Process for the preparation of the crystalline monohydrate of 7-(D-α-aα-(p-hydroxyphenyl)acetamido)-3-methyl-3-cephem-4-carboxylic acid

Abstract

A novel crystalline monohydrate of 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-caphem-4-carboxylic acid is prepared and found to be astable useful form of the cephalosporin antibiotic especially advantageous for pharmaceutical formulations.

We claim: 
     
       1. A process for the preparation of crystalline 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate exhibiting essentially the following x-ray diffraction properties:   ______________________________________                                    
Line       Spacing d(A)                                                   
                      Relative Intensity                                  
______________________________________                                    
1          8.84       100                                                 
2          7.88       40                                                  
3          7.27       42                                                  
4          6.89       15                                                  
5          6.08       70                                                  
6          5.56       5                                                   
7          5.35       63                                                  
8          4.98       38                                                  
9          4.73       26                                                  
10         4.43       18                                                  
11         4.10       61                                                  
12         3.95       5                                                   
13         3.79       70                                                  
14         3.66       5                                                   
15         3.55       12                                                  
16         3.45       74                                                  
17         3.30       11                                                  
18         3.18       14                                                  
19         3.09       16                                                  
20         3.03       29                                                  
21         2.93       8                                                   
22         2.85       26                                                  
23         2.76       19                                                  
24         2.67       9                                                   
25         2.59       28                                                  
26         2.51       12                                                  
27         2.46       13                                                  
28         2.41       2                                                   
29         2.35       12                                                  
30         2.30       2                                                   
31         2.20       15                                                  
32         2.17       11                                                  
33         2.12       7                                                   
34         2.05       4                                                   
35         1.99       4                                                   
36         1.95       14                                                  
37         1.90       10                                                  
     which process comprises   (a) silylating 7-aminodesacetoxycephalosporanic acid in an inert substantially anhydrous aprotic solvent;   (b) acylating the so-produced silylated 7-aminodesacetoxycephalosporanic acid with D(-)-α-amino-α-(p-hydroxyphenyl)acetyl chloride hydrochloride in an inert substantially anhydrous aprotic solvent in the presence of an acid acceptor;   (c) cleaving any silyl groups of the acylation product by hydrolysis or alcoholysis; and   (d) forming the desired monohydrate product by a method selected from (1) upwardly adjusting the pH of the solution from step (c) in the presence of excess dimethylformamide to form the dimethylformamide solvate of 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid; dissolving said dimethylformamide solvate in acidified water or a mixture of acidified water and acetonitrile, and upwardly adjusting the pH of said acidified solution to precipitate the desired crystalline monohydrate;   (2) upwardly adjusting the pH of the solution from step (c) in the presence of excess dimethylformamide to form the dimethylformamide solvate of 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid and contacting said dimethylformamide solvate with water or a partially aqueous medium to precipitate the desired crystalline monohydrate.     
     
     
       2. A process as claimed in claim 1 wherein the silylation step (a) is accomplished by reacting 7-aminodesacetoxycephalosporanic acid with a silylating agent selected from those of the formulae ##STR8## wherein R 2 , R 3  and R 4  are hydrogen, halogen, (lower)alkyl, halo(lower)alkyl, phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of the said R 2 , R 3  and R 4  groups being other than halogen or hydrogen; R 1  is (lower)alkyl; m is an integer of 1 to 2 and X is halogen or ##STR9## wherein R 5  is hydrogen or (lower)alkyl and R 6  is (lower)alkyl or ##STR10## wherein R 2 , R 3  and R 4  are as defined above. 
     
     
       3. A process as claimed in claim 2 wherein the silylating agent in step (a) is trimethylchlorosilane or hexamethyldisilazane. 
     
     
       4. A process as claimed in claim 1 wherein disilylated 7-aminodesacetoxycephalosporanic acid is produced in step (a) by using at least two equivalents of silylating agent per mole of 7-aminodesacetoxycephalosporanic acid. 
     
     
       5. A process as claimed in claim 1 wherein step (a) is carried out by silylating 7-aminodesacetoxycephalosporanic acid with trimethylchlorosilane in a substantially anhydrous aprotic solvent in the presence of an acid acceptor. 
     
     
       6. A process as claimed in claim 5 wherein the silylation step is carried out in a substantially anhydrous methylene chloride solvent system in the presence of an acid acceptor comprising triethylamine or a mixture of triethylamine and dimethylaniline at a temperature of about 20°-30° C. 
     
     
       7. A process as claimed in claim 1 wherein step (a) is carried out by silylating 7-aminodesacetoxycephalosporanic acid with hexamethyldisilazane in a substantially anhydrous aprotic solvent with external heating. 
     
     
       8. A process as claimed in claim 7 wherein the silylation step is carried out in a substantially anhydrous methylene chloride solvent at reflux temperature. 
     
     
       9. A process as claimed in claim 1 wherein acylation step (b) is carried out in a substantially anhydrous methylene chloride solvent system at a temperature in the range of from about -10° C. to +10° C. in the presence of an acid acceptor selected fom a tertiary amine base having a pK.sub.α ≲7. 
     
     
       10. A process as claimed in claim 9 wherein the acid acceptor is dimethylaniline. 
     
     
       11. A process as claimed in claim 1 wherein in step (c) silyl groups are cleaved by treatment with water or a C 1  -C 4  alkanol, or a mixture thereof. 
     
     
       12. A process as claimed in claim 1 wherein in step (c) silyl groups are cleaved by treatment with a C 1  -C 4  alkanol. 
     
     
       13. A process as claimed in claim 1 wherein step (d) comprises (1) upwardly adjusting the pH of the solution from step (c) with triethylamine in the presence of excess dimethylformamide until the dimethylformamide solvate of 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid precipitates from solution;   (2) dissolving said dimethylformamide solvate in acidified water; and   (3) upwardly adjusting the pH of said solution by addition of triethylamine to precipitate the desired crystalline monohydrate.   
     
     
       14. A process as claimed in claim 13 wherein the final pH adjustment step to produce the desired crystalline monohydrate is conducted at a temperature of about 35°-60° C. 
     
     
       15. A process as claimed in claim 13 wherein acetonitrile is added as an antisolvent during the final pH adjustment step. 
     
     
       16. A process as claimed in claim 1 wherein step (d) comprises (1) upwardly adjusting the pH of the solution from step (c) with triethylamine in the presence of excess dimethylformamide until the dimethylformamide solvate of 7-[D-α-amino-α-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid precipitates from solution; and   (2) contacting said dimethylformamide solvate with a solvent system comprising water or a mixture of water with one or more organic solvents selected from acetonitrile, acetone or a C 1  -C 5  alkanol until the desired monohydrate crystallizes from solution.   
     
     
       17. A process as claimed in claim 16 wherein the monohydrate crystallization step (2) is carried out at a temperature of from about 35°-60° C. 
     
     
       18. A process as claimed in claim 16 wherein the crystallization solvent system of step (2) comprises water:acetonitrile:n-butanol in a v/v ratio of 1:2:1. 
     
     
       19. A process as claimed in claim 16 wherein the crystallization solvent system of step (2) comprises water:acetone (1:3) (v/v), water:isopropanol (1:3) (v/v), water-acetonitrile (1:3) (v/v) or water:n-butanol (1:1) (v/v).