CN114105884A

CN114105884A - Preparation method and crystal form of PDE4 inhibitor clobiplane

Info

Publication number: CN114105884A
Application number: CN202111012236.3A
Authority: CN
Inventors: 徐江平; 杨日芳; 罗国强
Original assignee: Lansheng Biomedicine Suzhou Co ltd
Current assignee: Lansheng Biomedicine Suzhou Co ltd
Priority date: 2020-08-31
Filing date: 2021-08-31
Publication date: 2022-03-01
Also published as: CN111808029A

Abstract

The present disclosure provides a novel process for the preparation of the PDE4 inhibitor clobiplan. By reducing the aldehyde group on the benzene ring to hydroxymethyl after the Suzuki reaction, column chromatography purification of an intermediate product can be omitted, so that a novel preparation method of the PDE4 inhibitor chloropipran, which has the advantages of simple operation, no need of column chromatography purification and industrial production, is provided. The disclosure also provides various crystalline forms of the PDE4 inhibitor clobiplane and processes for their preparation.

Description

Preparation method and crystal form of PDE4 inhibitor clobiplane

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method and a crystal form of a PDE4 inhibitor clobiplane.

Background

The chloropiperam (Chlorbipram) serving as a novel PDE4 inhibitor has a good improvement effect on a rat model with scopolamine-induced learning and memory acquired disorder, also has a good anti-depression activity on a rat model with forced swimming and tail suspension behavior despair, and is proved to have only weak or even no vomiting and nausea side effects by adopting beagle dogs.

In the prior art, the invention patent with publication number CN106632070A discloses a method for preparing PDE4 inhibitor clobiplane, and the proposed synthesis route is as follows:

in the synthetic route, after the intermediate chlorobenzene boric acid and bromobenzyl alcohol are subjected to Suzuki reaction (namely step 2), the product is liquid, column chromatography purification is needed, and the yield is low, so that the preparation method is not suitable for industrial production.

In addition, the crystal form of the topiramate is not researched in the prior art. For drugs, their crystalline forms affect the stability, solubility and bioavailability of the drug. Therefore, the crystal form has very important significance on the quality, safety and effectiveness of the pharmaceutical preparation.

Thus, there remains a need for an efficient process for the preparation of the PDE4 inhibitor clobiplan that is simple to operate. In addition, it remains desirable to provide various crystalline forms of topiramate that exhibit desirable properties.

Summary of The Invention

The inventors of the present invention have diligently studied and found that column chromatography purification of an intermediate product can be omitted by performing reduction of an aldehyde group on a benzene ring to a hydroxymethyl group after the Suzuki reaction, thereby providing a novel method for preparing chloropipran, which is a PDE4 inhibitor, and which is simple in operation, does not require column chromatography purification, and is advantageous for industrial production. Moreover, through a large amount of researches, the inventor discovers four crystal forms of the topiramate, namely Form A, Form 1, Form2 and amorphous Form, and determines the conversion conditions among the four crystal forms and the preparation method.

It is therefore an object of the present invention to provide a novel process for the preparation of the PDE4 inhibitor clobiplane.

It is another object of the present invention to provide crystalline forms of the compound of the PDE4 inhibitor clobiplane.

Still another object of the present invention is to provide a process for the preparation of various crystalline forms of clobiplane.

Other features and advantages of the present invention will be described in detail below.

Brief description of the drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:

FIG. 1 shows an XRPD pattern for Form A;

FIG. 2 shows a DSC profile of Form A;

FIG. 3 shows a TGA profile of Form A;

FIG. 4 shows a DVS map of Form A;

FIG. 5 shows the isothermal adsorption curve for Form A;

figure 6 shows the XRPD pattern of an amorphous stable placement experiment;

figure 7 shows an amorphous XRPD pattern;

figure 8 shows an amorphous hot-stage XRPD pattern;

figure 9 shows DSC profile of amorphous;

figure 10 shows a TGA profile of amorphous form;

FIG. 11 shows an XRPD pattern for Form 1;

FIG. 12 shows a DSC profile of Form 1;

FIG. 13 shows a TGA profile of Form 1;

FIG. 14 shows an XRPD pattern for Form 2;

FIG. 15 shows a DSC profile of Form 2;

FIG. 16 shows a TGA profile of Form 2;

FIG. 17 shows a DVS map of Form 2;

FIG. 18 shows an isothermal adsorption pattern for Form 2;

figure 19 shows the XRPD pattern of the starting mixed sample in competition experiment 1;

FIG. 20 shows an XRPD pattern for an n-heptane/ethyl acetate competition experiment in competition experiment 1;

figure 21 shows XRPD patterns of the starting mixed samples in competitive experiment 2;

FIG. 22 shows an XRPD pattern for competition experiments in water in competition experiment 2;

FIG. 23 shows the results of the Form A stability experiment, i.e., the XRPD pattern of the Form A stability standing experiment;

FIG. 24 shows the HPLC purity analysis results of the product before recrystallization of isopropanol from ZX-101 preparation method 2;

FIG. 25 shows the HPLC purity analysis results of the bulk drug substance after recrystallization from isopropanol of ZX-101 preparation method 2;

FIG. 26 shows the HPLC purity assay results for the drug substance of ZX-101 preparation method 3;

figure 27 shows an XRPD pattern of form a (form a) of a ZX-101 drug substance; and

FIG. 28 shows the conversion relationship between Form A, Form 1, Form2, amorphous Form of the PDE4 inhibitor clobiplan.

Description of The Preferred Embodiment

In a first aspect, the present invention provides a process for the preparation of the PDE4 inhibitor clobiplane, which process comprises the steps of:

1) reacting 2-aminoethyl o-methoxyphenyl ether (compound A1) with 3, 6-dichloropyridazine to obtain 3- (2-o-methoxyphenyloxyethyl) amino-6-chloropyridazine (compound A2);

2) treating the compound A2 prepared in the step 1) with acetate in an acetic acid solvent to obtain 1H-3- (2-o-methoxyphenyloxyethyl) aminopyridazin-6-one and/or a tautomer thereof (compound ZXSM 02);

3) reacting 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, alkali and urea in a polar protic organic solvent containing water, such as a solvent system consisting of isopropanol and water or water, in the presence of a palladium catalyst to obtain 3- (m-chlorophenyl) -4-methoxybenzaldehyde (compound ZXSM 01);

4) reducing the compound ZXSM01 in an organic solvent such as tetrahydrofuran with a reducing agent such as sodium borohydride, extracting and concentrating the reaction mixture to obtain 3- (m-chlorophenyl) -4-methoxybenzyl alcohol (compound ZX01), which is used in the next reaction step without further extensive purification;

5) chloridizing the compound ZX01 to obtain 1-chloromethyl-3- (m-chlorophenyl) -4-methoxybenzene (compound ZX 02);

6) reacting ZXSM02 prepared in step 2) with ZX02 prepared in step 5) in the presence of a base to obtain a target compound ZX-101, namely clenbuterol.

In some embodiments, step 1) is carried out in a polar protic organic solvent such as ethanol, isopropanol or an aprotic solvent such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), at a reaction temperature in the range of 40-120 ℃, for example in the range of 50-100 ℃, for example the reflux temperature of ethanol. The reaction can be monitored by TLC, so that an appropriate reaction time can be easily determined.

After the end of the reaction of step 1), the reaction mixture can be worked up by methods known per se, for example the reaction mixture can be concentrated to dryness to provide a crude product of compound a 2. The crude compound a2 can be recrystallized from solvents such as alcohols, ethers, etc. to give compound a 2.

In some embodiments, the acetate salt employed in step 2) may be at least one of an alkali metal acetate, an alkaline earth metal acetate, and hydrates thereof, such as at least one of sodium acetate, potassium acetate, and hydrates thereof.

In some embodiments, after the reaction of step 2) is complete, the reaction mixture may be poured into water and stirred, for example, for about 1-3 hours, and then filtered. The filter cake was washed with water and dried to give intermediate ZXSM 02.

It is within the scope of the present invention to provide intermediate ZXSM02 using other methods.

In some embodiments, step 3) is performed under an inert atmosphere, and the inert atmosphere employed may be, for example, nitrogen or argon.

In some embodiments, the base employed in step 3) is at least one selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, and alkaline earth metal bicarbonates, preferably at least one selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

In some embodiments, the amount of urea used in step 3) may be in the range of 0 to 2 molar equivalents, preferably 0.01 to 0.1 molar equivalents, for example 0.03 molar equivalents, relative to 3-bromo-4-methoxybenzaldehyde.

In some embodiments, the reaction of step 3) may be carried out in a polar aprotic organic solvent, a polar protic organic solvent, water, or a mixture of water and a polar aprotic organic solvent or a polar protic organic solvent, examples of polar protic organic solvents being methanol, ethanol, propanol, isopropanol. In a particularly preferred embodiment, the reaction of step 3) is carried out in a solvent system consisting of isopropanol and water, the mass ratio of isopropanol to water being in the range from 1:0.05 to 1:20,

in some embodiments, the palladium catalyst employed in step 3) is at least one selected from the group consisting of palladium acetate, palladium chloride, 5% palladium-carbon, 10% palladium-carbon, and tetrakis (triphenylphosphine) palladium, and may be used in an amount of 0.1 to 80 wt% based on the weight of 3-bromo-4-methoxybenzaldehyde.

In some embodiments, the reaction of step 3) is carried out at a temperature of 30-120 ℃, and it is within the knowledge of one skilled in the art to determine an appropriate reaction time by TLC monitoring.

The reaction of step 3) is known in the art as the Suzuki reaction. Suitable Suzuki reaction conditions are well known to those skilled in the art. It is therefore within the ability of the person skilled in the art to select suitable reaction conditions within the above preferred ranges or even outside the above preferred ranges.

Methods for working up the reaction products of step 3) are also known to the person skilled in the art. For example, after the reaction is complete, the reaction mixture can be filtered with suction and the organic phase concentrated to remove isopropanol. After concentration, the residue was transferred to a reaction vessel and stirred with added water overnight, then filtered off with suction, and the filter cake was washed thoroughly twice with ethanol and then dried to give intermediate compound ZXSM 01.

In some embodiments, the organic solvent employed in step 4) is selected from ethers, mixtures of ethers and alcohols, mixtures of ethers and water, alcohols, mixtures of alcohols and water, preferably tetrahydrofuran. The amount of the organic solvent may be 2 to 20 times, for example 2.6 to 6.2 times, the mass of ZXSM 01.

In some embodiments, the reducing agent employed in step 4) may be selected from the group consisting of negative hydrogen ion-based reducing agents and borane complex reducing agents, preferably sodium borohydride. The reducing agent may be used in an amount of 0.5 to 0.9 molar equivalent to 1 equivalent or more of ZXSM 01.

In some embodiments, the reaction of step 4) is carried out at a temperature of 20 to 120 ℃ for a reaction time of 0.5 to 24 h.

After the end of the reaction in step 4), the reaction mixture can be worked up by methods known per se. In one embodiment, the reaction mixture is quenched by addition to a mixed solution of water and concentrated hydrochloric acid, then the resulting mixture is concentrated to remove tetrahydrofuran, the remaining aqueous solution is extracted, e.g., 2-3 times, with Dichloromethane (DCM), the organic phases are combined and concentrated under reduced pressure to give compound ZX 01.

In some embodiments, the chlorination reaction of step 5) may be carried out in an organic solvent, which may be selected from aprotic solvents such as haloalkanes, aromatic hydrocarbons, ethers, e.g., tetrahydrofuran. The amount of the organic solvent may be 2 to 20 times, for example 2.6 to 6.2 times, the mass of ZX 01.

In some embodiments, the chlorinating reagent useful for the chlorination reaction of step 5) may be selected from thionyl chloride, phosphorus pentachloride, phosphorus trichloride, hydrochloric acid, and the chlorinating reagent is typically used in excess.

In some embodiments, the chlorination reaction of step 5) may be carried out at a temperature of 0-120 ℃, and determination of suitable reaction times by TLC monitoring is within the knowledge of one skilled in the art.

In some embodiments, after the chlorination reaction of step 5) is complete, the reaction mixture can be concentrated to dryness under normal or reduced pressure, and the residue can be used directly in the next reaction without further purification.

In some embodiments, the reaction of step 6) may be carried out under an inert atmosphere, such as a nitrogen or argon atmosphere.

In some embodiments, the base used in the reaction of step 6) may be selected from inorganic bases, such as alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, such as potassium carbonate and cesium carbonate; hydroxides, such as sodium hydroxide, potassium hydroxide; organic bases such as triethylamine and pyridine. The base may be added all at once or in portions.

In some embodiments, in the reaction of step 6), the amount of ZX02 used may be in the range of 0.9 to 1.2 molar equivalents, preferably in the range of 1.0 to 1.2 equivalents, relative to ZXSM 02.

In some embodiments, the reaction of step 6) may be carried out at a temperature of 10 to 120 ℃, preferably 50 to 100 ℃. In a preferred embodiment, the reaction of step 6) is carried out in a programmed temperature and base addition batch mode, for example by first stirring the reaction mixture to which most (e.g. 80-95 mol%) of the total base has been added at 20-40 ℃ for 10-60 minutes, then at 60-90 ℃ for a further 2-36 hours, and then at 60-90 ℃ for a further 0.5-2 hours after addition of the remaining small amount (e.g. 5-20 mol%) of base.

After the end of the reaction in step 6), the reaction mixture can be worked up by methods known per se. In one embodiment, the reaction mixture is added to water after cooling; and (3) performing suction filtration, dissolving the filter cake with dichloromethane, washing with water, concentrating to obtain a thick residue, then reheating the residue with acetonitrile, dissolving the residue clearly, cooling, performing suction filtration, and performing vacuum drying on the filter cake to obtain a crude product of the compound ZX-101. Recrystallizing the crude product of the compound ZX-101 twice by using acetonitrile, dissolving the obtained solid by using dichloromethane, slowly adding n-heptane into the dissolved solid, stirring, pulping the filtered solid by using isopropanol or acetonitrile, performing suction filtration, and drying to obtain a compound ZX-101, namely the chloropicrin.

In some embodiments, the methods of the invention have at least one of the following features:

-in step 1), the solvent used is ethanol and the reaction temperature is the reflux temperature;

-in step 2), the acetate used is an alkali metal acetate, the reaction solvent is acetic acid, and the reaction temperature is reflux temperature;

-in step 3), the solvents are isopropanol and water, after the heating reaction is completed, the filtration is carried out, the organic phase is concentrated to remove part of the isopropanol, the obtained product is transferred to a reaction kettle, water is added, the obtained product is pulped overnight and is filtered, the obtained filter cake is pulped with 95% ethanol, the obtained product is filtered, the obtained filter cake is pulped with ethanol and is filtered, and finally the obtained filter cake is air-dried to constant weight to obtain a compound ZXSM 01;

in the step 4), the solvent is tetrahydrofuran, the reducing agent is sodium borohydride, the mixture is added into a mixed solution composed of ice water and hydrochloric acid after the heating reaction is completed, the mixture is quenched, the tetrahydrofuran is removed by concentration, DCM is added for extraction twice, organic phases are combined, and the obtained organic phases are subjected to reduced pressure concentration and spin drying to obtain a compound ZX 01;

in the step 5), the solvent is tetrahydrofuran, the chlorinating agent is thionyl chloride, and after the reaction is completed, the reaction liquid is dried in a rotary mode to obtain a compound ZX 02;

-after the reaction in step 6) is completed, cooling the reaction solution, adding the reaction solution into water, performing suction filtration, dissolving and separating the solid by using dichloromethane, extracting, combining organic phases, concentrating the organic phases to a thick state, adding acetonitrile or isopropanol to dissolve, performing suction filtration, and performing vacuum drying on the solid to obtain a crude compound ZX-101; crystallizing the crude product of the compound ZX-101 by using acetonitrile or isopropanol once to twice to obtain a solid, adding dichloromethane, heating, dissolving, slowly adding n-heptane, stirring, carrying out suction filtration, drying a filter cake to obtain a solid, treating the solid obtained by drying the filter cake by using acetonitrile or isopropanol, and drying to obtain the compound ZX-101, namely the clobiplane.

In a specific embodiment, the method for preparing the PDE4 inhibitor clobiplane of the present invention comprises the steps of:

1) heating a raw material compound A1 and 3, 6-dichloropyridazine in ethanol to reflux reaction to obtain a compound A2;

2) mixing the prepared compound A2, acetate and acetic acid, stirring, heating to reflux reaction, pouring the reaction solution into water, stirring, filtering, leaching a filter cake with water, and drying to obtain a compound ZXSM 02;

3) adding 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, alkali and urea into a solution composed of isopropanol and water, replacing with nitrogen, adding a palladium catalyst, heating for reaction, performing suction filtration, concentrating an organic phase, removing isopropanol, concentrating, transferring to a reaction kettle, adding water, pulping overnight, performing suction filtration, adding 95% ethanol into a filter cake, pulping, filtering, pulping the filter cake with ethanol, filtering, and finally performing forced air drying on the filter cake to constant weight to obtain a compound ZXSM 01;

4) heating a compound ZXSM01, tetrahydrofuran and sodium borohydride for reaction, adding the mixture into a mixed solution consisting of water and hydrochloric acid for quenching after the reaction is completed, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and concentrating the obtained organic phases under reduced pressure and spin-drying the organic phases to obtain a compound ZX 01;

5) adding a compound ZX01, tetrahydrofuran and thionyl chloride into a three-necked bottle for reaction, and after the reaction is completed, carrying out spin drying on the reaction liquid to obtain a compound ZX 02;

6) adding a compound ZXSM02, an alkali and a solvent into a four-mouth bottle, stirring, performing nitrogen replacement for three times, adding a compound ZX02 under the protection of nitrogen, heating, supplementing the alkali, continuing to react for a certain time, cooling the reaction liquid, adding the reaction liquid into water, performing suction filtration, dissolving and separating the solid by using dichloromethane, extracting, combining organic phases, concentrating the organic phase to a thick state, adding isopropanol or acetonitrile crystal slurry, performing suction filtration, and performing vacuum drying on the solid to obtain a crude product of the compound ZX-101; adding dichloromethane into solid obtained by crystallizing a crude product of a compound ZX-101 twice by using isopropanol or acetonitrile, heating, dissolving, slowly adding n-heptane, stirring, performing suction filtration, drying a filter cake to obtain solid, adding the solid obtained by drying the filter cake into the isopropanol, pulping, performing suction filtration, and drying the filter cake to obtain qualified bulk drug ZX-101, namely the chlorobiplane, which refers to the following synthetic route:

in order to optimize the above embodiments, the specific measures that can be taken further include at least one of the following:

-in said step 2), said acetate salt is one of crystalline sodium acetate hydrate and potassium acetate hydrate;

in the step 2), after the reaction is finished, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02;

-in the above step 3), the reaction is carried out in a solution of isopropanol and water, wherein the mass ratio of isopropanol to water is 1: 0.1-10;

-in the step 3), the temperature of the heating medium is 50-100 ℃, after heating reaction is carried out for 7 hours, suction filtration is carried out, filtrate is separated, and an organic phase is concentrated; pulping the filter cake with water, 95% ethanol and ethanol, and air-drying at 25-85 deg.C for 23 hr to constant weight;

-in the above step 3), the palladium catalyst comprises one of palladium acetate, palladium chloride, 5% palladium-carbon, 10% palladium-carbon and tetrakis (triphenylphosphine) palladium in an amount of 0.1 to 80% by weight based on the weight of 3-bromo-4-methoxybenzaldehyde;

-the base used in the above step 3) is one of potassium carbonate, sodium hydroxide and potassium hydroxide, and is used in an amount of 1 to 5 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-in the above step 3), urea is used in an amount of 0-2 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-adding the compound ZXSM01, tetrahydrofuran and sodium borohydride in the step 4) into a single-neck bottle, heating and reacting for 1 hour at the temperature of the heating medium of 40-70 ℃, and stopping heating;

-in step 4) above, said sodium borohydride is used in an amount of 0.5 to 0.9 molar equivalents with respect to compound ZXSM 01;

in the step 4) above, the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZXSM 01;

-adding the compound ZX01, tetrahydrofuran and thionyl chloride in the step 5) into a three-neck flask for reaction at the temperature of 30-70 ℃ for 2-6 hours;

-in the above step 5), the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZX 01;

-in step 5) above, the completion of the reaction is checked by TLC;

-in the step 6) above, the solvent added into the four-mouth bottle is one of DMF, DMAC, NMP and DMSO, and the base added into the four-mouth bottle is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine; relative to ZXSM02, the addition amount of the alkali is in the range of 0.5-2.0 equivalent, the dosage of ZX02 is 1.0-1.2 equivalent, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02; displacing with nitrogen for three times, stirring at 30-40 ℃ for 30 minutes, adding ZX02 under the protection of nitrogen, stirring at the temperature for 30 minutes, heating to 60-90 ℃, stirring for 23 hours, adding 0.01-0.5 equivalent of alkali relative to ZXSM02, wherein the alkali is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine, and stirring at 60-90 ℃ for 1 hour;

after the reaction in the step 6) is finished, slowly cooling the reaction solution to room temperature, then slowly dripping the reaction solution into water, and filtering to obtain a crude ZX-101 product; dissolving a crude product of a compound ZX-101 by using dichloromethane, washing by using water, concentrating to be dry, adding the mixture into acetonitrile, heating to dissolve the mixture clearly, stirring for 1 hour, cooling to 0-25 ℃, separating out a solid, carrying out suction filtration, and drying a filter cake in vacuum to obtain the solid; and adding the solid obtained by vacuum drying into acetonitrile, heating for dissolving, stirring overnight, cooling, performing suction filtration, heating and dissolving the filter cake with acetonitrile again, cooling, and performing suction filtration to obtain a solid after twice crystallization. Dissolving the solid with dichloromethane, heating to dissolve, slowly adding n-heptane into the solution, stirring overnight, vacuum filtering to obtain solid, pulping with acetonitrile, and vacuum filtering to obtain ZX-101, i.e. chloropicrin.

In a more specific embodiment, the method of the invention comprises the steps of:

2) the obtained compound A2 and MOAc & nH₂O, e.g. NaOAc.3H₂Mixing and stirring O and acetic acid, heating to reflux reaction, pouring the reaction solution into water after the reaction is finished, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02;

3) adding 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, potassium carbonate and urea into a solution consisting of isopropanol and water, wherein the mass ratio of the isopropanol to the water in the solution is 1:0.1-10, and the optimal mass ratio is 1: 1; replacing nitrogen, adding a palladium catalyst accounting for 0.1-80 wt% of the mass of the 3-bromo-4-methoxybenzaldehyde, heating and reacting at a heating medium temperature of 50-100 ℃ for 7 hours (the optimal heating medium temperature is 68 ℃), then carrying out suction filtration, separating filtrate, concentrating an organic phase to remove isopropanol, transferring a concentrated residue to a reaction kettle, adding water, pulping overnight, carrying out suction filtration, adding 95% ethanol into a filter cake, pulping, filtering, pulping the filter cake with ethanol, filtering, and finally carrying out forced air drying on the filter cake at a temperature of 25-85 ℃ (the optimal temperature is 35 ℃) for 23 hours to constant weight to obtain a compound ZXSM 01; the palladium catalyst comprises one of palladium acetate, palladium chloride, 5 percent of palladium-carbon, 10 percent of palladium-carbon and tetrakis (triphenylphosphine) palladium;

4) adding a compound ZXSM01, tetrahydrofuran and sodium borohydride into a single-mouth bottle, heating and reacting for 1 hour under the condition that the temperature of a heating medium is 40-70 ℃ (optimally 55 ℃), stopping heating, after the reaction is completed, adding a reaction mixture into a mixed solution consisting of water and concentrated hydrochloric acid for quenching, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and concentrating the obtained organic phases under reduced pressure and spin-drying to obtain a compound ZX 01; wherein: the dosage of the sodium borohydride is 0.5 to 0.9 equivalent relative to ZXSM01, and the dosage of the tetrahydrofuran is 2.6 to 6.2 times of the mass of ZXSM 01;

5) adding a compound ZX01, tetrahydrofuran and thionyl chloride into a three-necked bottle for reaction at the temperature of 30-70 ℃ for 2-6 hours, wherein the using amount of the tetrahydrofuran is 2.6-6.2 times of the mass of ZX01, and after TLC detection reaction is completed, carrying out spin drying on reaction liquid to obtain a compound ZX 02;

6) adding to a four-necked flask compound ZXSM02, ZX02, a base and a solvent, wherein: the solvent is one of DMF, DMAC, NMP and DMSO, or a mixture of the solvents and tetrahydrofuran; the alkali is one of potassium carbonate, cesium carbonate, triethylamine and pyridine; adding ZXSM02, alkali and a solvent, stirring, replacing with nitrogen for three times, stirring for 30 minutes at 30-40 ℃, adding ZX02 under the protection of nitrogen, stirring for 30 minutes at the temperature, heating to 60-90 ℃, stirring for 23 hours, adding a trace amount of the added same alkali, stirring for 1 hour at 60-90 ℃, slowly cooling the reaction liquid to room temperature, slowly dripping the reaction liquid into water, performing suction filtration, dissolving and separating the solid with dichloromethane, extracting, combining organic phases, concentrating the organic phases to be thick, adding acetonitrile, heating to dissolve, cooling, performing suction filtration, and drying the obtained solid in vacuum to obtain a crude compound ZX-101; and (2) crystallizing the crude product of the compound ZX-101 twice by using acetonitrile to obtain a solid, adding dichloromethane, heating, dissolving, adding n-heptane, stirring, carrying out suction filtration, drying a filter cake to obtain a solid, adding the solid obtained by drying the filter cake into the acetonitrile, pulping, carrying out suction filtration, and drying the filter cake to obtain the compound ZX-101, namely the chloropicrin.

And the two times of crystallization are that the crude product of the compound ZX-101 is added into acetonitrile, heated to dissolve out, stirred for 1 hour, cooled to 13 ℃, solid is separated out, stirred overnight, filtered, filter cake is dried in vacuum to obtain solid, the solid obtained by vacuum drying is added into acetonitrile, heated to dissolve out, stirred overnight, cooled, filtered and dried to obtain solid after two times of crystallization.

Compared with the prior art, the preparation method specifically comprises 6 synthesis steps, namely the synthesis of A2, the synthesis of ZXSM02, the synthesis of ZXSM01, the synthesis of ZX01, the synthesis of ZX02 and the synthesis of ZX-101. The intermediate ZXSM01 obtained by coupling is solid, and the ideal solid is obtained by pulping with water, 95% and ethanol in sequence, so that the quality control is facilitated. And the product is directly used for the next step after reduction and chlorination without column chromatography purification, so the method is simple and convenient to operate and is more suitable for realizing industrial production.

In another aspect, the present invention relates to multiple crystalline forms of clobiplane and the preparation of said polymorphs, interconversion between polymorphs, and their stability.

Through a large amount of researches, the inventor discovers four crystal forms of the topiramate, namely Form A, Form 1, Form2 and amorphous Form, and determines the conversion conditions and the preparation method among the four crystal forms. Four crystal forms are characterized, including XPRD, DSC, TGA and DVS.

Thus, in a sub-aspect of this aspect, the present invention provides a Form a crystal Form of topiramate. The Form A crystal Form has diffraction peaks at 4.258 +/-0.2, 13.220 +/-0.2, 14.460 +/-0.2, 15.642 +/-0.2, 16.442 +/-0.2, 18.442 +/-0.2, 19.762 +/-0.2 and 21.461 +/-0.2 in an X-ray powder diffraction (XRPD) pattern measured by Cu-Kalpha radiation.

The Form A crystal melting point is about 110 + -2 deg.C as determined by DSC.

The Form a crystal Form (as an anhydrate) has a decomposition temperature of about 319 ± 2 ℃ as determined by TGA.

The DVS/isothermal adsorption curve for Form a crystal Form shows less than 0.1% weight change over the range of 0% RH to 80% RH, no moisture absorption.

In a sub-aspect of this aspect, the invention provides amorphous form of clobiplane.

Hot-table XRPD analysis showed that a small number of Form a diffraction peaks appeared on the amorphous warm-up to 90 ℃.

DSC in combination with hot-table XRPD showed that the amorphous sample recrystallized to Form a during the temperature rise, after which the Form a melting point appeared, about 107 ℃.

TGA analysis showed that the amorphous sample had a slow surface weight loss of about 2.5% before 120 ℃ and a decomposition temperature of about 317 ℃.

In a sub-aspect of this aspect, the present invention provides a Form 1 crystal Form of clobiplane. The Form 1 crystal Form has diffraction peaks expressed in degrees 2 theta at 7.901 +/-0.2, 11.844 +/-0.2, 12.381 +/-0.2, 15.841 +/-0.2, 18.565 +/-0.2 and 26.203 +/-0.2 in an XRPD pattern measured by Cu-Kalpha radiation.

DSC analysis shows that Form 1 crystal Form has 2 continuous dehydration endothermic peaks before 100 ℃, and the melting point is about 104 +/-2 ℃.

TGA analysis shows that about 3.5% of step weight loss exists between 27 and 40 ℃ in Form 1 crystal Form, about 1 water molecule is included, about 3.4% of step weight loss exists between 40 and 70 ℃, about 1 water molecule is included (theoretical proportion of one water molecule in dihydrate is 3.4%), and decomposition temperature is about 322 +/-2 ℃.

In a sub-aspect of this aspect, the present invention provides a Form2 crystal Form of topiramate. The Form2 crystal Form has diffraction peaks at 4.239 +/-0.2, 8.434 +/-0.2, 12.637 +/-0.2, 13.860 +/-0.2, 16.861 +/-0.2, 18.484 +/-0.2, 21.703 +/-0.2 and 26.645 +/-0.2 in an XRPD pattern measured by Cu-Kalpha radiation.

DSC analysis shows that the Form2 crystal Form has a wide dehydration endothermic peak between 50 and 100 ℃ and a melting point of about 110 +/-2 ℃.

TGA analysis showed that the Form2 sample had a step weight loss of about 3.6% before 90 ℃, about 1 water molecule (theoretical weight proportion of one water in monohydrate 3.5%) and a decomposition temperature of about 319 ± 2 ℃.

The DVS/isothermal adsorption curve for the Form2 crystal Form shows a weight change of 2.6% at an increase from 40% RH to 80% RH, suspected of forming dihydrate; the weight change from 80% RH to 0% RH was 3.0% and the dihydrate was changed back to the monohydrate.

The inventors have determined that there is a conversion relationship between Form a, Form 1, Form2, amorphous as shown in fig. 28.

For example, it has been found that:

the Form A and Form2 samples were mixed well and slurried in a mixed solvent of n-heptane and ethyl acetate for 6h at room temperature to give Form A.

The term "magma" as used in this disclosure means a supersaturated solution of a sample (with undissolved solids present) in a solvent, stirred for a period of time, then filtered, air dried, and the resulting solid polymorph determined. For example, "6 h" of a crystal slurry means that a supersaturated solution of a sample is placed in a solvent for 6 hours, and then filtered and dried to obtain a solid.

The Form A and Form2 samples are mixed evenly and added into water to Form a suspension, and the Form 1 is obtained after crystal mush in water for 22h at room temperature.

Form A is not changed in the conditions of 80 ℃ (drying, opening and keeping out of the light) for 24h and 40-75% RH (opening and keeping out of the light) for 10 days.

-adding the Form a sample to methanol, trifluoroethanol, acetone, ethanol/water, acetone/water, methanol/ethyl acetate, tetrahydrofuran/water, respectively, dissolving, filtering, and naturally evaporating at room temperature to obtain Form 1.

-adding the Form a sample to ethanol, nitromethane, diethyl ether, ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, methanol/water, nitromethane/acetonitrile, acetone/isopropyl acetate/n-heptane, diethyl ether/dichloromethane, ethyl acetate/methyl tert-butyl ether, acetonitrile/chloroform, respectively, dissolving, filtering, and naturally evaporating to dryness at room temperature to obtain Form a.

The Form A sample is added into butanone and acetonitrile respectively, dissolved, filtered and naturally evaporated at room temperature to obtain a mixture of Form 1 and Form A.

And (3) adding a sample of Form A into n-propanol, isopropanol, n-propanol, sec-butanol, methyl tert-butyl ether, isopropyl acetate, 1, 4-dioxane/water and dimethyl sulfoxide respectively for dissolving, filtering, and volatilizing at 40 ℃ to obtain Form A.

Samples of Form A were added to DMF, toluene, trifluoroethanol/water/ethyl acetate, butanone/toluene, n-propanol/isopropyl ether, DMF/water, ethanol/methylcyclohexane, respectively, and evaporated to dryness at 40 ℃ to give amorphous Form.

Samples of Form A, each added to acetonitrile/water and evaporated to dryness at 40 ℃ to give Form 2.

-Form a sample, adding to water to Form a suspension, stirring at room temperature for 5 days, centrifuging the suspension, and air drying to obtain Form 1.

And (3) adding a sample of Form A into methyl tert-butyl ether and n-heptane respectively to Form a suspension, stirring for 5 days at room temperature, centrifuging the suspension, and airing to obtain the Form A.

And (3) adding samples of Form A into water respectively to Form suspension, stirring for 5 days at 40 ℃, centrifuging the suspension, and airing to obtain Form 1.

And (3) adding a sample of Form A into isopropyl ether and methylcyclohexane respectively to Form a suspension, stirring for 5 days at 40 ℃, centrifuging the suspension, and airing to obtain the Form A.

And (3) adding a Form A sample into methanol/water and acetonitrile/isopropyl ether respectively to Form a suspension, stirring at room temperature for 5 days, centrifuging the suspension, and airing to obtain the Form A.

And (3) adding a sample of Form A into ethanol/water, acetone/water, saturated water of ethyl acetate and DMF/water respectively to obtain a suspension, stirring for 5 days at room temperature, centrifuging the suspension, and drying to obtain Form 1.

The sample of Form A was added to trifluoroethanol/water, tetrahydrofuran/water, and diethyl ether/n-heptane, respectively, to obtain a suspension, which was stirred at 4 ℃ for 5 days to obtain Form 1.

And (3) respectively adding the sample of the Form A into 1, 4-dioxane/water, acetonitrile/water and isopropanol/water to obtain suspension, and stirring for 5 days at 40 ℃ to obtain the Form 1 crystal Form.

And (3) respectively adding the sample of Form A into butanone/ethyl acetate/n-heptane and sec-butyl alcohol/methylcyclohexane to obtain suspension, stirring for 5 days at 40 ℃, centrifuging the suspension, and airing to obtain the Form A crystal Form.

Adding the amorphous sample into water, acetonitrile/water and ethanol/water respectively, stirring for 10-15min at room temperature, taking a suspension, centrifuging, and drying to obtain a Form 1 crystal Form solid.

Adding the amorphous sample into methyl tert-butyl ether, acetone/isopropyl ether, ethyl acetate/n-heptane, tetrahydrofuran/diethyl ether/methylcyclohexane and toluene/n-heptane respectively, stirring at room temperature for 10-15min, taking suspension, centrifuging, and airing to obtain Form A crystal Form solid.

Adding the amorphous sample into DMF/water, stirring for a period of time at room temperature, taking the suspension, centrifuging, and airing to obtain Form A and Form 1 mixed crystal Form solid.

Taking a Form a sample, adding the Form a sample into a solvent 1 to dissolve the Form a clear solution, filtering, adding a solvent 2 under stirring (forward addition), or adding a clear solution of the solvent 1 dissolved with the Form a sample into the solvent 2 (reverse addition), separating out a solid, stirring for 3min, and then sampling for XRPD characterization, wherein the specific results are as follows:

taking a Form A sample, adding the Form A sample into a corresponding solvent, heating to 60 ℃ for dissolving, filtering, cooling, stirring, separating out a solid, centrifuging, sampling for XRPD detection, stirring at 4 ℃ for overnight without separating out the solid, and sampling for XRPD detection after separating out the solid, wherein the results are shown in the following table.

Taking an amorphous sample and placing the amorphous sample in a centrifuge tube, then placing the amorphous sample in a solvent atmosphere of a corresponding solvent for standing for 4 days, and taking a solid sample for XRPD characterization, wherein the experimental results are shown in the following table.

Solvent(s)	Analysis of results
		Trifluoroethanol	Solutions of
Water (W)	Form A+Form 1
		Acetone (II)	Form A
Ethyl acetate	Form A
		Tetrahydrofuran (THF)	Solutions of
Acetonitrile	Form A
		Chloroform	Solutions of

And (3) transferring the clear liquid obtained by the experiment to a corresponding solvent atmosphere for standing, directly taking the solid after the solid is separated out for XRPD characterization, wherein the specific experiment and result are as follows:

solvent 1	Solvent 2	Results
			Trifluoroethanol	Isopropyl ether	Form A
Tetrahydrofuran (THF)	N-heptane	Form A+Form 1
			Chloroform	N-heptane	Form A

Amorphous samples were taken and placed in an environment of room temperature-97% RH, 25-60% RH, 40-75% RH for different time to characterize the solids, with the experimental results as given in the table below.

These results demonstrate that the four crystalline forms, Form a, Form 1, Form2, amorphous, can be interconverted. The results also indicate that Form A is an anhydride, Form 1 is a monohydrate, and Form2 is a dihydrate.

Examples

The following examples further illustrate the present invention and are not intended to limit the scope of the present invention.

In the following examples, the instrument information and detection methods used were as follows:

instrument information and detection method parameters

Example 1:

the PDE4 inhibitor clobiplane was prepared according to the following synthetic route:

the preparation method specifically comprises 6 synthesis steps, namely the synthesis of A2, the synthesis of ZXSM02, the synthesis of ZXSM01, the synthesis of ZX01, the synthesis of ZX02 and the synthesis of ZX-101. Wherein:

synthesis of a 2:

31.2g of the compound A1 and 28.2g of the compound 3, 6-dichloropyridazine were added into ethanol, the mixture was heated to reflux, the reaction was monitored by TLC, after the reaction was completed, the mixture was concentrated under reduced pressure to dryness to obtain a crude product, and the ethanol was crystallized to obtain a yellow solid compound A2 with a yield of 84.3%.

Synthesis of ZXSM 02:

compound A21528 g, NaOAc.3H₂O1490 g and acetic acid 4.584L were added to a 10L four-necked flask, and the mixture was stirred and heated to reflux for about 26 hours, and the reaction mixture was poured into 45L of water (about 45 minutes was completed), stirred for 1.5 hours, filtered, and the filter cake was washed with water and vacuum-dried to obtain compound ZXSM 021216.2 g.

ESI-MS:m/z 284.1002(M+Na)⁺；¹H NMR(400MHz,CDCl₃)δ3.44(q,2H), 3.73(s，3H),4.07(t,2H),6.55(t,1H),6.70(d,1H),6.85-7.00 (m,4H),7.04(d,1H),11.76(s,1H)。

Synthesis of ZXSM 01:

the method comprises the following steps: adding 5Kg of 3-bromo-4-methoxybenzaldehyde, 4.37Kg of m-chlorobenzoic acid, 9.64Kg of potassium carbonate and 41.93g of urea into isopropanol: the mixture was stirred into 55L of a water (1:1) solution. And (4) replacing with nitrogen. 156g of palladium acetate was added to the reaction mixture, and the reaction was heated at an oil bath temperature of 68. + -. 2 ℃ for 7 hours. And (3) post-treatment: the reaction mixture was filtered with suction, the filtrate was separated, the organic phase was concentrated, and 10L of isopropanol was removed. After the concentration is finished, the obtained mixture is transferred to a 100L reaction kettle, 10L of water is added, pulping is carried out at 20 ℃ overnight, and suction filtration is carried out, so as to obtain 6.45kg of filter cake. Taking 300g of filter cake, adding 250mL of ethanol (95%), pulping for 5 minutes, filtering the filter cake with 250mL of ethanol, and drying the filter cake by air blow at 35 ℃ for about 23 hours to obtain 86.5g of a compound ZXSM01186.

The method 2 comprises the following steps: adding 10.00g of 3-bromo-4-methoxybenzaldehyde, 8.70g of m-chlorobenzoic acid, 3.0g of palladium-carbon, 19.30g of potassium carbonate, 50mL of isopropanol and 50mL of water into a 250mL single-neck bottle, heating and reacting at 68 +/-2 ℃ in an oil bath after nitrogen replacement for 16h, filtering the reaction liquid, concentrating under reduced pressure, removing 20mL of isopropanol, adding 20mL of water into the residual liquid, pulping at 20 ℃ overnight, carrying out suction filtration, pulping the solid with petroleum ether, pulping at 95% and carrying out suction filtration, and drying the obtained solid at 35 ℃ in vacuum to constant weight to obtain 8.53 g.

ESI-MS:m/z 269.0339(M+Na)⁺；¹H NMR(400MHz,CDCl₃)δ3.91(s, 3H),7.09(d,1H),7.31～7.41(m,3H),7.52(s,1H),7.82(d,1H), 7.88(dd,1H),9.93(s,1H)。

Synthesis of ZX 01:

adding ZXSM 0180 g and THF 400mL (tetrahydrofuran) in a 1L single-neck bottle in sequence, stirring, and adding NaBH₄6.13g, the reaction was heated at a heating medium temperature of 55 ℃ for 1 hour. Heating was stopped and HPLC showed the reaction was complete. The reaction mixture was quenched by adding 300mL of a mixed solution of water and 1.5mL of concentrated hydrochloric acid, stirred, concentrated to remove THF, extracted twice with DCM (100 mL. times.2) as an organic solvent, the organic phases were combined, and the resulting organic phase was concentrated to dryness under reduced pressure to give ZX0167.1g of the compound.

ESI-MS:m/z 271.0496(M+Na)⁺；¹H NMR(400MHz,CDCl₃)δ3.77(s, 3H),4.47(s,2H),5.14(br,s,1H)，7.09(d,1H)，7.26(d,1H)， 7.32(dd,1H)，7.37-7.45(m,3H)，7.51(s,1H)。

Synthesis of ZX 02:

a500 mL three-necked flask was charged with ZX 0143 g and tetrahydrofuran 215mL, stirred, and added with SOCl₂24.7g (thionyl chloride) for 1 hour, and TLC had reacted to completion. The reaction solution was spin-dried to obtain ZX0246.0 g.

¹H NMR(400MHz,CDCl₃)δ3.793(s,3H)，4.776(s,2H)，7.134(d, 1H)，7.402-7.415(m,1H)，7.428-7.469(m,4H)，7.513(s,1H)。

Synthesis of ZX-101:

the method comprises the following steps: A1L four-necked flask was charged with compound ZXSM0288.8 g, cesium carbonate 132.9g, and DMAC 266mL, stirred, purged with nitrogen three times, and stirred at 30-40 ℃ for 30 minutes. Under nitrogen, compound ZX 02109 g was added and stirred at this temperature for 30 minutes. Then, the temperature was raised to 80 ℃ and the mixture was stirred for 23 hours, and 44.3g of cesium carbonate was added thereto and the mixture was stirred at 80 ℃ for 1 hour. The reaction mixture was slowly cooled to room temperature, then slowly added dropwise to 1.76L of water, filtered, the solid was dissolved with 880mL of dichloromethane until no solid was present, the solution was separated, the aqueous phase was extracted with dichloromethane (440 mL. times.2), the organic phases were combined and washed once with 440mL of water. Concentrating the organic phase to thick, adding 880 acetonitrile, heating to 50-60 deg.C to make the product completely dissolve, cooling to 10 deg.C, vacuum-filtering, and vacuum-drying the solid overnight to obtain 60.0g of crude ZX-101 compound. 48g of crude ZX-101 was added to 480mL of acetonitrile, heated to dissolve the mixture, and stirred for 1 hour. Cooling to 13 ℃, separating out solid, stirring overnight, filtering, and drying the filter cake in vacuum to obtain 42g of solid. And recrystallizing the solid once again by using acetonitrile, namely adding the solid into 420mL of acetonitrile, heating to dissolve the solid, stirring the mixture overnight, cooling, performing suction filtration, and drying a filter cake to obtain 35.4g of solid. Adding the solid into 35.4mL of dichloromethane, heating to dissolve the solid, slowly adding 354mL of n-heptane, stirring overnight, performing suction filtration, adding the solid into 5 volumes of acetonitrile, pulping for 1.5 hours, performing suction filtration, and drying a filter cake to obtain 27.5g of a compound ZX-101, namely the clobiplane.

HRMS:m/z 514.1501(M+Na)⁺，¹H NMR(400MHz，DMSO-d₆)δ3.46(q， 2H)，3.73(s，3H)，3.74(s，3H)，4.04(t，2H)，5.03(s，2H)，6.74 (t，1H)，6.77(d，1H)，6.89(m，4H)，7.02(d，1H)，7.04(d，1H)， 7.31(m，1H)，7.32(m，1H)，7.39(m，3H)，7，46(m，1H)。

The method 2 comprises the following steps: 8.42kg of DMAC, 3.74kg of ZXSM023 and 3.42 kg of potassium carbonate were added into a 30L reaction kettle and stirred for 30 minutes at the temperature of 30-40 ℃. ZX024.36kg was dissolved in DMAC 3.65 kg. Under the protection of nitrogen, stirring and dropwise adding DMAC solution of ZX02 into a 30L reaction kettle, heating to 90-100 ℃ after adding, reacting for 5 hours, and cooling to 30-40 ℃. Slowly dripping the reaction liquid into 130kg of water, carrying out suction filtration, rinsing the filter cake with purified water, dissolving the obtained filter cake with 57kg of dichloromethane until no solid exists, separating liquid, washing with water, concentrating the dichloromethane layer until the dichloromethane layer is dry, adding 63.5kg of acetonitrile, heating to 60-70 ℃, adding 1.3kg of activated carbon after dissolving, stirring for 1 hour at 60-70 ℃, filtering while hot, cooling to 0-10 ℃, then continuously stirring for 5 hours, carrying out suction filtration, rinsing the filter cake with cold acetonitrile, filtering, and carrying out vacuum drying to obtain 4.02 kg of ZX-101, namely chlorine ratio planum, wherein the HPLC purity is 98.77%, and the figure 24 shows.

Taking 5g of the prepared ZX-101, adding 50mL, heating to 70 ℃ under stirring, filtering while the solid is clear, rinsing the filter device with 3.7mL of isopropanol, combining the filtrates, slowly cooling the filtrate to room temperature under stirring, performing suction filtration, rinsing with a small amount of cold isopropanol, and performing vacuum drying at 40 ℃ to obtain 3.763 g, wherein the HPLC purity is 99.58%, as shown in figure 25. The crystal form is a crystal form A (form A) identified by XRPD. XRPD is shown in FIG. 27.

The method 3 comprises the following steps: A1L four-necked flask was charged with compound ZXSM0288.8 g, cesium carbonate 177.0g, and DMAC 266mL, stirred, purged with nitrogen three times, and stirred at 30-40 ℃ for 30 minutes. Under nitrogen, compound ZX 02109 g was added and stirred at this temperature for 30 minutes. Then the temperature was raised to 80 ℃ and stirred for 22 hours. The reaction mixture was slowly cooled to room temperature, then slowly added dropwise to 1.76L of water, filtered, the solid was dissolved with 880mL of dichloromethane until no solid was present, the solution was separated, the aqueous phase was extracted with dichloromethane (440 mL. times.2), the organic phases were combined and washed once with 440mL of water. Concentrating the organic phase to thick, adding 800 isopropanol, heating to 60-70 deg.C to completely dissolve the product, cooling to 10 deg.C, vacuum filtering, and vacuum drying the solid overnight to obtain 65.0g crude ZX-101. 48g of crude ZX-101 was added to 400mL of isopropanol, heated to dissolve the supernatant, and stirred for 1 hour. And cooling to 10 ℃, separating out solid, stirring overnight, performing suction filtration, and performing vacuum drying on a filter cake to obtain 43g of solid. Recrystallizing the solid with isopropanol, adding into 450mL isopropanol, heating to dissolve, stirring overnight, cooling to 15 deg.C, vacuum filtering, and drying the filter cake to obtain 36.45g solid, i.e. Chlorobipran, with HPLC purity of 99.88%, as shown in FIG. 26.

Form A characterization results overview

The XRPD pattern for Form A is shown in FIG. 1. The major diffraction peaks of the XRPD pattern of Form a are summarized in the table below.

Form A XRPD peak List

The DSC spectrum of Form A is shown in FIG. 2. The TGA profile for Form A is shown in FIG. 3. The DVS map for Form A is shown in FIG. 4. The isothermal adsorption curve for Form A is shown in FIG. 5.

As shown in the examples below, the Form2 Form is partially converted to Form A after standing for 3 days under room temperature open drying conditions.

Example 2 amorphous preparation

A400 mg sample of Form A from example 1 was dissolved in 2.0mL of dichloromethane, washed off, filtered and the filtrate was concentrated to dryness at 40 ℃ under reduced pressure to give amorphous Form.

The amorphous form has a crystal transformation phenomenon after being placed for 3 days at room temperature of-97% RH, 25-60% RH and 40-75% RH, which indicates that the amorphous form is unstable under 3 conditions, and the following table shows.

Results of amorphous placing experiment under different temperature and humidity

An amorphous stable resting XRPD pattern is shown in fig. 6.

The amorphous characterization results are summarized below:

result of amorphous characterization

The amorphous XRPD pattern is shown in figure 7. An amorphous hot-table XRPD pattern is shown in fig. 8. The amorphous DSC profile is shown in figure 9. An amorphous TGA profile is shown in figure 10.

Example 3 preparation of Form 1

Experiment 1: adding 100mg of Form A crystal Form sample into 2.5mL of tetrahydrofuran and 10mL of water, carrying out crystal slurry on the obtained mixture at 4 ℃ for 3 days, then carrying out vacuum filtration, and airing the filter cake to obtain the Form 1 crystal Form.

Experiment 2: taking a Form A crystal Form sample of 10mg, adding 1.0mL of ethanol and 0.2mL of water, and volatilizing to dryness at room temperature to obtain a Form 1 crystal Form.

Experiment 3: taking a Form A crystal Form sample of 15mg, adding 0.7mL of acetone and 0.8mL of water, heating the obtained mixture to 60 ℃, dissolving and filtering, placing the filtrate in a salt bath, stirring, and separating out a solid. And centrifuging and drying the mixture to obtain Form 1 crystal Form.

Experiment 4: taking an amorphous sample 15mg, adding 2mL of water, carrying out crystal mush at room temperature for 10-15 minutes, centrifuging, and airing to obtain a Form 1 crystal Form.

The XRPD pattern of Form 1 is shown in fig. 11, and the major diffraction peaks are shown in the table below.

Form 1 XRPD peak List

The DSC profile of Form 1 is shown in FIG. 12. The TGA profile for Form 1 is shown in FIG. 13.

Form 1 crystal Form characterization results are summarized below.

Form 1 crystal Form characterization result

Example 5 preparation of Form2

Experiment 1: taking a Form A crystal Form sample of 50mg, adding 5mL of tetrahydrofuran and 1mL of water, carrying out ultrasonic clearing, filtering, and volatilizing the filtrate at room temperature to dryness to obtain the Form 1 crystal Form. The Form 1 crystal Form is dried for 24 hours in vacuum at room temperature to obtain the Form2 crystal Form.

Experiment 2: taking a Form A crystal Form sample of 10mg, adding 1.0mL of acetonitrile and 0.4mL of water, ultrasonically dissolving, filtering, and volatilizing the filtrate at 40 ℃ until the filtrate is dry to obtain a Form2 crystal Form.

Form2 crystal Form characterization results are summarized below.

Form2 crystal Form characterization result

The XRPD pattern of Form2 Form is shown in fig. 14, and the main diffraction peaks are shown in the table below.

Form2 XRPD peak List

The DSC profile of Form2 is shown in FIG. 15. The TGA profile for Form2 is shown in FIG. 16. The DVS map for Form2 is shown in FIG. 17. The isothermal adsorption pattern of Form2 is shown in fig. 18.

Example 5 competitive assay 1

A10 mg Form A and 10mg Form2 sample was taken, mixed well and sampled for XRPD detection and the spectrum is shown in FIG. 19.

Then, 1mL of n-heptane and 1mL of ethyl acetate were added to the combined sample to form a suspension, which was then slurried at room temperature for 6h, centrifuged, air dried, and subjected to XRPD detection, and the spectrum is shown in FIG. 20.

Example 6 competitive experiment 2

Equal amounts of Form 1 and Form2 were sampled, mixed well, sampled for XRPD detection and the spectra are shown in fig. 21.

Then, 2mL of water was added to the mixed sample to form a suspension, which was then slurried at room temperature, centrifuged at various time points, air dried, and subjected to XRPD detection, and the spectrum is shown in fig. 22.

Example 7 Form A stability test

The Form A of the chloropicrin is stored for 24 hours under the condition of 80 ℃ (drying, opening and keeping out of the light), and is stored for 10 days under the condition of 40-75% RH (opening and keeping out of the light). As the results in fig. 23 show, none of the crystalline forms were changed.

Example 8 volatilization at Room temperature experiment

And (3) taking a sample of 5-10 mg of the chloropicrin Form A, adding the sample into a corresponding solvent, dissolving, filtering, naturally volatilizing at room temperature, and carrying out XRPD characterization on the obtained solid, wherein specific experimental results are shown in the following table.

Results of volatilization experiments at room temperature

Example 9 high temperature volatilization experiment

Taking a sample of 5-10 mg of the Clibypren Form A, adding the sample into a corresponding solvent, dissolving the sample clearly, filtering the solution, volatilizing the solution to be dry at 40 ℃, and carrying out XRPD characterization on the obtained solid, wherein specific experimental results are shown in the following table.

High temperature volatilization test results

Solvent 1	Solvent 2	Solvent 1/solvent 2(mL)	Analysis of results
				Isopropanol (I-propanol)	-	0.4	Form A
N-propanol	-	0.4	Form A
				Sec-butyl alcohol	-	0.4	Form A
N-butanol	-	0.4	Form A
				DMF	-	0.1	Amorphous form
Methyl tert-butyl ether	-	5.0	Form A
				Acetic acid isopropyl ester	-	1.0	Form A
1, 4-dioxane	-	0.1	Form A
				Toluene	-	0.2	Amorphous form
Dimethyl sulfoxide	-	0.1	Form A
				Ethanol	Methylcyclohexane	1.0/0.5	Amorphous form
Trifluoroethanol	Water/Ethyl acetate	0.4/0.4/0.2	Amorphous form
				Butanone	Toluene	0.6/0.4	Amorphous form
1, 4-dioxane	Water (W)	0.6/0.4	Form A
				Acetonitrile	Water (W)	1.0/0.4	Form 2
N-propanol	Isopropyl ether	0.5/1.0	Amorphous form
				DMF	Water (W)	0.3/0.1	Amorphous form

Example 10 Single solvent Room temperature Crystal syrup experiment

Taking a sample of 5-10 mg of the Clibopram Form A, adding a corresponding solvent to obtain a suspension, stirring at room temperature for 5 days, centrifuging the suspension, drying in the air, and performing XRPD characterization on the solid, wherein the result is as follows:

experimental results of single solvent room temperature crystal slurry

Solvent(s)	Amount of solvent used (mL)	Analysis of results
			Water (W)	2.0	Form 1
Methyl tert-butyl ether	1.0	Form A
			N-heptane	2.0	Form A

Example 11 Single solvent high temperature magma experiment

Taking a 10-15 mg sample of the Clibop Form A, adding a corresponding solvent to obtain a suspension, stirring for 5 days at 40 ℃, removing the suspension, centrifuging, drying, taking the solid, and performing XRPD characterization, wherein the result is as follows:

experimental results of single solvent high-temperature crystal slurry

Solvent(s)	Amount of solvent used (mL)	Analysis of results
			Water (W)	2.0	Form 1
Isopropyl ether	2.0	Form A
			Methylcyclohexane	2.0	Form A

Example 12 Mixed solvent Crystal syrup experiment

Taking a sample of the Clibop Form A, adding a corresponding mixed solvent to obtain a suspension, stirring at room temperature for 5 days, centrifuging the suspension, drying in the air, and taking the solid for XRPD characterization, wherein the result is as follows:

mixed solvent room temperature crystal slurry experimental result

Example 13 amorphous Crystal syrup experiment

Taking about 15mg of amorphous sample, adding a corresponding solvent, stirring for 10-15 minutes at room temperature, taking the suspension for centrifugation, airing, taking the solid for XRPD characterization, and obtaining the following results:

results of amorphous slurry experiments

Example 14 anti-solvent test

Adding a Form A sample into a solvent 1 to dissolve clear, filtering, adding a solvent 2 under stirring (positive addition), or adding a clear solution of the solvent 1 dissolved with the Form A sample into the solvent 2 (negative addition), stirring for 3 minutes after solid is separated out, and sampling for XRPD characterization, wherein the specific results are as follows:

results of anti-solvent experiments

Example 15 Cooling crystallization experiment

Taking a Form A sample of 15mg, adding the Form A sample into a corresponding solvent, heating to 60 ℃ for dissolving, filtering, placing in a cold salt bath for stirring, immediately taking out the solid after solid precipitation, sampling for XRPD detection, stirring at 4 ℃ overnight without precipitating the solid, sampling again after precipitating the solid for XRPD detection, and obtaining the specific experiments and results shown in the following table.

Cooling crystallization experimental results

Example 16 gas-solid diffusion experiment

10mg of amorphous sample is placed in a centrifuge tube, then the centrifuge tube is opened and placed in the solvent atmosphere of the corresponding solvent for standing for 4 days, and then the solid sample is taken for XRPD characterization, and the experimental results are shown in the following table.

Results of amorphous gas-solid diffusion experiments

Example 17 gas-liquid diffusion experiment

Taking a sample dissolved and clear in gas-solid diffusion, transferring the sample to a corresponding solvent atmosphere, standing, directly taking a solid sample after solid is separated out, and carrying out XRPD characterization on the solid sample, wherein the experimental results are shown in the following table.

Experimental results of gas-liquid diffusion

Solvent 1	Solvent 2	Analysis of results
			Trifluoroethanol	Isopropyl ether	Form A
Tetrahydrofuran (THF)	N-heptane	Form A+Form 1
			Chloroform	N-heptane	Form A

Example 18 Water vapor stress test

Result of amorphous water vapor stress experiment

Example 19 melt Cooling experiment

Taking a 10mg Form A sample, placing the sample on a hot table copper plate, heating to 120 ℃, melting the sample to be colorless and transparent, cooling to room temperature to be colorless and transparent solid, and measuring XRPD to be amorphous.

And (4) conclusion: according to the research and test results of the crystal form, the chloritepralene has four crystal forms: form a (Form a), amorphous (Form B), Form 1 (dihydrate) and Form2 (monohydrate). Wherein the crystal form A is most stable, the other three crystal forms are easy to be mutually transformed, and the approximate relative stability of the three crystal forms is as follows: form 1> Form 2> amorphous.

While the preferred embodiments of the present invention have been illustrated, various changes and modifications may be made by one skilled in the art without departing from the scope of the invention.

Claims

A process for the preparation of the PDE4 inhibitor clobiplane comprising the steps of:

1) reacting 2-aminoethyl o-methoxyphenyl ether (compound A1) with 3, 6-dichloropyridazine to obtain 3- (2-o-methoxyphenyloxyethyl) amino-6-chloropyridazine (compound A2);

2) treating the compound A2 prepared in the step 1) with acetate in an acetic acid solvent to obtain 1H-3- (2-o-methoxyphenyloxyethyl) aminopyridazin-6-one and/or a tautomer thereof (compound ZXSM 02);

3) reacting 3-bromo-4-methoxybenzaldehyde, m-chlorobenzoic acid, alkali and urea in a polar protic organic solvent or water containing water in the presence of a palladium catalyst to obtain 3- (m-chlorophenyl) -4-methoxybenzaldehyde (compound ZXSM 01);

4) reducing compound ZXSM01 in an organic solvent such as tetrahydrofuran with a reducing agent such as sodium borohydride, extracting and concentrating the reaction mixture to obtain 3- (m-chlorophenyl) -4-methoxybenzyl alcohol (compound ZX01), which is used in the next reaction step without further purification;

5) chloridizing the compound ZX01 to obtain 1-chloromethyl-3- (m-chlorophenyl) -4-methoxybenzene (compound ZX 02);

6) reacting ZXSM02 prepared in step 2) with ZX02 prepared in step 5) in the presence of a base to obtain a target compound ZX-101, namely clenbuterol,
2. the method of claim 1, having at least one of the following characteristics:

-step 1) is carried out in a polar protic organic solvent or an aprotic polar solvent, the reaction temperature being in the range of 40-120 ℃;

-the acetate employed in step 2) is at least one of an alkali metal acetate, an alkaline earth metal acetate and hydrates thereof;

-after the end of the reaction of step 2), the reaction mixture is poured into water and stirred for about 1-3 hours, then filtered, the filter cake is washed with water and dried, obtaining intermediate product ZXSM 02;

-the base employed in step 3) is at least one member selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates;

-the amount of urea used in step 3) is 0-2 molar equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-the palladium catalyst employed in step 3) is at least one member selected from the group consisting of palladium acetate, palladium chloride, 5% palladium-carbon, 10% palladium-carbon and tetrakis (triphenylphosphine) palladium, and may be used in an amount of 0.1-80 wt%, based on the weight of 3-bromo-4-methoxybenzaldehyde;

-the reaction of step 3) is carried out at a temperature of 30-120 ℃;

the organic solvent used in step 4) is selected from ethers, mixtures of ethers and alcohols, mixtures of ethers and water, alcohols, mixtures of alcohols and water, preferably tetrahydrofuran, in an amount of 2 to 20 times, for example 2.6 to 6.2 times, the mass of ZXSM 01;

-the reducing agent used in step 4) is selected from the group consisting of negative hydrogen ion-based reducing agents and borane complex reducing agents, preferably sodium borohydride, in an amount of 0.5-0.9 molar equivalents relative to more than 1 equivalent of ZXSM 01;

-the reaction of step 4) is carried out at a temperature of 20-120 ℃ for a reaction time of 0.5-24 h;

-the reaction mixture is quenched by adding it to a mixture of water and concentrated hydrochloric acid, then the resulting mixture is concentrated to remove tetrahydrofuran, the remaining aqueous solution is extracted, for example, 2-3 times with Dichloromethane (DCM), the organic phases are combined and concentrated under reduced pressure to give compound ZX 01;

-the chlorination reaction of step 5) is carried out in an aprotic organic solvent in an amount of 2-20 times the mass of ZX 01;

-the chlorinating agent of the chlorination reaction of step 5) is selected from thionyl chloride, phosphorus pentachloride, phosphorus trichloride, hydrochloric acid;

-the chlorination reaction of step 5) is carried out at a temperature of 0-120 ℃;

-the reaction of step 6) is carried out under an inert atmosphere, such as nitrogen or argon;

-the reaction of step 6) is carried out in a polar aprotic solvent;

-the base used in the reaction of step 6) is selected from inorganic bases and organic bases, which can be added all at once or in portions;

-in the reaction of step 6), the amount of ZX02 used is in the range of 0.9 to 1.2 molar equivalents with respect to ZXSM 02;

the reaction of step 6) is carried out at a temperature of 10 to 120 ℃, preferably the reaction of step 6) is carried out in a programmed temperature rise and base addition batch mode.
3. The method of claim 2, having at least one of the following characteristics:

-in step 1) the solvent used is ethanol and the reaction temperature is reflux temperature;

-in step 2), the acetate used is an alkali metal acetate, the reaction solvent is acetic acid, and the reaction temperature is reflux temperature;

-in step 3), the solvents are isopropanol and water, after the heating reaction is completed, suction filtration and organic phase concentration are carried out, part of isopropanol is removed, the mixture is transferred to a reaction kettle, water is added, pulping is carried out overnight, suction filtration is carried out, 95% ethanol is added into a filter cake for pulping, filtration is carried out, the filter cake is further pulped with ethanol and filtered, and finally the filter cake is air-dried to constant weight, so as to obtain a compound ZXSM 01;

-after the solvent used in step 4) is tetrahydrofuran and the reducing agent is sodium borohydride, heating and reacting completely, adding the mixture into a mixed solution composed of ice water and hydrochloric acid to quench, concentrating to remove tetrahydrofuran, adding DCM for extraction twice, combining organic phases, and concentrating the obtained organic phases under reduced pressure and spin-drying to obtain a compound ZX 01;

in the step 5), the solvent is tetrahydrofuran, the chlorinating agent is thionyl chloride, and after the reaction is completed, the reaction liquid is dried in a rotary mode to obtain a compound ZX 02;

-after the reaction in step 6) is completed, cooling the reaction solution, adding the reaction solution into water, performing suction filtration, dissolving and separating the solid by using dichloromethane, extracting, combining organic phases, concentrating the organic phases to a thick state, adding acetonitrile or isopropanol to dissolve, performing suction filtration, and performing vacuum drying on the solid to obtain a crude compound ZX-101; crystallizing a crude product of a compound ZX-101 by using acetonitrile or isopropanol once or twice to obtain a solid, adding dichloromethane, heating, dissolving, slowly adding n-heptane, stirring, performing suction filtration, drying a filter cake to obtain a solid, treating the solid obtained by drying the filter cake by using acetonitrile or isopropanol, and drying to obtain a compound ZX-101, namely the chloropicrin, according to the following synthetic line:
4. the method of claim 3, having at least one of the following characteristics:

-in said step 2), said acetate salt is one of crystalline sodium acetate hydrate and potassium acetate hydrate;

in the step 2), after the reaction is finished, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02;

-in the above step 3), the reaction is carried out in a solution of isopropanol and water, wherein the mass ratio of isopropanol to water is 1: 0.1-10;

-in the step 3), the temperature of the heating medium is 50-100 ℃, after heating reaction is carried out for 7 hours, suction filtration is carried out, filtrate is separated, and an organic phase is concentrated; pulping the filter cake with water, 95% ethanol and ethanol, and air-drying at 25-85 deg.C for 23 hr to constant weight;

-in the above step 3), the palladium catalyst comprises one of palladium acetate, palladium chloride, 5% palladium-carbon, 10% palladium-carbon and tetrakis (triphenylphosphine) palladium in an amount of 0.1 to 80% by weight based on the weight of 3-bromo-4-methoxybenzaldehyde;

-the base used in the above step 3) is one of potassium carbonate, sodium hydroxide and potassium hydroxide, and is used in an amount of 1 to 5 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-in the above step 3), urea is used in an amount of 0-2 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-adding the compound ZXSM01, tetrahydrofuran and sodium borohydride in the step 4) into a single-neck bottle, heating and reacting for 1 hour at the temperature of the heating medium of 40-70 ℃, and stopping heating;

-in step 4) above, said sodium borohydride is used in an amount of 0.5 to 0.9 molar equivalents with respect to compound ZXSM 01;

in the step 4) above, the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZXSM 01;

-adding the compound ZX01, tetrahydrofuran and thionyl chloride in the step 5) into a three-neck flask for reaction at the temperature of 30-70 ℃ for 2-6 hours;

-in the above step 5), the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZX 01;

-in step 5) above, the completion of the reaction is checked by TLC;

-in the step 6) above, the solvent added into the four-mouth bottle is one of DMF, DMAC, NMP and DMSO, and the base added into the four-mouth bottle is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine; relative to ZXSM02, the addition amount of the alkali is in the range of 0.5-2.0 equivalent, the dosage of ZX02 is 1.0-1.2 equivalent, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02; displacing with nitrogen for three times, stirring at 30-40 ℃ for 30 minutes, adding ZX02 under the protection of nitrogen, stirring at the temperature for 30 minutes, heating to 60-90 ℃, stirring for 23 hours, adding 0.01-0.5 equivalent of alkali relative to ZXSM02, wherein the alkali is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine, and stirring at 60-90 ℃ for 1 hour;

after the reaction in the step 6) is finished, slowly cooling the reaction solution to room temperature, then slowly dripping the reaction solution into water, and filtering to obtain a crude ZX-101 product; dissolving a crude product of a compound ZX-101 by using dichloromethane, washing by using water, concentrating to be dry, adding the mixture into acetonitrile, heating to dissolve the mixture clearly, stirring for 1 hour, cooling to 0-25 ℃, separating out a solid, carrying out suction filtration, and drying a filter cake in vacuum to obtain the solid; and adding the solid obtained by vacuum drying into acetonitrile, heating for dissolving, stirring overnight, cooling, performing suction filtration, heating and dissolving the filter cake with acetonitrile again, cooling, and performing suction filtration to obtain a solid after twice crystallization. Dissolving the solid with dichloromethane, heating to dissolve, slowly adding n-heptane into the solution, stirring overnight, vacuum filtering to obtain solid, pulping with acetonitrile, and vacuum filtering to obtain ZX-101, i.e. chloropicrin.
5. The method of claim 3, having at least one of the following characteristics:

-in said step 2), said acetate salt is one of crystalline sodium acetate hydrate and potassium acetate hydrate;

in the step 2), after the reaction is finished, pouring the reaction solution into water, stirring for 1.5 hours, filtering, washing a filter cake with water, and drying in vacuum to obtain a compound ZXSM 02;

-in the above step 3), the reaction is carried out in a solution of isopropanol and water, wherein the mass ratio of isopropanol to water is 1: 0.1-10;

-in the step 3), the temperature of the heating medium is 50-100 ℃, after heating reaction is carried out for 7 hours, suction filtration is carried out, filtrate is separated, and an organic phase is concentrated; pulping the filter cake with water, 95% ethanol and ethanol, and air-drying at 25-85 deg.C for 23 hr to constant weight;

-in the above step 3), the palladium catalyst comprises one of palladium acetate, palladium chloride, 5% palladium-carbon, 10% palladium-carbon and tetrakis (triphenylphosphine) palladium in an amount of 0.1 to 80% by weight based on the weight of 3-bromo-4-methoxybenzaldehyde;

-the base used in the above step 3) is one of potassium carbonate, sodium hydroxide and potassium hydroxide, and is used in an amount of 1 to 5 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-in the above step 3), urea is used in an amount of 0-2 equivalents with respect to 3-bromo-4-methoxybenzaldehyde;

-adding the compound ZXSM01, tetrahydrofuran and sodium borohydride in the step 4) into a single-neck bottle, heating and reacting for 1 hour at the temperature of the heating medium of 40-70 ℃, and stopping heating;

-in step 4) above, said sodium borohydride is used in an amount of 0.5 to 0.9 molar equivalents with respect to compound ZXSM 01;

in the step 4) above, the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZXSM 01;

-adding the compound ZX01, tetrahydrofuran and thionyl chloride in the step 5) into a three-neck flask for reaction at the temperature of 30-70 ℃ for 2-6 hours;

-in the above step 5), the amount of tetrahydrofuran is 2.6 to 6.2 times the mass of ZX 01;

-in step 5) above, the completion of the reaction is checked by TLC;

-in the step 6) above, the solvent added into the four-mouth bottle is one of DMF, DMAC, NMP and DMSO, and the base added into the four-mouth bottle is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine; relative to ZXSM02, the addition amount of the alkali is in the range of 0.5-2.0 equivalent, the dosage of ZX02 is 1.0-1.2 equivalent, and the dosage of the solvent is 2.5-3.5 times of the mass of ZXSM 02; displacing with nitrogen for three times, stirring at 30-40 ℃ for 30 minutes, adding ZX02 under the protection of nitrogen, stirring at the temperature for 30 minutes, heating to 60-90 ℃, stirring for 23 hours, adding 0.01-0.5 equivalent of alkali relative to ZXSM02, wherein the alkali is one of potassium carbonate, cesium carbonate, hydroxide, triethylamine and pyridine, and stirring at 60-90 ℃ for 1 hour;

after the reaction in the step 6) is finished, slowly cooling the reaction solution to room temperature, then slowly dripping the reaction solution into water, and filtering to obtain a crude ZX-101 product; dissolving a crude product of a compound ZX-101 by using dichloromethane, washing by using water, concentrating to be dry, adding the mixture into isopropanol, heating to dissolve the mixture clearly, stirring for 1 hour, cooling to 0-25 ℃, separating out a solid, performing suction filtration, and drying a filter cake in vacuum to obtain the solid; and adding the solid obtained by vacuum drying into isopropanol, heating to dissolve the solid clearly, stirring overnight, cooling, and performing suction filtration to obtain a crystallized solid. Dissolving the solid with dichloromethane, heating to dissolve, slowly adding n-heptane into the solution, stirring overnight, vacuum filtering to obtain solid, recrystallizing with isopropanol, and vacuum filtering to obtain ZX-101, i.e. clobiplane.
6. The Form A crystal Form of the chloroperplan, which has diffraction peaks at 4.258 +/-0.2, 13.220 +/-0.2, 14.460 +/-0.2, 15.642 +/-0.2, 16.442 +/-0.2, 18.442 +/-0.2, 19.762 +/-0.2 and 21.461 +/-0.2 in an X-PRD diagram measured by Cu-Kalpha radiation.
7. The Form a crystal Form of chloropicrin of claim 6 having at least one of the following characteristics:

-melting point of about 110 ± 2 ℃ by DSC;

-a decomposition temperature of about 319 ± 2 ℃ as determined by TGA;

DVS/isothermal sorption curves show a weight change of less than 0.1% in the range from 0% RH to 80% RH.
8. Amorphous form of topiramate having at least one of the following characteristics:

hot-table XRPD analysis showed that a small number of Form a diffraction peaks occurred at the amorphous temperature rise to 90 ℃;

DSC in combination with hot-table XRPD showed that the amorphous sample recrystallizes to Form a during the temperature rise, after which Form a melting point of about 107 ℃ appeared;

TGA analysis showed that the amorphous sample had a slow surface weight loss of about 2.5% before 120 ℃ and a decomposition temperature of about 317 ℃.
9. Form 1 crystal Form of clopyralid having diffraction peaks expressed in degrees 2 θ at 7.901 ± 0.2, 11.844 ± 0.2, 12.381 ± 0.2, 15.841 ± 0.2, 18.565 ± 0.2, 26.203 ± 0.2 in an X-PRD diagram measured using Cu-ka radiation.
10. The Form 1 crystalline Form of chloropicrin of claim 9 having at least one of the following characteristics:

DSC analysis shows 2 consecutive dehydration endotherms before 100 ℃ and melting point of about 104. + -.2 ℃;

TGA analysis shows that the material has a step weight loss of about 3.5% between 27 and 40 ℃, a step weight loss of about 3.4% between 40 and 70 ℃ and a decomposition temperature of about 322 +/-2 ℃.
11. Form2 crystal Form of topiramate having diffraction peaks at 4.239 ± 0.2, 8.434 ± 0.2, 12.637 ± 0.2, 13.860 ± 0.2, 16.861 ± 0.2, 18.484 ± 0.2, 21.703 ± 0.2, 26.645 ± 0.2 in degrees 2 θ in an X-PRD diagram measured using Cu-ka radiation.
12. The Form2 crystalline Form of chloropicrin of claim 11 having at least one of the following characteristics:

DSC analysis shows a broad dehydration endotherm between 50 and 100 ℃ with a melting point of about 110. + -. 2 ℃;

TGA analysis showed a step weight loss of about 3.6% before 90 ℃ with a decomposition temperature of about 319 ± 2 ℃;

DVS/isothermal sorption curve shows a weight change of 2.6% at an increase from 40% RH to 80% RH; the 80% RH was reduced to 0% RH with a weight change of 3.0%.