RU2006134478A - CHEMICAL METHOD AND NEW CRYSTAL FORM - Google Patents

Claims (21)

1. The method of producing monohydrochloride salt of compound (I)

, where * C and ** C denote asymmetric carbon atoms, including stages: a) bringing the compounds of formula (II)

, where P ¹ represents a hydroxyl protective group, and P ² and P ³ each independently represents hydrogen or a protective group, in contact with a weak acid to effect selective protonation; b) bringing the product of step (a) into contact with a source of chloride ions to effect anion exchange; c) deprotection with the removal of P ¹ and, if necessary, P ² and P ³ ; g) isolation of compound (I) in the form of monohydrochloride; and, perhaps d) crystallization or recrystallization of compound (I). 2. The method according to claim 1, where the compound of formula (I) is a compound (Ia)

, and the compound of formula (II) is a compound (IIa)

, where P ¹ is as defined in claim 1. 3. The method according to claim 1, where the weak acid is acetic acid. 4. The method according to claim 1, where the group P ¹ represents benzyl. 5. The method according to claim 1, where the source of chloride ions is sodium chloride. 6. The method according to any one of claims 1 to 5, designed to obtain a crystalline monohydrochloride salt of the compounds of formula (Ia). 7. The method according to claim 6, where the product of this method is characterized by a pattern of x-ray diffraction on the powder, where the positions of the peaks essentially correspond to the positions of the peaks of the pattern shown in figure 1. 8. The crystalline monohydrochloride of compound (Ia), which is characterized by a differential scanning calorimetry curve showing the absence of noticeable endothermic features at temperatures below about 125 ° C. 9. The crystalline monohydrochloride of compound (Ia) according to claim 8, which is characterized by a differential scanning calorimetry curve showing the absence of noticeable endothermic features at temperatures below about 125 ° C and the appearance of significant endothermic heat flux at a temperature of about 229 ° C. 10. The crystalline monohydrochloride of compound (Ia) according to claim 8 or 9, which is characterized by a differential scanning calorimetry curve showing the absence of noticeable endothermic features at temperatures below about 125 ° C, two or more minor endothermic phenomena between about 130 ° C and about 180 ° C, and the appearance of a significant endothermic heat flux at a temperature of approximately 229 ° C. 11. The crystalline monohydrochloride of compound (1a) of claim 10, wherein said minor endothermic phenomena occur at a temperature of approximately 133 ° C., at a temperature of approximately 151 ° C., and at a temperature of approximately 170 ° C. 12. Form 2 of crystalline monohydrochloride of compound (Ia) in substantially pure form. 13. A method of obtaining form 2 of crystalline monohydrochloride of compound (Ia) in essentially pure form, comprising Ba) the formation of a mixture of monohydrochloride N- {2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine in an aqueous organic solvent by contacting said monohydrochloride with said solvent and heating at a temperature in the range of from about 60 to about 70 ° C, for example at about 65 ° C; Bb) bringing the temperature of said mixture to a temperature in the range of from about 52 to about 58 ° C, for example to about 55 ° C; Bv) introducing into the specified mixture a seed crystal of form 2; Bg) cooling the specified mixture to a temperature in the range from about 15 to 25 ° C; Bd) heating said mixture to a temperature in the range of from about 47 to about 52 ° C, for example to about 50 ° C; Be) the repetition of stages (Bg) and (Bd) to obtain the desired form 2. 14. A method for the prevention or treatment of a clinical condition in a mammal, for example, a human, which requires a selective β ₂ -adrenoreceptor agonist, comprising administering a therapeutically effective amount of Form 2 of crystalline monohydrochloride of compound (Ia). 15. Form 2 of crystalline monohydrochloride of compound (Ia) for use in therapeutic treatment. 16. The use of Form 2 of crystalline monohydrochloride of compound (Ia) in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition in which a selective β ₂ -adrenoreceptor agonist is required. 17. A pharmaceutical preparation containing Form 2 of crystalline monohydrochloride of compound (Ia), and a pharmaceutically acceptable carrier or excipient, and possibly one or more than one other therapeutic ingredient. 18. A combination comprising crystalline monohydrochloride form 2 of compound (Ia) and one or more than one other therapeutic ingredient. 19. The combination of claim 17, wherein the other therapeutic ingredient is a PDE4 (phosphodiesterase 4) inhibitor, or an anticholinergic, or a corticosteroid. 20. The combination according to any one of claims 17 or 18, containing Form 2 of crystalline monohydrochloride of compound (Ia) and 6α, 9α-difluoro-17α - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl S-fluoromethyl ester -3-oxo-androsta-1,4-diene-17β-carbothioacids. 21. The combination according to any one of Claims 17 or 18, containing Form 2 of crystalline monohydrochloride of compound (Ia) and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α - [(4-methyl-1, 3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioacids.