Intermediates in the synthesis of cephalosporin compounds
Described herein are crystalline forms of a compound of formula (III′), including toluene solvates of TATD-CLE, as well as processes for the preparation thereof and use thereof in the preparation of cephalosporin compounds such as ceftolozane.
1. A process for making a compound of formula (VI):
comprising admixing a crystalline form of a compound of formula (III):
wherein PMB is 4-methoxybenzyl and wherein the crystalline form of a compound of formula (III) is a solvate of an aromatic solvent,
with a compound of formula (IV):
to give a compound of formula (V):
and contacting the compound of the formula (V) with a strong acid, followed by crystallization with sulfuric acid to provide the compound of formula (VI).
2. The process of claim 1 , wherein the compound of formula (III), the aromatic solvent is toluene, xylene, ethylbenzene, benzene, cumene, or mixtures thereof.
3. The process of claim 2 , wherein the compound of formula (III), the aromatic solvent is a toluene solvate.
4. The process of claim 1 , wherein the compound of formula (III), the molar ratio of compound (III) to aromatic solvent is about 1:1.
5. The process of claim 3 , wherein the crystalline form of the compound of formula (III) has an X-ray powder diffraction pattern comprising one or more characteristic peaks expressed in degrees 2θ at 6.1±0.2, 12.1±0.2, 13.1±0.2, 18.5±0.2, and 24.3±0.2.
6. The process of claim 1 , wherein the strong acid is trifluoroacetic acid, sulfuric acid, formic acid, hydrochloric acid, or mixtures thereof.
7. The process of claim 1 , wherein the strong acid is trifluoroacetic acid.
8. A process for making a compound of formula (VI):
comprising admixing a crystalline form of a compound of formula (III′):
wherein
X is Cl, Br, or I; and
R 1 and R 2 are each independently an oxygen protecting group, and wherein the crystalline form of a compound of formula (III) is a solvate of an aromatic solvent, with a compound of formula (IV′):
wherein
R 5 and R 6 are each independently a nitrogen protecting group;
to give a compound of formula (V″):
wherein A ⊖ is a pharmaceutically acceptable anion;
and contacting the compound of the formula (V′) with a strong acid, followed by crystallization with sulfuric acid to provide the compound of formula (VI).
9. The process of claim 8 , wherein R 1 and R 2 are each independently tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl.
10. The process of claim 8 , wherein R 5 and R 6 are each independently tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or triphenylmethyl.
11. The process of claim 8 , wherein the compound of formula (III), the aromatic solvent is toluene, xylene, ethylbenzene, benzene, cumene, or mixtures thereof.
12. The process of claim 11 , wherein the compound of formula (III), the aromatic solvent is a toluene solvate.
13. The process of claim 8 , wherein the compound of formula (III), the molar ratio of compound (III) to aromatic solvent is about 1:1.
14. The process of claim 12 , wherein the crystalline form of the compound of formula (III) has an X-ray powder diffraction pattern comprising one or more characteristic peaks expressed in degrees 2θ at 6.1±0.2, 12.1±0.2, 13.1±0.2, 18.5±0.2, and 24.3±0.2.
15. The process of claim 8 , wherein A ⊖ is chloride, bromide, iodide, sulfate, bisulfate, tosylate, mesylate, acetate, trifluoroacetate, or triflate.
16. The process of claim 8 , wherein A ⊖ is sulfate.
17. The process of claim 8 , wherein A ⊖ is bisulfate.
18. The process of claim 8 , wherein A ⊖ is trifluoroacetate.
19. The process of claim 11 , wherein the strong acid is trifluoroacetic acid, sulfuric acid, formic acid, hydrochloric acid, or mixtures thereof.
20. The process of claim 11 , wherein the strong acid is trifluoroacetic acid.