Resolution of enantiomeric complexes of nickelous chloride and alpha-aminocaprolactam
BACKGROUND OF THE INVENTION 
     It is known that alpha-aminocaprolactam (&#34;ACL&#34;) exists in the form of enantiomeric optical isomers, the D-form and the L-form. It is further known that the racemic mixture of these forms can be resolved, i.e. separated, by producing the D, L- (i.e. racemic) mixture of the aminocaprolactam complex with nickelous chloride in situ in solution, at concentration resulting in supersaturation; then preferentially crystallizing the desired form, e.g. the L-form, from such solution by use of seed crystals of the desired form. It is also known that when the complex with nickelous chloride is used for such resolution, conditions can be adopted under which the racemization of the undesired form of the complex into the desired form proceeds simultaneously with the resolution process. The resulting desired enantiomer of the complex can then be decomposed to afford the desired alpha-aminocaprolactam enantiomer; and this enantiomer can be converted to the corresponding enantiomer of lysine e.g. to L-lysine, a valuable nutritional product. See U.S. Pat. No. 3,988,320 of Oct. 26, 1976 to Sifniades, Boyle, and Van Peppen. 
     The process of resolution of the enantiomer mixture and simultaneous racemization of the undesired enantiomer to replenish the mixture, described in the above patent, is a useful advance in the art. However, it would be desirable to obtain the results of that patent without necessity of using seed crystals of the desired enantiomeric form of the complex at the startup, when the mixture of D- and L-enantiomers is the racemic mixture. 
     The present invention enables resolution of racemic mixtures of the nickelous chloride complexes with alpha-aminocaprolactam without use of seed crystals of the desired enantiomer of the ACL/NiCl 2  complex. 
     SUMMARY OF THE INVENTION 
     This invention consists essentially in a process for resolution of a mixture of D- and L-forms of tris(alpha-aminocaprolactam) NiCl 2 . ROH--wherein R is methyl, ethyl, or isopropyl--to increase the ratio of one form of the aminocaprolactam/nickel chloride complex in the crystalline product obtained, as compared to the ratio in the starting material. Preferably the undesired form of the complex is simultaneously racemized, under conditions such as described in U.S. Pat. Nos. 3,941,776 of Mar. 2, 1976 and 3,988,320 of Oct. 26, 1976 both to Sifniades, Boyle, and Van Peppen. Such conditions provide for presence of a strong base, and utilize an excess of aminocaprolactam over that stoichiometrically required for formation of the complex (ACL) 3  NiCl 2 . 
     The present process comprises forming a supersaturated solution of said complex; including one optically active form of lysine in said solution, namely L-lysine as crystallization inhibitor of the D-form of said complex when the L-form is desired and D-lysine when the D-form of the complex is desired; and crystallizing a portion of the complex from said supersaturated solution. More specifically since L-lysine is the commonly desired enantiomer of lysine, L-lysine is included in the saturated solution of the alpha-aminocaprolactam/nickelous chloride complex enantiomers in the range between 1 mol percent and 20 mol percent based on the content of the complex in the solution. We have found that such addition of L-lysine has an inhibitory effect on the crystallization, from the supersaturated solution, of the D-form of the complex in solution; so that the crystals precipitated are therefore enriched in the L-form of the complex. 
     DETAILED DESCRIPTION 
     This invention can be used to produce a crystalline product enriched in the desired enantiomer of the alpha-aminocaprolactam nickel chloride complex without use of seed crystals of the desired enantiomer, although desirably seed crystals of the racemic form of the complex are used. The invention is especially useful to allow starting up a process of resolving a racemic mixture of the D- and L-forms of said complex by preferentially repressing crystallization of the undesired enantiomer, e.g. the D-form of the complex. Once the process is started, the precipitated crystals rich in the L-form of the complex can function as seed crystals in carrying out procedures, described in the above cited U.S. Pat. No. 3,988,320, whereby to obtain simultaneous resolution and racemization of the dissolved ACL/NiCl 2  enantiomeric complexes. 
    
    
     The examples which follow are illustrative of the present invention but are not to be interpreted in a limiting sense. 
     EXAMPLE 1 
     An ethanol solution was made up to contain 25 g (ACL) 3  NiCl 2 . EtOH per 100 ml of total volume using 4.5 moles of ACL per mole of NiCl 2  plus 0.033 mole of lithium ethoxide base per mole of ACL and 0.047 mole of L-lysine per mole of ACL all dissolved in ethanol. A 2 mL aliquot of the solution was placed in a sealed vial and heated in an 80° C. oil bath for 72 h. No crystallization was evident during that period. Then 2 mg of D,L-(ACL) 3  NiCl 2 . EtOH (i.e. racemic) seed crystals were added and heating was resumed. After 48 h from the addition of the seed crystals, 57 mg of crystalline L-(ACL) 3  NiCl 2 . EtOH had formed, and was recovered by filtration. The optical rotation [α] of these product crystals was [α] D   20  =-12.7° (c 4, 1N HCl), corresponding to 54% excess of L-ACL complex over D-ACL complex in the product crystals. 
     EXAMPLES 2-7 
     In a similar manner experiments were performed, also at 80° C. and 2 mL volume, with other concentrations and mole ratios. The conditions and results of all these experiments are summarized in Table 1 below. In all cases when L-lysine was added, the product crystals contained an excess of L-ACL complex over D-ACL complex. In comparison examples 4 and 6, in which no L-Lysine was added, the product crystals were the racemic compound. 
     
                       TABLE 1                                                     
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L-Lysine Assisted Resolution                                              
of (ACl).sub.3 NiCl.sub.2 . EtOH Complex                                  
(A)    Conc. of Mole                Mole                                  
Example                                                                   
       Complex  Ratio     Mole Ratio                                      
                                    Ratio                                 
No.    g/100 mL ACL/Ni    Lysine/ACL                                      
                                    Li/ACL                                
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1      25       4.5       0.047     0.033                                 
2      20       3.5       0.088     0.29                                  
3      20       3.5       0.088     0                                     
4      20       3.5       0         0.029                                 
5      25       3.5       0.020     0.028                                 
6      25       3.5       0         0.028                                 
7      25       3.5       0.051     0.028                                 
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                Racemic                                                   
(B)             Comp&#39;d    Precipitated Product                            
Example                                                                   
       Time     Seed      Total                                           
No.    h        mg        mg        Excess L-,%*                          
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1      48       2          57       54                                    
2      24       2          9        67                                    
3      24       0          75       10                                    
4      24       0         155        0                                    
5      18       0         273       11                                    
6      18       0         223        0                                    
7      18       0         468       16                                    
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 Volume in Example 7 was 5 mL initially and was concentrated to 3.5 mL    
 after 24 h.                                                              
 *Percent of Lcomplex minus percent of Dcomplex in product crystals.      
 
    
     Further experiments similarly conducted are summarized in Tables 2 and 3 below. In all these runs, lithum ethoxide was added in molar excess over the lysine taken, thus providing free strong base in the reaction mixture. (The carboxyl group of the lysine reduces the amount of base present by reaction to form the equivalent amount of salt). Moreover, the ACL taken was in excess of the 3 moles per mole of NiCl 2 , stoichiometrically required for formation of the complex, (ACL) 3  NiCl 2 . EtOH. Under these conditions, simultaneous racemization of complex occurred in solution along with the resolution process, so that the ACL remaining in the solution after removal of the crystallized product was essentially racemic. 
     
                       TABLE 2                                                     
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L-Lysine Assisted Resolution of (ACL).sub.3 NiCl.sub.2 . EtOH             
              Total Product                                               
Example                                                                   
       Seeds                      % Excess.sup.(b)                        
No.    mg     Enantiomer                                                  
                        mg.sup.(a)                                        
                               [ ].sub.D                                  
                                      Enantiomer                          
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8      5.0    D,L-      32.9   -14.0  60% L-                              
9      4.9    L-        36.7   -22.3  96% L-                              
10     5.1    D-        20.8   +22.6  97% D-                              
Conditions: 80° C., 2 mL volume, 23 h. Concentration               
of complex, 25 g/100 mL; mole ratios ACL/Ni = 3.5; -L-Lysine/ACL = 0.10;  
LiOEt/ACL = 0.13                                                          
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 .sup.(a) Combined seeds and precipitated crystals                        
 .sup.(b) Percent of stated (ACL).sub.3 NiCl.sub.2 . EtOH enantiomer minus
 percent of the other enantiomer in the product crystals                  
 
    
     
                       TABLE 3                                                     
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D-Lysine Assisted Resolution of D,L-(ACL).sub.3 NiCl.sub.2 . EtOH         
Ex-                                                                       
am-                              Total Product                            
ple  Mole Ratios       Seeds          % Excess                            
No.  D-Lys/ACL  LiOEt/ACL  mg D,L-                                        
                                  mg.sup.(a)                              
                                         D-.sup.(b)                       
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11   0.10       0.13       5.0    19.9  52                                
12   0.052      0.0795     5.1    79.7  44                                
13   0.021      0.049      5.2    254   27                                
14   0.021      0.049      0      203   23                                
Conditions: 80° C., 2 mL volume, 19 h. Concentration               
of complex, 25 g/100 mL; ACL/Ni = 3.5 mole ratio                          
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 .sup.(a) Seeds plus precipitate                                          
 .sup.(b) Percent of D(ACL).sub.3 NiCl.sub.2 . EtOH minus percent of L in 
 product crystals                                                         
 
    
     Experiments similarly conducted to show the effect of L-lysine and of D-lysine on the rate of resolution of the complex are summarized in Tables 4-6 below. In all these experiments the seed crystals were L-(ACL) 3  NiCl 2 . EtOH taken from a single preparation, and the experimental conditions were essentially identical. 
     
                       TABLE 4                                                     
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Kinetics of Resolution of (ACL).sub.3 NiCl.sub.2 . EtOH in                
the Presence of L-Lysine                                                  
Ex-                Total Product                                          
ample Time   Seeds (L-)      % Excess                                     
                                    mg   L-Growth                         
No.   Min.   mg.sup.(b)                                                   
                       mg.sup.(a)                                         
                             L-.sup.(c)                                   
                                    L-.sup.(d)                            
                                         Factor.sup.e                     
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15    10     19.8      47.8  98     47.3 2.38                             
16    20     19.8      72.3  91     69.0 3.47                             
17    30     19.9      79.3  91     75.7 3.79                             
18    40     19.7      71.3  77     80.8 4.10                             
Conditions: 80° C., 2 mL volume. Concentration of com-             
plex, 25 g/100 mL. Mole ratios ACL/Ni = 3.05; L-Lysine/                   
ACL = 0.02; LiOEt/ACL = 0.02.                                             
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 .sup.(a) Seeds plus precipitate                                          
 .sup.(b) mg of L(ACL).sub.3 NiCl.sub.2 . EtOH used as seed crystals in th
 experiment                                                               
 .sup.(c) Percent of L(ACL).sub.3 NiCl.sub.2 . EtOH minus percent of D in 
 product crystals                                                         
 .sup.(d) mg of L(ACL).sub.3 NiCl.sub.2 . EtOH in product crystals        
 .sup.(e) mg of L in product crystals/mg seed crystals                    
 
    
     
                       TABLE 5                                                     
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Kinetics of Resolution of (ACL).sub.3 NiCl.sub.2 . EtOH in                
the Presence of D-Lysine                                                  
Ex-                Total Product                                          
ample Time   Seeds (L-)      % Excess                                     
                                    mg   L-Growth                         
No.   Min.   mg.sup.(b)                                                   
                       mg.sup.(a)                                         
                             L-.sup.(c)                                   
                                    L-.sup.(d)                            
                                         Factor.sup.(e)                   
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19    10     19.9      42.9  95     41.8 2.09                             
20    20     20.0      51.9  91     49.6 2.48                             
21    30     19.8      65.8  91     62.8 3.14                             
Conditions: 80° C. 2 mL volume. Concentration of com-              
plex, 25 g/100 mL. Mole ratios: ACL/Ni = 3.05;                            
D-Lysine/ACL = 0.02; LiOEt/ACL = 0.02.                                    
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 .sup.(a) Seeds plus precipitate                                          
 .sup.(b) mg of L(ACL.sub.3 NiCl.sub.2 . EtOH used as seed crystals       
 .sup.(c) Percent of L(ACL).sub.3 NiCl.sub.2 . EtOH minus percent of D in 
 product crystals                                                         
 .sup.(d) mg of L(ACL).sub.3 NiCl.sub.2 . EtOH in product crystals        
 .sup.(e) mg of L in product crystals/mg seed crystals                    
 
    
     It will be noted by comparing Table 5 above vs. Table 4, that when D-lysine was the additive instead of L-lysine in otherwise the same operations as in Table 4, the effect of the D-lysine was to lower the rate of formation of the L-(ACL) 3  NiCl 2 . EtOH complex, seeded by crystals of this L-complex. 
     
                       TABLE 6                                                     
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kinetics of Resolution of (ACL).sub.3 NiCl.sub.2 . EtOH in                
the Absence of Lysine                                                     
Ex-                Total Product                                          
ample Time   Seeds (L-)      % Excess                                     
                                    mg   L-Growth                         
No.   Min.   mg.sup.(b)                                                   
                       mg.sup.(a)                                         
                             L-.sup.(c)                                   
                                    L-.sup.(d)                            
                                         Factor.sup.(e)                   
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22    10     20.0      59.2  91      56.5                                 
                                         2.83                             
23    20     19.7      83.4  91      79.6                                 
                                         3.98                             
24    30     19.8      115.6 61      93.1                                 
                                         4.65                             
25    40     20.3      192.8 27     122.4                                 
                                         6.12                             
Conditions: 80° C., 2 mL volume. Concentration of com-             
plex, 25 g/100 mL. ACL/Ni = 3.05 mole ratio                               
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 .sup.(a) Seeds plus precipitate                                          
 .sup.(b) mg of L(ACL).sub.3 NiCl.sub.2 . EtOH used as seed crystals      
 .sup.(c) Percent of L(ACL).sub.3 NiCl.sub.2 . EtOH minus percent of D in 
 product crystals                                                         
 .sup.(d) mg of L(ACL).sub.3 NiCl.sub.2 . EtOH in product crystals        
 .sup.(e) mg of L in product crystals/mg seed crystals                    
 
    
     Comparison of this Table 6 vs. Table 4 above shows that use of L-lysine as additive (Table 4) lowers the rate of formation of the L-(ACL) 3  NiCl 2 . EtOH complex, seeded by crystals of this L-complex, as compared to no additive (but such lowering is not as pronounced as when D-lysine is the additive per Table 5 above).