CN108948018A

CN108948018A - Benzodiazepine * * derivative and its salt and related crystalline form, preparation method and purposes

Info

Publication number: CN108948018A
Application number: CN201810424060.4A
Authority: CN
Inventors: 刘钢; 唐建川; 胡昊; 唐毅; 梁勇; 于华; 王利春; 王晶翼
Original assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Current assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Priority date: 2017-05-17
Filing date: 2018-05-07
Publication date: 2018-12-07
Anticipated expiration: 2038-05-07
Also published as: CN108948018B

Description

Benzodiazepine * * derivative and its salt and related crystalline form, preparation method and purposes

Technical field

The present invention relates to 3- (8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole simultaneously [4, 3-a] [1,4] diaza- 4- base) methyl propionate (hereinafter referred to as " compound of formula (I) ") and its S- configuration of compound 3 (S) -3- (8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole simultaneously [4,3-a] [1,4] diaza- 4- base) crystal form of methyl propionate (hereinafter referred to as " compound of formula (Ia) "), the compound salt and its crystal Form, preparation method, comprising its pharmaceutical composition and its preparation for calmness, hypnosis, antianxiety, it is of flaccid muscles or Purposes in anticonvulsant drug.

Background technique

Benzodiazepine *Analog derivative (benzodiazepines) is a kind of short-acting central nervous system depressant, is had Calmness, hypnosis, antianxiety, of flaccid muscles and anticonvulsant action.The vein that such drug can be used in following clinical treatment Administration: for example perioperative operation consent calmness, antianxiety and forgetting；During short-term diagnosis, operation or endoscopic procedure Associated with conscious sedation；As the induction and maintenance for being used for general anesthesia before and/or at the same time of applying other anesthetic and analgesic Component；And ICU calmness etc..

Clinically used benzodiazepine *Analog derivative has more than 20.Although their structures are similar, different derivatives it Between indication clinically it is then different.Midazolam (midazolam) has in early 1980s as first There is water-soluble benzodiazepine *Compound is introduced into market, and is short-term operation or intensive care unit as intravenous injection Sedation anesthesia means are provided.However, midazolam can generate active interior metabolism product, azoles is reached from miaow so as to cause patient The state of the sedation anesthesia of logical sequence induction restores awake and needs the long period.Metabolism additionally, due to midazolam is thin dependent on liver enzyme Born of the same parents cytochrome p 450 3A4, thus if be administered to the patient of liver function damage, drug-drug interactions may be generated Problem.

Therefore, it is desirable to research and develop, onset time is shorter, the drug effect continuous action time is shorter, recovery time is shorter, thus to the heart The lower benzodiazepine * of vascular study adverse reaction rateThe short-acting central nervous system of class (CNS) inhibitor, and research and develop and obtain It is suitable for preparing the crystal of pharmaceutical preparation and salt.

Summary of the invention

One aspect of the present invention provides the crystal form of the compound of formula as follows (I):

Another aspect of the present invention provides the crystal form of the compound of formula as follows (Ia):

The compound and its preparation and use of above-mentioned formula (I) or formula (Ia) are recorded in the PCT/ of applicant's submission In CN2016/110075 international patent application.Above-mentioned international patent application quotes addition herein with its entirety.The compound is not But it keeps to GABA_AThe high-affinity and selectivity of receptor, and have the advantage that and reach the predictable fast of sedation anesthesia Fast duration of seizure, effective acting time is short, recovery time is short, to reduce anti-to cardiovascular and respiratory system bad inhibition Answer, and reduce to side effect caused by patient's nervous system, including it is drowsiness, dizzy the problems such as.

The crystal of the compound of formula (I) provided by the present invention or formula (Ia) not only has the advantages that above, also shows it Its advantageous physical property (such as good dissolubility, low draw moist (hygroscopicity) and good solid-state stability etc.) and medicine Object dynamic metabolism property (such as due to different lattice energies raising dissolution rate and raising bioavilability) etc..

Another aspect of the present invention provides the method for the crystal of the compound of preparation formula (I) or formula (Ia), the method packet Include but be not limited to gas-solid osmosis, antisolvent crystallisation method, room temperature suspension paddling process, high temperature suspension paddling process, gas-liquid osmosis, room Warm slowly volatility process, slow cooling method etc..

Another aspect of the present invention provides the salt of the compound of formula as shown above (Ia), such as the compound of formula (Ia) Hydrochloride, succinate, hexanedioic acid salt, sulfate, phosphate, fumarate, malate, glycollate, sticks maleate Hydrochlorate, lactate, gentisate, benzene sulfonate, ethanedisulphonate, napadisilate, mesylate, tartrate, hippuric acid Salt, citrate, nicotinate, lactate, oxalates, malonic acid, nicotinoyl amine salt and tosilate, especially formula (Ia) Hydrochloride, oxalates and the malonate of compound, more particularly the hydrochloric acid salt crystal, oxalic acid salt crystal of the compound of formula (Ia) With malonate crystal.

The salt of the compound of formula (Ia) provided by the present invention have well can preparative (convenient for preparation), various salt Dissolvent residual in crystal form is lower, and without significant difference between the product of each batch preparation.At salt institute in the present invention The acid safety with higher utilized, will not cause undesirable toxicity.In addition, various salt of the invention and its crystal form It is more easily largely prepared with high-purity, to be particularly suited for preparing pharmaceutical preparation, but also can express other advantageous physics Property (such as good dissolubility, low draw moist (hygroscopicity) and good solid-state stability etc.) and pharmacokinetics Property (such as due to different lattice energies raising dissolution rate and raising bioavilability) etc..

Another aspect of the present invention provides the method for the salt of the compound of preparation formula (Ia) comprising makes any solid form Formula (Ia) compound and inorganic acid or organic acid reaction, be precipitated solid, then the solid of precipitation is separated and dried.It is described The method that solid is precipitated includes but is not limited to gas-solid osmosis, antisolvent crystallisation method, room temperature suspension paddling process, high temperature suspension stirring Method, gas-liquid osmosis, the slow volatility process of room temperature, slow cooling method etc..

Another aspect of the present invention provides pharmaceutical composition, and it includes the crystal of the compound of above-mentioned formula (I), formula (Ia) Salt (especially hydrochloride, oxalates or the malonic acid of the compound of formula (Ia) of the compound of the crystal or formula (Ia) of compound Hydrochloric acid salt crystal, oxalic acid salt crystal or the malonate crystal of the compound of salt, more particularly formula (Ia)) or any combination thereof, And one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides the calmness for individual, hypnosis, antianxiety, of flaccid muscles or anticonvulsant side Method comprising to the crystal of the compound of the above-mentioned formula (I) of individuals in need dosage treatment effective amount, the chemical combination of formula (Ia) The compound of the crystal or formula (Ia) of object salt (especially hydrochloride, oxalates or the malonate of the compound of formula (Ia), more The especially hydrochloric acid salt crystal, oxalic acid salt crystal or malonate crystal of the compound of formula (Ia)) or any combination thereof.

Another aspect of the present invention provide the crystal of the compound of above-mentioned formula (I), formula (Ia) compound crystal or formula (Ia) salt (especially hydrochloride, oxalates or the malonate of the compound of formula (Ia), more particularly formula (Ia) of compound Compound hydrochloric acid salt crystal, oxalic acid salt crystal or malonate crystal) or any combination thereof, be used for calmness, hypnosis, anti- It is anxiety, of flaccid muscles or anticonvulsion.

Another aspect of the present invention provide the crystal of the compound of above-mentioned formula (I), formula (Ia) compound crystal or formula (Ia) salt (especially hydrochloride, oxalates or the malonate of the compound of formula (Ia), more particularly formula (Ia) of compound Compound hydrochloric acid salt crystal, oxalic acid salt crystal or malonate crystal) or any combination thereof preparation for it is calm, urge Dormancy, antianxiety, the purposes in of flaccid muscles or anticonvulsant drug.

The crystal of the compound or its salt of formula (I) or formula (Ia) of the invention has one or more following favorable properties:

I) high-dissolvability, high dissolution rate, agent of low hygroscopicity, high fluidity and the viscous stickiness being obviously improved.

Ii) excellent physical and chemical stability, including but not limited to photostability, thermal stability, resistance to height are moist etc..Example Such as, good photostability can guarantee reliability of the crystal in storage and transport, to guarantee the safety of preparation；Make It obtains the crystal not needing to take extra package to handle to prevent from being illuminated by the light influence, to reduce costs；So that the crystalline substance Body will not generate degradation because of illumination effect, thus the safety for improving preparation and the validity after long-term storage；And make The patient for taking the crystal will not worry preparation and generate photosensitized reaction because being exposed under daylight.Good thermal stability makes The crystal is able to maintain long-time stable, and is suitable for the formulation manufacturing processes of standard.Good physical and chemical stability institute It is easily prepared and be particularly suited for the preparation of preparation to state crystal.

Iii the safety of the metabolism, the bioavilability of raising, the toxicity of reduction and raising that) improve.

Iv) it is suitble to and convenient for a large amount of preparations, save the cost.

Detailed description of the invention

The XRPD map of the crystal B of the compound of Fig. 1 display type (Ia).

The DSC map of the crystal B of the compound of Fig. 2 display type (Ia).

Fig. 3 shows the XRPD map of the crystal C of the compound of formula (I).

Fig. 4 shows the DSC map of the crystal C of the compound of formula (I).

The XRPD map of the hydrochloric acid salt crystal of the compound of Fig. 5 display type (Ia).

The DSC map of the hydrochloric acid salt crystal of the compound of Fig. 6 display type (Ia).

The XRPD map of the oxalic acid salt crystal A of the compound of Fig. 7 display type (Ia).

The DSC map of the oxalic acid salt crystal A of the compound of Fig. 8 display type (Ia).

The XRPD map of the oxalic acid salt crystal B of the compound of Fig. 9 display type (Ia).

The DSC map of the oxalic acid salt crystal B of the compound of Figure 10 display type (Ia).

The XRPD map of the oxalic acid salt crystal C of the compound of Figure 11 display type (Ia).

The DSC map of the oxalic acid salt crystal C of the compound of Figure 12 display type (Ia).

The XRPD map of the oxalic acid salt crystal D of the compound of Figure 13 display type (Ia).

The DSC map of the oxalic acid salt crystal D of the compound of Figure 14 display type (Ia).

The XRPD map of the malonate crystal A of the compound of Figure 15 display type (Ia).

The DSC map of the malonate crystal A of the compound of Figure 16 display type (Ia).

The XRPD map of the malonate crystal B of the compound of Figure 17 display type (Ia).

The DSC map of the malonate crystal B of the compound of Figure 18 display type (Ia).

Specific embodiment

Definition

Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this Field technical staff is generally understood identical.It refers to that technology used herein is intended to refer to be generally understood in the art Technology, the replacement of variation or equivalence techniques including those technologies that will be apparent to those skilled in the art.While it is believed that with Lower term is for those skilled in the art it is well understood that but still illustrating defined below preferably to explain the present invention.

"include", "comprise", " having ", " containing " or " being related to " and its herein as used herein, the term Other variant forms are the (inclusive) or open of inclusive, and are not excluded for other unlisted elements or method step Suddenly.

Word " about " as used herein refers to that those skilled in the art think in the acceptable of described value Standard error in, such as ± 0.05, ± 0.1, ± 0.2, ± 0.3, ± 1, ± 2 or ± 3 etc..

Term " salt of the compound of formula (Ia) " used in the present invention include the compound of formula (Ia) inorganic acid salt or Acylate.The inorganic acid is selected from but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and its any Combination；And the organic acid but be not limited to selected from formic acid, acetic acid, acetoacetate, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, Caproic acid, enanthic acid, hendecanoic acid, lauric acid, stearic acid, palmitinic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, Malaysia Acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, flutters acid, niacin, cream at fumaric acid Clear acid, methylsulfuric acid, dodecyl sulphate, methanesulfonic acid, trifluoromethanesulfonic acid, ethionic acid, isethionic acid, two sulphur of 1,5- naphthalene Acid, 2- naphthalene sulfonic acids, camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and any combination thereof.

Term " solid form " used in the present invention includes the compound of formula (I), the compound of formula (Ia) and formula (Ia) Compound salt all solid-state forms, such as crystal form or amorphous form.

" amorphous " refers to any solid matter in three-dimensional without sequence as used herein, the term.In some cases In, amorphous solid can be characterized by known technology, and the technology includes XRPD crystallography, solid state nmr (ssNMR) wave Some combinations of spectroscopy, DSC or these technologies.As explained below, amorphous solid generates the XRPD map of disperse, usually Including one or two broad peak (i.e. the peak with about 5 ° of 2 θ or bigger sound stage width).

" crystal form " or " crystal " refers to any solid matter that three-dimensional sequence is presented as used herein, the term, with nothing White amorphous solid substance is on the contrary, it generates the characteristic XRPD map with the peak of clear border.

" X-ray powder diffraction pattern (XRPD map) " refers to the diffraction pattern of Germicidal efficacy as used herein, the term Or the parameter derived from it.XRPD map is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).

" 2 θ " refers to indicating with degree for the experimental setup based on x-ray diffraction experiment as used herein, the term Peak position, and be usually the abscissa unit in diffracting spectrum.If reflecting quilt when incident beam and certain lattice plane shape are into θ angle Diffraction, then experimental setup needs to record reflecting bundle with 2 angles θ.It should be appreciated that the particular crystalline mentioned herein is specific 2 θ values are intended to indicate using 2 θ values (being indicated with degree) measured by x-ray diffraction experiment condition as described herein.For example, such as this Described in text, using Cu-K α (1.540598 and1.544426) it is used as radiation source.

" thermogravimetric analysis (TGA) map " refers to the curve being recorded by thermogravimetric analyzer as used herein, the term.

" differential scanning calorimetry (DSC) map " refers to as used herein, the term is recorded by differential scanning calorimeter Curve.

As used herein, the term " substantially the same " of X-ray diffraction peak position is meant representative peak position It is taken into account with Strength Changes.For example, it will be understood by those skilled in the art that peak position (2 θ) can show some variations, usually up to 0.1-0.2 degree, and the instrument for measuring diffraction can also show some variations.In addition, it will be understood by those skilled in the art that phase Between the variation peak intensity meeting display instrument and due to crystallinity degree, preferred orientation, the sample surfaces of preparation and ability The variation of other factors known to field technique personnel, and should be regarded as only observational measurement.Similarly, as made herein With, for DSC map and TGA map " substantially the same " also be intended to cover it is well known by persons skilled in the art with these analysis The related variation of technology.For example, would generally have up to ± 0.2 DEG C in Differential Scanning Calorimetry for the peak of clear border Variation, it is even more big (such as up to ± 1 DEG C) for broad peak.

" good solvent " means compound for dissolving (I) of the invention or (I) as used herein, the term The solvent of the salt of compound.

" anti-solvent " means deliquescent in good solvent for reducing object to be crystallized as used herein, the term Solvent.

" antisolvent crystallisation method " means for good solvent to be used in combination with anti-solvent as used herein, the term, to drop Deliquescent method of the low object to be crystallized in good solvent.According to the order of addition of solvent, antisolvent crystallisation method can be divided into anti-molten Agent additive process and anti-anti-solvent additive process.Anti-solvent additive process is that object to be crystallized is dissolved in good solvent, is then added thereto Add anti-solvent to the method for crystallization, and anti-anti-solvent addition rule is that object to be crystallized is dissolved in good solvent, then by institute The solution obtained is added to the method in anti-solvent to crystallization.

" hydro carbons " preferably means the hydrocarbon with 1-10 carbon atom as used herein, the term comprising alkanes, Alkyl halide hydro carbons, olefines, alkynes class and aromatic hydrocarbons, including but not limited to methylene chloride, chloroform (chloroform), n-hexane, Normal heptane and toluene.

" alcohols " preferably means the alcohol with 1-10 carbon atom as used herein, the term comprising but be not limited to Methanol, ethyl alcohol, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and the tert-butyl alcohol.

" ethers " preferably means the ether with 2-6 carbon atom as used herein, the term comprising chain ethers With ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class), it is specifically including but not limited to ether, two different Propyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, methyl phenyl ethers anisole and diformazan Oxygroup ethane.

" nitrile " preferably means the nitrile with 2-6 carbon atom as used herein, the term comprising but be not limited to Acetonitrile and propionitrile.

" ketone " preferably means the ketone with 2-6 carbon atom as used herein, the term comprising but be not limited to Acetone, butanone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) and metacetone.

" esters " preferably mean the ester with 3-10 carbon atom as used herein, the term comprising but be not limited to Ethyl acetate, propyl acetate, isopropyl acetate, isopropyl acetoacetic ester, dimethyl carbonate and butyl acetate.

" organic acid " preferably means the organic acid with 1-10 carbon atom as used herein, the term comprising But it is not limited to formic acid and acetic acid.

" sulfone class " preferably means the sulfone or sulfoxide with 2-10 carbon atom as used herein, the term comprising but It is not limited to dimethyl sulfoxide.

" amides " preferably mean the amide with 1-10 carbon atom as used herein, the term comprising but not It is limited to dimethylformamide or dimethyl acetamide.

" nitrogen heterocycles " preferably mean former with 3-10 carbon atom and at least one nitrogen as used herein, the term The nitrogen-containing heterocycle of son comprising but it is not limited to N-Methyl pyrrolidone.

Numberical range (such as " 1-10 ") as used herein and its subrange are (such as " 2-10 ", " 2-6 ", " 3- 10 ") etc. cover in the numberical range it is any (such as 1,2,3,4,5,6,7,8,9 or 10).

It can be by the crystal form of the compound of the formula (I) of preparation or formula (Ia), the salt or its crystal of the compound of formula (Ia) Form passes through to be used for including decantation, centrifugation, evaporation, gravity filtration, suction filtration or under elevated pressure or under reduced pressure any other Method including the technology of solid recycling is recycled.The solid of recycling can be optionally dried.It is " dry in the present invention It is dry " it is to carry out under decompression (preferably vacuum) until the content of residual solvent is reduced to International Conference on Harmonisation of Technical Requirements for Registration of In the range of limit given by Pharmaceuticals for Human Use (" ICH ") guide.Residual solvent levels depend on In the type of solvent, but no more than about 5000ppm or preferably from about 4000ppm or more preferably from about 3000ppm.The drying can be with It is dry in pan dryer, vacuum drying oven, air -oven, conical vacuum drier (cone vacuum dryer), rotary type vacuum It is carried out in dry device, fluidized bed dryer, spin flash dryer, flash dryer etc..The drying can be below about 100 DEG C, below about 80 DEG C, below about 60 DEG C, below about at 50 DEG C, the temperature below about 30 DEG C or any other suitable temperature, Atmospheric pressure or decompression (preferably vacuum) under within any desired time that can be realized desired result (such as from about 1,2,3,5, 10,15,20,24 hours or overnight) carry out, as long as the quality of product does not deteriorate.The drying can carry out any desired Number, the product qualities needed for realizing.Dry product can be optionally subjected to crushing operation, to generate desired grain Degree.It can be ground or be micronized before the drying of product or after the completion of dry.The technology that can be used for reducing granularity includes but not It is limited to ball milling, roller mill and sledge mill and jet grinding (jet milling).

" anhydrous crystal forms " preferably mean wherein without containing hydrone as structural element as used herein, the term Crystal form.

The crystal of compound and preparation method thereof of formula (I) or formula (Ia)

It is an object of the present invention to provide the crystal form of the compound of formula as shown below (Ia),

An embodiment according to the present invention, the present invention provide the crystal B of the compound of formula (Ia), the crystal B's XRPD map is included in 6.8 ± 0.2 °, 11.5 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, 22.0 ± 0.2 ° of the angle of diffraction (2 θ) the characteristic peak at place.In preferred embodiments, the XRPD map of the crystal B of the compound of the formula (Ia) is included in 6.8 ±0.2°、10.1±0.2°、11.5±0.2°、14.4±0.2°、15.4±0.2°、17.1±0.2°、19.4±0.2°、19.9 ± 0.2 °, 22.0 ± 0.2 °, the characteristic peak at 22.6 ± 0.2 ° of the angle of diffraction (2 θ).In a more preferred embodiment, described The XRPD map of the crystal B of the compound of formula (Ia) be included in 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4 ± 0.2°、15.4±0.2°、17.1±0.2°、19.4±0.2°、19.9±0.2°、20.6±0.2°、21.5±0.2°、22.0± 0.2°、22.6±0.2°、23.6±0.2°、24.6±0.2°、25.3±0.2°、26.1±0.2°、27.4±0.2°、27.8± 0.2 °, 28.3 ± 0.2 °, the characteristic peak at 29.4 ± 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, described The XRPD map of the crystal B of the compound of formula (Ia) is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		6.8	24.6
10.1	25.3
		11.5	26.1
14.4	27.4
		15.4	27.8
17.1	28.3
		19.4	29.4
19.9	30.5
		20.6	30.8
21.5	32.2
		22.0	32.9
22.6	37.3
		23.6

In particularly preferred embodiments, the XRPD map of the crystal B of the compound of the formula (Ia) is included in following Peak at the angle of diffraction (2 θ):

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			6.8	12.9	33.2
10.1	8.7	7.0
			11.5	7.7	15.5
14.4	6.1	10.6
			15.4	5.8	11.3
17.1	5.2	12.7
			19.4	4.6	68.2
19.9	4.5	38.3
			20.6	4.3	6.1
21.5	4.1	13.7
			22.0	4.0	100.0
22.6	3.9	25.8
			23.6	3.8	9.2
24.6	3.6	4.3
			25.3	3.5	10.7
26.1	3.4	5.0
			27.4	3.3	6.3
27.8	3.2	10.0
			28.3	3.2	7.9
29.4	3.0	7.1
			30.5	2.9	6.2
30.8	2.9	6.7
			32.2	2.8	5.4
32.9	2.7	1.3
			37.3	2.4	10.7

In particularly preferred embodiments, the XRPD map of the crystal B of the compound of the formula (Ia) includes and Fig. 1 institute Show the peak at the substantially the same angle of diffraction (2 θ).In particularly preferred embodiments, the crystalline substance of the compound of the formula (Ia) The XRPD peak position of body B is substantially the same with shown in Fig. 1.

In preferred embodiments, the DSC map of the crystal B of the compound of formula of the invention (Ia) is included in about Characteristic peak at 160.9 ± 0.2 DEG C.In a more preferred embodiment, the DSC figure of the crystal B of the compound of the formula (Ia) Spectrum includes the characteristic peak at the temperature substantially the same with shown in Fig. 2.In particularly preferred embodiments, the formula (Ia) The feature peak position of the DSC map of the crystal B of compound is substantially the same with shown in Fig. 2.

In a particularly preferred embodiment, the crystal B of the compound of formula of the invention (Ia) is non solvate.More excellent In the embodiment of choosing, the crystal B of the compound of formula of the invention (Ia) is anhydrous crystal forms.

Another object of the present invention is to provide the crystal form of the compound of formula as shown below (I),

An embodiment according to the present invention, the present invention provide the crystal C of the compound of formula (I), the crystal C's XRPD map be included in 8.4 ± 0.2 °, 14.0 ± 0.2 °, 16.7 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± Characteristic peak at 0.2 ° of the angle of diffraction (2 θ).In preferred embodiments, the XRPD of the crystal C of the compound of the formula (I) Map is included in 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, 25.2 ± 0.2 ° is spread out Characteristic peak at firing angle (2 θ).In a more preferred embodiment, the XRPD map packet of the crystal C of the compound of the formula (I) Include 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2°、16.7±0.2°、17.9±0.2°、18.5±0.2°、19.4±0.2°、20.3±0.2°、21.2±0.2°、21.8± 0.2°、22.4±0.2°、22.7±0.2°、23.5±0.2°、24.5±0.2°、25.2±0.2°、26.6±0.2°、28.1± 0.2 °, the characteristic peak at 29.2 ± 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the chemical combination of the formula (I) The XRPD map of the crystal C of object is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		8.4	21.2
9.3	21.8
		9.6	22.4
11.0	22.7
		13.2	23.5
14.0	24.5
		15.3	25.2
16.7	26.6
		17.9	28.1
18.5	29.2
		19.4	33.1
20.3	36.2

In particularly preferred embodiments, the XRPD map of the crystal C of the compound of the formula (I) is included in following spread out Peak at firing angle (2 θ):

2θ(°)±0.2°	Intensity %	2θ(°)±0.2°	Intensity %
				8.4	41.5	21.2	8.8
9.3	11.9	21.8	11.3
				9.6	9.0	22.4	17.0
11.0	2.1	22.7	40.8
				13.2	13.5	23.5	6.9
14.0	43.1	24.5	6.5
				15.3	21.9	25.2	100.0
16.7	63.1	26.6	13.8
				17.9	8.6	28.1	18.1
18.5	9.3	29.2	11.4
				19.4	37.9	33.1	6.6
20.3	3.7	36.2	2.5

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			8.4	10.6	41.5
9.3	9.5	11.9
			9.6	9.2	9.0
11.0	8.0	2.1
			13.2	6.7	13.5
14.0	6.3	43.1
			15.3	5.8	21.9
16.7	5.3	63.1
			17.9	5.0	8.6
18.5	4.8	9.3
			19.4	4.6	37.9
20.3	4.4	3.7
			21.2	4.2	8.8
21.8	4.1	11.3
			22.4	4.0	17.0
22.7	3.9	40.8
			23.5	3.8	6.9
24.5	3.6	6.5
			25.2	3.5	100.0
26.6	3.3	13.8
			28.1	3.2	18.1
29.2	3.1	11.4
			33.1	2.7	6.6
36.2	2.5	2.5

In particularly preferred embodiments, the XRPD map of the crystal C of the compound of the formula (I) includes and Fig. 3 institute Show the peak at the substantially the same angle of diffraction (2 θ).In particularly preferred embodiments, the crystal of the compound of the formula (I) The XRPD peak position of C is substantially the same with shown in Fig. 3.

In preferred embodiments, the DSC map of the crystal C of the compound of formula of the invention (I) is included in about 185.5 Characteristic peak at ± 0.2 DEG C.In a more preferred embodiment, the DSC map of the crystal C of the compound of the formula (I) includes Characteristic peak at the temperature substantially the same with shown in Fig. 4.In particularly preferred embodiments, the compound of the formula (I) Crystal C DSC map feature peak position it is substantially the same with shown in Fig. 4.

In a particularly preferred embodiment, the crystal C of the compound of formula of the invention (I) is non solvate.More excellent In the embodiment of choosing, the crystal C of the compound of formula of the invention (I) is anhydrous crystal forms.

Another object of the present invention is to provide the crystal B for the compound for preparing above-mentioned formula (Ia) or the compounds of formula (I) Crystal C method, the method includes but be not limited to: gas-solid osmosis, antisolvent crystallisation method, room temperature suspension paddling process, height Warm suspension paddling process, gas-liquid osmosis, the slow volatility process of room temperature, slow cooling method etc..

Some embodiments according to the present invention prepare crystal using gas-solid osmosis, and the method includes formula will be housed (I) or the first container of the compound of formula (Ia) is placed in the second container equipped with solvent, wherein the formula of the solid-state form (I) or the compound of formula (Ia) is not directly contacted with the solvent, and second container is sealed, crystal is obtained after placement.It is using Gas-solid osmosis is prepared in some embodiments of crystal, and the solvent includes but is not limited to inorganic solvent (such as water) and organic Solvent (such as alcohols, amides, sulfone class, ketone, hydro carbons (including alkanes, alkyl halide hydro carbons, olefines, alkynes class and aromatic hydrocarbons Class), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), nitrile And esters, such as methanol, ethyl alcohol, isopropanol, chloroform, acetone, isopropyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrofuran, two Six ring of oxygen, acetonitrile, methylene chloride, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate etc.).Legal system is being permeated using gas-solid In some embodiments of standby crystal, the w/v (mg/mL) of the compound and solvent of the formula (I) or formula (Ia) is about (1-20): 1, preferably (2-10): 1.In some embodiments for preparing crystal using gas-solid osmosis, the placement crystallization packet Standing or stirring and crystallizing are included, preferably standing crystallization.

Some embodiments according to the present invention prepare crystal using anti-solvent additive process, the method includes but it is unlimited Dissolved in good solvent in by the compound of formula (I) or formula (Ia), formed clear solution (solution can be optionally filtered with Obtain clear solution), anti-solvent then is added into the clear solution, (stirring can be in room temperature or cooling in stirring It precipitates crystal, or stands under condition (such as being cooled to 0-20 DEG C, carry out at preferably 0-10 DEG C, such as 0 DEG C, 5 DEG C or 10 DEG C) (such as at room temperature place) (preferably while slowly solvent flashing) is to precipitate crystal.It is prepared using anti-solvent additive process In some embodiments of crystal, the good solvent includes but is not limited to organic solvent, such as alcohols, ketone, nitrile, hydro carbons (be selected from alkyl halide hydro carbons, aromatic hydrocarbons), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran Class) and dioxane class)), sulfone class, esters, amides and organic acid, such as methanol, ethyl alcohol, acetone, acetonitrile, tetrahydro furan It mutters, dimethyl sulfoxide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, methyl ethyl ketone, ethyl acetate, 2- methyl tetrahydro Furans, cyclopentyl methyl ether, methyl phenyl ethers anisole, toluene, methylene chloride etc..In some embodiment party for preparing crystal using anti-solvent additive process In case, the anti-solvent include but is not limited to inorganic solvent (such as water) and organic solvent (such as hydro carbons (selected from alkanes, Olefines, alkynes class), such as n-hexane, normal heptane, hexamethylene etc.).In some realities for preparing crystal using anti-solvent additive process Apply in scheme, the volume ratio of the good solvent and anti-solvent is 1:(1-60), preferably 1:(1-40).In some embodiments In, the w/v (mg/mL) of the compound and good solvent of the formula (I) or formula (Ia) is (1-80): 1, preferably (1- 40):1。

Some embodiments according to the present invention prepare crystal using room temperature suspension paddling process, the method includes but not It is limited to for the compound of formula (I) or formula (Ia) to be added in solvent and obtains suspension, is stirred at room temperature, then isolated crystal. In some embodiments for preparing crystal using room temperature suspension paddling process, the solvent includes but is not limited to inorganic solvent (example Such as water) and organic solvent (such as alcohols, ketone, hydro carbons (including alkanes, alkyl halide hydro carbons, olefines, alkynes class and aromatic hydrocarbons Class), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), ester Class, nitrile, amides and organic acid, such as methyl tertiary butyl ether(MTBE), isopropanol, isobutyl acetate, methanol, acetone, tetrahydro furan Mutter, acetonitrile, dimethyl sulfoxide, 2- methyltetrahydrofuran, methylene chloride, ethyl acetate, toluene etc.), or in above-mentioned solvent The mixed solvent of two or more.In some embodiments for preparing crystal using room temperature suspension paddling process, the formula (I) or the w/v (mg/mL) of the compound of formula (Ia) and solvent is (1-80): 1, preferably (1-50): 1.

Some embodiments according to the present invention prepare crystal using high temperature suspension paddling process, the method includes but not It is limited to for the compound of formula (I) or formula (Ia) to be added into solvent, obtains suspension, suspension heating (such as is heated To 40-100 DEG C, preferably 40-80 DEG C, such as 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C or 70 DEG C) stirring, then isolated crystalline substance Body.In some embodiments for preparing crystal using high temperature suspension paddling process, the solvent includes but is not limited to inorganic solvent (such as water) and organic solvent (such as alcohols, ketone, hydro carbons (including alkanes, alkyl halide hydro carbons, olefines, alkynes class and virtue Hydro carbons), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), ester Class, nitrile, sulfone class, amides and nitrogen heterocycles, such as methyl ethyl ketone, isobutanol, isobutyl acetate, methanol, acetone, four Hydrogen furans, acetonitrile, dimethyl sulfoxide, 2- methyltetrahydrofuran, chloroform, ethyl acetate, toluene, n-hexane etc.), or be selected from The mixed solvent of two or more in above-mentioned solvent.In some embodiments for preparing crystal using high temperature suspension paddling process In, the w/v (mg/mL) of the compound and solvent of the formula (I) or formula (Ia) is (1-80): 1, preferably (5-60): 1.

Some embodiments according to the present invention prepare crystal using gas-liquid osmosis, the method includes by formula (I) or The compound of formula (Ia) dissolved in the good solvent of the first container with formed clear solution (solution can be optionally filtered with Obtain clear solution), it is packed into anti-solvent into second container, the first container opening is placed in second container, second is held Device is sealed and is stood, and crystal is obtained by filtration in the solid of precipitation.

In some embodiments for preparing crystal using gas-liquid osmosis, the good solvent includes but is not limited to organic molten Agent, such as hydro carbons (selected from alkyl halide hydro carbons and aromatic hydrocarbons), alcohols, ketone, ethers (including chain ethers and ring-type ethers (example Such as furans (including tetrahydrofuran derivatives) and dioxane class)), esters, nitrile, sulfone class, amides and nitrogen heterocycles, tool Body such as methanol, ethyl alcohol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, isopropanol, methyl iso-butyl ketone (MIBK), isopropyl acetate, first Base tertbutyl ether, Isosorbide-5-Nitrae-dioxane, methyl phenyl ethers anisole, cyclopentyl methyl ether, toluene, chloroform, or by two in above-mentioned solvent The mixed solvent that kind or more is formed.In some embodiments for preparing crystal using gas-liquid osmosis, the anti-solvent Including but not limited to inorganic solvent (such as water) and organic solvent (such as hydro carbons (be selected from alkanes, olefines, alkynes class), Such as n-hexane, normal heptane, hexamethylene etc.), or by two or more mixed solvents formed in above-mentioned solvent.It is adopting It is prepared in some embodiments of crystal with gas-liquid osmosis, the weight of the compound and good solvent of the formula (I) or formula (Ia) Volume ratio (mg/mL) is about (1-80): 1, preferably (10-60): 1.In some embodiments, the anti-solvent and good solvent Volume ratio is 1:(1-20), preferably 1:(1-10).It is in some embodiments, described that seal second container and stand can be in room Temperature is lower to be carried out.

Some embodiments according to the present invention prepare crystal using the slow volatility process of room temperature, and the method includes by formula (I) or in the compound of formula (Ia) solvent in a reservoir dissolution formed clear solution (solution can be optionally filtered with Obtain clear solution), container is sealed into (such as using sealed membrane), aperture or gap are stayed in sealing part, by the clear solution It places, so that solvent is volatilized, obtain crystal.It is described molten in some embodiments for preparing crystal using the slow volatility process of room temperature Agent includes but is not limited to inorganic solvent (such as water) and organic solvent (such as alcohols, amides, hydro carbons (including alkanes, halogen For alkanes, olefines, alkynes class and aromatic hydrocarbons), ethers (including chain ethers and ring-type ethers (such as furans (including four Hydrogen furans) and dioxane class)), ketone, nitrile or esters, specifically for example isopropanol, methyl ethyl ketone, isopropyl acetate, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methanol, acetone, acetonitrile, ethyl acetate, n-hexane, tetrahydrofuran, methylene chloride Deng), or by two or more mixed solvents formed in above-mentioned solvent.Crystal is being prepared using the slow volatility process of room temperature Some embodiments in, the w/v (mg/mL) of the compound and solvent of the formula (I) or formula (Ia) is (1-50): 1, preferably (1-30): 1.In some embodiments, the placement can carry out at room temperature.

Some embodiments according to the present invention prepare crystal using slow cooling method, the method includes by formula (I) or The compound of formula (Ia) is added into solvent, and heating stirring makes it dissolve, and gained clear solution (can optionally be carried out solution Filtering is to obtain clear solution) it places, slow cooling obtains crystal.In some implementations for preparing crystal using slow cooling method In scheme, the solvent includes but is not limited to inorganic solvent (such as water) and organic solvent (such as alcohols, ketone, hydro carbons (packet Include alkanes, alkyl halide hydro carbons, olefines, alkynes class and aromatic hydrocarbons), ethers (including chain ethers and ring-type ethers (such as furan Class of muttering (including tetrahydrofuran derivatives) and dioxane class)), nitrile, amides and esters, specific such as methyl iso-butyl ketone (MIBK), different Butanol, isobutyl acetate, methanol, tetrahydrofuran, ethyl alcohol, 2- methyltetrahydrofuran, n-hexane etc.), or by above-mentioned solvent Two or more formed mixed solvents.It is described slow in some embodiments for preparing crystal using slow cooling method Slowly the cooling rate to cool down is 0.1-0.5 DEG C/min, preferably 0.1-0.3 DEG C/min, more preferable 0.1 DEG C/min.In some realities It applies in scheme, heating temperature is 30-80 DEG C, preferably 40-70 DEG C, such as 45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C.In some embodiment party In case, temperature at the end of the cooling is room temperature or 0-10 DEG C, such as 3 DEG C, 5 DEG C or 7 DEG C.It is prepared using slow cooling method In some embodiments of crystal, the w/v (mg/mL) of the compound and solvent of the formula (I) or formula (Ia) is (2- 100): 1, preferably (10-80): 1.

Some embodiments according to the present invention prepare crystal using anti-anti-solvent additive process, the method includes but not It is limited to dissolve the compound of formula (I) or formula (Ia) in good solvent, forming clear solution (can optionally be filtered solution To obtain clear solution), then the clear solution is added in anti-solvent, stirring (stirring can in room temperature or Heating condition (such as it is heated to 30-100 DEG C, and preferably 30-80 DEG C, more preferable 35-65 DEG C, such as 45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C) under carry out) under precipitate crystal, or stand (such as at room temperature place) (preferably while slowly solvent flashing) to analyse Crystal out.In some embodiments for preparing crystal using anti-anti-solvent additive process, the good solvent includes but is not limited to have Solvent, such as alcohols, ketone, hydro carbons (selected from alkyl halide hydro carbons and aromatic hydrocarbons), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), sulfone class, amides and organic acid, such as N- methyl pyrrole Pyrrolidone, ethyl alcohol, acetone, acetonitrile, tetrahydrofuran, methylene chloride, methyl iso-butyl ketone (MIBK), ethyl acetate, 2- methyltetrahydrofuran, Toluene etc..In some embodiments for preparing crystal using anti-anti-solvent additive process, the anti-solvent includes but is not limited to nothing Solvent (such as water) and organic solvent (such as hydro carbons (being selected from alkanes, olefines, alkynes class), for example, hexamethylene, just oneself Alkane, normal heptane etc..In some embodiments for preparing crystal using anti-anti-solvent additive process, the good solvent and anti-solvent Volume ratio is (1-20): 1, preferably (1-10): 1.In some embodiments, the compound of the formula (I) or formula (Ia) with The w/v (mg/mL) of good solvent is (1-80): 1, preferably (1-50): 1.

The salt and its crystal and preparation method of the compound of formula (Ia)

Another object of the present invention is to provide the hydrochlorides of the compound of formula (Ia).Preferably, in the formula (Ia) In the hydrochloride of compound, the compound of formula (Ia) and the molar ratio of hydrochloric acid are 1:1.

An embodiment according to the present invention, the present invention provide the hydrochloric acid salt crystal of the compound of formula (Ia), the salt The XRPD map of hydrochlorate crystal be included in 5.4 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, the characteristic peak at 23.0 ± 0.2 ° of the angle of diffraction (2 θ).In preferred embodiments, institute State the hydrochloric acid salt crystal of the compound of formula (Ia) XRPD map be included in 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8±0.2°、13.2±0.2°、16.2±0.2°、17.0±0.2°、17.5±0.2°、18.7±0.2°、22.1±0.2°、 Characteristic peak at 23.0 ± 0.2 ° of the angle of diffraction (2 θ).In a more preferred embodiment, the salt of the compound of the formula (Ia) The XRPD map of hydrochlorate crystal be included in 5.4 ± 0.2 °, 7.7 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 15.3±0.2°、16.2±0.2°、17.0±0.2°、17.5±0.2°、18.0±0.2°、18.7±0.2°、20.3±0.2°、 22.1 ± 0.2 °, 23.0 ± 0.2 °, 25.0 ± 0.2 °, 25.4 ± 0.2 °, the characteristic peak at 27.5 ± 0.2 ° of the angle of diffraction (2 θ). In particularly preferred embodiments, the XRPD map of the hydrochloric acid salt crystal of the compound of the formula (Ia) is included in following diffraction Peak at angle (2 θ):

In particularly preferred embodiments, the XRPD map of the hydrochloric acid salt crystal of the compound of the formula (Ia) is included in Peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Intensity %	2θ(°)±0.2°	Intensity %
				5.4	63.0	18.7	52.3
7.7	14.2	20.3	31.7
				9.3	68.4	22.1	43.5
10.8	74.0	23.0	50.3
				13.2	31.4	25.0	30.1
15.3	11.6	25.4	14.1
				16.2	100.0	27.5	25.8
17.0	58.5	30.0	18.7
				17.5	17.5	30.9	13.3
18.0	18.2

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			5.4	16.3	63.0
7.7	11.5	14.2
			9.3	9.5	68.4
10.8	8.2	74.0
			13.2	6.7	31.4
15.3	5.8	11.6
			16.2	5.5	100.0
17.0	5.2	58.5
			17.5	5.1	17.5
18.0	4.9	18.2
			18.7	4.7	52.3
20.3	4.4	31.7
			22.1	4.0	43.5
23.0	3.9	50.3
			25.0	3.6	30.1
25.4	3.5	14.1
			27.5	3.2	25.8
30.0	3.0	18.7
			30.9	2.9	13.3

In particularly preferred embodiments, the XRPD map of the hydrochloric acid salt crystal of the compound of the formula (Ia) include with Peak at the substantially the same angle of diffraction shown in Fig. 5 (2 θ).In particularly preferred embodiments, the compound of the formula (Ia) Hydrochloric acid salt crystal XRPD peak position it is substantially the same with shown in Fig. 5.

In preferred embodiments, the DSC map of the hydrochloric acid salt crystal of the compound of formula of the invention (Ia) is included in Characteristic peak at about 185.2 ± 0.2 DEG C.In a more preferred embodiment, the hydrochloric acid salt crystal of the compound of the formula (Ia) DSC map include characteristic peak at the temperature substantially the same with shown in Fig. 6.In particularly preferred embodiments, described The feature peak position of the DSC map of the hydrochloric acid salt crystal of the compound of formula (Ia) is substantially the same with shown in Fig. 6.

In a particularly preferred embodiment, the hydrochloric acid salt crystal of the compound of formula of the invention (Ia) is non solvate. In a more preferred embodiment, the hydrochloric acid salt crystal of the compound of formula of the invention (Ia) is anhydrous crystal forms.

Another object of the present invention is to provide the oxalates of the compound of formula (Ia).Preferably, in the formula (Ia) In the oxalates of compound, the compound of formula (Ia) and the molar ratio of oxalic acid are 1:1.

An embodiment according to the present invention, the present invention provide the oxalic acid salt crystal A of the compound of formula (Ia), the grass The XRPD map of hydrochlorate crystal A be included in 8.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, the characteristic peak at 24.7 ± 0.2 ° of the angle of diffraction (2 θ).In preferred embodiments, the formula (Ia) the XRPD map of the oxalic acid salt crystal A of compound is included in 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 23.0 ± 0.2 °, at 24.7 ± 0.2 ° of the angle of diffraction (2 θ) Characteristic peak.In a more preferred embodiment, the XRPD map of the oxalic acid salt crystal A of the compound of the formula (Ia) is included in 8.5±0.2°、13.5±0.2°、14.0±0.2°、17.8±0.2°、20.3±0.2°、20.5±0.2°、20.9±0.2°、 22.1±0.2°、22.8±0.2°、23.0±0.2°、24.1±0.2°、24.7±0.2°、25.3±0.2°、25.8±0.2°、 26.5 ± 0.2 °, the characteristic peak at 28.2 ± 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the formula (Ia) The XRPD map of oxalic acid salt crystal A of compound be included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		8.5	23.0
13.5	24.1
		14.0	24.7
17.8	25.3
		20.3	25.8
20.5	26.5
		20.9	28.2
22.1	34.6
		22.8

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal A of the compound of the formula (Ia) includes Peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Intensity %	2θ(°)±0.2°	Intensity %
				8.5	100.0	23.0	13.2
13.5	6.1	24.1	8.5
				14.0	61.0	24.7	29.6
17.8	15.9	25.3	8.2
				20.3	18.0	25.8	9.0
20.5	8.9	26.5	9.2
				20.9	26.7	28.2	2.1
22.1	6.8	34.6	2.1
				22.8	15.7

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal A of the compound of the formula (Ia) includes Peak at the angle of diffraction (2 θ) substantially the same with shown in Fig. 7.In particularly preferred embodiments, the chemical combination of the formula (Ia) The XRPD peak position of the oxalic acid salt crystal A of object is substantially the same with shown in Fig. 7.

In preferred embodiments, the DSC map of the oxalic acid salt crystal A of the compound of formula of the invention (Ia) is included in Characteristic peak at about 178.6 DEG C ± 0.2 DEG C and 213.6 DEG C ± 0.2 DEG C.In a more preferred embodiment, the formula (Ia) The DSC map of the oxalic acid salt crystal A of compound includes the characteristic peak at the temperature substantially the same with shown in Fig. 8.Especially excellent In the embodiment of choosing, base shown in the feature peak position and Fig. 8 of the DSC map of the oxalic acid salt crystal A of the compound of the formula (Ia) It is identical in sheet.

In a particularly preferred embodiment, the oxalic acid salt crystal A of the compound of formula of the invention (Ia) is non solvate. In a more preferred embodiment, the oxalic acid salt crystal A of the compound of formula of the invention (Ia) is anhydrous crystal forms.

An embodiment according to the present invention, the present invention provide the oxalic acid salt crystal B of the compound of formula (Ia), the grass The XRPD map of hydrochlorate crystal B be included in 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 °, the characteristic peak at 23.3 ± 0.2 ° of the angle of diffraction (2 θ).Preferred real Apply in scheme, the XRPD map of the oxalic acid salt crystal B of the compound of the formula (Ia) be included in 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2±0.2°、8.4±0.2°、8.8±0.2°、12.1±0.2°、12.7±0.2°、15.4±0.2°、15.8±0.2°、 16.7 ± 0.2 °, 20.0 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, the characteristic peak at 23.3 ± 0.2 ° of the angle of diffraction (2 θ). In a more preferred embodiment, the XRPD map of the oxalic acid salt crystal B of the compound of the formula (Ia) be included in 5.0 ± 0.2°、7.7±0.2°、8.2±0.2°、8.4±0.2°、8.8±0.2°、10.2±0.2°、10.7±0.2°、12.1± 0.2°、12.7±0.2°、14.0±0.2°、15.4±0.2°、15.8±0.2°、16.7±0.2°、17.8±0.2°、18.5± 0.2°、19.1±0.2°、20.0±0.2°、21.6±0.2°、22.8±0.2°、23.3±0.2°、25.7±0.2°、26.6± Characteristic peak at 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the oxalates of the compound of the formula (Ia) The XRPD map of crystal B is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		5.0	17.8
7.7	18.5
		8.2	19.1
8.4	20.0
		8.8	20.4
10.2	21.6
		10.7	22.8
12.1	23.3
		12.7	24.3
14.0	24.9
		15.4	25.7
15.8	26.6
		16.7	28.0

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal B of the compound of the formula (Ia) includes Peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			5.0	17.5	3.8
7.7	11.4	20.7
			8.2	10.8	82.1
8.4	10.5	55.2
			8.8	10.0	100.0
10.2	8.7	5.6
			10.7	8.3	3.4
12.1	7.3	12.5
			12.7	7.0	16.6
14.0	6.3	4.9
			15.4	5.7	11.4
15.8	5.6	14.4
			16.7	5.3	32.5
17.8	5.0	7.9
			18.5	4.8	7.0
19.1	4.6	7.6
			20.0	4.4	10.5
20.4	4.4	7.1
			21.6	4.1	15.1
22.8	3.9	12.9
			23.3	3.8	29.8
24.3	3.7	6.7
			24.9	3.6	9.1
25.7	3.5	11.8
			26.6	3.3	10.3
28.0	3.2	6.1

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal B of the compound of the formula (Ia) includes Peak at the angle of diffraction (2 θ) substantially the same with shown in Fig. 9.In particularly preferred embodiments, the chemical combination of the formula (Ia) The XRPD peak position of the oxalic acid salt crystal B of object is substantially the same with shown in Fig. 9.

In preferred embodiments, the DSC map of the oxalic acid salt crystal B of the compound of formula of the invention (Ia) is included in Characteristic peak at about 81.9 ± 0.2 DEG C, 136.6 ± 0.2 DEG C and 166.1 ± 0.2 DEG C.In a more preferred embodiment, described The DSC map of the oxalic acid salt crystal B of the compound of formula (Ia) includes the characteristic peak at the temperature substantially the same with shown in Figure 10. In particularly preferred embodiments, the feature peak position of the DSC map of the oxalic acid salt crystal B of the compound of the formula (Ia) and figure It is substantially the same shown in 10.

An embodiment according to the present invention, the present invention provide the oxalic acid salt crystal C of the compound of formula (Ia), the grass The XRPD map of hydrochlorate crystal C be included in 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 18.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, 23.2 ± 0.2 ° of the angle of diffraction (2 θ) The characteristic peak at place.In preferred embodiments, the XRPD map of the oxalic acid salt crystal C of the compound of the formula (Ia) is included in 5.0±0.2°、6.4±0.2°、7.7±0.2°、8.5±0.2°、9.1±0.2°、10.7±0.2°、11.9±0.2°、12.9 ±0.2°、13.2±0.2°、14.0±0.2°、17.8±0.2°、18.3±0.2°、19.3±0.2°、20.3±0.2°、22.2 ± 0.2 °, the characteristic peak at 23.2 ± 0.2 ° of the angle of diffraction (2 θ).In a more preferred embodiment, the chemical combination of the formula (Ia) The XRPD map of the oxalic acid salt crystal C of object be included in 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2°、10.7±0.2°、11.9±0.2°、12.9±0.2°、13.2±0.2°、14.0±0.2°、15.5±0.2°、15.8± 0.2°、17.3±0.2°、17.8±0.2°、18.3±0.2°、19.3±0.2°、20.3±0.2°、22.2±0.2°、23.2± Characteristic peak at 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the oxalates of the compound of the formula (Ia) The XRPD map of crystal C is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		5.0	17.3
6.4	17.8
		7.7	18.3
8.5	19.3
		9.1	20.3
10.7	22.2
		11.9	23.2
12.9	24.0
		13.2	24.7
14.0	25.8
		15.5	26.5
15.8

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal C of the compound of the formula (Ia) includes Peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Intensity %	2θ(°)±0.2°	Intensity %
				5.0	3.3	17.3	9.7
6.4	11.7	17.8	12.0
				7.7	17.3	18.3	35.9
8.5	100.0	19.3	16.9
				9.1	88.3	20.3	23.8
10.7	6.4	22.2	31.8
				11.9	10.6	23.2	27.8
12.9	13.5	24.0	12.4
				13.2	23.7	24.7	11.7
14.0	28.7	25.8	11.2
				15.5	3.6	26.5	11.3
15.8	5.0

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal C of the compound of the formula (Ia) includes Peak at the angle of diffraction (2 θ) substantially the same with shown in Figure 11.In particularly preferred embodiments, the change of the formula (Ia) The XRPD peak position for closing the oxalic acid salt crystal C of object is substantially the same with shown in Figure 11.

In preferred embodiments, the DSC map of the oxalic acid salt crystal C of the compound of formula of the invention (Ia) is included in Characteristic peak at about 67.5 ± 0.2 DEG C, 106.5 ± 0.2 DEG C and 168.5 ± 0.2 DEG C.In a more preferred embodiment, described The DSC map of the oxalic acid salt crystal C of the compound of formula (Ia) includes the characteristic peak at the temperature substantially the same with shown in Figure 12. In particularly preferred embodiments, the feature peak position of the DSC map of the oxalic acid salt crystal C of the compound of the formula (Ia) and figure It is substantially the same shown in 12.

An embodiment according to the present invention, the present invention provide the oxalic acid salt crystal D of the compound of formula (Ia), the grass The XRPD map of hydrochlorate crystal D be included in 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 15.9 ± 0.2 °, the characteristic peak at 19.9 ± 0.2 ° of angles of diffraction (2 θ).In preferred embodiments, the chemical combination of the formula (Ia) The XRPD map of the oxalic acid salt crystal D of object be included in 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 13.9 ± 0.2 °, 15.9 ± 0.2 °, 19.9 ± 0.2 °, the spy at 22.2 ± 0.2 ° of the angle of diffraction (2 θ) Levy peak.In a more preferred embodiment, the XRPD map of the oxalic acid salt crystal D of the compound of the formula (Ia) is included in 7.9 ±0.2°、8.4±0.2°、8.5±0.2°、9.0±0.2°、12.1±0.2°、12.7±0.2°、13.9±0.2°、15.9± 0.2 °, 16.7 ± 0.2 °, 17.1 ± 0.2 °, 19.9 ± 0.2 °, 21.7 ± 0.2 °, the spy at 22.2 ± 0.2 ° of the angle of diffraction (2 θ) Levy peak.In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal D of the compound of the formula (Ia) be included in Characteristic peak at the lower angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		7.9	16.7
8.4	17.1
		8.5	19.9
9.0	20.5
		12.1	21.7
12.7	22.2
		13.9	23.8
15.9	24.8

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal D of the compound of the formula (Ia) includes Characteristic peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			7.9	11.2	21.2
8.4	10.6	36.1
			8.5	10.4	37.0
9.0	9.9	100.0
			12.1	7.3	12.6
12.7	7.0	7.4
			13.9	6.4	7.1
15.9	5.6	34.7
			16.7	5.3	3.4
17.1	5.2	4.3
			19.9	4.5	10.5
20.5	4.3	4.8
			21.7	4.1	10.0
22.2	4.0	20.9
			23.8	3.7	4.1
24.8	3.6	2.5

In particularly preferred embodiments, the XRPD map of the oxalic acid salt crystal D of the compound of the formula (Ia) includes Peak at the angle of diffraction (2 θ) substantially the same with shown in Figure 13.In particularly preferred embodiments, the change of the formula (Ia) The XRPD peak position for closing the oxalic acid salt crystal D of object is substantially the same with shown in Figure 13.

In preferred embodiments, the DSC map of the oxalic acid salt crystal D of the compound of formula of the invention (Ia) is included in Characteristic peak at about 91.5 ± 0.2 DEG C, 176.0 ± 0.2 DEG C and 203.7 ± 0.2 DEG C.In a more preferred embodiment, described The DSC map of the oxalic acid salt crystal D of the compound of formula (Ia) includes the characteristic peak at the temperature substantially the same with shown in Figure 14. In particularly preferred embodiments, the feature peak position of the DSC map of the oxalic acid salt crystal D of the compound of the formula (Ia) and figure It is substantially the same shown in 14.

Another object of the present invention is to provide the malonates of the compound of formula (Ia).Preferably, at the formula (Ia) Compound malonate in, the molar ratio of the compound of formula (Ia) and malonic acid is 1:1.

An embodiment according to the present invention, the present invention provides the malonate crystal A of the compound of formula (Ia), described The XRPD map of malonate crystal A is included in 6.9 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ).Excellent In the embodiment of choosing, the XRPD map of the malonate crystal A of the compound of the formula (Ia) is included in 6.9 ± 0.2 °, 9.7 ±0.2°、12.7±0.2°、13.7±0.2°、14.8±0.2°、17.7±0.2°、19.2±0.2°、20.7±0.2°、21.0 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.5 ± 0.2 °, at 23.8 ± 0.2 ° of the angle of diffraction (2 θ) Characteristic peak.In a more preferred embodiment, the XRPD map of the malonate crystal A of the compound of the formula (Ia) is included in 6.9±0.2°、9.7±0.2°、12.7±0.2°、13.7±0.2°、14.8±0.2°、15.7±0.2°、17.7±0.2°、 18.7±0.2°、19.2±0.2°、19.7±0.2°、20.7±0.2°、21.0±0.2°、22.1±0.2°、22.6±0.2°、 23.0±0.2°、23.5±0.2°、23.8±0.2°、24.2±0.2°、25.6±0.2°、25.8±0.2°、26.6±0.2°、 Characteristic peak at 27.1 ± 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the compound of the formula (Ia) The XRPD map of malonate crystal A is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		6.9	22.6
9.7	23.0
		12.7	23.5
13.7	23.8
		14.8	24.2
15.7	25.6
		17.7	25.8
18.7	26.6
		19.2	27.1
19.7	29.1
		20.7	29.8
21.0	35.7
		22.1

In particularly preferred embodiments, the XRPD map packet of the malonate crystal A of the compound of the formula (Ia) Include the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Intensity %	2θ(°)±0.2°	Intensity %
				6.9	31.7	22.6	31.2
9.7	7.4	23.0	27.8
				12.7	24.1	23.5	35.1
13.7	38.4	23.8	53.8
				14.8	25.9	24.2	30.9
15.7	8.9	25.6	24.2
				17.7	100.0	25.8	22.6
18.7	16.6	26.6	19.1
				19.2	70.2	27.1	16.1
19.7	20.9	29.1	10.3
				20.7	28.3	29.8	16.9
21.0	57.2	35.7	8.9
				22.1	34.6

In particularly preferred embodiments, the XRPD map packet of the malonate crystal A of the compound of the formula (Ia) Include the peak at the angle of diffraction substantially the same with shown in Figure 15 (2 θ).In particularly preferred embodiments, the formula (Ia) The XRPD peak position of the malonate crystal A of compound is substantially the same with shown in Figure 15.

In preferred embodiments, the DSC map of the malonate crystal A of the compound of formula of the invention (Ia) includes Characteristic peak at about 72.8 ± 0.2 DEG C and 85.8 ± 0.2 DEG C.In a more preferred embodiment, the chemical combination of the formula (Ia) The DSC map of the malonate crystal A of object includes the characteristic peak at the temperature substantially the same with shown in Figure 16.Particularly preferred Embodiment in, base shown in the feature peak position of the DSC map of the malonate crystal A of the compound of the formula (Ia) and Figure 16 It is identical in sheet.

An embodiment according to the present invention, the present invention provides the malonate crystal B of the compound of formula (Ia), described The XRPD map of malonate crystal B be included in 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ).Preferred Embodiment in, the XRPD map of the malonate crystal B of the compound of the formula (Ia) be included in 7.0 ± 0.2 °, 9.3 ± 0.2°、9.8±0.2°、12.8±0.2°、13.7±0.2°、14.0±0.2°、14.6±0.2°、15.1±0.2°、15.8± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ).More excellent In the embodiment of choosing, the XRPD map of the malonate crystal B of the compound of the formula (Ia) is included in 7.0 ± 0.2 °, 9.3 ±0.2°、9.8±0.2°、12.8±0.2°、13.7±0.2°、14.0±0.2°、14.6±0.2°、15.1±0.2°、15.8 ±0.2°、18.1±0.2°、19.2±0.2°、19.7±0.2°、20.4±0.2°、20.7±0.2°、21.1±0.2°、22.5 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ).In particularly preferred embodiments, the change of the formula (Ia) The XRPD map for closing the malonate crystal B of object is included in the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	2θ(°)±0.2°
		7.0	19.2
9.3	19.7
		9.8	20.4
12.8	20.7
		13.7	21.1
14.0	22.5
		14.6	23.8
15.1	26.7
		15.8	27.0
18.1	35.8

In particularly preferred embodiments, the XRPD map packet of the malonate crystal B of the compound of the formula (Ia) Include the peak at the following angle of diffraction (2 θ):

2θ(°)±0.2°	Interplanar distance (interval d)	Intensity %
			7.0	12.6	100.0
9.3	9.5	37.0
			9.8	9.0	26.2
12.8	6.9	8.1
			13.7	6.5	35.0
14.0	6.3	87.0
			14.6	6.1	16.4
15.1	5.9	17.2
			15.8	5.6	17.2
18.1	4.9	64.9
			19.2	4.6	60.0
19.7	4.5	41.3
			20.4	4.4	21.1
20.7	4.3	23.0
			21.1	4.2	36.4
22.5	4.0	22.2
			23.8	3.7	46.2
26.7	3.3	14.7
			27.0	3.3	10.8
35.8	2.5	3.7

In particularly preferred embodiments, the XRPD map packet of the malonate crystal B of the compound of the formula (Ia) Include the peak at the angle of diffraction substantially the same with shown in Figure 17 (2 θ).In particularly preferred embodiments, the formula (Ia) The XRPD peak position of the malonate crystal B of compound is substantially the same with shown in Figure 17.

In preferred embodiments, the DSC map of the malonate crystal B of the compound of formula of the invention (Ia) includes Characteristic peak at about 99.4 ± 0.2 DEG C.In a more preferred embodiment, the malonate of the compound of the formula (Ia) is brilliant The DSC map of body B includes the characteristic peak at the temperature substantially the same with shown in Figure 18.In particularly preferred embodiments, The feature peak position of the DSC map of the malonate crystal B of the compound of the formula (Ia) is substantially the same with shown in Figure 18.

Another object of the present invention is to provide the hydrochloride of the compound of preparation formula (Ia), oxalates, malonate and The method of its various crystal form comprising make the compound of the formula (Ia) of any solid form (such as crystal form or amorphous) with Hydrochloric acid, oxalic acid or malonic acid reaction, are precipitated solid, are then separated and dried the solid of precipitation.

It is described be precipitated solid method include but is not limited to gas-solid osmosis, antisolvent crystallisation method, room temperature suspension paddling process, High temperature suspension paddling process, gas-liquid osmosis, the slow volatility process of room temperature, slow cooling method etc..

It is being precipitated in some embodiments of solid by anti-solvent additive process, is being prepared by the following method the change of formula (Ia) It closes the various crystal forms of the hydrochloride of object, oxalates or malonate: making any solid form (such as crystal form or amorphous) The compound of formula (Ia) reacted in good solvent with hydrochloric acid, oxalic acid or malonic acid, add anti-solvent thereto after reaction, Stirring (stirring can room temperature or cooling conditions (such as be cooled to 0-20 DEG C, preferably 0-10 DEG C, such as 0 DEG C, 5 DEG C or 10 DEG C) under carry out) under precipitate crystal, or stand (such as at room temperature place) (preferably while slowly solvent flashing) to It precipitates crystal, is then separated and dried the crystal of precipitation.The good solvent includes but is not limited to organic solvent, such as alcohols, Ketone, nitrile, hydro carbons (be selected from alkyl halide hydro carbons, aromatic hydrocarbons), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), sulfone class, esters, amides and organic acid, such as methanol, ethyl alcohol, acetone, Acetonitrile, tetrahydrofuran, dimethyl sulfoxide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, methyl ethyl ketone, ethyl acetate, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methyl phenyl ethers anisole, toluene, methylene chloride etc..The anti-solvent includes but is not limited to inorganic molten Agent (such as water) and organic solvent (such as hydro carbons (being selected from alkanes, olefines, alkynes class), for example, n-hexane, normal heptane, Hexamethylene etc.).The volume ratio of the good solvent and anti-solvent is 1:(0.1-60), preferably 1:(0.3-40).The formula (Ia) Compound and good solvent w/v (mg/mL) be (1-100): 1, preferably (10-60): 1.The change of the formula (Ia) The molar ratio for closing object and hydrochloric acid, oxalic acid or malonic acid is (1-5): (1-5), preferably (1-3): (1-3).

It is precipitated in some embodiments of solid by the slow volatility process of room temperature, is prepared by the following method formula (Ia) The various crystal forms of the hydrochloride of compound, oxalates or malonate: make any solid form (such as crystal form or without fixed Shape) the compound of formula (Ia) dissolve and react in a solvent with hydrochloric acid, oxalic acid or malonic acid, delay at room temperature after reaction The crystal of precipitation is then separated and dried by slow vaporization with precipitating crystal.The solvent include but is not limited to inorganic solvent (such as Water) and organic solvent (such as alcohols, amides, hydro carbons (including alkanes, alkyl halide hydro carbons, olefines, alkynes class and virtue Hydro carbons), ethers (including chain ethers and ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class)), ketone Class, nitrile or esters, specifically for example isopropanol, methyl ethyl ketone, isopropyl acetate, 2- methyltetrahydrofuran, cyclopentyl methyl ether, Methanol, acetone, acetonitrile, ethyl acetate, n-hexane, tetrahydrofuran, methylene chloride etc.), or by two kinds in above-mentioned solvent or The mixed solvent of more kinds of formation.The compound of the formula (Ia) and the w/v (mg/mL) of solvent are (1-100): 1, It is preferred that (1-50): 1.The compound of the formula (Ia) and the molar ratio of hydrochloric acid, oxalic acid or malonic acid are 1-5:1-5, preferably 1- 3:1-3。

Pharmaceutical composition and purposes

Another object of the present invention is to provide a kind of pharmaceutical composition, it includes:

I) any one or more in following substance:

The crystal C of the compound of formula (I) of the invention；

The crystal B of the compound of formula (Ia) of the invention；Or

The salt of the compound of formula (Ia) of the invention, the especially hydrochloride of the compound of formula (Ia), oxalates or the third two The solid form of the hydrochloride of the compound of hydrochlorate, more particularly formula (Ia), oxalates or malonate, more particularly formula (Ia) The hydrochloric acid salt crystal of compound, formula (Ia) compound oxalic acid salt crystal A, B, C or D or formula (Ia) compound third Diacid salt crystal A or B；And

Ii) one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide for the calmness of individual, hypnosis, antianxiety, of flaccid muscles or anticonvulsant Method comprising to any one or more following substance of individuals in need dosage treatment effective amount:

The crystal C of the compound of formula (I) of the invention；

The crystal B of the compound of formula (Ia) of the invention；Or

The salt of the compound of formula (Ia) of the invention, the especially hydrochloride of the compound of formula (Ia), oxalates or the third two The solid form of the hydrochloride of the compound of hydrochlorate, more particularly formula (Ia), oxalates or malonate, more particularly formula (Ia) The hydrochloric acid salt crystal of compound, formula (Ia) compound oxalic acid salt crystal A, B, C or D or formula (Ia) compound third Diacid salt crystal A or B.

Another object of the present invention is to provide any one or more following substances:

The crystal C of the compound of formula (I) of the invention；

The crystal B of the compound of formula (Ia) of the invention；Or

The salt of the compound of formula (Ia) of the invention, the especially hydrochloride of the compound of formula (Ia), oxalates or the third two The solid form of the hydrochloride of the compound of hydrochlorate, more particularly formula (Ia), oxalates or malonate, more particularly formula (Ia) The hydrochloric acid salt crystal of compound, formula (Ia) compound oxalic acid salt crystal A, B, C or D or formula (Ia) compound third Diacid salt crystal A or B,

It is used for calmness, hypnosis, antianxiety, of flaccid muscles or anticonvulsion.

Another object of the present invention is to provide any one or more following substances to prepare for calmness, hypnosis, resist Purposes in anxiety, of flaccid muscles or anticonvulsant drug:

The crystal C of the compound of formula (I) of the invention；

The crystal B of the compound of formula (Ia) of the invention；Or

As used herein, the term " pharmaceutically acceptable carrier " refer to the diluent being administered together with therapeutic agent, Adjuvant, excipient or medium, and it is adapted for contact with the mankind and/or other animals in the range of reasonable medical judgment Tissue without excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk than corresponding other problems or concurrent Disease.

Workable pharmaceutically acceptable carrier includes but is not limited to sterile liquid in pharmaceutical composition of the invention, Such as water and oil, the oil including those petroleum, animal, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame Oil etc..When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and grape can also be used Sugar and glycerine water solution are especially used for injection as liquid-carrier.Suitable drug excipient include starch, glucose, Lactose, sucrose, gelatin, maltose, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, skimmed milk power, Glycerol, propylene glycol, water, ethyl alcohol etc..The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffering Agent.Oral preparation may include standard vector, such as the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, fiber Element, magnesium carbonate etc..The example of suitable pharmaceutically acceptable carrier is such as in Remington ' s Pharmaceutical Described in Sciences (1990).

Pharmaceutical composition of the invention can be acted on systematically and/or locally be acted on.For this purpose, they can be suitble to Approach administration, such as by injection, intravenous, intra-arterial, subcutaneous, peritonaeum, intramuscular or percutaneous dosing；Or by taking orally, Buccal, intranasal, it is transmucosal, local, in the form of eye-drops preparations or pass through inhalation.

For these administration routes, composition of the invention is administered in the dosage form that can be suitble to.

The dosage form can be solid pharmaceutical preparation, semisolid preparation, liquid preparation or gaseous state preparation, including but not limited to tablet, Capsule, granule, pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, paste, is washed powder Agent, ointment, aqueous suspension, injectable solutions, suspension, elixir, syrup.

Pharmaceutical composition of the present invention can be prepared by any method well known in the art, such as by mixed Conjunction, granulation, the processing such as sweet tablet, mills, emulsifies, being lyophilized to prepare at dissolution.

" therapeutically effective amount " refers to as used herein, the term be administered after can alleviate to a certain extent and treat disease The amount of the compound of one or more symptoms of disease.

Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, can be administered at any time several Divided dose, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It should be noted that dose value can be with will subtract The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition Break to adjust at any time.

The amount of the compound of the present invention being administered can depend on individual treated, the seriousness of illness or the patient's condition, to The rate of medicine, the disposition of compound and the judgement of prescriber.In general, effective dose is in per kg body weight per day about 0.0001 To about 50mg, for example, about 0.01 to about 10mg/kg/ days (single or divided doses).For the people of 70kg, this can be added up to about 0.007mg/ to about 3500mg/, for example, about 0.7mg/ to about 700mg/.In some cases, it is not higher than aforementioned model The dosage level of the lower limit enclosed can be it is enough, and in other cases, still can be in the feelings for not causing any harmful side effect Larger dose is used under condition, condition is that the larger dose is divided into several smaller doses to be administered throughout the day first.

Content or dosage of the compound of the present invention in pharmaceutical composition can be about 0.01mg to about 1000mg, be suitble to Ground is 0.1-500mg, preferably 0.5-300mg, more preferable 1-150mg, particularly preferred 1-50mg, for example, 1.5mg, 2mg, 4mg, 10mg and 25mg etc..

Unless otherwise stated, otherwise as used herein, term " treatment " means to reverse, mitigates, inhibits such art The progress of one or more symptoms of illness or the patient's condition applied by language or such illness or the patient's condition, or prevent such illness Or one or more symptoms of the patient's condition or such illness or the patient's condition.

" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this Disease described in text) individual human (referred to as patient) or normal individual." non-human animal " includes all vertebrates in the present invention, Such as nonmammalian (such as birds, amphibian, reptile) and mammal, such as non-human primates, domestic animal and/or Domesticated animal (such as sheep, dog, cat, milk cow, pig etc.).

Embodiment

The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention Art scheme, is not intended to limit the scope of the present invention, and those skilled in the art can carry out some nonessential modifications and adaptations, still It belongs to the scope of protection of the present invention.

Experiment test equipment information and method used

Method 1, XRPD

XRPD map acquires on PANalyticalEmpyrean X-ray powder diffraction analyzer, and the X of XRPD test is penetrated Line be Cu-k α (1.540598；1 intensity of 1.544426K α 2/K α: 0.50).

Method 2, dsc analysis

DSC data is acquired on TAQ200/2000 differential scanning calorimeter.

Method 3, ion chromatography (IC)

Gegenion content is measured using ion chromatography (IC), and it is combined with HPLC with the resulting salt Chinese style of determination (Ia) molar ratio of compound and salt-forming ion.

Method 4, petrographic microscope (PLM) test

PLM test is acquired at room temperature by Axio Lab.A1 positively fixed type microscope.

Method 5, dynamic water absorption (DVS)

DVS numerical value acquires on the DVS Intrinsic of SMS (Surface Measurement Systems).DVS is surveyed Try relative humidity LiCl, Mg (NO at 25 DEG C₃)₂It is corrected with the deliquescence point of KCl.

Embodiment 1

(8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole simultaneously [1,4] two [4,3-a] 3- Azepine- 4- base) methyl propionate (compound of formula (I)) preparation

Step 1: the chloro- 5- of 7- (2- fluorophenyl) -1H- benzo [e] [1,4] diaza- 2 (3H)-thioketones (compound B) Preparation

By the chloro- 5- of 7- (2- fluorophenyl) -1H- benzo [e] [1,4] diaza- 2 (3H) -one (compound A, 5.0g, 17.3mmol) it is dissolved in tetrahydrofuran (150mL).It is added phosphorus pentasulfide (5.77g, 6.55mmol), heats the mixture to 78 DEG C, it reacts 2 hours.Filtering is washed 3 times, and water is added into filtrate, is extracted with ethyl acetate 3 times, is dried and concentrated, through column chromatography Method purifies to obtain the chloro- 5- of target product 7- (2- fluorophenyl) -1H- benzo [e] [1,4] diaza- 2 (3H)-thioketones (compounds B, 4.2g, yield: 79%).

MS m/z(ESI):305[M+H]+

Step 2: 8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole [4,3-a] [1,4] DiazaThe preparation of (compound C)

By the chloro- 5- of 7- (2- fluorophenyl) -1H- benzo [e] [1,4] diaza- 2 (3H)-thioketones (compound B, 400mg, 1.31mmol is synthesized referring to embodiment 7, the first step) it is dissolved in dioxane (15mL), addition cyclopropyl formylhydrazine (394mg, 3.93mmol) and mercuric acetate (513mg, 1.97mmol).100 DEG C are heated the mixture to, is reacted 5 hours.It is cooling, it is poured into ice water In, it is extracted with ethyl acetate, organic phase is washed with water 5 times, is dried and concentrated, obtain the chloro- 1- cyclopropyl -6- of target product 8- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole [4,3-a] [1,4] diaza(compound C, 280mg, yield: 68.5%)

MS m/z(ESI):353[M+H]+

Step 3: (8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole is simultaneously [4,3-a] by 3- [1,4] diaza- 4- base) methyl propionate (compound of formula (I)) preparation

By compound 8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole [4,3-a] [1, 4] diaza(compound 12b, 150mg, 0.43mmol) and methyl acrylate (366mg, 4.3mmol) are dissolved in dry THF (2mL).Mixture is cooled to -15 DEG C, is added portionwise potassium tert-butoxide (95mg, 0.86mmol), stirring 1 hour until LCMS is aobvious Show that reaction terminates.After reaction solution is concentrated, inverted HPLC purifies to obtain target product 3- (chloro- 1- cyclopropyl -6- (the 2- fluorine of 8- Phenyl) -4H- benzo [f] [1,2,4] triazole simultaneously [4,3-a] [1,4] diaza- 4- base) methyl propionate (chemical combination of formula (I) Object, 31mg, yield: 16.6%).

MS m/z(ESI):439[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ: 7.99 (d, J=8.8Hz, 1H), 7.87 (dd, J=8.8,6.4Hz, 1H), 7.66-7.54(m,2H),7.38-7.32(m,2H),7.25-7.20(m,1H),4.25-4.22(m,1H),3.61(s,3H), 2.76-2.53(m,4H),2.12-2.08(m,1H),1.17-1.14(m,1H),1.03-0.90(m,3H)。

Embodiment 2

(8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole is simultaneously [4,3-a] by 3 (S) -3- [1,4] diaza- 4- base) methyl propionate (compound of formula (Ia)) preparation

Step 1: (S) -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -4- ((tertbutyloxycarbonyl) amino) -5- oxygen For the methyl valerate (preparation of compound c)

By the chloro- 2'- fluorine benzophenone of 2- amino -5- (compound a, 20g, 0.083mol are commercially available) and the tertiary fourth oxygen of N- Carbonyl-Pidolidone -5- methyl esters (compound b, 23g, 0.088mol, be commercially available) is dissolved in methylene chloride (300mL).It will mixing Object is cooled to 0 DEG C, is added dicyclohexylcarbodiimide (DCC, 18.2g, 0.088mmol), and stirs 24 hours.Through liquid chromatography mass spectrometric Combined instrument (LCMS) test display reaction terminates.Reaction solution is poured into ice water, is extracted with ethyl acetate, organic phase is washed with water It 3 times, is dried and concentrated, obtains crude product (S) -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -4- ((tertbutyloxycarbonyl) ammonia Base) -5- oxopentanoic (compound 17c, 50g), it is directly used in and is reacted in next step.

Step 2: (S) -4- amino -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -5- oxopentanoic (is changed Close the preparation of object d)

By (S) -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -4- ((tertbutyloxycarbonyl) amino) -5- oxo penta Sour methyl esters (compound c, 50g) is dissolved in methylene chloride (200mL).It is added trifluoroacetic acid (TFA, 100mL), heats the mixture to 40 DEG C, stirring 2 hours until LCMS display reaction terminates.Reaction solution is concentrated, gained residue is crude product (S) -4- amino -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -5- oxopentanoic (compound d, 40g) is directly used in next step Reaction.

Step 3: (S) -3- (7- chloro-2-oxo -5- (2- fluorophenyl) -2,3- dihydro -1H- benzo [e] [1,4] diaza- 3- base) methyl propionate (preparation of compound e)

By (S) -4- amino -5- ((the fluoro- benzoyl -4- chlorphenyl of 2-) amino) -5- oxopentanoic (compound d, 40g) it is dissolved in methanol (500mL).NaHCO is added₃PH to about 10 is adjusted, and is stirred 24 hours.LCMS display reaction terminates.It will be anti- It answers liquid to filter, filtrate is poured into ice water, be extracted with ethyl acetate.Organic phase is washed with water 3 times, after being dried and concentrated, it will be residual Excess purifies to obtain target product (S) -3- (7- chloro-2-oxo -5- (2- fluorophenyl) -2,3- dihydro-through silica gel column chromatography 1H- benzo [e] [1,4] diaza- 3- base) methyl propionate (compound e, 22g, yield: 73%).

MS m/z(ESI):374[M+H]+

Step 4: 3 (S) -3- (the chloro- 2- of 7- ((two morpholine phosphoryls) oxygroup) -5- (2- fluorophenyl) -3H- benzo [e] [1,4] diaza- 3- base) methyl propionate (preparation of compound f)

By 3 (S) -3- (7- chloro-2-oxo -5- (2- fluorophenyl) -2,3- dihydro -1H- benzo [e] [1,4] diaza- 3- yl) methyl propionate (compound e, 6g, 0.016mol) is dissolved in dry tetrahydrofuran (100mL).Mixture is cooled to 0 DEG C, It is added NaH (963mg, 0.024mol), and stirs 30 minutes.Then chlorine phosphonate, morpholino ester (8.21g, 0.032mmol) is added, stirs It mixes 1 hour until LCMS display reaction terminates.Reaction solution is poured into ice water, is extracted with ethyl acetate, organic phase is washed with water 3 It is secondary, it is dried and concentrated, obtains crude product 3 (S) -3- (the chloro- 2- of 7- ((two morpholine phosphoryls) oxygroup) -5- (2- fluorophenyl) -3H- Benzo [e] [1,4] diaza- 3- base) methyl propionate (compound f, 12g), it is directly used in and is reacted in next step.

Step 5: (S) -3- (8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] [1,2,4] triazole simultaneously [4, 3-a] [1,4] diaza- 4- base) methyl propionate (compound of formula (Ia)) preparation

By (S) -3- (the chloro- 2- of 7- ((two morpholine phosphoryls) oxygroup) -5- (2- fluorophenyl) -3H- benzo [e] [1,4] two Azepine- 3- base) methyl propionate (compound f, 13.0g) is dissolved in Isosorbide-5-Nitrae-dioxane (150mL).Cyclopropyl formylhydrazine is added (4.81g, 0.048mol) is heated to 100 DEG C, and stirs 14 hours.LCMS display reaction terminates.It, will after reaction solution is concentrated Residue purifies to obtain target product 3 (S) -3- (8- chloro- 1- cyclopropyl -6- (2- fluorophenyl) -4H- benzo [f] through preparing HPLC [1,2,4] triazole simultaneously [4,3-a] [1,4] diaza- 4- base) methyl propionate (compound of formula (Ia), 2.8g, yield 30%).

MS m/z(ESI):439[M+H]⁺

Embodiment 3

The preparation and representation of the crystal B of the compound of formula (Ia)

The crystal B of preparation formula (Ia) compound in accordance with the following methods:

Embodiment 3.1. gas-solid osmosis

The compound for weighing the formula (Ia) of about every part of 15mg, is added into 3mL bottle.Separately it is added about in 20mL bottles 3mL bottle opening is placed in 20mL bottle, 20ml bottle is sealed by solvent shown in 2mL following table.Stand 13 days at room temperature After collect solid.The experimental results are shown inthe following table.

Solvent	Obtained solid
		Water	Crystal B
Ethyl alcohol	Crystal B
		Isopropanol	Crystal B

According to method 1, XRPD analysis is carried out to obtained solid, gained XRPD map is as shown in fig. 1.It is right according to method 2 Obtained solid carries out dsc analysis, and gained DSC map is as shown in Figure 2.

Experimental example 3.2. anti-solvent additive process

The compound for weighing the formula (Ia) of about every part of 15mg, is added into the bottle of 20mL.Shown in 0.5mL following table Good solvent dissolution after, corresponding anti-solvent shown in following table is added dropwise into resulting clear solution, while be added dropwise while stir to There is solid precipitation.Clarified solution is suspended at 5 DEG C if being still precipitated without solid after about 15mL anti-solvent is added and is stirred overnight；If still No solid is precipitated then slowly volatilizees clarified solution crystallization at room temperature.Solid be precipitated is collected, the experimental results are shown inthe following table.

The XRPD map and DSC map of obtained solid and the XRPD map in embodiment 3.1 and DSC map substantially phase Together, show to have obtained crystal B.

Embodiment 3.3. room temperature suspension paddling process

The compound for weighing the formula (Ia) of about every part of 15mg, is added into 1.5mL vial, adds thereto respectively Enter solvent shown in 0.6mL following table, obtains suspension.After gained suspension is stirred 14 days at room temperature, solid is collected by centrifugation, The experimental results are shown inthe following table.

Solvent	Obtained solid
		Methyl tertiary butyl ether(MTBE)	Crystal B
Methanol/water (1:2)	Crystal B
		Acetone/water (1:2)	Crystal B
Acetonitrile/water (1:2)	Crystal B
		Dimethyl sulfoxide/water (1:2)	Crystal B
2- methyltetrahydrofuran/n-hexane (1:2)	Crystal B
		Ethyl acetate/n-hexane (1:2)	Crystal B
Toluene/n-hexane (1:2)	Crystal B

Embodiment 3.4. high temperature suspension paddling process

The compound for weighing the formula (Ia) of about every part of 15mg, is added into 1.5mL vial, adds thereto respectively Enter 0.6mL solvent as shown in the following chart, obtains suspension.After gained suspension is stirred 14 days at 50 DEG C, it is collected by centrifugation solid Body, the experimental results are shown inthe following table.

Solvent	Obtained solid
		Methyl tertiary butyl ether(MTBE)	Crystal B
Methanol/water (1:2)	Crystal B
		Acetone/water (1:2)	Crystal B
Dimethyl sulfoxide/water (1:2)	Crystal B
		2- methyltetrahydrofuran/n-hexane (1:2)	Crystal B
Ethyl acetate/n-hexane (1:2)	Crystal B
		Toluene/n-hexane (1:2)	Crystal B

Embodiment 3.5. gas-liquid osmosis

The compound for weighing the formula (Ia) of about every part of 15mg, is added into 3mL bottle, is added under 0.5mL thereto Good solvent shown in table is to dissolve.Corresponding anti-solvent shown in about 3mL following table is separately added in the bottle of 20mL, by 3mL bottle Opening is placed in 20mL bottle, sealing, and is stood at room temperature.When having observed solid precipitation, then solid, experiment knot are taken out Fruit is as shown in the table.

The slow volatility process of embodiment 3.6. room temperature

The compound for weighing the formula (Ia) of about every part of 15mg, is added into 3mL bottle.It is added thereto respectively Solvent shown in 1.0mL following table ensures that sample is completely dissolved to obtain clear solution through ultrasound or concussion.It is covered and is equipped with sealed membrane The bottle of clear solution, and 3~4 apertures are pricked on sealed membrane, then slowly volatilization at room temperature.It collects resulting solid Body, the experimental results are shown inthe following table.

Solvent	Obtained solid
		Isopropanol	Crystal B
Methyl ethyl ketone	Crystal B
		Isopropyl acetate	Crystal B
2- methyltetrahydrofuran	Crystal B
		Cyclopentyl methyl ether	Crystal B
Methanol/water (4:1)	Crystal B
		Acetone/water (4:1)	Crystal B
Acetonitrile/water (4:1)	Crystal B
		Ethyl acetate/n-hexane (4:1)	Crystal B
Tetrahydrofuran/n-hexane (4:1)	Crystal B
		Methylene chloride/n-hexane (4:1)	Crystal B

Embodiment 3.7. slow cooling method

The compound for weighing a certain amount of formula (Ia) is added into 3mL bottle, and 1.0mL following table institute is added thereto The solvent shown, with the speed magnetic agitation of 800RPM 3 hours at 50 DEG C.With 0.45 micron of PTFE membrane filtration, supernatant is taken. Gained supernatant is cooled to 5 DEG C from 50 DEG C with the speed of 0.1 DEG C/min, and constant temperature at 5 DEG C.The solid being precipitated is collected, it is real It is as shown in the table to test result.

Solvent	Obtained solid
		Methyl tertiary butyl ether(MTBE)	Crystal B
Isobutanol	Crystal B
		Isobutyl guanidine-acetic acid	Crystal B
Methanol/water (1:1)	Crystal B
		Acetone/water (1:1)	Crystal B
Ethyl alcohol/n-hexane (1:1)	Crystal B
		2- methyltetrahydrofuran/n-hexane (1:1)	Crystal B

The anti-anti-solvent additive process of embodiment 3.8.

The compound for weighing the formula (Ia) of about every part of 15mg, is added into the bottle of 20mL, shown in 0.5mL following table Good solvent dissolve to obtain clear solution.Gained clear solution is rapidly joined to equipped with corresponding to anti-solvent shown in 4mL following table In 5mL bottle, while magnetic agitation.After balancing a few minutes, solid is collected, the experimental results are shown inthe following table.

Embodiment 4

The preparation and representation of the crystal C of the compound of formula (I)

Room temperature suspension paddling process

The compound for weighing the formula (I) of about every part of 15mg, is added into 1.5mL vial, adds thereto respectively Enter solvent shown in following table in 0.6mL, obtains suspension.Gained suspension is placed in after stirring 14 days at room temperature, is collected by centrifugation Solid.The experimental results are shown inthe following table.

Solvent	Obtained solid
		Isopropanol	Crystal C

According to method 1, XRPD analysis is carried out to obtained solid, gained XRPD map is as shown in Figure 3.It is right according to method 2 Obtained solid carries out dsc analysis, and gained DSC map is as shown in Figure 4.

Embodiment 5

The preparation and representation of the hydrochloric acid salt crystal of the compound of formula (Ia)

The slow volatility process of room temperature

The compound for weighing 200.1mg formula (Ia) is added into 20ml vial, and the acetic acid second of 1.5mL is added Ester is allowed to dissolve.Hydrochloric acid solution after adding from 3.6mL dilution to resulting solution is (by by 76 μ L hydrochloric acid (37%, 12mol/ L) diluted and obtained with 6.0mL ethyl acetate), after being stirred at room temperature 22 hours, slowly volatilize in room temperature.Solid is collected by filtration, 50 It is dried in vacuo at DEG C.

It according to method 3, measures in the hydrochloride of the compound of formula (Ia), the compound of formula (Ia) and the molar ratio of hydrochloric acid For 1:1.According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 5.According to method 2, Dsc analysis is carried out to crystal obtained, gained DSC map is as shown in Figure 6.According to method 4, crystal obtained is carried out PLM test, gained crystal grain is smaller, average grain diameter < 10 micron, has extraordinary mobility, is convenient for preparation.

Embodiment 6

The preparation and representation of the oxalic acid salt crystal A of the compound of formula (Ia)

6.1. anti-solvent additive process

Pass through the oxalic acid salt crystal A of the compound of following steps preparation formula (Ia):

The compound of 299.5mg formula (Ia) and the oxalic acid of 97.2mg are weighed, is added into 20mL vial.To the glass 7.5mL acetone is added in glass bottle to be allowed to dissolve.Then the normal heptane of 11.0mL is added into resulting solution.It is small to be stirred at room temperature 24 When, by the way that solid is collected by centrifugation.

It according to method 3, measures in the oxalates of the compound of formula (Ia), the compound of formula (Ia) and the molar ratio of oxalic acid For 1:1.According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 7.According to method 2, Dsc analysis is carried out to crystal obtained, gained DSC map is as shown in Figure 8.According to method 4, crystal obtained is carried out PLM test, gained crystal are stick solid, and crystal grain is smaller, average grain diameter < 10 micron, have extraordinary mobility, just In preparation.

6.2. the slow volatility process of room temperature

The compound of the formula (Ia) of about every part of 299.5mg and the oxalic acid of 97.2mg are weighed, is added into small to 20mL glass In bottle.10mL ethyl acetate is added to be allowed to dissolve, is placed in after stirring 3 days at room temperature, slowly volatilizees in room temperature, obtain solid.It is logical It crosses and resulting solid is collected by centrifugation, it is dry in room temperature in vacuo.

The XRPD map and DSC map of obtained solid and the XRPD map in embodiment 6.1 and DSC map substantially phase Together, show to have obtained the oxalic acid salt crystal A of the compound of formula (Ia).

Embodiment 7

The preparation and representation of the oxalic acid salt crystal B of the compound of formula (Ia)

The slow volatility process of room temperature

The compound of the formula (Ia) of about every part of 299.5mg and the oxalic acid of 97.2mg are weighed, is added into small to 20mL glass In bottle.10mL acetone is added to be allowed to dissolve, is placed in after stirring 3 days at room temperature, slowly volatilizees in room temperature, obtain solid.By from The heart collects resulting solid, dry in room temperature in vacuo.

According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 9.According to method 2, dsc analysis is carried out to crystal obtained, gained DSC map is as shown in Figure 10.

Embodiment 8

The preparation and representation of the oxalic acid salt crystal C of the compound of formula (Ia)

The slow volatility process of room temperature

The compound of the formula (Ia) of about every part of 299.5mg and the oxalic acid of 97.2mg are weighed, is added into small to 20mL glass In bottle.10mL tetrahydrofuran/water (V/V, 19:1) is added to be allowed to dissolve, is placed in after stirring 3 days at room temperature, is slowly waved in room temperature Hair, obtains solid.It is dry in room temperature in vacuo by the way that solid is collected by centrifugation.

According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 11.According to side Method 2 carries out dsc analysis to crystal obtained, and gained DSC map is as shown in Figure 12.

Embodiment 9

The preparation and representation of the oxalic acid salt crystal D of the compound of formula (Ia)

The slow volatility process of room temperature

The compound of the formula (Ia) of about every part of 299.5mg and the oxalic acid of 97.2mg are weighed, is added into small to 20mL glass It in bottle, is separately added into 10mL ethyl acetate and is allowed to dissolve, be placed in after stirring 12 hours at room temperature, slowly volatilize, obtain in room temperature Solid.By the way that solid is collected by centrifugation, it is dried in vacuo in 50 DEG C.

According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 13.According to side Method 2 carries out dsc analysis to crystal obtained, and gained DSC map is as shown in Figure 14.

Embodiment 10

The preparation and representation of the malonate crystal A of the compound of formula (Ia)

Anti-solvent additive process:

The compound of 200.2mg formula (Ia) and the malonic acid of 50.7mg are weighed, is added into 20mL vial.To this 4.5mL ethyl acetate is added in vial to be allowed to dissolve, the normal heptane of 4.0mL is then added into resulting solution.Room temperature is stirred It mixes 24 hours, by the way that solid is collected by centrifugation, is dried in vacuo at 50 DEG C.

It according to method 3, measures in the malonate of the compound of formula (Ia), the compound of formula (Ia) and rubbing for malonic acid You are than being 1:1.According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 15.According to Method 2 carries out dsc analysis to crystal obtained, and gained DSC map is as shown in Figure 16.According to method 4, to obtained Crystal carries out PLM test, and gained crystal is granular solids, and crystal grain is smaller, average grain diameter < 20 micron, and it is very good to have Mobility, be convenient for preparation.

Embodiment 11

The preparation and representation of the malonate crystal B of the compound of formula (Ia)

The slow volatility process of room temperature

The compound of 200.2mg formula (Ia) and the malonic acid of 50.7mg are weighed, is added into 20mL vial.To this 4.5mL ethyl acetate is added in vial slowly to volatilize in room temperature after stirring 12 hours, obtain solid.It is solid by being collected by centrifugation Body is dried in vacuo at 50 DEG C.

According to method 1, XRPD analysis is carried out to crystal obtained, gained XRPD map is as shown in Figure 17.According to side Method 2 carries out dsc analysis to crystal obtained, and gained DSC map is as shown in Figure 18.

Experimental example

The test of 1. equilbrium solubility of experimental example

At room temperature, by the crystal B of the compound of suitable formula (Ia) in water with the speed magnetic agitation of 500RPM, with shape At suspension.The suspension is centrifuged after 24 hours and passes through 0.45 micron of PTFE membrane filtration by balance.It will be isolated upper Clear liquid and remaining solid carry out concentration mensuration and crystal form verifying respectively.

Experimental result shows that, under room temperature, the solubility of the crystal B of the compound of formula (Ia) in water can reach 0.084mg/mL, unformed and other crystal forms of the compound better than formula (Ia).Also, it is solid to separate the residue after magnetic agitation Body, through XRPD, analysis shows that, the crystal form of remaining solid remains as the crystal B of the compound of formula (Ia), has no there is no variation Other impurities generate, and are also not converted into other crystal forms.It is excellent molten that this experiment shows that the crystal B of the compound of formula (Ia) has Xie Du and stability, the property with excellent dynamic stabilization.In addition, this property of the crystal B of the compound of formula (Ia) It is also allowed to be especially advantageous for preparation, can guarantee the stabilization in production process.

Experimental example 2. draws the test of moist and solid-state stability

According to method 5, respectively to hydrochloric acid salt crystal, the formula of the crystal B of the compound of formula (Ia), the compound of formula (Ia) (Ia) the malonate crystal A of the compound of the oxalic acid salt crystal A and formula (Ia) of compound carries out DVS characterization, to study it Draw moist and solid-state stability under different humidity.

The experimental results are shown inthe following table:

From the above results, the crystal form of the invention weight change caused by moisture absorption under 80% high humidity is small In 1%, show that it is moist almost without drawing.Further, through XRPD analysis shows that, the crystal form of above-mentioned crystal form under high humidity conditions XRPD data are unchanged, show the crystal form of the invention excellent in terms of drawing moist and solid-state stability.Particularly, this hair Weight change of the crystal B of the compound of bright formula (Ia) under 80% high humidity is only 0.1%, show its almost without Hygroscopicity.This shows that the crystal B of the compound of formula of the invention (Ia) is highly stable to super-humid conditions, and its hygroscopicity is significant Better than other crystal forms of the compound of formula (Ia).

The test of 3. physical and chemical stability of experimental example

3.1. the physical and chemical stability test of the crystal of the compound of the present invention and its salt

The compound of formula of the invention shown in suitable following table (Ia) and its crystal form of salt are taken respectively, in following 3 items Detect its physical and chemical stability under part: 80 DEG C silent to place 24 hours, 25 DEG C/60%RH opening places 1 week and 40 DEG C/75% RH opening is placed 1 week.Then XRPD and HPLC analysis is carried out, respectively to sample shown in table to determine that crystal form and purity become Change.The experimental results are shown inthe following table:

It should be pointed out that the ratio of " relative purity " i.e. relative to starting HPLC purity shown in upper table.

From the above results, the crystal of the compound of the present invention and its salt purity under high temperature and/or super-humid conditions becomes Change very small, the malonate crystal form A of the compound of the crystal B and formula (Ia) of the compound of formula (Ia) especially of the invention, Its purity under high temperature and/or super-humid conditions absolutely not changes.Also, through XRPD analysis shows that, formula of the invention (Ia) The change of crystal form does not occur after placement for the crystal of compound and its salt, this show formula of the invention (Ia) compound and The crystal of its salt not only stablizes super-humid conditions and/or hot conditions, also stablizes under this condition to air (such as oxygen), tool There is very excellent physical and chemical stability.Above-mentioned experimental result shows that the crystal of the compound of formula of the invention (Ia) is to fortune Defeated condition is without particular/special requirement, without sealing, being protected from light, the special condition such as low temperature, can also protect even if under high humidity and hot conditions Demonstrate,prove the quality and safety of its transport and storage.The crystal B of the compound of formula (Ia) especially of the invention and the chemical combination of formula (Ia) The malonate crystal form A of object, physical and chemical stability are more prominent, it is ensured that it is long-term under high temperature and/or super-humid conditions Placement will not generate impurity, ensure that the safety of clinical application.

3.2. the physical and chemical stability test of the salt of the compound of the present invention

The oxalic acid salt crystal A of the hydrochloric acid salt crystal of the compound of suitable formula (Ia), the compound of formula (Ia) is weighed respectively With the malonate crystal A of the compound of formula (Ia), and its crystal form in a heated condition is detected through XRPD and is changed.Experimental result It is as shown in the table:

From the above results, the crystal of the salt of the compound of formula of the invention (Ia) under extreme hot conditions not Crystal form or purity variation occurs, shows that it all has good physical and chemical stability under room temperature and hot conditions, meanwhile, on Stating the crystal for testing the salt for the compound for also showing formula (Ia) has good photostability.

The test of 4. dynamic solubility of experimental example

Respectively by the oxalic acid salt crystal A of the compound of the hydrochloric acid salt crystal of the compound of formula (Ia), formula (Ia) and formula (Ia) Compound malonate crystal A in water environment, SGF (simulated gastric fluid) environment, FaSSIF (simulation mankind starvation before the meal Under enteral intestinal juice) environment, be configured to suspension in FeSSIF (simulation the postprandial fed state of the mankind under enteral intestinal juice) (about 10mg solid is added in every milliliter of solvent), and (25 revs/min) are mixed by turntable at room temperature.In spin balancing process In, it samples after 1h respectively, supernatant measures concentration through filtering, measures the XRPD figure of solid.Experimental result such as following table institute Show.

From the above results: the crystal of the salt of the compound of formula (Ia) of the invention water environment, SGF environment, There is good solubility, and compared with the free alkali of the compound of formula (Ia) in FaSSIF environment, FeSSIF, formula of the invention (Ia) solubility of the crystal of the salt of compound in water, FaSSIF and SGF significantly improves.Also, it is detected through XRPD, these Crystal does not occur crystal form variation in above-mentioned detection process.Above-mentioned experimental result shows, the compound of formula of the invention (Ia) Salt crystal upon administration, it is rapidly dissolvable in vivo, conducive to the absorption of drug.

Experimental example 5

The test of the compound of the present invention inducing mouse righting reflex loss

Kunming mice (male, 18~25g) random grouping is recorded into mouse after tail vein bolus single-dose The incubation period and duration of righting reflex loss.Experimental result is shown in the following table 1 and 2.

The incubation period result that table 1 influences mouse righting reflex

As can be seen from Table 1, the compound of the present invention has the incubation period more shorter than compareing, and shows the chemical combination of formula (Ia) Object onset time is short, it is rapid-action, with the very good onset of action time.

The duration result that table 2. influences mouse righting reflex

Compound (dosage) (60mg/kg)	Duration (min)
		The compound of formula (Ia)	25.61

The data of upper table 2 show that the compound of the present invention has the duration of the anesthesia and revival that are particularly suitable for, thus table The compound of Ming Dynasty style (Ia) has excellent duration of anaesthesia, and this special efficacy is very for the clinical application of anesthetic Crucial.

Experimental example 6

Whole-cell patch-clamp detects influence of the compound of the present invention to cell GABA activated current

Untested compound is dissolved in external solution (NaCl 140mM, KCl 4.7mM, HEPES 10mM, CaCl₂2mM, grape Sugared 11mM, MgCl₂1mM, pH 7.4) in.By the HEK 293T cell inoculation of high expression people GABAa receptor on coverslip, in In 37 DEG C and 5%CO in DMEM culture medium₂Under the conditions of cultivate for 24 hours.

GABA Cl^-Electric current carries out whole-cell recording technique using HEKA EPC 10USB patch clamp amplifier.1 μM of GABA is used for Excite Cl^-Electric current, film potential are clamped down in -60mV.Cell is handled simultaneously with the untested compound of various concentration and 1 μM of GABA, is remembered Record is to same cell Cl^-The inducing effect of electric current, electric current maximum enhance percentage (E_max) and electric current maximum enhancing percentage reach Concentration (the EC of untested compound when to half₅₀)。

Table 3: E when compound concentration is 10 μM_max

Untested compound (10 μM of concentration)	E_max
		The compound of formula (Ia)	346.8%

The electric current maximum of vehicle control group enhances percentage E_maxIt is calculated as 100%, the compound of formula (Ia) is under 10 μM E_maxGreater than 100%, the compound of formula (Ia) has good activation to people's GABAa receptor.

The EC of 4. compound of table₅₀

Compound	EC₅₀(μM)
		The compound of formula (Ia)	0.47

The EC of the compound of formula (Ia)₅₀Value is less than 1 μM, the EC with very little₅₀Concentration, the compound tool of formula (Ia) Having has good activation to people's GABAa receptor.

Upper table 3 and 4 shows that the compound of the present invention has excellent anesthetic effect and specific mechanism of action.

Experimental example 7

The machin safety testing of the compound of the present invention

After machin is grouped at random, to the formula of each group machin administration various dose (4mg/kg, 6mg/kg, 8mg/kg) (Ia) compound.Then general symptom, anesthetic effect duration and the anesthesia of machin are observed.Before administration and give After medicine, II lead electrocardiogram is detected using the noninvasive physiological signal telemetry system (emkaPACK4G) of big animal, it is noninvasive using intelligence Sphygmomanometer measures arterial pressure (systolic pressure, diastolic pressure, mean arterial pressure), detects anus temperature using TH-212 intelligent digital temperature measurer And use monitor monitors detecting sphygmus and blood oxygen saturation (SpO2).

The result shows that the compound of formula (Ia) all has proper effect in anesthetic latencies and duration.It is breathing It does not find significantly to fluctuate in the parameters such as frequency, body temperature, blood pressure and blood oxygen saturation.Most of the time section upon administration, QTc is not See significant change.This shows that after the compound of machin Medicine-feeding type (Ia), cardiovascular and respiratory system is showed no significant pair Function influence.

In addition, the compound of formula (Ia) under the conditions of single-dose high dose, is shown in tolerance and toxicity test To mouse, rat, monkey, the good safety of sheep and tolerance.

The present invention is described in further detail for above-mentioned specific embodiment.But it is above-mentioned that this should not be interpreted as to the present invention The range of theme is only limitted to embodiment below, and all technical solutions implemented based on the content of present invention are each fallen in of the invention Range.

Claims

1. the crystal B of the compound of formula (Ia):

The XRPD map of the crystal B of the compound of the formula (Ia) be included in 6.8 ± 0.2 °, 11.5 ± 0.2 °, 19.4 ± 0.2 °, 19.9 ± 0.2 °, the characteristic peak at 22.0 ± 0.2 ° of the angle of diffraction (2 θ), be preferably included in 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5±0.2°、14.4±0.2°、15.4±0.2°、17.1±0.2°、19.4±0.2°、19.9±0.2°、22.0±0.2°、 Characteristic peak at 22.6 ± 0.2 ° of the angle of diffraction (2 θ), be more preferably included in 6.8 ± 0.2 °, 10.1 ± 0.2 °, 11.5 ± 0.2 °, 14.4±0.2°、15.4±0.2°、17.1±0.2°、19.4±0.2°、19.9±0.2°、20.6±0.2°、21.5±0.2°、 22.0±0.2°、22.6±0.2°、23.6±0.2°、24.6±0.2°、25.3±0.2°、26.1±0.2°、27.4±0.2°、 27.8 ± 0.2 °, 28.3 ± 0.2 °, the characteristic peak at 29.4 ± 0.2 ° of the angle of diffraction (2 θ), most preferably include as shown in Figure 1 Characteristic peak.

2. the method for preparing the crystal B of the compound of the formula (Ia) of claim 1 is selected from gas-solid osmosis, antisolvent crystallisation Method, room temperature suspension paddling process, high temperature suspension paddling process, gas-liquid osmosis, the slow volatility process of room temperature and slow falling temperature method.

3. the crystal C of the compound of formula (I):

The XRPD map of the crystal C of the compound of the formula (I) be included in 8.4 ± 0.2 °, 14.0 ± 0.2 °, 16.7 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, the characteristic peak at 25.2 ± 0.2 ° of the angle of diffraction (2 θ), be preferably included in 8.4 ± 0.2 °, 9.3±0.2°、9.6±0.2°、11.0±0.2°、13.2±0.2°、14.0±0.2°、15.3±0.2°、16.7±0.2°、 17.9 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 22.7 ± 0.2 °, the characteristic peak at 25.2 ± 0.2 ° of the angle of diffraction (2 θ), Be more preferably included in 8.4 ± 0.2 °, 9.3 ± 0.2 °, 9.6 ± 0.2 °, 11.0 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 15.3±0.2°、16.7±0.2°、17.9±0.2°、18.5±0.2°、19.4±0.2°、20.3±0.2°、21.2±0.2°、 21.8±0.2°、22.4±0.2°、22.7±0.2°、23.5±0.2°、24.5±0.2°、25.2±0.2°、26.6±0.2°、 28.1 ± 0.2 °, the characteristic peak at 29.2 ± 0.2 ° of the angle of diffraction (2 θ), most preferably include characteristic peak as shown in Figure 3.

4. the method for preparing the crystal C of the compound of the formula (I) of claim 3 is selected from gas-solid osmosis, antisolvent crystallisation Method, room temperature suspension paddling process, high temperature suspension paddling process, gas-liquid osmosis, the slow volatility process of room temperature and slow falling temperature method.

5. the salt of the compound of formula (Ia):

The salt is preferably the acylate or inorganic acid salt of the compound of formula (Ia), the hydrochloric acid of the compound of preferred formula (Ia) Salt, maleate, succinate, hexanedioic acid salt, sulfate, phosphate, fumarate, malate, glycollate, mucic acid Salt, lactate, gentisate, benzene sulfonate, ethanedisulphonate, napadisilate, mesylate, tartrate, hippurate, Citrate, nicotinate, lactate, oxalates, malonic acid, nicotinoyl amine salt and tosilate, the change of more preferable formula (Ia) Close hydrochloride, oxalates and the malonate of object.

6. the method for preparing the salt of the compound of the formula (Ia) of claim 5 comprising make the formula (Ia) of any solid form Compound and the inorganic acid or the organic acid reaction are precipitated solid, are then separated and dried the solid of precipitation.

7. the salt of the compound of the formula (Ia) of claim 5 is the hydrochloride of the compound of formula (Ia), the wherein change of formula (Ia) The molar ratio for closing object and hydrochloric acid is preferably 1:1.

8. the salt of the compound of the formula (Ia) of claim 7 is the hydrochloric acid salt crystal of the compound of formula (Ia), the crystal XRPD map be included in 5.4 ± 0.2 °, 9.3 ± 0.2 °, 10.8 ± 0.2 °, 16.2 ± 0.2 °, 17.0 ± 0.2 °, 18.7 ± 0.2 °, 22.1 ± 0.2 °, the characteristic peak at 23.0 ± 0.2 ° of the angle of diffraction (2 θ), be preferably included in 5.4 ± 0.2 °, 7.7 ± 0.2°、9.3±0.2°、10.8±0.2°、13.2±0.2°、16.2±0.2°、17.0±0.2°、17.5±0.2°、18.7± 0.2 °, 22.1 ± 0.2 °, the characteristic peak at 23.0 ± 0.2 ° of the angle of diffraction (2 θ), be more preferably included in 5.4 ± 0.2 °, 7.7 ± 0.2°、9.3±0.2°、10.8±0.2°、13.2±0.2°、15.3±0.2°、16.2±0.2°、17.0±0.2°、17.5± 0.2°、18.0±0.2°、18.7±0.2°、20.3±0.2°、22.1±0.2°、23.0±0.2°、25.0±0.2°、25.4± 0.2 °, the characteristic peak at 27.5 ± 0.2 ° of the angle of diffraction (2 θ), most preferably include characteristic peak as shown in Figure 5.

9. the method for preparing the salt of the compound of the formula (Ia) of claim 7 or 8 comprising make the formula (Ia) of any solid form Compound reacted with hydrochloric acid, be precipitated solid, then the solid of precipitation is separated and dried.

It 10. the salt of the compound of the formula (Ia) of claim 5, is the oxalates of the compound of formula (Ia), wherein formula (Ia) The molar ratio of compound and oxalic acid is preferably 1:1.

11. the salt of the compound of the formula (Ia) of claim 10 is the oxalic acid salt crystal A of the compound of formula (Ia), the crystalline substance The XRPD map of body A is included in 8.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, the characteristic peak at 24.7 ± 0.2 ° of the angle of diffraction (2 θ), be preferably included in 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 20.9 ± 0.2 °, 22.8 ± 0.2 °, 23.0 ± 0.2 °, 24.7 ± 0.2 ° of diffraction Characteristic peak at angle (2 θ) is more preferably included in 8.5 ± 0.2 °, 13.5 ± 0.2 °, 14.0 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ±0.2°、20.5±0.2°、20.9±0.2°、22.1±0.2°、22.8±0.2°、23.0±0.2°、24.1±0.2°、24.7 ± 0.2 °, 25.3 ± 0.2 °, 25.8 ± 0.2 °, 26.5 ± 0.2 °, the characteristic peak at 28.2 ± 0.2 ° of the angle of diffraction (2 θ), it is optimal Choosing includes characteristic peak as shown in Figure 7.

12. the salt of the compound of the formula (Ia) of claim 10 is the oxalic acid salt crystal B of the compound of formula (Ia), the crystalline substance The XRPD map of body B be included in 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2 °, 12.1 ± 0.2 °, 12.7 ± 0.2 °, 16.7 ± 0.2 °, the characteristic peak at 23.3 ± 0.2 ° of the angle of diffraction (2 θ), it is preferably included in 5.0 ± 0.2°、7.7±0.2°、8.2±0.2°、8.4±0.2°、8.8±0.2°、12.1±0.2°、12.7±0.2°、15.4± 0.2 °, 15.8 ± 0.2 °, 16.7 ± 0.2 °, 20.0 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, 23.3 ± 0.2 ° of diffraction Characteristic peak at angle (2 θ), be more preferably included in 5.0 ± 0.2 °, 7.7 ± 0.2 °, 8.2 ± 0.2 °, 8.4 ± 0.2 °, 8.8 ± 0.2°、10.2±0.2°、10.7±0.2°、12.1±0.2°、12.7±0.2°、14.0±0.2°、15.4±0.2°、15.8± 0.2°、16.7±0.2°、17.8±0.2°、18.5±0.2°、19.1±0.2°、20.0±0.2°、21.6±0.2°、22.8± 0.2 °, 23.3 ± 0.2 °, 25.7 ± 0.2 °, the characteristic peak at 26.6 ± 0.2 ° of the angle of diffraction (2 θ), most preferably include such as Fig. 9 institute The characteristic peak shown.

13. the salt of the compound of the formula (Ia) of claim 10 is the oxalic acid salt crystal C of the compound of formula (Ia), the crystalline substance The XRPD map of body C be included in 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 13.2 ± 0.2 °, 14.0 ± 0.2 °, 18.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, the spy at 23.2 ± 0.2 ° of the angle of diffraction (2 θ) Levy peak, be preferably included in 5.0 ± 0.2 °, 6.4 ± 0.2 °, 7.7 ± 0.2 °, 8.5 ± 0.2 °, 9.1 ± 0.2 °, 10.7 ± 0.2 °, 11.9±0.2°、12.9±0.2°、13.2±0.2°、14.0±0.2°、17.8±0.2°、18.3±0.2°、19.3±0.2°、 20.3 ± 0.2 °, 22.2 ± 0.2 °, the characteristic peak at 23.2 ± 0.2 ° of the angle of diffraction (2 θ), be more preferably included in 5.0 ± 0.2 °, 6.4±0.2°、7.7±0.2°、8.5±0.2°、9.1±0.2°、10.7±0.2°、11.9±0.2°、12.9±0.2°、13.2 ±0.2°、14.0±0.2°、15.5±0.2°、15.8±0.2°、17.3±0.2°、17.8±0.2°、18.3±0.2°、19.3 ± 0.2 °, 20.3 ± 0.2 °, 22.2 ± 0.2 °, the characteristic peak at 23.2 ± 0.2 ° of the angle of diffraction (2 θ), most preferably include as schemed Characteristic peak shown in 11.

14. the salt of the compound of the formula (Ia) of claim 10 is the oxalic acid salt crystal D of the compound of formula (Ia), the crystalline substance The XRPD map of body D be included in 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2 °, 12.1 ± 0.2 °, 15.9 ± 0.2 °, the characteristic peak at 19.9 ± 0.2 ° of the angle of diffraction (2 θ), be preferably included in 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2°、9.0±0.2°、12.1±0.2°、12.7±0.2°、13.9±0.2°、15.9±0.2°、19.9±0.2°、22.2± Characteristic peak at 0.2 ° of the angle of diffraction (2 θ), be more preferably included in 7.9 ± 0.2 °, 8.4 ± 0.2 °, 8.5 ± 0.2 °, 9.0 ± 0.2°、12.1±0.2°、12.7±0.2°、13.9±0.2°、15.9±0.2°、16.7±0.2°、17.1±0.2°、19.9± 0.2 °, 21.7 ± 0.2 °, the characteristic peak at 22.2 ± 0.2 ° of the angle of diffraction (2 θ) most preferably include feature as shown in fig. 13 that Peak.

15. the method for preparing the salt of the compound of the formula (Ia) of any one of claim 10-14 comprising make any solid shape The compound of the formula (Ia) of formula is reacted with oxalic acid, and solid is precipitated, is then separated and dried the solid of precipitation.

16. the salt of the compound of the formula (Ia) of claim 5 is the malonate of the compound of formula (Ia), wherein formula (Ia) Compound and the molar ratio of malonic acid be preferably 1:1.

It is the malonate crystal A of the compound of formula (Ia) 17. the salt of the compound of the formula (Ia) of claim 16, it is described The XRPD map of crystal A be included in 6.9 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 19.2 ± 0.2 °, 20.7 ± 0.2 °, 21.0 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ), are preferably included in 6.9±0.2°、9.7±0.2°、12.7±0.2°、13.7±0.2°、14.8±0.2°、17.7±0.2°、19.2±0.2°、 20.7±0.2°、21.0±0.2°、22.1±0.2°、22.6±0.2°、23.0±0.2°、23.5±0.2°、23.8±0.2° The angle of diffraction (2 θ) at characteristic peak, be more preferably included in 6.9 ± 0.2 °, 9.7 ± 0.2 °, 12.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8±0.2°、15.7±0.2°、17.7±0.2°、18.7±0.2°、19.2±0.2°、19.7±0.2°、20.7±0.2°、 21.0±0.2°、22.1±0.2°、22.6±0.2°、23.0±0.2°、23.5±0.2°、23.8±0.2°、24.2±0.2°、 25.6 ± 0.2 °, 25.8 ± 0.2 °, 26.6 ± 0.2 °, the characteristic peak at 27.1 ± 0.2 ° of the angle of diffraction (2 θ) most preferably include Characteristic peak as shown in figure 15.

It is the malonate crystal B of the compound of formula (Ia) 18. the salt of the compound of the formula (Ia) of claim 16, it is described The XRPD map of crystal B is included in 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ), it is preferably included in 7.0 ± 0.2°、9.3±0.2°、9.8±0.2°、12.8±0.2°、13.7±0.2°、14.0±0.2°、14.6±0.2°、15.1± 0.2 °, 15.8 ± 0.2 °, 18.1 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, the spy at 23.8 ± 0.2 ° of the angle of diffraction (2 θ) Levy peak, be more preferably included in 7.0 ± 0.2 °, 9.3 ± 0.2 °, 9.8 ± 0.2 °, 12.8 ± 0.2 °, 13.7 ± 0.2 °, 14.0 ± 0.2°、14.6±0.2°、15.1±0.2°、15.8±0.2°、18.1±0.2°、19.2±0.2°、19.7±0.2°、20.4± 0.2 °, 20.7 ± 0.2 °, 21.1 ± 0.2 °, 22.5 ± 0.2 °, the characteristic peak at 23.8 ± 0.2 ° of the angle of diffraction (2 θ), most preferably Including characteristic peak as shown in figure 17.

19. the method for preparing the salt of the compound of the formula (Ia) of any one of claim 16-18 comprising make any solid shape The compound of the formula (Ia) of formula is reacted with malonic acid, and solid is precipitated, is then separated and dried the solid of precipitation.

20. pharmaceutical composition, it includes:

I) any one or more in following substance:

The crystal B of the compound of the formula (Ia) of claim 1；

The crystal C of the compound of the formula (I) of claim 3；Or

The salt of the compound of the formula (Ia) of any one of claim 5,7-8,10-14 and 16-18；And

Ii) one or more pharmaceutically acceptable carriers.

21. any one or more following substance is in preparation for calmness, hypnosis, antianxiety, of flaccid muscles or anticonvulsant medicine Purposes in object:

The crystal B of the compound of the formula (Ia) of claim 1；

The crystal C of the compound of the formula (I) of claim 3；Or

The salt of the compound of the formula (Ia) of any one of claim 5,7-8,10-14 and 16-18.