Intermediates in the synthesis of cephalosporin compounds
View Patent ↗Described herein are crystalline forms of a compound of formula (IIΓ), including toluene solvates off A TD-CLE, as well as processes for the preparation thereof and use thereof in the preparation of cephalosporin compounds such as ceftolozane. Provided herein is a crystalline form of a compound of formula (IIΓ): wherein X is CI, Br, or I; and R1 and R2 are each independently an oxygen protecting group; processes for making the crystalline form, and use of said form in the synthesis of antibacterial cephalosporins such as ceftolozane.
1. A crystalline form of a compound of formula (III):
wherein PMB is 4-methoxybenzyl;
and which is a solvate of an aromatic solvent.
2. The crystalline form of claim 1 , wherein the aromatic solvent is toluene, xylene, ethylbenzene, benzene, cumene, or mixtures thereof.
3. The crystalline form of claim 2 , which is a toluene solvate.
4. The crystalline form of claim 1 , which is in a 1:1 molar ratio of compound (III) to solvent.
5. A process of making a crystalline form of a compound of formula (III′):
wherein
X is Cl or Br; and
R 1 and R 2 are each independently tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl,
comprising the step of admixing a non-crystalline form of a compound of formula (III′) and an aromatic solvent to form an admixture comprising the crystalline form of a compound of formula (III′), and
further comprising the step of cooling the admixture after the step of forming the admixture comprising the crystalline form.
6. The process of claim 5 , wherein X is Cl.
7. The process of claim 5 , wherein the compound of formula (III′) has the structure of compound (III):
wherein PMB is 4-methoxybenzyl.
8. The process of claim 5 , wherein the aromatic solvent comprises toluene.
9. The process of claim 8 , wherein the crystalline form is a toluene solvate.
10. The process of claim 7 , wherein the crystalline form 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.
11. The process of claim 5 , wherein after the cooling step the process further comprises the step of isolating the crystalline form of compound (III).
12. A process of making a compound of formula (V″):
comprising admixing a crystalline form of a compound of formula (III′):
wherein
X is Cl or Br; and
R 1 and R 2 are each independently tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl;
with a compound of formula (IV′):
wherein
R 1 and R 2 are each independently an oxygen protecting group;
R 5 and R 6 are each independently a nitrogen protecting group; and
A ⊖ is a pharmaceutically acceptable anion.
13. The process of claim 12 , wherein R 1 and R 2 are each independently tert-butyldimethylsilyl, tert-butyl, 4-methoxybenzyl, 2-methoxybenzyl, or triphenylmethyl wherein X is Cl.
14. The process of claim 12 , wherein R 5 and R 6 are each independently tert-butyl, tert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or triphenylmethyl.
15. The process of claim 12 , wherein A ⊖ is chloride, bromide, iodide, sulfate, bisulfate, tosylate, mesylate, acetate, trifluoroacetate, or triflate.
16. The process of claim 12 , wherein A ⊖ is chloride, acetate, sulfate, bisulfate or trifluoroacetate.
17. The process of claim 12 , wherein A ⊖ is sulfate.
18. The process of claim 12 , wherein A ⊖ is bisulfate.
19. The process of claim 12 , wherein A ⊖ is trifluoroacetate.