阅读说明：本技术 制备阿塞那平的方法 (Process for the preparation of asenapine ) 是由 郑志国 于 2019-08-13 设计创作，主要内容包括：本发明涉及制备阿塞那平的方法。具体而言,本发明涉及制备可药用的阿塞那平游离碱以及其晶型的方法,还涉及该方法中所用的中间体化合物的制备方法。(The present invention relates to a process for the preparation of asenapine. In particular, the invention relates to a process for the preparation of pharmaceutically acceptable asenapine free base and crystalline forms thereof, and to a process for the preparation of intermediate compounds used in the process.)

1. A method for preparing Asenapine (Asenapine) with a formula I,

characterized in that the method comprises the following steps:

(a-1) subjecting the intermediate II to intramolecular nucleophilic substitution reaction under alkaline condition to obtain a cyclic ether intermediate III,

wherein X is F, Cl, Br or I,

wherein the base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a metal hydride, a metal organic compound or a non-nucleophilic organic strong base,

(a-2) reducing the nitro group in the intermediate III to obtain an intermediate IV,

(a-3) carrying out diazotization deamination reaction on the intermediate IV, then recrystallizing and purifying to obtain the pure asenapine product shown in the formula I,

2. a process for the preparation of asenapine of formula I according to claim 1, wherein the step (a-1) is carried out in the presence of a catalystThe base is selected from LiOH, NaOH, KOH, RbOH, CsOH, FrOH, Li₂CO₃、Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃、LiHCO₃、NaHCO₃、KHCO₃、NaH、KH、CaH₂Butyl lithium, methyl magnesium chloride, tert-butyl magnesium chloride, ethyl magnesium bromide, butyl magnesium bromide, LDA, LiHMDS or NaHMDS.

3. A process for the preparation of asenapine of formula i according to any of claims 1 to 2, wherein the solvent reacted in step (a-1) is an aprotic solvent, such as selected from toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, dioxane, acetonitrile, sulfolane, N-methylpyrrolidone, DMF, DMSO, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or a mixture of two or more thereof.

4. A process for the preparation of asenapine of formula i according to any of claims 1 to 3 wherein the reducing agent used in the diazotization deamination reaction in step (a-3) is methanol, ethanol, isopropanol, hypophosphorous acid, sodium borohydride, potassium borohydride or nitrite.

5. The process for preparing asenapine of formula I according to any of claims 1 to 4, wherein in the step (a-3), the solvent used for the recrystallization purification is selected from the group consisting of C_5-9An alkane (e.g., n-pentane, hexane, n-hexane or n-heptane, or a mixture of two or more thereof), an aromatic hydrocarbon solvent (e.g., benzene, toluene, xylene, chlorobenzene, or a mixture of two or more thereof), an ester solvent (e.g., ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, or a mixture of two or more thereof), a ketone solvent (e.g., acetone, methyl ethyl ketone, or a mixture thereof), an ether solvent (e.g., diethyl ether, isopropyl ether, methyl tert-ether, tetrahydrofuran), a solvent mixture thereof, a solvent mixturePyran, methyltetrahydrofuran, or a mixture of two or more thereof), an alcohol solvent (for example, methanol, ethanol, propanol, isopropanol, or a mixture of two or more thereof), water, or a mixed solvent of two or more of the above solvents, preferably n-heptane or a mixed solvent thereof with another solvent.

6. A process for preparing asenapine of formula I comprising the steps of:

wherein the intermediate IV is subjected to diazotization deamination reaction and then recrystallization purification to obtain asenapine of the formula I.

7. The production method according to claim 6: the method is characterized in that a reducing reagent used in the diazotization deamination reaction in the step is methanol, ethanol, isopropanol, hypophosphorous acid, sodium borohydride or nitrite.

8. A crystal of asenapine of formula I,

the method is characterized in that when powder X-ray diffraction analysis is carried out under CuK alpha ray experimental conditions, diffraction signal peaks exist at 2 theta angle positions of 9.0 +/-0.2 degrees, 11.2 +/-0.2 degrees, 18.0 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.4 +/-0.2 degrees and 22.6 +/-0.2 degrees.

9. A crystal of asenapine of formula I according to claim 8, characterized in that it has diffraction signal peaks at angular positions 2 θ of 9.0 ± 0.2 °, 10.9 ± 0.2 °, 11.2 ± 0.2 °, 18.0 ± 0.2 °, 19.4 ± 0.2 °, 19.7 ± 0.2 °, 21.5 ± 0.2, 22.1 ± 0.2 °, 22.4 ± 0.2 °, 22.6 ± 0.2 °, 25.3 ± 0.2 ° when analyzed by powder X-ray diffraction using CuK α ray test conditions.

10. A process for the preparation of the crystalline form of asenapine of formula I which comprises dissolving a crude asenapine in the recrystallization solvent of claim 5, cooling, stirring for crystallization, and vacuum drying to give the crystalline form compound of formula I.

11. The method for preparing asenapine crystal form of formula I according to claim 10, wherein hexane, n-hexane or n-heptane, or a mixed solvent thereof with toluene, xylene, ethyl acetate, isopropyl ether, tetrahydrofuran or methyltetrahydrofuran is added to the crude asenapine, heated, stirred and dissolved, and then cooled to separate out a solid, and the product is collected by filtration and dried in vacuum to obtain the crystal form compound of formula I.

12. The process for preparing asenapine crystalline form of formula I according to claim 10, wherein the crystalline form compound of formula I is obtained by adding acetone, methanol, ethanol, propanol or isopropanol to crude asenapine, heating to dissolve, then adding water, cooling to crystallize, or adding a mixed solvent of acetone, methanol, ethanol, propanol or isopropanol and water, heating to dissolve, cooling to crystallize, filtering to collect the product, and vacuum drying.

13. A process for the preparation of asenapine crystalline form of formula I according to claim 10 wherein the acid salt of asenapine is dissolved in water or an organic solvent, neutralized with an equivalent amount of a base, concentrated to dryness by extraction with an aprotic solvent and then prepared according to the process of claim 11 or 12.

14. The method of claim 13, wherein the organic solvent is selected from methanol, ethanol, isopropanol, N-methylpyrrolidone, DMF, DMSO, acetonitrile, tetrahydrofuran, or methyltetrahydrofuran; the acid salt of asenapine is selected from hydrochloride, hydrobromide, hydroiodide, maleate, fumarate or tartrate.

15. A compound of formula II:

wherein X is F, Cl, Br or I.

16. A process for the preparation of a compound of formula ii comprising the steps of:

wherein X is F, Cl, Br or I,

step (b-1): under the action of sulfuric acid and halogen acid, hydroxyl in the structure of the compound (V) is substituted by halogen atom, and then the compound reacts with triethyl phosphite in an aprotic organic solvent under the catalysis of Lewis acid to obtain an intermediate VI,

step (b-2): the intermediate VI and 5-chloro salicylaldehyde VII are reacted under the alkaline condition to obtain an intermediate VIII,

step (b-3): the intermediate VIII and acetic anhydride are acetylated under the alkaline condition to obtain an intermediate IX,

step (b-4): intermediate IX is subjected to Huisgen cycloaddition reaction with N- (alkoxymethyl) -N-methyl- (trimethylsilyl) methylamine (X) under the catalysis of trifluoroacetic acid to obtain intermediate II, wherein R is C_1-6An alkyl group.

17. The method according to claim 16, wherein the hydrohalic acid used in step (b-1) is selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; the Lewis acid being FeCl₂、FeCl₃、FeBr₃、ZnCl₂、ZnBr₂Or InBr₂(ii) a The aprotic organic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixed solvent of two or more thereof.

18. The production method according to any one of claims 16 to 17, wherein the base used in step (b-2) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium tert-butoxide, or sodium tert-butoxide.

19. The process according to any one of claims 16 to 18, wherein R in the compound of formula X in step (b-4) is C_1-4Alkyl, preferably methyl or n-butyl.

20. A process for the preparation of a compound of formula II comprising the steps of:

wherein X is F, Cl, Br or I,

step (c-1): under the action of sulfuric acid and halogen acid, hydroxyl in the compound (V) is replaced by halogen atom, and then the compound is reacted with triphenylphosphine in an aprotic organic solvent to obtain an intermediate XI,

step (c-2): the intermediate XI and 5-chloro salicylaldehyde VII are subjected to Witting reaction under the alkaline condition to obtain an intermediate VIII,

step (b-3): the intermediate VIII and acetic anhydride are acetylated under the alkaline condition to obtain an intermediate IX,

step (b-4): intermediate IX is subjected to Huisgen cycloaddition reaction with N- (alkoxymethyl) -N-methyl- (trimethylsilyl) methylamine (X) under the catalysis of trifluoroacetic acid to obtain intermediate II, wherein R is C_1-6Alkyl, preferably methyl or n-butyl.

21. The method according to claim 20, wherein the hydrohalic acid used in step (c-1) is selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid. The aprotic organic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, methyl tetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixed solvent of two or more of them.

22. The process according to any one of claims 20 to 21, wherein the base used in step (c-2) is selected from inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium tert-butoxide or potassium tert-butoxide, or organic bases such as triethylamine, pyridine, p-dimethylaminopyridine or diisopropylethylamine.

Technical Field

The present invention relates to the field of synthesis of organic compounds. In particular, the invention relates to a preparation method of an antipsychotic drug Asenapine (Asenapine), namely a compound trans-5-chloro-2-methyl-2, 3,3a,12 b-tetrahydro-1H-dibenzo [2,3:6,7] -oxepino [4,5-c ] pyrrole and a novel crystal form thereof.

Background

Asenapine (Asenapine), a compound trans-5-chloro-2-methyl-2, 3,3a,12 b-tetrahydro-1H-dibenzo [2,3:6,7] -oxepino [4,5-c ] pyrrole, the maleate salt of which is useful in the emergency treatment of adult schizophrenia, mania or mixed episodes with type I bipolar disorder. The action mechanism of asenapine may be related to the antagonism of dopamine D2 and 5-hydroxytryptamine 2A, and is suitable for treating mania or mixed type attack of schizophrenia and bipolar I disorder, and has good antipsychotic effect. Antipsychotics have now become the 5 th treatment category behind cholesterol lowering medications, with sales reaching $ 162 billion in the global market. In China, the antipsychotic drug market keeps more than 40% of the compound growth rate every year, and the market share of the anti-schizophrenia drugs is about 30% and is growing at a rate of 9.8% every year. Therefore, research and development of a new preparation method of asenapine suitable for industrial production are necessary.

At present, a plurality of documents and patents are reported about the synthesis of asenapine. Initially, U.S. Pat. No. 4,45434 and the literature (Vader, J.; Kasperssen, F.; Sperling, E.; Schlactiter, I.; Terpsra, A.; Hilberink, P.; Wagenaars, G.J. Labelled composite. radiopharm.1994,34,845) 869, respectively, reported the preparation of asenapine, the synthetic route of which is as follows:

the main problems of the synthetic route are that the obtained asenapine is a mixture of cis-trans isomers, the separation operation of the isomers is very complicated, and the yield is low, so that the method is difficult to be used for industrial production.

The 2008 document (org. process res. dev.,2008,12(2), 196-201) reports the improvement of the above synthesis process, which is as follows:

the method is characterized in that strong base is utilized to hydrolyze and open loop lactam, isomerization reaction is carried out simultaneously, then the loop is closed to obtain a needed trans lactam intermediate, and finally lithium aluminum hydride is used for reduction to obtain asenapine. Through the improvement, the problem of separation and purification of the product is solved, and the total yield is improved. However, this synthetic route is lengthy, and the starting material 2- (5-chloro-2-phenoxy) phenylacetic acid still needs to be synthesized by the following method. In addition, the multi-step reaction of the above method uses a reagent which is highly polluting to the environment and a dangerous reagent such as lithium aluminum hydride, etc., and thus is not favorable for industrial production.

Afterwards, the 2008 patent US2008009619 reports that ortho-bromobenzyl bromide is used as a raw material to react with triethyl phosphite to obtain benzyl phosphonate, then the benzyl phosphonate reacts with salicylaldehyde through Horner-Wadsworth-Emmons to obtain a trans-tetrahydropyrrole intermediate, and finally a target compound is obtained through intramolecular ullmann reaction.

The method has short synthetic route and obtains single isomer. However, when preparing benzyl phosphonate ester, a strong irritant raw material of o-bromobenzyl bromide is needed, and a long-time high-temperature reaction is needed. In addition, the yield of the last walking-step ullmann reaction is low, and the reaction needs to be carried out for a long time at high temperature in the presence of cesium carbonate, cuprous halide and N, N-dimethylglycine, so that the problems of environmental pollution and high production cost exist.

Similar to the above synthesis method, in 2011 CN102229613 reports a new synthesis process of asenapine:

the method takes 2-bromo-beta-nitrostyrene and 2-methoxy-5-chlorophenylacetic acid methyl ester as initial raw materials, obtains cis-trans isomeric mixture through condensation, reduction, cyclization and methylation reaction, and obtains the target product asenapine through de-etherification, intramolecular Ullmann cyclization and reduction. Although the synthesis method can isomerize cis-trans isomeric mixture into single trans compound, the operation is simplified and the yield is improved. However, the n-butyllithium used in the process needs to be controlled below-60 ℃, and LiAlH is used for lactam reduction₄And is inflammable and explosive, so that the reaction in industrial production is limited.

Recently, CN104974168 in 2015 reported a preparation method of asenapine and intermediates used for preparing asenapine. The method uses 2-chloro-5-nitrobenzaldehyde and o-methoxybenzyl acetonitrile as starting materials, obtains a trans-form single isomer through condensation, addition and cyclization reactions, and obtains a target product asenapine through substitution, reduction, de-etherification, cyclization and diazotization reactions. However, the synthesis method needs to use highly toxic cyanide and flammable and explosive reagent LiAlH₄. The reaction operation has risks in industrial production.

In conclusion, the synthesis method of asenapine reported at present generally has the defects of complex process operation, great environmental pollution, use of flammable and explosive reagents, long synthesis route and the like. Therefore, there is a need for further research on a simple and efficient synthesis method suitable for industrialization of asenapine.

In order to overcome the defects of the above route, the invention provides a novel synthetic method of asenapine. The method has the characteristics of convenient operation, high product yield, good purity of the intermediate and the target product and the like, and is easy for industrial production.

Disclosure of Invention

In the present invention, the following terms have the meanings as described below:

“C_5-9alkane "means a branched or linear alkane having 5 to 9 carbon atoms, such as pentane, n-pentane, hexane, n-hexane or n-heptane.

“C_1-6Alkyl "and" C_1-4Alkyl "denotes branched or straight-chain alkyl groups having 1 to 6 and 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, respectively.

"halogen" or "halo" or "halogen atom" means fluorine, chlorine, bromine or iodine.

The "Huisgen cycloaddition reaction" is a cycloaddition reaction between a 1, 3-dipole and an alkene, alkyne or corresponding derivative, the product being a five-membered heterocyclic compound. Olefinic compounds are known as dipolar donors in reactions. The German chemist Rolf Huisgen first of all uses this type of reaction extensively to prepare five-membered heterocyclic compounds, and is therefore also referred to as the Huisgen reaction.

"diazo deamination" refers to a process in which a diazotization reaction of an amino group and a reaction in which the diazo group is substituted with a hydrogen atom are combined to remove the amino group, and is called diazo deamination. Namely, the amino is firstly subjected to diazotization reaction to obtain a diazo compound, and then the diazo compound is reacted with a reduction reagent to obtain the reaction of the deamination compound with the diazo substituted by hydrogen atoms.

The invention aims to provide a novel preparation method of asenapine and obtain a novel crystal form of asenapine free base.

In a first aspect, the present invention provides a process for the preparation of asenapine of formula I:

the method comprises the following steps:

(a-1) carrying out intramolecular nucleophilic substitution reaction on the intermediate II under an alkaline condition to obtain a cyclic ether intermediate III,

wherein X is F, Cl, Br or I,

wherein the base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a metal hydride, a metal organic compound or a non-nucleophilic organic strong base,

(a-2) reducing the nitro group in the intermediate III to obtain an intermediate IV,

and (a-3) carrying out diazotization deamination reaction on the intermediate IV, and then recrystallizing and purifying to obtain the pure asenapine product shown in the formula I.

In the step (a-1): and carrying out intramolecular nucleophilic substitution reaction on the intermediate II and phenolic hydroxyl on another benzene ring under the conditions of alkaline, aprotic solvent and mild reaction to obtain a cyclic ether intermediate III.

The base used in this step can be selected from alkali metal hydroxides LiOH, NaOH, KOH, RbOH, CsOH, FrOH, alkali metal carbonates Li₂CO₃、Na₂CO₃、K₂CO₃、Rb₂CO₃、Cs₂CO₃Alkali metal bicarbonate NaHCO₃、KHCO₃Metal organic compounds butyl lithium, methyl magnesium chloride, tert-butyl magnesium chloride, ethyl magnesium bromide, butyl magnesium bromide, metal hydrides NaH, KH, CaH₂The strong non-nucleophilic organic base LDA, LiHMDS or NaHMDS.

The solvent for the reaction is an aprotic solvent, for example selected from toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, dioxane, acetonitrile, sulfolane, N-methylpyrrolidone, DMF, DMSO, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or a mixture of two or more thereof.

The reaction temperature is 0-100 ℃, preferably 20-70 ℃.

After the reaction is finished, cooling to room temperature, adding drinking water to separate out a product, filtering, and drying in vacuum to constant weight to obtain a cyclic ether intermediate III.

In the step (a-2): and (3) carrying out catalytic hydrogenation reduction on the nitro in the intermediate III to obtain an intermediate IV.

The solvent used in this step is C_1-4Alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, water, or a mixture of two or more thereof.

The reaction temperature is 30-70 ℃.

In the reaction, nitro is reduced into amino by catalytic hydrogenation, and the adopted reducing agent can be selected from Pd/C, Ni, iron, zinc and sodium sulfide.

In the step (a-3): and carrying out diazotization deamination reaction on the intermediate IV, and recrystallizing and purifying to obtain the asenapine pure product shown in the formula I.

And dissolving the intermediate IV in a reduction reagent for diazotization deamination reaction, dropwise adding the diazotization reagent at the temperature of-5-30 ℃, reacting by a one-pot method, adjusting the pH value to be neutral by using alkali, separating out a solid, and filtering to obtain a crude product. And then recrystallized to give asenapine in crystalline form.

The diazotizing agent employed in the reaction is a nitrite salt, such as sodium nitrite or potassium nitrite.

The reducing agent for diazotization deamination reaction used in the reaction can be selected from methanol, ethanol, isopropanol, hypophosphorous acid, borohydride (including sodium borohydride and potassium borohydride) or nitrite.

The nitrite is selected from methyl nitrite, ethyl nitrite, tert-butyl nitrite, n-amyl nitrite or isoamyl nitrite.

The base used in this step may be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia, aqueous methylamine solution or triethylamine.

The solvent used for recrystallization purification can be selected from C_5-9An alkane (e.g., n-pentane, hexane, n-hexane, or n-heptane, or a mixture of two or more thereof), an aromatic hydrocarbon solvent (e.g., benzene, toluene, xylene, chlorobenzene, or a mixture of two or more thereof), an ester solvent (e.g., ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, or a mixture of two or more thereof), a ketone solvent (e.g., acetone, methyl ethyl ketone, or a mixture thereof), an ether solvent (e.g., diethyl ether, isopropyl ether, methyl tert-ether, tetrahydrofuran, methyl tetrahydrofuran, or a mixture of two or more thereof), an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, or a mixture of two or more thereof), water, or a mixed solvent of two or more of the above solvents, n-heptane or a mixed solvent thereof with other solvents is preferable.

In a second aspect, a process for preparing asenapine of formula I, comprising the steps of:

wherein the intermediate IV is subjected to diazotization deamination reaction and then recrystallization purification to obtain asenapine of the formula I.

Dissolving the intermediate IV in a reducing reagent used for diazotization deamination reaction, dropwise adding the diazotization reagent at the temperature of-5-30 ℃, reacting by a one-pot method, adjusting the pH value to be neutral by alkali, separating out solid, and filtering to obtain a crude product. And then recrystallized to give asenapine in crystalline form.

The diazotization reagent adopted by the reaction is sodium nitrite or potassium nitrite.

The reducing agent used in the reaction may be selected from methanol, ethanol, isopropanol, hypophosphorous acid, borohydride (including sodium borohydride and potassium borohydride) or nitrite.

The nitrite is selected from methyl nitrite, ethyl nitrite, tert-butyl nitrite, n-amyl nitrite or isoamyl nitrite.

In a third aspect, the invention provides crystals of asenapine of formula I, and a process for the preparation of the crystals.

The invention provides asenapine represented by formula I in the form of a crystal characterized in that, when powder X-ray diffraction analysis is performed using CuK alpha ray experimental conditions, the characteristic diffraction positions are represented by 2 theta angles of 9.0 + -0.2 degrees, 11.2 + -0.2 degrees, 18.0 + -0.2 degrees, 22.1 + -0.2 degrees, 22.4 + -0.2 degrees, 22.6 + -0.2 degrees.

More specifically, in the powder X-ray diffraction pattern of the asenapine crystal of the formula I, the characteristic diffraction positions have 2 theta angles of 9.0 + -0.2 DEG, 10.9 + -0.2 DEG, 11.2 + -0.2 DEG, 18.0 + -0.2 DEG, 19.4 + -0.2 DEG, 19.7 + -0.2 DEG, 21.5 + -0.2 DEG, 22.1 + -0.2 DEG, 22.4 + -0.2 DEG, 22.6 + -0.2 DEG, 25.3 + -0.2 deg.

The crystal PXRD spectrum of asenapine in formula I is shown in figure 1, the infrared spectrum is shown in figure 2, and the DSC spectrum is shown in figure 3.

The preparation and purification method of the invention is adopted to obtain a crystal form of asenapine of formula I, which is characterized in that when powder X-ray diffraction analysis is carried out under CuK alpha ray experimental conditions, the diffraction position is 2 theta angle value (DEG) or d valueThe diffraction peak relative intensity peak Height (Height%) or peak Area (Area%) is shown in the following table:

a process for preparing a crystalline form of asenapine of formula I comprising: dissolving the asenapine crude product in a recrystallization solvent, stirring at room temperature for crystallization, filtering, and drying in vacuum to obtain the asenapine free base with the crystal form.

The solvent used for recrystallization purification can be selected from C_1-9An alkane (e.g., n-pentane, hexane, n-hexane, or n-heptane, or a mixture of two or more thereof), an aromatic hydrocarbon solvent (e.g., benzene, toluene, xylene, chlorobenzene, or a mixture of two or more thereof), an ester solvent (e.g., ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, or a mixture of two or more thereof), a ketone solvent (e.g., acetone, methyl ethyl ketone, or a mixture thereof), an ether solvent (e.g., diethyl ether, isopropyl ether, methyl tert-ether, tetrahydrofuran, methyl tetrahydrofuran, or a mixture of two or more thereof), an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, or a mixture of two or more thereof), water, or a mixed solvent of two or more of the above solvents, n-heptane or a mixed solvent thereof with other solvents is preferable.

In one embodiment, a process for preparing a crystalline form of asenapine of formula I comprises: adding a recrystallization solvent, such as hexane, n-hexane or n-heptane, or a mixed solvent of the recrystallization solvent and toluene, xylene, ethyl acetate, isopropyl ether, tetrahydrofuran or methyltetrahydrofuran, into the asenapine crude product, heating, stirring, dissolving, cooling to separate out a solid, filtering, collecting a product, and drying in vacuum to obtain the crystal form compound of the formula I.

The dissolving temperature is 30-70 ℃, preferably 35-50 ℃.

And (3) carrying out heat preservation crystallization at the crystallization temperature of 15-25 ℃ for 1.0-1.5 h, cooling to-20-0 ℃, preferably to-20-10 ℃ at the speed of 5-10 ℃ per hour, stirring for 1.0-1.5 h under the heat preservation condition, filtering, washing with a proper amount of hexane, n-hexane or n-heptane, filtering, and carrying out vacuum drying at the temperature of 30-60 ℃ to obtain the crystal form compound of the formula I.

In another embodiment, a process for preparing a crystalline form of asenapine of formula I comprises: adding a recrystallization solvent such as acetone, methanol, ethanol, propanol or isopropanol into the asenapine crude product, heating for dissolving, then adding water, cooling for crystallizing, or adding a mixed solvent of acetone, methanol, ethanol, propanol or isopropanol and water, heating for dissolving, cooling for crystallizing, filtering and collecting a product, and vacuum-drying to obtain the crystal form compound of the formula I.

The dissolving temperature is 30-70 ℃, preferably 35-50 ℃.

And (3) carrying out heat preservation crystallization at the temperature of 20-25 ℃ for 1.0-1.5 h at the crystallization temperature of 20-25 ℃, cooling to-5-15 ℃, preferably to-5 ℃ at the speed of 5-10 ℃ per hour, stirring for 1.0-1.5 h at the heat preservation temperature, filtering, washing with a proper amount of crystallization solvent, filtering, and carrying out vacuum drying at the temperature of 30-60 ℃ to obtain the crystal form compound of the formula I.

The process for preparing asenapine crystals of formula I may further comprise: dissolving asenapine acid salt with water or organic solvent, neutralizing with equivalent amount of alkali, extracting with aprotic solvent, concentrating to dry, and recrystallizing.

The organic solvent used for dissolving can be selected from methanol, ethanol, isopropanol, N-methyl pyrrolidone, DMF, DMSO, acetonitrile, tetrahydrofuran or methyl tetrahydrofuran.

The acidic salt of asenapine may be selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, maleate, fumarate or tartrate.

The base may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide or potassium tert-butoxide.

The aprotic organic solvent can be selected from hexane, n-heptane, toluene, xylene, isopropyl ether, methyl tert-butyl ether, or a mixture of two or more thereof.

The obtained asenapine of the formula I can also be salified with acid to prepare a pharmaceutically acceptable salt thereof, and the preparation method comprises the steps of reacting asenapine with hydrochloric acid to prepare asenapine hydrochloride, and reacting asenapine with maleic acid to prepare asenapine maleate.

In a fourth aspect, the present invention provides a compound of formula II, having the structure:

wherein X is F, Cl, Br or I.

Specifically, the compound of formula II includes the following four compounds:

furthermore, the present invention provides a process for the preparation of a compound of formula II, comprising the steps of:

in the step (b-1): under the action of sulfuric acid and halogen acid, hydroxyl in the structure of 2-halogen-5-nitrobenzol (V) is substituted by halogen atom, and then the 2-halogen-5-nitrobenzol (V) and triethyl phosphite react in an aprotic organic solvent under the catalysis of Lewis acid to obtain an intermediate VI.

The hydrohalic acid used in this step includes hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid. The Lewis acid being FeCl₂、FeCl₃、FeBr₃、ZnCl₂、ZnBr₂Or InBr₂。

The aprotic organic solvent may be selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, etc., or a mixed solvent of two or more thereof.

Specifically, a compound V (2-halogen-5-nitrobenzol), halogen acid and sulfuric acid are mixed according to the weight ratio of 1.0: 1.2-3.0: 0.2-1.0 equivalent, heated to 20-55 ℃, kept warm and stirred for reaction for 5-14 hours, then extracted by an aprotic solvent, washed by drinking water and weak base, and dried by a drying agent to remove water, so as to obtain an intermediate solution. And then adding catalyst Lewis acid and triethyl phosphite, heating the reaction solution to 30-50 ℃, stirring and reacting for 6-12 h, slightly cooling after the reaction is finished, adding drinking water for washing, separating, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain the compound in the formula VI, wherein the next step of reaction is directly carried out without purification.

The weight ratio of the compound V, the halogen acid and the sulfuric acid is preferably 1.0: 1.5-2.0: 0.5-0.8. The reaction time is preferably 8-12 h.

The weak base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate. The drying agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.

In the step (b-2): and (3) reacting the intermediate VI with 5-chlorosalicylaldehyde VII under an alkaline condition to obtain an intermediate VIII through Horner-Wadsworth-Emmons reaction.

The molar ratio of the intermediate VI to the 5-chlorosalicylaldehyde in the step is that the intermediate VI to the 5-chlorosalicylaldehyde is 1.0: 1.2.

The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, or a mixture of two or more thereof.

The reaction solvent is aprotic solvent, and can be selected from benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or mixture of two or more thereof.

The reaction temperature is-5 to 25 ℃, preferably-5 to 10 ℃.

In the step (b-3): and (4) acetylating the intermediate VIII and acetic anhydride under an alkaline condition to obtain an intermediate IX.

In this step, the molar ratio of the intermediate VIII to acetic anhydride is 1.0:1.8, preferably 1.2: 1.5.

The base employed may be selected from organic bases such as diethylamine, triethylamine, isopropylamine, pyridine or p-dimethylaminopyridine, or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydride or potassium hydride.

The reaction solvent may be selected from benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or a mixed solvent of two or more thereof.

The reaction temperature is 5-55 ℃.

Water, methanol, ethanol or isopropanol can be added for the post-treatment to separate out the compound IX.

In the step (b-4): the intermediate IX is subjected to a Huisgen cycloaddition reaction with N- (alkoxymethyl) -N-methyl- (trimethylsilyl) methylamine in an aprotic solvent at ambient temperature under the catalysis of trifluoroacetic acid, and then deprotection is carried out under alkaline conditions to obtain an intermediate II.

Wherein R in the compound of formula X is C_1-6Alkyl, R is preferably-CH₃and-Bu-n.

The molar ratio of intermediate ix to compound of formula X is intermediate ix to compound X is 1.0:1.5, preferably 1.1: 1.3.

The reaction solvent in the step can be one or a mixture of two or more of benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether and methyl tert-butyl ether.

The solvent used for deacetylation is C_1-4An alcoholic solvent selected from methanol, ethanol, propanol, isopropanol or butanol. The alkali is alkali metal aqueous solution, and can be selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide aqueous solution.

In a fifth aspect, the present invention provides another process for preparing a compound of formula II:

wherein X is F, Cl, Br or I.

In the step (c-1): under the action of sulfuric acid and halogen acid, hydroxyl in the structure of the compound (V) is replaced by halogen atoms, and then the compound is reacted with triphenylphosphine in an aprotic organic solvent to obtain an intermediate XI.

The hydrohalic acid used in this step includes hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid of various concentrations.

The aprotic organic solvent used may be selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixed solvent of two or more thereof.

Specifically, a compound V (2-halogen-5-nitrobenzol), halogen acid and sulfuric acid are mixed according to the weight ratio of 1.0: 1.0-3.0: 0.2-1.0 equivalent, heated to 20-85 ℃, kept warm and stirred for reaction for 5-14 hours, then extracted by an aprotic solvent, washed by drinking water and weak alkali, and dried by a drying agent to remove water, so as to obtain an intermediate solution. And then adding triphenylphosphine, heating the reaction solution to 30-70 ℃, stirring for reaction for 6-12 h, cooling to room temperature after the reaction is finished, and filtering to obtain the compound shown in the formula XI.

The weight ratio of the compound V to the halogen acid to the sulfuric acid is preferably 1.0: 1.2-1.5: 0.2-0.5. The reaction time is preferably 8-12 h.

The weak base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate. The drying agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.

In the step (c-2): and carrying out Witting reaction on the intermediate XI and 5-chlorosalicylaldehyde VII under an alkaline condition to obtain an intermediate VIII.

The base used in this step may be selected from inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, or organic bases such as triethylamine, pyridine, p-dimethylaminopyridine, diisopropylethylamine.

The molar ratio of the intermediate XI to 5-chlorosalicylaldehyde in the step is 1: 1.05-1.5, preferably 1: 1.05-1.3.

The reaction temperature is 20-80 ℃, and preferably 40-70 ℃.

The reaction solvent is an aprotic organic solvent, and can be selected from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, or a mixed solvent of two or more of the above.

In the step (b-3): and (4) acetylating the intermediate VIII and acetic anhydride under an alkaline condition to obtain an intermediate IX.

In this step, the molar ratio of the intermediate VIII to acetic anhydride is 1.0:1.8, preferably 1.2: 1.5.

The base employed may be selected from organic bases such as diethylamine, triethylamine, isopropylamine, pyridine or p-dimethylaminopyridine, or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydride or potassium hydride.

The reaction solvent can be one or a mixture of two or more of benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether and methyl tert-butyl ether.

The reaction temperature is 5-55 ℃.

Water, methanol, ethanol or isopropanol can be added for the post-treatment to separate out the compound IX.

In the step (b-4): the intermediate IX is subjected to a Huisgen cycloaddition reaction with N- (alkoxymethyl) -N-methyl- (trimethylsilyl) methylamine in an aprotic solvent at ambient temperature under the catalysis of trifluoroacetic acid, and then deprotection is carried out under alkaline conditions to obtain an intermediate II.

Wherein R in the compound of formula X may be C_1-6Alkyl, R is preferably-CH₃and-Bu-n.

The molar ratio of intermediate ix to compound of formula X is intermediate ix to compound X is 1.0:1.5, preferably 1.1: 1.3.

The reaction solvent in the step can be one or a mixture of two or more of benzene, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether and methyl tert-butyl ether.

The solvent used for deacetylation is C_1-4Alcohol solvent selected from methanol, ethanol, propanol, isopropanol, and butanol. The alkali is alkali metal aqueous solution, and can be selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide aqueous solution.

The core points of the invention are as follows: the 2-halogen-5-nitrobenzyl halide and triethyl phosphite are catalyzed by Lewis acid to obtain an intermediate IV under mild reaction conditions, so that the high-temperature long-time reaction of 2-bromine-benzyl bromide used for preparing phosphonate ester in the prior art (US2008009619) is avoided. By utilizing the strong electron-withdrawing effect of halogen atoms of a pyrrolidine benzene ring in the intermediate II on a para-nitro group, the dibenzo [2,3:6,7] oxepino [4,5-c ] pyrrole ring is constructed by intramolecular nucleophilic substitution reaction with phenolic hydroxyl on another benzene ring under mild alkaline conditions, and the defect that the dibenzo [2,3:6,7] oxepino [4,5-c ] pyrrole ring of asenapine constructed by the prior art (US2008009619) needs to be subjected to long-time high-temperature intramolecular Ullmann reaction is overcome. And the crystallization method and the obtained crystal can simplify the post-treatment, improve the purification efficiency and reduce the cost, thereby being very beneficial to the industrialized mass production.

Compared with the prior art, the method for preparing asenapine avoids the use of inflammable and explosive hazardous reducing agents LiAlH in the prior art (US4145434, org. Process Res. Dev.,2008,12(2), 196-containing 201, CN102229613, CN104974168)₄And the separation and purification process of isomers is also avoided, and the process is simplified. Meanwhile, the invention does not need high-temperature long-time reaction operation (US2008009619), avoids using dangerous and toxic reagents of butyl lithium and methyl iodide (CN102229613), and does not use methyl iodide, boron tribromide and hydrazine hydrate (CN 104974168). The method has the advantages of mild reaction conditions, simple operation, little environmental pollution, low cost and the like, thereby being more suitable for industrial production.

Drawings

Fig. 1 is a PXRD pattern of asenapine crystals of the present invention. Fig. 2 is an infrared spectrum of an asenapine crystal of the present invention. Figure 3 is a DSC profile of asenapine crystals of the present invention.

Detailed Description

The process of the present invention is further illustrated by the following examples. It should be understood that the following examples are provided only for the purpose of enabling a better understanding of the present invention, and are not intended to limit the scope of the present invention in any way.