D-NHg-CL. (Yield: 490 ^Å ). The optical purity of the D-form was 95%.

Example 13

2.3 g of IN-p-nitrobenzoyl-L-glutamic acid were dissolved in 30 ml of a solvent mixture consisting of methanol and ic. Ethanol and water (composition, 3-weight ratio 45:45:10) were dissolved and the solution was mixed with another solution, which was obtained by dissolving 1.0 g of an equimolar mixture of 0.1 L-KKg- CL has been prepared in 10 ml of the solvent mixture given above, using a procedure similar to that described above in Example 9, with the modification that the temperature of the thermostatic bath was set to 30 ⁰ O, 2.6 g of a poorly soluble Salt obtained with a crystallization yield of 10% . -—- "" - *

009832/1916

The salt was decomposed by treatment with a resin in accordance with the procedure given in Example 35, 0.93 g of the hydrochloride of the D, L-NH ₂ -CL mixture being obtained, with a content of 63 % of the L-form. (Yield: 93/0.

Example 14

2.3 g of Np-nitrobenzoyl-L-glutamic acid were dissolved in 43 ml of a methanol-acetone-water solvent mixture .es (composition weight ratio 80:10:10) and the resulting solution was 1.0 g of an L and was D-NHp-CL-mixture was added and dissolved, followed by stirring at 30 ⁰ C. After about 15 minutes of stirring, the precipitation of a sparingly soluble salt began. After stirring for a further 1 hour, the salt was centrifuged off and then dried, 1.3 g of the salt being obtained with a crystallization yield of 39 % . The salt was treated by resin treatment according to the procedure described in Example 34 below in 0.91 g of Np-nitrobenzoyl-L-glutamic acid and 0.46 g of _{O, L-NH 2} -CL mixture with a content of 1% of the L- Form (yield: 36%) · decomposed.

Example 15

2.3 g of Np-nitrobenzoyl-L-glutamic acid were dissolved in 45 ml of an ethanol-water-toluene-detergent mixture (composition-weight ratio 92: 6: 2). This solution was mixed with another solution which had been prepared by dissolving _{1.0 g of an equimolar mixture of L- and D-NH 2} -CL in 15 ml of the above-mentioned solvent mixture, and

009832/1916

the mixture was ^{stirred rapidly at 3C C} C for 1 hour, after which the procedure described in Example 9 above was followed *. There were then obtained 2.5 g of a crystalline sparingly soluble salt with a crystallization rate of 76%.

The salt was made according to the example below disassembled procedure described, with 0.79 g of the hydrochloride of ujL- ^ IKp-CL- ^ ischung with a content of 64% of the L-shape were obtained. (Yield: 61%).

Example 16

2.3 g of Np-nitrobenzoyl-D-glutamic acid were suspended in 100 ml of iGopropanol. Separately, 1, og of an equimolar mixture of L- and D-NH ₂ -CL was dissolved in 50 ml of isopropanol. The suspension and the solution were subjected to a procedure similar to that given in Example 9 at 30 ^° C., 2.9 g of a crystalline sparingly soluble salt being obtained with a crystallization yield of 88%.

The salt was broken down according to the procedure described in Example 28, 1.15 g of the hydrochloride of the D, L-IiH ₂ -CL mixture having a content of 57% of the D-form (yield 88%).

Example 17

A solution made by dissolving 2.3 g of N-p-nitrobenzoyl-L-glutamic acid in 80ml of a solvent mixture s consisting of 80% by weight isopropanol and 20% by weight water, had been prepared and a

BAD 009832/1918

Another solution obtained by dissolving 1.0 g of a liquid mixture of L- and DI-JIi ₀ -CL in 20 nl of the above-mentioned solvent mixture _: ~ c ~ -.cllt was * v. ^r ar, were treated in accordance with the procedure described in Example 9 at 3G ^{C C.} 1.4 g of a crystalline sparingly soluble alr * ec were thereby obtained with a crystallization rate of 42;

£ z v ~ Arden thereby 0.52 g of K3 ^r droChlorids of L-IIh obtained ₉ -CL. (Extensions: 40> ό). The optical purity of the L-Forrs was

Example 18

/.a Lcsunr of 1.15 g of h'-p-ITitrobenzcrl-L-gluta ::.!:; - acid in 7C nl of an n-Bu

gerr.iscr.es {} .O: IC, based on weight) ur.d a vx-ifore Lösur.r before. 0.5 g of an outer molar Ilicci'ui.g of L- and DTI ₀ -CL in 3'δ nl of the above mentioned solvent ? described, treated at 30'C. There were C, 5? ^; of a crystalline, rapidly soluble salt with a crystallization yield of 35%. The SaIs ν .-.;: Αε after the work published in Beispfel 25, v / above 0.22 g of the hydrochloride of L-MI ₀ -CL with an optical purity of 10055 were obtained. (Yield 3 ^).

009832/1916

Example 19

A solution of 3.45 "g of Np-nitroberizoyl-L-glutaniic acid in 80 ml of an acetone / water solvent mixture (7C: 50, based on weight) and a further solution of;, 5 g of an equimolar mixture of L and D -KTH ₂ ^- CL (optical purity: 50%) in 20 ml of the above-mentioned solvent solution were ^{kept at 3 C 3} C in a manner similar to that described in Example 9, with 1.2 g of an oil crystalline sparingly soluble salt obtained with a crystallization yield of 24%.

The salt was decomposed according to the procedure described in Example 23 below, giving _{C.43 g of the hydrochloride of L-NH 2} -CL. (Yield: 22Jo). The optical purity of the L-shape was 94SC

Example 20

A solution that was prepared by dissolving 4.6 g of Np-nitrobenzoyl-L-glutamic acid in 50 ml of a solvent mixture of ethylene glycol water (90:10, based on weight) and another solution that was prepared by dissolving 2, was 0 g of an equimolar Ilischung of L- and D-NH ₂ in 10 ml of -CL \ ^r orstehend stated solvent mixture prepared were similarly: else treated 'as in the above example 9 at 30 ⁰ C \. 5.5 g of a crystalline, sparingly soluble salt were obtained with a crystallization yield of 50? O. The salt was broken down according to the procedure described in Example 28 below, 1.28 g of the hydrochloride of D, I> -NH ₂ -CL-Miechung having a content of 58 % of the L-form were obtained. (Yield: 50%) · .- ·

BATH 0 0 9 8 3 2/1916

(II) Examples of the decomposition of isomeric salts with hydrogen halide

Example 21

0.80 g of the needle-shaped crystals obtained in step (B) of Example 1, ie the salt consisting of L-NHo-CL and Np-nitrobenzoyi-L-glutamic acid, were dissolved in 5 ml of 1η hydrochloric acid and stirred at room temperature . About 2 minutes later the precipitation of Lp-nitrobenzoyl-L-glutamic acid began. One hour after the stirring, the precipitate was filtered off with suction and thereby removed. That. The filtrate was concentrated and dried to give the hydrochloride of L-NHp-CL, which was still contaminated with a minor amount of Np-nitrobenzoyl-L-glutamic acid. 5 ml of an isopropanol solution containing 5N hydrochloric acid was therefore added to the product, followed by stirring for 50 minutes. The hydrochloride remaining undissolved was filtered, washed twice with 2 ml of isopropanol each time and dried under reduced pressure. The yield of the hydrochloride of Ii-NHp-CL was 0.22 g (yield; 71 %) . The melting point of L-NH ₂ -CL was 285 ° C (decomposition); / S / ²² _β _ ₂ 5.0 ° (K = 1 ", 6, ln-hydrochloric acid); (literature ^{value: / ^ 2} = -24.5 ° * 1.2 °); (K - 3.2, These data show that the optical purity of the above hydrochloride is 100 % and that no racemization took place during the above decomposition treatment.

009832/1016

Example 22

1 * 50 g of the needle-shaped crystals obtained in step (B) of Example 5, ie the salt consisting of D-NH ₂ -CL, and Np-nitrobenzoyl-D-glutamic acid were dissolved in 10 ml of hydrochloric acid, whereupon a procedure similar to that described in Example 21 above was carried out. This gave 0.40 g of hydrochloride of D-NHp-CL (yield: 68 <f>) . The optical purity of the D-form was 100 %.

The filtered solid from the treatment hydrochloric acid and the concentrate of the isopropanol solution were dried under reduced pressure, whereby 1.03 g of N-p-nitrobenzoyl-D-glutamic acid were obtained (yield? 100 #).

Example 23

1.40 g of the poorly soluble salt of O, L-NHp-CL mixture with Np-nitrobenzoy.lL-glutamic acid, which was prepared in step (A) of Example 1 (F = 186 ° C ^ / ö / q = -0.8; K = 3 * 0, water), were suspended in 8 ml of water and 2 ml of 5N hydrochloric acid were added to form a solution. The solution was treated in a manner similar to that described in Example 21. This gave 0.46 g of the hydrochloride of the O, L-NHp-CL mixture with a content of 75 % of the L-form (yield: 84 %).

009832/1916

Example 24

2.30 g of a sparingly soluble salt of the D, L-NHp-CL mixture with N'-p-nitrobenzoyl-L-glutaniic acid, which was obtained in Example 1, were suspended in 10 ml of water, and hydrogen chloride gas was added to the suspension blown in at room temperature to lower the pH of the solution to 1. About 10 minutes later, the precipitation of Np-nitrobenzpy1-L-glutamic acid began. After stirring continuously for 30 minutes , the mixture was treated in a similar manner to Example 21, whereby 0.78 g of the hydrochloride of D, L-NH ₂ -CL mixture containing 66 % of the L-form was obtained (Yield: 87 %)

Example 25

1.20 g of the poorly soluble "* ίθρ of the D, L-NHg-CL mixture with Np-nitrobenzoyl-D-glutamic acid, which was obtained in Example 8, were dissolved in 8 ml of lN hydrochloric acid at 40 ° C., whereupon the The procedure described in Example 21 was carried out in a similar manner, giving 0.14 g of the hydrochloride of DjL-NHg-CL mixture with a content of 85 % of the D-form (yield:

Example 26

1.50 g of the sparingly soluble salt of the D, L-NH ₂ -CL mixture with Np-nitrobenzoyl-L-glutamic acid which was obtained in Example 11 was suspended in 10 ml of water and hydrogen bromide gas was blown into the suspension at room temperature to lower the pH of the solution to 1 and stir for 1 hour.

009832/1916

The precipitated Np-nitrobenzoyl-L-glutamic acid was then filtered. The filtrate was concentrated and dried to _{obtain the hydrobromide of L-NH 2} -CL, which was suspended in 10 ml of an isopropanol solution containing 3.0 n-hydrogen bromide. A procedure similar to that described in Example 21 was then followed. 0.67 g of the hydrobromide of L-NH _Q -CL were obtained (yield: 91 %) . The product had a «specific rotatory power of Ζαφ« 21.1 (K β 2.0, water), and an optical purity of 98 ^ ·

Example 27

2.2 g of the crystalline "sparingly soluble salt" obtained in Example 9 was dissolved in 20 ml of an aqueous solvent of hydrochloric acid containing 2% by weight of methanol and stirred at room temperature. After about 3 minutes, the precipitation of Np-nitrobenzoyl-L-glutamic acid began. After stirring for one hour, the precipitate was removed by suction filtration. The filtrate was concentrated and dried to give the hydrochloride of L-NHp-CL which still contained a small amount of Np-nitrobenzoylr-L-glutamic acid. Therefore, 20 ml of isopropanol was added to the hydrochloride, followed by stirring for 30 minutes to extract the glutamic acid derivative. The hydrochloride remaining undissolved was collected by filtration, washed twice with 2 ml of isopropanol each time and dried under reduced pressure. This gave -0.75 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 70 # of the L-form (yield: 88 #).

009832/1916

(III) Examples of the decomposition of the isomeric salts using cations containing sulfonic acid groups from ohharζen

Example 28

1 * 52 g of the sparingly soluble salt consisting of L-NHp-CL and N-p-nitrobenzoyl-L-glutamic acid, the in the step (B) in Example 1 was dissolved in 50 ml of water. The solution thus obtained was passed through a resin column with a diameter of 1.0 cm and a height of ΐβ cm, the one with 12 mm a cation exchange resin, the sulfonic acid groups (trade names DIAION SK-IB) was packed. then the column was washed with .5 ml of water. From the effluent leaving the column and the washing liquid N-p-nitrobenzoyl-L-glutamic acid was obtained quantitatively.

Then, the resin column was eluted and washed with 100 ml of 1N hydrochloric acid, and the eluate was concentrated under reduced pressure at 50 ° C to obtain 0.58 g of the hydrochloride of L-NHp-CL (yield: 98 %) having a melting point of 285 ⁰ C (dec.) And Tt ^ ² - -25.0 ° (K = 5.2, ln-hydrochloric acid). Literature value: ßC / ^ m - 24.5 - 1.2 ° (K - 3.2, ln hydrochloric acid). The characteristic values of the infrared absorption spectrum of the hydrophloride coincide with those of the separately synthesized hydrochloride of D, L-NHp-CL.

00 * β32 / 19Ίβ

Example 29

1.84 g of the sparingly soluble salt consisting of D-NHp-CL and Np-nitrobenzoyl-D-glutamic acid, which had been obtained in step (B) of Example 5, was dissolved in 50 ml of water and then in a similar manner, as indicated in Example 28, treated. Using hydrochloric acid, 0.69 g of the hydrochloride of D-NH ₂ -CL were obtained from the eluate (yield: 96%) . The optical purity of the hydrochloride was 0 %, while that related to the D-form was 100 % .

Example 30

A mixture of 2.07 g of a salt of L-NH ₂ -CL with Np -nitrobenzoyl-L-glutamic acid and 0.69 g of another salt of -D-NHp-CL with Np-nitro-likeyl-L-glutamic acid (optical purity of D, L-NH ₂ -CL contained in the mixture: 75 %>) was dissolved in 100 ml of water and passed through a resin column with a diameter of 0.9 cm and a height of 22 cm containing 15 ml of a sulfonated cation exchange resin (trade name: DOWEX 5OW-X8), and a similar procedure as described in Example 28 was followed. 1.05 g of the hydrochloride of the D> L-NH ₀ -CL mixture with a content of 75 % of the L-form were obtained from the hydrochloric acid eluate; Yield $ 98.

The resin column was also washed thoroughly with water until the pH of the washing liquid was 5 * 0, whereupon with this resin column the one described in this example Working method with achievement of similar results could be repeated.

009832/1916

Example 31

The same mixture of optically active sparingly soluble salts as used in Example 30 above was dissolved in an amount of 2.76 g in 100 nil of water and passed through the same resin column as in Example 30 above. The resin column was thoroughly washed with water, and the above aqueous solution was passed through the thus treated column again. Subsequent treatments were identical to those of Example 28 except that 250 ml of 0 _# 5N hydrochloric acid was used for elution. 2.12 g of the Hydrochloride den D, L-NH ₂ -CL mixture with a content of 7 ² ^ % of the L-Forra were obtained (yield: 99 $),

Example 32

4.30 g of the easily soluble salt of D ₅ L-NH ₂ -CL with Np-nitrobenzoylrL-glutamic acid (D-form content in _{O, L-NH 2} -CL: 66 %), which is used in Example 1 (C) was dissolved in 50 ml of water. 40 ml of a cation exchange resin having sulfonic acid groups (trade name: AMBERLITE 120) was suspended in 40 ml of water, and the suspension was added to the first solution with stirring over 30 minutes. The resin was then separated off by filtration, after which it was washed with 50 ml of water.

The same resin was washed five times with 300 ml of 1N hydrochloric acid. After concentration of the washing liquids under reduced pressure, 1.58 g of the hydrochloride den D, L-NH ₂ -CL mixture with a content of 66% of the D-form were obtained (Aut> today: 95%).

009832/1916

Example 33

3 * 30 g of the sparingly soluble salt, as obtained in Example 7 (content of the L-form of NHg-CL: 100 $>), were dissolved in 120 ml of water and passed through a column with a diameter of 1.0 cm and a height of 24 cm, which was packed with 18 ml of a cation exchange resin containing sulfonic acid groups (trade name: DIAION pK-208). The column was washed with 160 ml of water.

Further, the column was eluted and washed with 400 ml of 1N-hydrobromic acid. After the eluate was concentrated under reduced pressure and dried, 1.54 g of the hydrobromide of L-NHg-CL with an optical purity of 100 % was obtained (yield! 95 %) . .

Example 34

1 * 90 g of the easily soluble salt obtained in the above Example 7 (content of D-form in the NHg-CL component: S%) was dissolved in 20 ml of water and passed through an acidic cation exchange resin column (trade name : DIAION PK ^ 208; - amount of resin 6 ml; diameter and height of the column 1.0 cm or 8 cm) and the column was washed with 60 ml of warm water. Then the resin column was eluted and washed with 120 ml of 10 # aqueous ammonia. After concentration of the eluate under reduced pressure, 0.57 g of D, L-NH ₂ -CL mixture (free form) with a content of 86 % of the D form were obtained (yield: 99 %) »

009832/1916

Example 35

2.6 g of the product obtained in Example 13, crystalline, sparingly soluble salt were dissolved in 150 ml of an aqueous solvent with a content of 25 wt -.% Methanol dissolved as described in Example 30 followed by a similar operation, is executed. 0.93 g of the hydrochloride of the D, L-NHp-CL mixture with a content of 63 % of the L-form were obtained (yield: 92 Ji).

Example 36

2.2 g of the crystalline sparingly soluble salt which was obtained in Example 9 *, was dissolved in 150 ml of an aqueous solvent with a content of 20 wt -. Ethanol dissolved, followed by a similar procedure as described in Example 30 was carried out . There were 0.8l g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 70 % of the. Preserved L shape (yield; 95 #)

009832/1916

(IV) Examples showing the relationship between the amount of

and the amount of solvent

explained

Example 37

Into a flask equipped with a mechanical stirrer and a thermometer, three-neck flask 23.0 g (0.078 mol) of were Np-nitrobenzoyl-L-glutamic acid and 730 ml of a solvent mixture consisting of 94Gew .-% of methanol and 6 g of _p w .- ^ Water poured and with stirring in a thermostatic bath, which is kept at 25 ⁰ C, introduced in order to form a solution of the separating or decomposing agent. In another three-necked flask similarly equipped with a stirrer and thermometer, 10.0 g of a racemic L- and D-NHg-CL mixture (0.078KoI, optical purity: 50%) in 370 ml of the above-mentioned solvent mixture dissolved at 25 ⁰ C and the resulting solution was poured into the first flask (solution of the separating agent), mixed with it, whereupon the temperature was maintained at 25 ⁰ C, stirred, -

One hour after the start of precipitation of white crystals, the crystals formed were filtered off. In this case the crystallized continued Salt did not settle on the bottom of the flask but remained suspended in the solution, the condition being a liquid (fluid) slurry was maintained, which was very easily maintained by a tap at the bottom of the flask could be withdrawn in a centrifugal separator for filtration. The mother liquor was found

009832 / 191S

light squeezed out of the crystals; after drying of the crystals with hot air were 12.3 g of a sparingly soluble salt with a crystallization yield of 3796 received.

The salt was decomposed using the cation exchange resin according to the procedure of Example 28 and 4.7 g of the hydrochloride of L-KK ₂ -CL were obtained by elution with hydrochloric acid (yield: 31% _f yield from the L-form: 7h% ) . In this example, the total amount of the isomeric salt was 33.0 g, the total amount of the solvent was 1,100 ml, and the solubility ratio as defined above was 2.7. The optical purity with respect to the L-form 'in the hydrochloride of L-NHg-CL thus obtained was 995 *.

Separately, the filtrate from which the crystals had been removed was concentrated and dried, and the resulting easily soluble salt was decomposed using the cation exchange resin in a manner similar to that in Example 34 above. By eluting with aqueous ammonia, 6.1 g of the D, LN ^ -CL mixture with a content of 79? ' the D-form obtained (yield: 61 %).

Examples 36 to 45

In the above Example 37, the solubility ratio of 4.5 of the total amount of isomeric salt of 35.0 g and crystallization temperature were set at 3O ⁰ C. These conditions have remained unchanged

009832/1916

■ Maintained while setting up the solution (Percent by weight of methanol in methanol-water solvent mixtures) and the total amount of solvent in the manner given in Table I below for each optical separation experiment were varied. The quantities of the sparingly soluble salts obtained in this way and the optical purity "τοη L-NHp-CL samples, which were obtained after the decomposition of the salts mentioned are also listed in Table I:

Table I.

By- Löc- Gesaratspiel average amount of no. Composition solvent medium (wt. % (Ml) methanol)

Amount of sparingly soluble salt (g)

'optical purity of'L-NH ₂ -CL (JO

38 100 39 94 40 90 41 80 42 60 43 40 44 20th 45 1

1o48 560 386 282 204 163 131 105

13.1 14.0 15.4 13.9 13.5 13.0 14.4 12.2

98 99 95 94

95 92 89 89

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Examples 46 and 47

The optical separation or decomposition according to the procedure described in Example 37 was repeated with the modification that the crystallization temperature was set to 20 ° C and the solvent composition was 100% methanol, the solubility ratio and the total amount of solvent in each experiment in the table in the table below II was varied, and that the mixing of the two solutions was carried out in such a way that the solution of the separating or disintegrating agent was poured into the solution of the L and D-NHg-CL mixture. The results obtained are shown in Table II below.

Solution Dissolvable Table II Amount of Optical Ex. middle ability total difficult to solve purity No. together- ■ behaved lot lichem from settlement to Lö- salt L-NHo-CL (Methanol sungsm.
(ml! (S) 100 2.5 2481 0.9 100 46 100 6.0 1038 13.8 93 47

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Examples 48 and 49

The optical separation was repeated according to the procedure given in Example 37, except that the crystallization temperature was set to 50 ° C, the solvent composition was 100 % methanol and the solubility ratio and the total amount of solvent were varied as shown in Table III the. The results are shown in Table III below.

Solution Tabel III Amount of Optical Ex. middle- Dissolvable total difficult to solve purity No. together- ability lot lichem from settlement behaved to Lö- salt L-NH ₀ -CL (Methanol sungsm. (s) Weight %) (ml)

100 100

2.5 6.0

1100

458

2.2
14.7

96 88

009632/1916

Examples 50 to 52

The optical separation was repeated according to the procedure of Example yj with the modification that the crystallization temperature was set to 25 ° G, the separation solvent was a mixed solvent consisting of 94 wt .- # methanol and 6 wt .- # water, the solvent ratio and the total amount of solvent in each experiment was varied as indicated in Table IV and that the crystalline racemic D, L-NH ₂ -CL mixture was added directly to the solution of the resolving agent dissolved in the total amount of solvent. The results are shown in Table IV below.

Table IV

Belsp. Soluble- Soluble- Total-No, medium- amount together- to solution- (methanol medium -%) (ml)

Amount of sparingly soluble salt

(κ)

Optical purity of L-NH ₂ -CL

94 94 94

2.7 4.5 5.0

1100

700 600

12.3 14.6 15.2

100 100

90

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Examples 53 bl & 55

The "optical separation or separation according to the beschriebenen.Arbeitsweise in Example 37 was repeated with the changes, the crystallization temperature dä'ß to 30 ° C was set, a Lösungsmifctelmischung from 94 wt -.% Of methanol and 6 wt -.% Of water as a separating solvent was used and that the solubility ratio and the total amount of solvent were varied in the manner given in Example 5. The results are shown in Table V below.

Table V

Ex. Solution Soluble- total Amount of optical No. middle- ability lot difficult to solve purity together- behaved- at Lö lichem from ' settlement nis sungs salt L-NH ₀ -CL (Methanol middle Weight %) (ml) U) (<&) 53 94 2.5 10.4 100 54 94 4.6 600 13.2 99 55 9 ^ 5.1 500 15.6 98

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Examples 56 to 59

m *

The optical separation "according to the procedure described in Example yj was repeated with the modification that the crystallization temperature

C was set, a solvent ^{mixture of 9 2} J- wt .- # methanol and .6 wt .- ^ water was used as the separating solvent and that the molar ratio of D, L-NHp-CL: separating agent, the total amount of isomeric salt, the solubility ratio and the total amount of solvent were varied in each case in the manner shown in Table VI. The results are also shown in Table VI.

009832/1916

Table VI

Example D, L-MIi ₉ -CL

^No. (e)

in

N-p-nitrobenzoyl- total- soluble- total- amount optical

L-glütarnin acid amount of purity

(g) to behave- sn Lö- hard- of

isomeric solution soluble L-NH ₉ -CL
Salt medium chem

(g) (ml) salt

56 10.0
(o, o78 moles) 13.9
(0.047 moles) 19.9 3.6 . ' 430 3.1 90 57 10.0
(0.078 moles) 18.5
(0.062 moles) 26.4 3.8 530 10.1 91 58 10.0
(0.078 moles) 23.0
(0.078 moles) 33.0 3.7 690 14.0 98 59 10.0
(0.078 moles) 27.7
(0.094 moles) 33.0 3.7 690 13.7 95

Example 6o

The optical separation according to the procedure described in Example 37 was repeated with the modification that the Np-nitrobenzoyl-L-glutamic acid was replaced by 2j5 »O g of Np-nitrobenzoyl-D-glutamic acid, a total of 600 ml of a solvent mixture consisting of the crystallization temperature of 350 ° C was 95 parts by weight J ^ methanol and 5 wt .- ^ water is used as separation solvent, and the solubility ratio was was geeändert to 4.6. Were doing Γ5> 2 g of a crystalline poorly soluble salt at a Kristallisatinnsausbeute of 40% was obtained. 5.1 S of the hydrochloride of D-NH ₂ -CL were obtained from the sparingly soluble salt. The optical purity of the D-form was 97 %. The yield of hydrochloride from the D, L mixture was 40 % and the yield from the D-form was 80 Ji.

Examples 61 to 74

The optical resolution or separation according to the procedure described in Example 37 was repeated except that the crystallization temperature was set at 25 ° C, the separation solvent, a solvent mixture consisting of 94 wt .- ^ methanol and 6 wt -.% 'Water , the total amount of isomeric salt was decreased to 3.30 g, and that the solubility ratio and the total amount of solvent were varied for each experiment according to the manner shown in Table YII to determine the relationship between the solubility ratio and the amount of the sparingly soluble salt precipitated and to examine the optical purity of L-NH _{2 -CL contained in the salt.} The results are shown in Table VII.

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Table VII

With- Soluble- total amount of play- ness: related- to solvent (ml) poor optical purity soluble of L-NH ₉ -CL salt ^ώ

(G)

2.0 2.2 2.7 3.2 3.6 4.0 4.3 4.5 '5.0 5.5 6.0

6.5 7.0

7.5

150

136

110

94

83

75

70

66

60

55 50 46

43 40 0.00 0.98 1.23 1.35 1.42 1.45 1.46 1.50 1.52 1.54 1.55 1.57 1.62 1.69

99 99 99 99, 100 94 91 88

85 80 76 69

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1961T80

Examples 75- and 76

The optical separation according to the procedure described in the example was repeated with the modification that the crystallization temperature was set to 30 ° C, the separation solvent was a solvent mixture consisting of 90 wt .-% ethanol and 10 wt .- # water, and that the The solubility ratio and the total amount of solvent in each experiment were varied according to the manner shown in Table VIII. The sparingly soluble salts were obtained in the beauty in T _a given amount VIII and L-NH ₂ -CL in the direction indicated in Table VIII optical purity.

Table 8

Ex. Solution Dissolvable 2.5 total Amount of Optical No. middle- ability 6.0 lot difficult to solve purity together- behaved- Examples 77 at Lö lichem from settlement nis sungs salt L-NH ₀ -CL (Ethanol middle C. Wt .- ^) (ml) (ff) (%) 75 90 600 6.7 99 76 90 250 14.1 98 to 82

The optical separation according to the procedure described in Example 37 was carried out with the modification repeats that the crystallization temperature was set to 30 ° C, a solvent mixture 60 wt .- # water and 40 wt .- ^ ethanol as release solvents was used, and that the solubility ratio and total amount of solvent in each experiment

009832/1916

were varied according to the manner indicated in Table IX, the sparingly soluble salts in the manner indicated in Table IX indicated amount and L-NHp-CL in the optical purity indicated in Table IX. were lten.

Solution
middle-
together-
settlement
(Ethanol
Wt .- ^) Table IX Total-
lot-
to Lö-
sensational
middle
CmI) Amount of
difficult to solve
lichem
salt
(κ) Optical
purity
from
L-NH ₂ -CL
(%) Ex.
No. 40 Solubility
relationship 70 0.0 - 77 40 2.0 56 0.4 93 78 40 2.5 43 10.8 86 79 40 3.3 24 13.1 84 80 40 6.0 20th 15.3 78 81 40 7.0 19th 16.4 70 82 7.5

(V) Examples of optical resolution using N-benzoyl-L-glutamic acid and N-benzoyl-D-glutamic acid

Example 83

1.3 g of an equimolar mixture of L- and D-NHp-CL (optical purity: 50 $) were dissolved in 10 ml of war-mem water at 60 ° C. and 2.5 g of N-benzoyl-L-glutamic acid were obtained added and dissolved. The solution was allowed to stand for 10 hours, after which a large amount of crystal - _t precipitated nem, sparingly soluble salt. The salt was filtered, washed with a small amount of water and then under

009832/1916

dried under reduced pressure, whereby 2.4 g of crystals were obtained in a crystallization yield of 63 % .

The crystalline salt was dissolved in 20 ml of water and passed through a resin column 1.0 cm in diameter and 18 cm in height, with 15 ml of a cation exchange resin in acidic form with a content of sulfonic acid groups (Trade name: DIAION SK-IB) was packed. The column was then washed with 200 ml of water. The above liquid passed through the column and the washing liquids were combined, from which N-benzoyl-L-glutamic acid was quantitatively obtained.

The resin column was then eluted and washed with 200 ml of 1N hydrochloric acid. The eluate was concentrated under reduced pressure at 50 ° C. to _{obtain 1.0 g of the hydrochloride of the D, L-NH 2} -CL mixture containing 70 % of the L-form (yield: 62 %).

Example 84

2.0 g of N-benzoyl-L-glutamic acid were dissolved in 160 ml of methanol, and 1.0 g of an equimolar mixture of L- and D-NH ₂ -CL, dissolved in 60 ml of methanol, was added. The solvent was evaporated from the system to dryness under reduced pressure. To the isomeric salt obtained as a residue, 50 ml of methanol were again added and the mixture was stirred at room temperature. The salt was. partially insoluble. The system was cooled in an ice bath, 0.54 g of a sparingly soluble salt (crystallization yield: 18 ^) being obtained.

009832/1916

- -60 "

The salt was treated with resin in a manner similar to that described in Example 83. This gave 0.22 g of the hydrochloride of the D, L-NHp-CL mixture with a content of 8l # of the L-form (yield: 17 %)

Example 85

2.5'g of N-benzoyl-L-glutamic acid were in 44 ml a solution mlifcel mixture consisting of 94 wt .- ^ methanol and 6 wt .- # water, dissolved. The solution would be in a 3-necked flask with a mechanical stirrer and a Thermometer was given. The flask was immersed in a thermostatic bath to treat its contents at a Maintain temperature of 30 ° C.

In another vessel, 1.3 S of an equimolar mixture of L- and D-NHp-CL was dissolved in 25 ml of the above mixed solvent kept at 30 ° C and then poured into the above 3-necked flask. After a crystalline salt began to precipitate, the contents were stirred for an additional hour. The precipitate was separated by filtration and dried under reduced pressure. 1.5 g of a crystalline, sparingly soluble salt were obtained, the crystallization yield being 40 % . F ο 210 to 213 ° C, A ^ ²² - -4.0 ° (K - 3.0, water).

0.75 g of the sparingly soluble salt was decomposed using a resin similar to that in Example 83. 0.32 g of the hydrochloride of L-NHg-CL were obtained from the hydrochloric acid eluate (yield 20 %) . The optical purity of the L-shape was 94 %.

009832/1916

Separately, 0.75 g of the above-mentioned sparingly soluble salt was recrystallized from 20 ml of the above-mentioned mixed solvent to obtain 0.50 g of needle-shaped crystals. The yield from the crystallization procedure was 67 %.

The crystals were disassembled in a manner similar to that given in Example 83 above using the same resin to obtain 0.21 g of the hydrochloride of L-NHg-CL (yield: Γ5 %).

The rotatability of L-NHp-CL was ■ - -24.8 ° (K β 3.2, In-hydrochloric acid) and the optical purity thereof was 100 #.

Example 86

A solution containing ml by dissolving 12.8 g (0.10 mole) of an equimolar mixture of L- and D-NH ^ CL 200 in a solvent mixture consisting of 9 ^ wt -.% Of methanol and 6 parts by weight ^ Water, was mixed with another solution made by dissolving 25.1 g (0.10 mol) of N-benzoyl-L-glutamic acid in 600 ml of the above-mentioned mixed solvent. The system was stirred for 2 hours at j50 ° C. and then treated in a manner similar to that in Example 85 *. 11.8 g of a white, sparingly soluble salt were obtained in a yield of 31% .

The salt was decomposed with resin in a manner similar to that in Example 83 #, with 5.1 g of the hydrochloride of L-NHg-CL being obtained (yield: ~ j> ±%, yield based on the L-form: 62 #). The optical purity of the hydrochloride was 100 %,

009832/1916

- • 62 -

Example 8-7

A solution containing g by dissolving 2.5 N-benzoyl-L-glutamic acid in 50 ml of a solvent mixture consisting of 90 wt.% Methanol and 10 wt. # Of water, was prepared, was mixed with another solution obtained by Dissolve 1.3 g of an equimolar mixture of L- and D-NHp-CL in 25 ml of the above-mentioned solvent mixture, mixed and treated in a similar manner as in Example 85 *. 1.2 g of a crystalline, sparingly soluble salt were obtained (yield of crystallization: 32 %). The salt was resin decomposed in a manner similar to Example 83 to _{obtain 0.51 g of the hydrochloride of L-NH 2} -CL (yield 31 #)

The optical purity thereof was 98 #. Example 88

A solution prepared by dissolving 2.0 g of N-benzoyl-L-glutamic acid in 800 ml of ethanol was mixed with another solution made by dissolving 1.0 g of an equimolar mixture of L- and D-NHg-CL in 200 ml of ethanol had been prepared similarly to Example 85. To the system was added a small amount of a salt consisting of N-benzoyl-L-glutamic acid and D, L-NH ₂ -CL mixture as a nucleating agent followed by stirring for 7 hours. 0.75 g of a crystalline, SChWe ¹ IOsliehen salt were obtained (crystallization yield: 25 #) · -.

009832/1916

The salt was decomposed in a similar manner to Example 83 using the same resin to obtain 0.32 g of the hydrochloride of L-NHp-CL (yield: 25 %, optical purity 92 #).

Example 89

A solution which had been prepared by dissolving 2.5 g of N-benzoyl-L-glutamic acid in 60 ml of a solvent mixture of 92% by weight of ethanol and 8% by weight of water was mixed with another solution. which was formed by dissolving 1.3 g of an equimolar mixture of L- and D-NHp-CL in 25 ml of the solvent mixture given above, and treated in a manner similar to that in Example 85. 2.6 g of a crystalline, sparingly soluble salt were obtained with a crystallization yield of 69 % .

The salt was decomposed with resin in a manner similar to Example- 83, whereby 1.1 g of the hydrochloride were obtained from the D, L-NHp-CL mixture containing 59 % of the L-Porm (yield: 68 % ).

Example 90

A solution which had been prepared by dissolving 0.66 g of N-benzoyl-L-glutamic acid in 70 ml of a solvent mixture consisting of 90% by weight of isopropanol and 10% by weight of water, and another solution which By dissolving 0.3 ^ S of an equimolar mixture of L- and D-NH ₂ -CL in 30 ml of the above-mentioned solution

009832/1916

Medium mixture had formed were treated in a similar manner to Example 85, 0.42 g of a crystalline, sparingly soluble salt being obtained with a crystallization yield of 42 % .

The salt was decomposed with resin in a similar manner to Example 83, 0.18 g of the hydrochloride of the D, L-NH ₂ -CL mixture having a content of 88 % of the L-form being obtained (yield: 42 %) ,

Example 91

One . Solution prepared by dissolving 1.3 g of N-benzoyl-L-glutamic acid in 80 ml of a Lösungsmittelgemjaehes, .bestehend of 90 wt .- ^ n-butanol and 10 weight -% of water was prepared, and a further solution. which had been formed by dissolving 0.68 g of an equimolar mixture of L- and D-NHg-CL in 20 ml of the above-mentioned solvent mixture were treated in a similar manner to Example 85, whereby 1.15 g of a crystalline, sparingly soluble Of salt. The crystallization yield was 57 %

The salt obtained in this way was broken down with resin in a similar manner as in Example 83, 0.49 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 72 % of the L-Porm being obtained (yield: 56%) #).

Example 92

A suspension obtained by suspending 1.3 g of N-benzoyl-L-glutamic acid in 700 ml of acetone and another solution obtained by dissolving 0.68 g of an equimolar mixture of L- and D-NH ₂ -CL in 300 ml

009832/1916

Acetone was treated in a similar manner to Example 85, whereby 1.8 g of a crystalline, sparingly soluble salt was obtained in a crystallization yield of 89 % .

The salt was resin decomposed in a manner similar to Example 83 to obtain 0.77 g of the hydrochloride of the D, L-NHp-CL mixture containing 52 % of the L-form (yield: 88 %).

Example 93

A solution made by dissolving 3.8 g of N-benzoyl-L-glutamic acid in 22 ml. Ethylene glycol was formed and another solution prepared by dissolving 1.9 g of an equimolar mixture of L- and D-NHp-CL in 5 ml of ethylene glycol were treated in a manner similar to Example 88, with 2 , 0 g of a crystalline, sparingly soluble salt were obtained with a crystallization yield of 35 % .

The sparingly soluble salt was dissolved in 10 ml of 1N hydrochloric acid dissolved and stirred at room temperature. After stirring for about 30 minutes, precipitation of N-benzoyl-L-glutamic acid continued a. After stirring for 2 hours, the precipitate was removed by filtration with suction. The Piltrat was concentrated and dried to obtain the hydrochloride of NHp-CL. Because the hydrochloride is still a small amount contained in N-benzoyl-L-glutamic acid, 10 ml of isopropanol containing 3N hydrochloric acid were added, whereupon was stirred for 30 minutes.

009832/1916

The remaining undissolved hydrochloric! was separated by filtration, 2 times. washed with 2 ml each of isopropanol and dried under reduced pressure. This gave 0.85 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 80 % of the L-form (yield: 35%)

Example 94

A solution that was formed by dissolving 2.5 g of N-benzoyl-D-glutamic acid in 44 ml of a solvent mixture consisting of 94% by weight of methanol and 6% by weight of water, and another solution which by dissolving 1.3 S of an equimolar mixture of L- and D-NH ₂ -CL in 25 ml of the same solvent mixture were treated in a manner similar to Example 85, whereby 1.6 g of a crystalline, sparingly soluble salt were won. The crystallization yield was 41 %,

The salt was broken down with resin in a similar manner as in Example 83, whereby 0.67 g of the hydrochloride of the D, L-NH ₂ -CL mixture with a content of 88 % of the D-form were obtained (yield 41 %),

009832/1916

Claims (8)

- 6.7 Claims 1. A method for the optical separation of a mixture of L- and D-a-Araino-6 -caprolactam, characterized in that that you have a mixture of L- and D-a-amino-6-caprolactam with one of the derivatives of L- or D-glutamic acid of the formula below Hooc-CH-NH-C- CH ₂ 0 t CH ₂ COOH where R is a hydrogen atom or a nitro group (-NO ₂ ), treated in a homogeneous liquid medium containing at least 90 vol- # of at least one solvent from the group of water, aliphatic alcohols with 1 to 4 carbon atoms, acetone and Contains ethylene glycol, and a sparingly soluble "salt, consisting of L- or D-oc-amino- t -caprolactam and the derivative of optically active glutamic acid precipitates, said sparingly soluble salt from the liquid medium, .das, a readily soluble salt of the Contains oc-amino- t- caprolactams and the derivative of glutamic acid, separates and then breaks down the sparingly soluble salt and / or the easily soluble salt separated from the liquid medium. 009832/1916 - 66 - 2. The method according to claim 1, characterized in that the liquid medium used is water, methanol, Ethanol or mixtures thereof used in any proportions. . . 3. The method according to claim 1 or 2, characterized in that 0.8 to 1.3 mol of said derivative of L- or D-glutamic acid 1 mol each of L- and D-oc-amino ttt 6 -caprolactam mixture used. 4. The method according to any one of claims 1 to 3 » characterized in that the derivative of glutamic acid is N-p-nitrobenzoyl-L-glutamic acid or N-p-nitrobenzpyl-D-glutamic acid used. . f>. Method according to one of Claims 1 to 4, characterized in that the sparingly soluble or the easily soluble salt with a hydrohalic acid in an aqueous medium for decomposition or separation. in L- or D-a-Amirio- £ -caprolactam and the derivative of L- or D-glutamic acid treated. 6. The method according to any one of claims 1 to 4, characterized in that the sparingly soluble salt or the readily soluble salt is dissolved or suspended in an aqueous medium and with a sulfonic acid group containing cation exchange resin for decomposition or separation into L- or D-oc-amino-S-caprolactam and that L- or D-glutamic acid derivative ■ brings into contact. 009832/1916 7. The method according to any one of claims 1 to 6, characterized in that one L- and D-cc-amino E-caprolactam mixture with N-p-nitrobenzoyl-L-glutamic acid or N-p-nitrobenzoyl-D-glutamic acid in a solvent consisting of methanol, methanol-water mixtures, Treated ethanol or ethanol-water mixtures and thereby the precipitation of the sparingly soluble salt of L- or D-a-amino- £ -caprolactam and the above>, Derivative of glutamic acid, the i Relative amounts of the caprolactam mixture used and the derivative of glutamic acid with respect to the solvent can be regulated so as to below. expression 2.5K = XA £ 7, OK to meet, wherein X has a value of the number of moles in the lesser Amount of components present in the L- und'D-a-amino-C caprolactam mixture or said glutamic acid derivative (where, if these are in equimolar amounts are present, X represents the number of moles of each individual component) multiplied by 424.4 (gram-moles of the between formed salt), Y is a value of the amount (ml) of the solvent divided by 100, and K is a value " the amount (g) of the salt of the L- and D-α-amino-6-caprolactam mixture and either from N-p-nitrobenzoyl-L-glutamic acid or N-p-nitrobenzoyl-D-glutamic acid, which is in 100 ml of the solvent at saturation concentration in that used for the optical separation according to the invention is soluble at a specific temperature. 009832/1916 8. The method according to claim 7, characterized in that that one regulates the value of X / Y so around the following expression 2.5 K = XA - 6.0 K to meet where X, Y and K are those given above Have meaning. 009832/1916