Method for preparation of Asenapine

1. A compound of formula II:

wherein X is F, Cl, Br or I.

2. A method for preparing the compound of formula II according to claim 1 , comprising the following steps:

wherein X is F, Cl, Br or I,

Step (b-1): Compound (V) is subjected to the action of sulfuric acid and hydrohalogen acid, thereby replacing the hydroxy group in its structure with a halogen atom, and then is reacted with triethyl phosphite under the catalysis of Lewis acid in an aprotic organic solvent to yield Intermediate VI,

Step (b-2): Intermediate VI is reacted with 5-chlorosalicylaldehyde VII under basic condition through Horner-Wadsworth-Emmons reaction to obtain Intermediate VIII,

Step (b-3): Intermediate VIII is acetylated with acetic anhydride under basic condition to obtain Intermediate IX, and

Step (b-4): Intermediate IX is reacted with N-(alkoxymethyl)-N-methyl-(trimethylsilyl)methylamine (X) under the catalysis of trifluoroacetic acid to perform Huisgen cycloaddition reaction, to obtain the compound of formula II, wherein R is C 1-6 alkyl.

3. The method according to claim 2 , characterized in that, in step (b-1), the hydrohalogen acid used is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid; the Lewis acid is FeCl 2 , FeCl 3 , FeBr 3 , ZnCl 2 , ZnBr 2 or InBr 2 ; the aprotic organic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixture of two or more thereof.

4. The method according to claim 2 , characterized in that, in step (b-2), the base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, or sodium tert-butoxide.

5. The method according to claim 2 , characterized in that, in the compound of formula X in step (b-4), R is C 1-4 alkyl.

6. A method for preparing the compound of formula II according to claim 1 , comprising the following steps:

wherein X is F, Cl, Br or I,

Step (c-1): Compound (V) is subjected to the action of sulfuric acid and hydrohalogen acid, thereby replacing the hydroxy group in its structure with a halogen atom, and then is reacted with triphenylphosphine in an aprotic organic solvent to obtain Intermediate XI,

Step (c-2): Intermediate XI is reacted with 5-chlorosalicylaldehyde VII under basic condition through Witting reaction to yield Intermediate VIII,

Step (b-3): Intermediate VIII is acetylated with acetic anhydride under basic condition to obtain Intermediate IX, and

Step (b-4): Intermediate IX is reacted with N-(alkoxymethyl)-N-methyl-(trimethylsilyl)methylamine (X) under the catalysis of trifluoroacetic acid to perform Huisgen cycloaddition reaction, to obtain the compound of formula II, wherein R is C 1-6 alkyl.

7. The method according to claim 6 , characterized in that, in step (c-1), the hydrohalogen acid used is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid; and the aprotic organic solvent used is selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixture of two or more thereof.

8. The method according to claim 6 , characterized in that, in step (c-2), the base used is selected from inorganic bases or organic bases.

9. The method according to claim 8 , characterized in that the inorganic bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, or potassium tert-butoxide; and the organic bases are selected from triethylamine, pyridine, p-dimethylaminopyridine, or diisopropylethylamine.