CN108218846A - New solid-state form of thiophene derivant and its preparation method and application - Google Patents

New solid-state form of thiophene derivant and its preparation method and application Download PDF

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Publication number
CN108218846A
CN108218846A CN201611195986.8A CN201611195986A CN108218846A CN 108218846 A CN108218846 A CN 108218846A CN 201611195986 A CN201611195986 A CN 201611195986A CN 108218846 A CN108218846 A CN 108218846A
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compound
crystal form
powder
values
illustrative plates
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Inventor
王文晶
刘振红
魏用刚
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

New solid-state form the present invention relates to thiophene derivant and its preparation method and application, the new solid-state form of the thiophene derivant is the crystal form I of compound 1, the crystal form II of the crystal form II of compound 1, the crystal form I of compound 2, compound 2, the invention further relates to the pharmaceutical composition of the new solid-state form containing thiophene derivant and its in preparation for the application in local anaesthesia and/or field of medicament of easing pain.New solid-state form provided by the present invention with apparent powder X-ray x ray diffraction TuPu method, preparation method is simple, storage is convenient, is suitable for preparing several formulations,

Description

New solid-state form of thiophene derivant and its preparation method and application
Technical field
New solid-state form the present invention relates to thiophene derivant and its preparation method and application and contain thiophene derivant New solid-state form pharmaceutical composition and its prepare for local anaesthesia and/or ease pain field of medicament in application.
Background technology
Local anesthetic refers to those, and energy temporarily, completely, reversibly conduct by block nerves within the scope of the restriction of human body, i.e., Certain part of human body is made to lose sensibility under the situation not disappeared in consciousness, in order to the drug that surgical operation carries out, effect Mechanism be by being combined with certain privileged sites on the sodium-ion channel on neu after, pass through the sodium ion of sodium-ion channel It reduces so as to change neural membrane potentials, the conduction of nerve impulse is caused to be blocked, finally realizes anaesthetic effect.
Common sodium-ion channel inhibitor is mainly cacaine class in local anaesthetics at present, such as procaine, totokaine, benefit Cacaine, Bupivacaine (anesthesia duration is 2~3 times longer than lidocaine) or Ropivacaine.Ropivacaine is after Bupivacaine One New-type long-acting local anaesthetics, toxic reaction are mainly shown as the toxicity of nervous centralis and cardiovascular system.Blood concentration is excessively high When may occur in which CNS intoxication symptom；There is toxic effect to cardiovascular system, the heart is can inhibit when blood concentration is excessively high Dirty conduction and myocardial contractive power.It is related with drug concentration to motorial retardation, a concentration of 0.2% pair of sensory nerve resistance It is stagnant preferable, but almost without kinesitherapy nerve retardation, 0.75% generates preferable kinesitherapy nerve retardation.
Chinese patent application 201611024055.1 describe a kind of heterocyclic amide derivatives and preparation method thereof and Application pharmaceutically, the invention compound have longer anaesthetic effect, particularly such as compound represented 1 shown below and compound 2 have preferably anesthesia continuous action compared with other derivatives.
They are slightly water-soluble compounds, are generally used in solid form, therefore its solid-state form is ground in the formulation Study carefully and have a very important significance.
Invention content
One of the objects of the present invention is to provide thiophene derivant (compound 1 and compound 2) new solid-state form and its Preparation method.
Another object of the present invention is to provide containing the new solid-state form of thiophene derivant (compound 1 and compound 2) Pharmaceutical composition.
Another object of the present invention is to provide the new solid-state form of thiophene derivant (compound 1 and compound 2) or containing it Composition prepare for local anaesthesia and/or ease pain field of medicament in application.
In order to achieve the above-mentioned object of the invention, the present invention provides the new solid forms of compound 1.
The present invention provides a kind of crystal form I of compound 1, powder x-ray diffraction collection of illustrative plates 2 θ values be 10.9 ± 0.2 °, 26.7±0.2°、16.6±0.2°、13.4±0.2°、19.8±0.2°、24.4±0.2°、22.1±0.2°、23.8±0.2° Place is corresponding with characteristic diffraction peak or with the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 1,
In one embodiment, the powder x-ray diffraction collection of illustrative plates of the crystal form I of compound 1 of the present invention is also in 2 θ Be worth at 30.2 ± 0.2 °, 20.2 ± 0.2 ° to there is characteristic diffraction peak or with powder x-ray diffraction collection of illustrative plates as shown in Figure 1 Representative feature.
Further, the powder X-ray diffracting spectrum that 1 crystal form I of compound of the present invention is represented with 2 θ angles There is characteristic diffraction peak, relative intensity and d values in the position shown in the following table 1：
Table 1
In one embodiment, 1 crystal form I of compound provided by the invention has powder X-ray as shown in Figure 1 Feature representated by diffracting spectrum.
The present invention provides a kind of crystal form II of compound 1, powder x-ray diffraction collection of illustrative plates 2 θ values for 10.9 ± Characteristic diffraction peak is corresponding at 0.2 °, 10.6 ± 0.2 °, 16.3 ± 0.2 °, 26.1 ± 0.2 °, 24.6 ± 0.2 °, 19.6 ± 0.2 ° Or with the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 4.
In one embodiment, the powder x-ray diffraction collection of illustrative plates of the crystal form II of compound 1 of the present invention is also 2 θ values at 26.9 ± 0.2 °, 24.0 ± 0.2 °, 17.7 ± 0.2 ° to have characteristic diffraction peak or with powder X-ray as shown in Figure 4- Feature representated by x ray diffraction collection of illustrative plates.
Further, the powder X-ray diffraction pattern that 1 crystal form II of compound of the present invention is represented with 2 θ angles Spectrum has characteristic diffraction peak, relative intensity and d values in the position shown in the following table 2：
Table 2
2θ(°) D values Relative intensity %
10.9±0.2 8.1 100
10.6±0.2 8.3 44.1
16.3±0.2 5.4 23.3
26.1±0.2 3.4 12.7
24.6±0.2 3.6 9.8
19.6±0.2 4.5 6.7
26.9±0.2 3.3 4.9
24.0±0.2 3.7 4.6
17.7±0.2 5.0 3.2
21.3±0.2 4.2 1.8
22.0±0.2 4.0 1.7
26.7±0.2 3.3 1.4
20.2±0.2 4.4 1.3
23.8±0.2 3.7 1.3
33.1±0.2 2.7 1.0
In one embodiment, 1 crystal form II of compound provided by the invention has powder X-ray as shown in Figure 4 Feature representated by diffracting spectrum.
The present invention provides the new solid forms of compound 2.
The present invention provides a kind of crystal form I of compound 2, powder x-ray diffraction collection of illustrative plates 2 θ values for 10.3 ± At 0.2 °, 18.7 ± 0.2 °, 24.0 ± 0.2 °, 12.8 ± 0.2 °, 25.8 ± 0.2 °, 16.1 ± 0.2 ° to have characteristic diffraction peak or With the feature representated by powder x-ray diffraction collection of illustrative plates as shown in Figure 7,
In one embodiment, the powder x-ray diffraction collection of illustrative plates of the crystal form I of compound 2 of the present invention is also in 2 θ Be worth for be corresponding at 20.5 ± 0.2 °, 17.6 ± 0.2 °, 31.3 ± 0.2 ° characteristic diffraction peak or with powder X-ray as shown in Figure 7- Feature representated by x ray diffraction collection of illustrative plates.
Further, the powder X-ray diffracting spectrum that 2 crystal form I of compound of the present invention is represented with 2 θ angles There is characteristic diffraction peak, relative intensity and d values in the position shown in the following table 3：
Table 3
2θ(°) Relative intensity % D values
10.3±0.2 100.0 8.6
18.7±0.2 23.6 4.7
24.0±0.2 14.0 3.7
12.8±0.2 10.2 6.9
25.8±0.2 9.1 3.4
16.1±0.2 9.0 5.5
20.5±0.2 5.1 4.3
17.6±0.2 3.1 5.0
31.3±0.2 2.3 2.9
16.5±0.2 1.6 5.4
25.1±0.2 1.5 3.5
22.1±0.2 1.4 4.0
23.0±0.2 1.3 3.9
26.5±0.2 1.3 3.4
35.6±0.2 1.3 2.5
20.7±0.2 1.2 4.3
39.1±0.2 1.0 2.3
In one embodiment, 2 crystal form I of compound provided by the invention has powder X-ray as shown in Figure 7 Feature representated by diffracting spectrum.
The present invention provides a kind of crystal form II of compound 2, powder x-ray diffraction collection of illustrative plates 2 θ values for 10.4 ± 0.2°、10.1±0.2°、17.5±0.2°、15.8±0.2°、18.8±0.2°、23.6±0.2°、24.2±0.2°、26.4± Characteristic diffraction peak is corresponding at 0.2 °, 35.5 ± 0.2 °, 25.4 ± 0.2 ° or with powder x-ray diffraction as shown in Figure 10 Feature representated by collection of illustrative plates.
In one embodiment, the powder X-ray that 2 crystal form II of compound of the present invention is represented with 2 θ angles Powder diffraction spectrum has characteristic diffraction peak, relative intensity and d values in the position shown in the following table 4：
Table 4
2θ(°) Relative intensity % D values
10.4±0.2 100.0 8.5
10.1±0.2 54.4 8.7
17.5±0.2 38.6 5.1
15.8±0.2 29.7 5.6
18.8±0.2 21.8 4.7
23.6±0.2 18.5 3.8
24.2±0.2 17.6 3.7
26.4±0.2 15.4 3.4
35.5±0.2 11.7 2.5
25.4±0.2 8.2 3.5
20.3±0.2 4.3 4.4
22.0±0.2 3.4 4.0
8.6±0.2 2.5 10.2
20.4±0.2 2.0 4.3
18.3±0.2 1.9 4.9
32.8±0.2 1.7 2.7
In one embodiment, 2 crystal form II of compound provided by the invention has powder X-ray as shown in Figure 10-penetrate The representative feature of ray diffraction diagram spectrum.
The present invention also provides a kind of pharmaceutical composition, the crystal form of the aforesaid compound of the present invention containing treatment effective dose One of or its mixture and pharmaceutically acceptable carrier and excipient.
The present invention also provides one of aforementioned crystal forms of compound of the present invention or its mixture or foregoing pharmaceutical composition to exist It prepares for the application in local anaesthesia and/or field of medicament of easing pain.
New solid-state form provided by the present invention with apparent powder x-ray diffraction TuPu method, preparation method letter Single, storage conveniently, is suitable for preparing several formulations.
Description of the drawings
Fig. 1 is the XRD spectrum of 1 crystal form I of compound made from the embodiment of the present invention 1.
Fig. 2 is differential scanning calorimetry (DSC) curve of 1 crystal form I of compound made from the embodiment of the present invention 1.
Fig. 3 is thermogravimetry (TGA) curve of 1 crystal form I of compound made from the embodiment of the present invention 1.
Fig. 4 is the XRD spectrum of 1 crystal form II of compound made from the embodiment of the present invention 1.
Fig. 5 is differential scanning calorimetry (DSC) curve of 1 crystal form II of compound made from the embodiment of the present invention 1.
Fig. 6 is thermogravimetry (TGA) curve of 1 crystal form II of compound made from the embodiment of the present invention 1.
Fig. 7 is the XRD spectrum of 2 crystal form I of compound made from the embodiment of the present invention 2.
Fig. 8 is differential scanning calorimetry (DSC) curve of 2 crystal form I of compound made from the embodiment of the present invention 2.
Fig. 9 is thermogravimetry (TGA) curve of 2 crystal form I of compound made from the embodiment of the present invention 2.
Figure 10 is the XRD spectrum of 2 crystal form II of compound made from the embodiment of the present invention 2.
Figure 11 is differential scanning calorimetry (DSC) curve of 2 crystal form II of compound made from the embodiment of the present invention 2.
Figure 12 is thermogravimetry (TGA) curve of 2 crystal form II of compound made from the embodiment of the present invention 2.
Specific embodiment
Specific embodiment with reference to embodiments is described in further detail the above of the present invention again. But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.The above-mentioned thought feelings of the present invention are not being departed from Under condition, the various replacements or change made according to ordinary skill knowledge and customary means should all be included in the present invention's In the range of.
Part instrument of the present invention is with detection parameters as shown in the following table 5~7：
Table 5
Table 6
Table 7
Embodiment 1
The preparation of compound 1：
(S)-N- (2,4- thioxene -3- bases) -1- propylpiperdine -2- carbamides (1)
(S)-N-(2,4-dimethylthiophen-3-yl)-1-propylpiperidine-2-carboxamide
The first step：2,4- thioxene -3- ammonia (1B)
2,4-dimethylthiophen-3-amine
By LiAlH4(30g, 0.788mol) is added in reaction bulb, addition THF (300mL), being added dropwise under ice bath stirring THF (300mL) solution of object 3- amino -4- methylthiophene -2- methyl formates (60g, 0.350moL) is closed, rate of addition is kept to cause System is made to keep pico- reflux, finishes, is heated to reflux 3 hours after being stirred 30 minutes under ice bath.Reaction solution is dropped with ice salt bath Temperature is added dropwise to water (30mL) to 0 DEG C into reaction solution under stirring, 15% NaOH solution (30mL) simultaneously stirs 1 hour, uses diatom Soil filtering, filter cake are washed with THF (50mL × 3), and merging filtrate is simultaneously dried with anhydrous sodium sulfate, and filtrate is evaporated by filtering, remains Object adds in petroleum ether (400mL) and stirs 30 minutes, and filtering, filter cake washs with petroleum ether (50mL × 2), merging filtrate and by filtrate It is evaporated to obtain yellow oil 2,4- thioxene -3- ammonia (1B) (27g, yield：60.6%) it, is directly used in next step.
Ms m/z(ESI):128.2[M+H+]。
Second step：(S) -1- propylpiperdines -2- carboxylic acids (1D)
(S)-1-propylpiperidine-2-carboxylic acid
By (S)-piperidines -2- carboxylic acids (40g, 0.910mol), methanol (500mL), propionic aldehyde (150mL) Pd/c (20g, 10%) Add in hydrogenation bottle, middle H2Displacement three times, adds H2(35PSI) waves hydrogenation 32 hours.LC-MS detection reactions are finished, and use diatomite Filtering, filter cake are washed with absolute methanol (50ml × 2), are merged organic phase and are evaporated, residue with Ethyl acetate (100mL) stirring Washing, filtering, filter cake is dried to obtain white solid (S) -1- propylpiperdine -2- carboxylic acids (1D) (44.5g, yield 83.9%), It is directly used in next step.
Ms m/z(ESI):172.2[M+H+]。
Third walks：(S)-N- (2,4- thioxene -3- bases) -1- propylpiperdine -2- formamides (1)
(S)-N-(2,4-dimethylthiophen-3-yl)-1-propylpiperidine-2-carboxamide
By compound：(S) -1- propylpiperdines -2- carboxylic acids (1D) (41g, 0.240mol) are dissolved in dichloromethane (300mL), It adds in triethylamine (26.63g, 0.264mol) and is cooled to 0 DEG C, isobutyl chlorocarbonate (36g, 0.264mol) is added dropwise under stirring, It finishes and is stirred 1 hour under ice bath, be added dropwise to the dichloromethane of 2,4- thioxene -3- ammonia (1B) (33.5g, 0.264mol) (100mL) solution, finishes, and stirs 3 hours at room temperature.Saturated salt solution (400mL) liquid separation is added in into reaction solution, water phase is used Dichloromethane (200mL × 2) extracts, and merges organic phase and is washed with saturated salt solution (200mL × 2), the anhydrous sulphur of organic phase Sour sodium drying, filtering, filtrate is evaporated, with 300-400 mesh silica gel column chromatographies, mobile phase：Petrol ether/ethyl acetate=10/1 to 4/ 1.It obtains yellow solid to be washed with petroleum ether (50mL × 3), solid drying obtains white solid (S)-N- (2,4- dimethyl thiophenes Fen -3- bases) -1- propylpiperdine -2- formamides (1) (47g, yield:70%).
Ms m/z(ESI):281.2[M+H+]。
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),δ6.85(d,1H),δ3.10-3.05(dt,1H),δ2.81- 2.78(dd,1H),2.58-2.52(m,1H),δ2.21-2.12(m,4H),δ2.12-1.99(dd,1H),δ1.97-1.96(dd, 3H),1.81-1.78(m,1H),δ1.73-1.44(m,6H),δ1.32-1.22(m,1H),δ0.85-0.82(t,3H)。
The preparation of 1 hydrochloride of compound：
(S)-N- (2,4- thioxene -3- bases) -1- propylpiperdine -2- carbamides (1) are separately added into reaction bulb (0.96g, 3.43mmol) and ethyl acetate (2mL), ice bath cooling, is added dropwise hydrochloric ethyl acetate solution (1mL), adds and rise to It is stirred at room temperature 30 minutes, solvent is removed under reduced pressure and obtains white solid (S)-N- (2,4- thioxene -3- bases) -1- propyl piperazines Pyridine -2- phosphinylidynes amine hydrochlorate (1-H) (1.20g, yield 98%).
MS m/z(ESI):281.2[M-Cl]。
1H NMR(400MHz,MeOD)δ6.85(s,1H),4.14(d,1H),3.71(d,1H),3.15–3.18(m,3H), 2.40(d,1H),2.30(s,3H),2.09(s,3H),1.75-2.02(m,7H),1.06(t,3H)。
The preparation of 1 crystal form I of compound：
It takes compound 1 (20mg), hexahydrotoluene is added at 60 DEG C to solution dissolved clarification or close to dissolved clarification, after heat preservation 30 minutes It is placed under ice salt bath and stirs, crystal is precipitated, 1 crystal form I of compound is obtained after centrifuging and taking is admittedly dry.
The X-ray diffracting spectrum of 1 crystal form I of compound is shown in Fig. 1, and measured value is shown in Table 8 and (takes relative intensity spreading out more than 1% Penetrate the corresponding measured value in peak)：
The X-ray diffraction result of 8 compound of table, 1 crystal form I
2θ(°) Relative intensity % D values
10.9 100 8.1
26.7 9.8 3.3
16.6 8.5 5.3
13.4 7.2 6.6
19.8 5.8 4.5
24.4 4.9 3.6
22.1 3.0 4.0
23.8 2.6 3.7
30.2 1.4 3.0
20.2 1.3 4.4
17.8 1.1 5.0
20.4 1.1 4.4
32.8 1.1 2.7
Differential scanning calorimetry (DSC) curve of 1 crystal form I of compound is shown in Fig. 2, and DSC collection of illustrative plates is shown, the fusing point of sample is 132℃。
Thermogravimetry (TGA) curve of 1 crystal form I of compound is shown in Fig. 3, and TGA collection of illustrative plates is shown, slip of the sample at 100 DEG C 0.3% is weighed, is anhydride, decomposition temperature is 173 DEG C.
The preparation of 1 crystal form II of compound：
Compound 1 (20mg) is taken, methanol/water (v is added at 60 DEG C:V=7:5) it to solution dissolved clarification or close to dissolved clarification, keeps the temperature It is placed within 30 minutes under ice salt bath and stirs, crystal is precipitated, 1 crystal form II of compound is obtained after centrifuging and taking is admittedly dry.
The X-ray diffracting spectrum of 1 crystal form II of compound is shown in Fig. 4, and measured value is shown in Table 9 and (takes relative intensity more than 1% The corresponding measured value of diffraction maximum)：
The X-ray diffraction result of 9 compound of table, 1 crystal form II
Differential scanning calorimetry (DSC) curve of 1 crystal form II of compound is shown in Fig. 5, and DSC collection of illustrative plates is shown, fusing point is 128 DEG C.
Thermogravimetry (TGA) curve of 1 crystal form II of compound is shown in Fig. 6, and TGA collection of illustrative plates shows slip of the sample at 100 DEG C 0.3% is weighed, is anhydride, decomposition temperature is 168 DEG C.
Embodiment 2
The preparation of compound 2：
(S) the third methyl of -1- rings-N- (2,4- thioxene -3- bases)-piperidines -2- carbamides (2)
(S)-1-(cyclopropylmethyl)-N-(2,4-dimethylthiophen-3-yl)piperidine-2- carboxamide
(S)-N- (2,4- thioxene -3- bases) -2- carbamides (2A) are added in into reaction bulb and (can refer to embodiment 1 Prepare) (0.95g, 4.0mmol), potassium carbonate (1.66g, 12.0mmol), the third methyl bromide of ring (1.16mL, 12.0mmol) and different Propyl alcohol (12mL) and water (3mL), after stirring and dissolving, back flow reaction 5 hours.It is concentrated under reduced pressure into dry, addition water (50mL) and acetic acid Ethyl ester (50mL) stirs liquid separation, and water layer is extracted (40mL × 2) with ethyl acetate, merges organic phase, anhydrous sodium sulfate drying, mistake Filter, filtrate decompression is concentrated, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=5:1) yellow solid S- is obtained The third methyl of 1- rings-N- (2,4- thioxene -3- bases)-piperidines -2- carbamides (2) (0.8g, yield 68.4%).
1H NMR(400MHz,CDCl3)δ8.04(s,1H),6.69(s,1H),3.40(d,1H),2.88–2.92(m,2H), 2.00–2.11(m,3H),2.29(s,3H),2.08(s,3H),1.49-1.80(m,4H),1.26-1.38(m,1H),0.87- 0.94(m,1H),0.58-0.64(m,1H),0.44-0.51(m,1H),0.16-0.22(m,1H),0.05-0.11(m,1H)。
The preparation of 2 hydrochloride of compound：
(S) -1- the third methyl of ring-N- (2,4- thioxene -3- bases)-piperidines -2- phosphinylidynes are separately added into reaction bulb Amine (2) (0.78g, 3.43mmol) and ethyl acetate (2mL), ice bath cooling, are added dropwise hydrochloric ethyl acetate solution (1mL), add Stirring 30 minutes is warmed to room temperature, solvent is removed under reduced pressure, obtained solid ethyl acetate (2mL × 2) is washed 2 times, and it is solid that drying obtains white Body S-1- the third methyl of ring-N- (2,4- thioxene -3- bases)-piperidines -2- phosphinylidynes amine hydrochlorate (2-H) (0.78g, yield 89%).
MS m/z(ESI):293.3[M-Cl]。
1H NMR(400MHz,MeOD)δ6.85(s,1H),4.19(dd,1H),3.88(d,1H),3.20(m,2H),3.06 (dd,1H),2.41(dd,1H),2.29(s,3H),2.09(s,3H),1.90–2.08(m,4H),1.68-1.80(m,1H), 1.19-1.28(m,1H),0.76-0.88(m,2H),0.43-0.51(m,1H)。
The preparation of 2 crystal form I of compound：
Compound 2 (20mg) is taken, isopropanol is added at 70 DEG C and is placed under ice salt bath within 30 minutes to dissolved clarification liquid, heat preservation is obtained Stirring is precipitated crystal, 2 crystal form I of compound is obtained after centrifuging and taking is admittedly dry.
The X-ray diffracting spectrum of 2 crystal form I of compound is shown in Fig. 7, and measured value is shown in Table 10 and (takes relative intensity more than 1% The corresponding measured value of diffraction maximum)：
The X-ray diffraction result of 10 compound of table, 2 crystal form I
Compound 2 crystal form I differential scanning calorimetries (DSC) curve is shown in Fig. 8, and DSC collection of illustrative plates is shown, the fusing point of sample is 136 ℃。
Thermogravimetry (TGA) curve of 2 crystal form I of compound is shown in Fig. 9, and TGA collection of illustrative plates shows that sample is anhydride, decomposes Temperature is about 193 DEG C.
The preparation of 2 crystal form II of compound：
It takes compound 2 (20mg), ethanol/water (v/v=4/5) is added at 70 DEG C to obtaining dissolved clarification liquid, after heat preservation 30 minutes It is placed under ice salt bath and stirs, crystal is precipitated, 2 crystal form II of compound is obtained after centrifuging and taking is admittedly dry.
The X-ray diffracting spectrum of 2 crystal form II of compound is shown in Figure 10, and measured value is shown in Table 11 and (relative intensity is taken to be more than 1% The corresponding measured value of diffraction maximum)：
The X-ray diffraction result of 11 compound of table, 2 crystal form II
2θ(°) Relative intensity % D values
10.4 100.0 8.5
10.1 54.4 8.7
17.5 38.6 5.1
15.8 29.7 5.6
18.8 21.8 4.7
23.6 18.5 3.8
24.2 17.6 3.7
26.4 15.4 3.4
35.5 11.7 2.5
25.4 8.2 3.5
20.3 4.3 4.4
22.0 3.4 4.0
8.6 2.5 10.2
20.4 2.0 4.3
18.3 1.9 4.9
32.8 1.7 2.7
Differential scanning calorimetry (DSC) curve of 2 crystal form II of compound is shown in Figure 11, and DSC collection of illustrative plates shows that fusing point is 132 DEG C.
Thermogravimetry (TGA) curve of 2 crystal form II of compound is shown in Figure 12, and TGA collection of illustrative plates shows that sample is anhydride, decomposes Temperature is 185 DEG C.
3 biological test of embodiment
1. the infiltration anesthesia effect of pair guinea pig skin
Ropivacaine and the compounds of this invention measure the infiltration anesthesia of guinea pig skin by the intradermal papule method of cavy
The cavy of 300~400g of weight in experiment proxima luce (prox. luc), shaves a diameter of 4~5cm sizes at each one before and after its net back Dermatotome.Embodiment compound is dissolved in physiological saline, concentration 0.5%；With 27g syringe needle intracutaneous injections in the dermatotome got ready in cavy 0.25 milliliter, form papule.Skin at papule is stimulated with appropriate dynamics with pin at time point shown in following table, test every time exists Papule center and periphery randomly choose at 6 points and stimulate, the stimulus intervals between every bit 3~6 seconds, observe and record experiment cavy Nociceptive reflex (is shouted, tremble)；There is nociceptive reflex to be denoted as 1, without pain reflection is denoted as 0, until all stimulation point full recoveries Pain reaction.Every group of 6 animals, the stimulation number for calculating without pain reflection account for the percentage of total stimulation number, are denoted as inhibiting rate, increase Add and be determined as that local anaesthesia is effective more than 50%.Compound carries out the infiltration anesthesia effect of guinea pig skin by above experiment It measures, measures and the results are shown in Table 12：
Table 12 is to the infiltration anesthesia effect of guinea pig skin
Compound number Compound concentration (mg/ml) Local anaesthesia effective duration (hour)
Ropivacaine 5 2
1-H 5 3
2-H 5 5
Conclusion：It is measured by the intradermal papule method of cavy the results show that the compounds of this invention is to the part of guinea pig skin Anaesthetize effective duration >=2 hour, hence it is evident that better than control group Ropivacaine.
2. the feeling retardance of pair rat nervus coccygeus
Ropivacaine and the compounds of this invention measure the feeling retardance of rat nervus coccygeus by the hot tail-flick method of rat.
200-250g male SD rats, clean rat-tail, prepared Chinese ink is applied to tail portion before experiment with 75% ethyl alcohol gauze by every group 5 Lower 1/3 at mark as light stimulus.Rat is fixed on fixator, with YLS-12A rat-tail illumination pain threshold detector (Jinan Yi Yan sections Skill Development Co., Ltd) rat is resistance to is illuminated by the light the hot pain time for test (latent time starts to expose to the time for removing tail). To protect rat-tail from burn, the maximum illumination time is set as 10 seconds.Each animal basic latent time is first tested, adjusts temperature, It is 3-4 seconds to make basic latent time.0.5% embodiment compound is dissolved in physiological saline, is noted respectively by rat-tail bilateral nervus coccygeus Penetrate 100 microlitres.Time point shown according to the form below tests reaction latent time of the tail portion to thermostimulation after injection.The feeling of rat tails Function retardance judges the reaction latent time increase degree of thermostimulation by comparing rat before and after being administered, and is calculated by following equation Calculate maximum possible effect percentage MPE%：MPE%=100 × (test latent time-basis latent time)/(maximum illumination When m- basic irradiation time).50% is increased above to be judged to feeling retardance.Repeatedly during follow-on test, pain position will be surveyed and slightly moved It is dynamic.The compounds of this invention is measured the feeling retarding effect of rat nervus coccygeus by above experiment, measures and the results are shown in Table 13：
Table 13 is to the feeling retarding effect of rat nervus coccygeus
Compound number Feel retardance duration (hour)
Ropivacaine 2
1-H 4
2-H 2
Conclusion：Show that the compounds of this invention is to feeling residence time >=2 of rat by the hot tail-flick method measurement result of rat Hour, particularly 1-H is substantially better than control group Ropivacaine.

Claims (10)

1. a kind of crystal form I of compound 1, wherein：Its powder x-ray diffraction collection of illustrative plates 2 θ values for 10.9 ± 0.2 °, 26.7 ± It is corresponded at 0.2 °, 16.6 ± 0.2 °, 13.4 ± 0.2 °, 19.8 ± 0.2 °, 24.4 ± 0.2 °, 22.1 ± 0.2 °, 23.8 ± 0.2 ° There is characteristic diffraction peak,
Preferably, the powder x-ray diffraction collection of illustrative plates is to be corresponding with feature at 30.2 ± 0.2 °, 20.2 ± 0.2 ° also in 2 θ values Diffraction maximum；
2θ(°) Relative intensity % D values 10.9±0.2 100 8.1 26.7±0.2 9.8 3.3 16.6±0.2 8.5 5.3 13.4±0.2 7.2 6.6 19.8±0.2 5.8 4.5 24.4±0.2 4.9 3.6 22.1±0.2 3.0 4.0 23.8±0.2 2.6 3.7 30.2±0.2 1.4 3.0 20.2±0.2 1.3 4.4 17.8±0.2 1.1 5.0 20.4±0.2 1.1 4.4 32.8±0.2 1.1 2.7
It is further preferred that the powder X-ray diffracting spectrum that the crystal form I of the compound 1 is represented with 2 θ angles is upper Epitope is put with characteristic diffraction peak, relative intensity and d values.
2. the crystal form I of compound 1 according to claim 1, wherein：The crystal form I of the compound 1 has as shown in Figure 1 Powder x-ray diffraction collection of illustrative plates representated by feature.
3. a kind of crystal form II of compound 1, wherein：Its powder x-ray diffraction collection of illustrative plates 2 θ values for 10.9 ± 0.2 °, 10.6 ± Characteristic diffraction peak is corresponding at 0.2 °, 16.3 ± 0.2 °, 26.1 ± 0.2 °, 24.6 ± 0.2 °, 19.6 ± 0.2 °；
Preferably, the powder x-ray diffraction collection of illustrative plates is at 26.9 ± 0.2 °, 24.0 ± 0.2 °, 17.7 ± 0.2 ° also in 2 θ values It is corresponding with characteristic diffraction peak；
2θ(°) D values Relative intensity % 10.9±0.2 8.1 100 10.6±0.2 8.3 44.1 16.3±0.2 5.4 23.3 26.1±0.2 3.4 12.7 24.6±0.2 3.6 9.8 19.6±0.2 4.5 6.7 26.9±0.2 3.3 4.9 24.0±0.2 3.7 4.6 17.7±0.2 5.0 3.2 21.3±0.2 4.2 1.8 22.0±0.2 4.0 1.7 26.7±0.2 3.3 1.4 20.2±0.2 4.4 1.3 23.8±0.2 3.7 1.3 33.1±0.2 2.7 1.0
It is further preferred that the crystal form II of the compound 1 is existed with the powder X-ray diffracting spectrum that 2 θ angles represent Upper table position has characteristic diffraction peak, relative intensity and d values.
4. the crystal form II of compound 1 according to claim 3, wherein：The crystal form II of the compound 1 has such as Fig. 4 institutes The feature representated by powder x-ray diffraction collection of illustrative plates shown.
5. a kind of crystal form I of compound 2, wherein：Its powder x-ray diffraction collection of illustrative plates 2 θ values for 10.3 ± 0.2 °, 18.7 ± Characteristic diffraction peak is corresponding at 0.2 °, 24.0 ± 0.2 °, 12.8 ± 0.2 °, 25.8 ± 0.2 °, 16.1 ± 0.2 °,
Preferably, the powder x-ray diffraction collection of illustrative plates is at 20.5 ± 0.2 °, 17.6 ± 0.2 °, 31.3 ± 0.2 ° also in 2 θ values It is corresponding with characteristic diffraction peak；
It is further preferred that the powder X-ray diffracting spectrum that the crystal form I of the compound 2 is represented with 2 θ angles is upper Epitope is put with characteristic diffraction peak, relative intensity and d values.
6. the crystal form I of compound 2 according to claim 5, wherein：The crystal form I of the compound 2 has as shown in Figure 7 Powder x-ray diffraction collection of illustrative plates representated by feature.
7. a kind of crystal form II of compound 2, wherein：Its powder x-ray diffraction collection of illustrative plates 2 θ values for 10.4 ± 0.2 °, 10.1 ± 0.2°、17.5±0.2°、15.8±0.2°、18.8±0.2°、23.6±0.2°、24.2±0.2°、26.4±0.2°、35.5± Characteristic diffraction peak is corresponding at 0.2 °, 25.4 ± 0.2 °；
2θ(°) Relative intensity % D values 10.4±0.2 100.0 8.5 10.1±0.2 54.4 8.7 17.5±0.2 38.6 5.1 15.8±0.2 29.7 5.6 18.8±0.2 21.8 4.7 23.6±0.2 18.5 3.8 24.2±0.2 17.6 3.7 26.4±0.2 15.4 3.4 35.5±0.2 11.7 2.5 25.4±0.2 8.2 3.5 20.3±0.2 4.3 4.4 22.0±0.2 3.4 4.0 8.6±0.2 2.5 10.2 20.4±0.2 2.0 4.3 18.3±0.2 1.9 4.9 32.8±0.2 1.7 2.7
Preferably, the powder X-ray diffracting spectrum that the crystal form II of the compound 2 is represented with 2 θ angles is in upper epitope It puts with characteristic diffraction peak, relative intensity and d values.
8. the crystal form II of compound 2 according to claim 7, wherein：The crystal form II of the compound 2 has such as Figure 10 institutes The feature representated by powder x-ray diffraction collection of illustrative plates shown.
9. a kind of pharmaceutical composition, the crystal form I of the compound 1 described in claims 1 or 2 containing treatment effective dose, power Profit requires the crystal form II of the compound 1 described in 3 or 4, the crystal form I of compound described in claim 5 or 62, and/or right will Ask the crystal form II of the compound 2 described in 7 or 8 and pharmaceutically acceptable carrier or excipient.
10. the crystal form I of the compound 1 described in claims 1 or 2, the crystal form II of the compound 1 described in claim 3 or 4, power Profit requires the crystal form I of the compound 2 described in 5 or 6, the crystal form II or claim 9 of the compound 2 described in claim 7 or 8 The pharmaceutical composition is being prepared for the application in local anaesthesia and/or field of medicament of easing pain.
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