CN105237493A - Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof - Google Patents
Crystalline form I of acotiamide hydrochloride hydrate, preparation method therefor and use thereof Download PDFInfo
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- CN105237493A CN105237493A CN201410323327.2A CN201410323327A CN105237493A CN 105237493 A CN105237493 A CN 105237493A CN 201410323327 A CN201410323327 A CN 201410323327A CN 105237493 A CN105237493 A CN 105237493A
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Abstract
The present invention relates to a crystalline form I of an acotiamide hydrochloride hydrate, a preparation method therefor and use thereof. The preparation method comprises: mixing acotiamide with an organic solvent so as to obtain a first mixture containing the acotiamide and the organic solvent; adding a salt-forming solvent into the first mixture to carry out a salt-forming reaction so as to obtain a second mixture containing an acotiamide hydrochloride; filtering the second mixture, and washing and drying a filter cake by an organic solvent so as to obtain a third mixture containing a crude product of the acotiamide hydrochloride; dissolving the third mixture in an aqueous organic solvent and performing slowly cooling crystallization after heating dissolution, so as to obtain a fourth mixture of an acotiamide hydrochloride hydrate crystal; and separating the crystal from the fourth mixture, and heating the separated crystal at 50-90 DEG C so as to obtain the acotiamide hydrochloride hydrate. The method is mild in reaction condition and simple in process and can be used for efficiently obtaining a highly pure acotiamide hydrochloride hydrate and a stable crystalline form thereof.
Description
Technical field
The invention belongs to the field of chemical synthesis, specifically, the present invention relates to the I crystal and its production and use of Ah examining for amine hydrochlorate hydrate.
Background technology
Ah examining is first the functional dyspepsia medicine for treatment in the whole world for amine (shown in formula I compound), is developed by Japanese Ze Li new drug Co., Ltd., and goes on the market in February, 2013 in Japan's approval.Be applicable to feeling of repletion after the meal, functional dyspepsia, epigastrium is glutted, early full treatment.
But, prepare the method for Ah examining for amine crystal formation at present, still have much room for improvement.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is to propose a kind of Ah examining of preparation for the method for the I crystal of amine hydrochlorate hydrate and Ah the examining that utilize the method effectively the to prepare I crystal for amine hydrochlorate hydrate, Ah the examining that the present invention prepares for amine hydrochlorate hydrate I crystal comparatively acotiamide hydrochloride trihydrate have good solvability and yield.
According to a first aspect of the invention, the present invention proposes a kind of method of Ah examining for amine hydrochlorate hydrate I crystal preparing above-described embodiment, the method comprises: Ah examining mixed with organic solvent for amine, to obtain containing first mixture of Ah examining for amine and organic solvent; Salt-forming reaction is carried out, to obtain containing second mixture of Ah examining for amine hydrochlorate by adding into salt solvent in described first mixture; Described second mixture is filtered, filter cake organic solvent washing, dry, to obtain containing three mixture of Ah examining for amine hydrochlorate crude product; Described 3rd mixture is dissolved in moisture organic solvent, slow cooling crystallization after heating for dissolving, to obtain the 4 mixture of Ah examining for amine hydrochlorate hydrate crystal; And be separated described crystal from described 4 mixture, and at 50 ~ 90 DEG C, be separated crystal is heated, to obtain the I crystal of Ah examining for amine hydrochlorate hydrate.Utilize the method effectively can prepare the I crystal of Ah examining for amine hydrochlorate hydrate.
In addition, method according to the above embodiment of the present invention can also have following additional technical characteristic:
According to embodiments of the invention, Ah the examining utilizing aforesaid method to prepare for the I crystal of amine hydrochlorate hydrate for Ah examining is for amine hydrochlorate monohydrate.
According to embodiments of the invention, described organic solvent is at least one being selected from methyl alcohol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, t-butyl methyl ether, methyltetrahydrofuran, at least one in particular methanol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, t-butyl methyl ether, the most preferably at least one of methyl alcohol, ethanol, Virahol.
According to embodiments of the invention, described one-tenth salt solvent is aqueous hydrochloric acid.According to embodiments of the invention, the concentration of described aqueous hydrochloric acid is 10% ~ 40% weight, is preferably 30% ~ 40% weight.
According to embodiments of the invention, the temperature of described salt-forming reaction is 20 ~ 100 DEG C, preferably 30 ~ 80 DEG C, most preferably 40 ~ 60 DEG C.
According to embodiments of the invention, at least one in solvent selected from methanol, ethanol, Virahol, tetrahydrofuran (THF), acetone in described moisture organic solvent, particular methanol, ethanol, Virahol, tetrahydrofuran (THF), the most preferably at least one of methyl alcohol, ethanol, Virahol.In described moisture organic solvent, organic solvent accounts for 40% ~ 95% volume, and preferred organic solvent accounts for 60% ~ 90% volume.
According to a particular embodiment of the invention, applicant finds through repetition test research, adopts aforesaid method of the present invention not only effectively can prepare Ah examining for amine hydrochlorate monohydrate, and adopts aforesaid method to have better productive rate.So far Ah the examining of bibliographical information is not had for the preparation method of amine monohydrate.
According to another aspect of the present invention, the invention allows for the I crystal of Ah examining for amine hydrochlorate hydrate, described Ah examining is prepared for the method for the I crystal of amine hydrochlorate hydrate by foregoing preparation Ah examining for the I crystal of amine hydrochlorate hydrate, described Ah examining for the X-ray powder diffraction figure of the I crystal of amine hydrochlorate hydrate at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, there is X-ray diffraction peak in 28.61 ° ± 0.2 ° (2 θ).
According to embodiments of the invention, described Ah examining for the I crystal of amine hydrochlorate hydrate for Ah examining is for amine hydrochlorate monohydrate, described Ah examining has endotherm(ic)peak for amine hydrochlorate monohydrate at about 70 DEG C, weightless 1.41%, for solvent and surface water, there is endotherm(ic)peak at 120.3-144.6 DEG C, weightless 3.75%, show that it contains a part water, 151.6-166.0 DEG C of fusing.
According to embodiments of the invention, described Ah examining in amine hydrochlorate monohydrate containing Ah the examining of at least 99.5% weight for amine hydrochlorate monohydrate,
Optionally, containing compound shown in the formula I below 0.5% weight
Formula I.
According to a third aspect of the invention we, the invention allows for Ah examining and preparing the purposes in medicine for the I crystal of amine hydrochlorate hydrate, described medicine is used for the treatment of functional dyspepsia.Ah the examining utilizing aforesaid method of the present invention to prepare may be used for the medicine for the preparation for the treatment of functional dyspepsia for amine hydrochlorate monohydrate.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or additional aspect of the present invention and advantage will become obvious and easy understand from accompanying drawing below combining to the description of embodiment, wherein:
Fig. 1 is according to Ah the examining of the embodiment of the present invention HPLC-UV detection for amine hydrochlorate monohydrate;
Fig. 2 schemes for the DSC of amine hydrochlorate monohydrate according to Ah the examining of the embodiment of the present invention;
Fig. 3 is according to Ah the examining of the embodiment of the present invention X-ray diffractogram for amine hydrochlorate monohydrate (I crystal);
Fig. 4 is according to Ah the examining of the embodiment of the present invention HPLC-UV detection for amine hydrochlorate trihydrate;
Fig. 5 schemes for the DSC of amine hydrochlorate trihydrate according to Ah the examining of the embodiment of the present invention;
Fig. 6 is according to Ah the examining of the embodiment of the present invention X-ray diffractogram for amine hydrochlorate trihydrate (I crystal);
Fig. 7 composes for the hydrogen of amine hydrochlorate trihydrate according to Ah the examining of the embodiment of the present invention.
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to text or the synthesis of known method, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
Embodiment 1 Ah examining is for the synthesis of amine hydrochlorate monohydrate
Step (1) Ah examining is for the preparation of amine hydrochlorate
Get 3.0g free state Ah examining for amine, add 30ml Virahol, be heated to 50 DEG C of dissolvings.At this temperature, add 4g, 35% aqueous hydrochloric acid, stir 5h, naturally cool to 15 DEG C.Filter, filter cake 20ml washed with isopropyl alcohol.Dry under 50 DEG C of conditions, obtain 2.6g Ah examining for amine hydrochlorate crude product.
Step (2) Ah examining refining for amine hydrochlorate monohydrate
Get Ah the examining of above-mentioned preparation for amine hydrochlorate crude product 2.6g, adding 25ml volume ratio is 70% isopropanol water solution, is heated to 70 DEG C of dissolvings.Stir 4h.Filter, filter cake 10ml washed with isopropyl alcohol.Then dry 6h under 50 DEG C of conditions.Finally obtain 2.36g Ah examining for amine salt acid acid hydrate, yield 88.0%.Through HPLC detect, purity is 99.6%, through moisture content tester detect moisture value be 3.33%, through thermal weight loss and differential thermal analysis, presumption preparation for Ah examining is for amine hydrochlorate monohydrate.
Through XRD analysis, there is X-ray diffraction peak at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, 28.61 ° ± 0.2 ° (2 θ) in it.Judge that crystal formation is I crystal.
Embodiment 2 Ah examining is for the synthesis of amine hydrochlorate monohydrate
Step (1) Ah examining is for the preparation of amine hydrochlorate
Get 30g free state Ah examining for amine, add 300ml methyl alcohol, be heated to 70 DEG C of dissolvings.At this temperature, add 40g20% aqueous hydrochloric acid, stir 5h, naturally cool to 15 DEG C.Filter, filter cake 50ml methanol wash.Dry under 70 DEG C of conditions.Finally obtain 29.2g Ah examining for amine hydrochlorate crude product.
Step (2) Ah examining is for the preparation of amine hydrochlorate hydrate
Get Ah the examining of above-mentioned preparation for amine hydrochlorate crude product 29.2g, adding 300ml volume ratio is 80% isopropanol water solution, is heated to 70 DEG C of dissolvings.Stir 4h.Filter, filter cake 100ml washed with isopropyl alcohol.Then dry 4h under 60 DEG C of conditions.Finally obtain 27.06g Ah examining for amine hydrochlorate hydrate, total recovery 89.7%.Through HPLC detect, purity is 99.5%, through moisture content tester detect moisture value be 3.33%, through thermal weight loss and differential thermal analysis, presumption preparation for Ah examining is for amine hydrochlorate monohydrate.
Through XRD analysis, there is X-ray diffraction peak at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, 28.61 ° ± 0.2 ° (2 θ) in it.Judge that crystal formation is I crystal.
Embodiment 3 Ah examining is for the synthesis of amine hydrochlorate monohydrate
Step (1) Ah examining is for the preparation of amine hydrochlorate
Get 130g free state Ah examining for amine, add 450ml methyl alcohol, be heated to 30 DEG C of dissolvings.At this temperature, add 75g35% aqueous hydrochloric acid, stir 5h, naturally cool to 15 DEG C.Filter, filter cake 100ml methanol wash.Dry under 70 DEG C of conditions.Finally obtain 110g Ah examining for amine hydrochlorate crude product.
Step (2) Ah examining is for the preparation of amine hydrochlorate hydrate
Get Ah the examining of above-mentioned preparation for amine hydrochlorate crude product 110g, adding 770ml volume ratio is 80% isopropanol water solution, is heated to 70 DEG C of dissolvings.Stir 4h.Filter, filter cake 100ml washed with isopropyl alcohol.Then dry 4h under 60 DEG C of conditions.Finally obtain 104.7g Ah examining for amine salt acid hydrate, yield 92.1%.Through HPLC detect, purity is 99.7%, through moisture content tester detect moisture value be 3.33%, through thermal weight loss and differential thermal analysis, presumption preparation for Ah examining is for amine hydrochlorate monohydrate.
Through XRD analysis, there is X-ray diffraction peak at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, 28.61 ° ± 0.2 ° (2 θ) in it.Judge that crystal formation is I crystal.
Comparative example 1 Ah examining is for the synthesis of amine hydrochlorate trihydrate
Step (1) Ah examining is for the preparation of amine hydrochlorate
Get 30g free state Ah examining for amine, add 300ml Virahol, be heated to 70 DEG C of dissolvings.At this temperature, add the 35g35% hydrochloride aqueous solution, stir 5h, naturally cool to 15 DEG C.Filter, filter cake 100ml washed with isopropyl alcohol.Dry under 70 DEG C of conditions.Finally obtain 25g Ah examining for amine hydrochlorate crude product.
Step (2) Ah examining is for the preparation of amine hydrochlorate hydrate
Get Ah the examining of above-mentioned preparation for amine hydrochlorate crude product 25g, adding 300ml volume ratio is 60% isopropanol water solution, is heated to 70 DEG C of dissolvings.Stir 4h.Filter, filter cake 100ml washed with isopropyl alcohol.Then dry 4h under 20 DEG C of conditions.Finally obtain 19.9g Ah examining for amine hydrochlorate hydrate, yield 72.2%.Detect through HPLC, purity 99.7%, moisture KF value 10.03% is measured through moisture content tester, through thermal weight loss and differential thermal analysis, prepared sample its have endotherm(ic)peak at about 70 DEG C, weightless 6.48%, show that it contains two molecular waters, there is endotherm(ic)peak at 122.1-143.6 DEG C, weightless 3.27%, show that it contains a part water.152.6-167.0 DEG C of fusing, this compound is trihydrate, through XRD analysis, there is X-ray diffraction peak at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, 28.61 ° ± 0.2 ° (2 θ) in it.
Through presumption, the compound crystal form of preparation is I crystal.
Target product
1h-NMR (400MHzDMSO-d6): δ 1.30-1.33 (m, 12H), 3.20-3.25 (m, 2H), 3.56-3.61 (m, 2H), 3.67-3.70 (t, 2H), 3.77-3.84 (ss, 6H), 6.69-6.70 (s, 1H), 7.51-7.52 (s, 1H), 7.91-7.95 (s, 1H), 8.63-8.68 (m, 2H), 11.68-11.69 (s, 1H), 11.74-11.76 (s, 1H)., as shown in Figure 7.
Comparative example 2 Ah examining is for the synthesis of amine hydrochlorate trihydrate
Step (1) Ah examining is for the preparation of amine hydrochlorate
Get 130g free state Ah examining for amine, add 450ml methyl alcohol, be heated to 30 DEG C of dissolvings.At this temperature, add 75g35% aqueous hydrochloric acid, stir 5h, naturally cool to 15 DEG C.Filter, filter cake 100ml methanol wash.Dry under 70 DEG C of conditions.Finally obtain 110g Ah examining for amine hydrochlorate crude product.
Step (2) Ah examining is for the preparation of amine hydrochlorate hydrate
Get Ah the examining of above-mentioned preparation for amine hydrochlorate crude product 110g, adding 770ml volume ratio is 80% isopropanol water solution, is heated to 70 DEG C of dissolvings.Stir 4h.Filter, filter cake 100ml washed with isopropyl alcohol.Then dry 4h under 20 DEG C of conditions.Finally obtain 86.2g Ah examining for amine salt acid hydrate, yield 71.2%.Through HPLC detect, purity 99.5%, through moisture content tester detect moisture value be 10.0%, through thermal weight loss and differential thermal analysis, presumption preparation for Ah examining is for amine hydrochlorate trihydrate, through XRD analysis, the crystal formation of preparation is for Ah examining is for amine hydrogen salt hydrochlorate trihydrate.
Embodiment 3 contrasts Ah examining for the physico-chemical property of amine hydrochlorate monohydrate and trihydrate and stripping
Ah the examining prepared in mensuration embodiment 2 is respectively for the fusing point of Ah the examining prepared in amine hydrochlorate monohydrate and comparative example 1 for amine hydrochlorate trihydrate.Surveying instrument is VRR type melting point apparatus.
Result: Ah examining is 158.6-160.2 DEG C for the fusing point of amine hydrochlorate monohydrate; Ah examining is 158.6-161.2 DEG C for the fusing point of amine hydrochlorate trihydrate.
Monitored by solubility curve, Ah examining is better for amine hydrochlorate trihydrate than Ah examining for amine hydrochlorate monohydrate solvability.
Embodiment 4 Ah examining be the stability under high humidity and hot conditions for amine hydrochlorate monohydrate and trihydrate
According to embodiment 2 and comparative example 1, the applicant prepares Ah examining for amine hydrochlorate monohydrate and A Kao for amine hydrochlorate trihydrate, now investigates its stability under high temperature and super-humid conditions.In this embodiment, high humidity environment is the moisture eliminator being placed with saturated sodium-chloride water solution.Hot environment is 60 DEG C of air dry ovens.
Table 1 Ah examining be the change of (25 DEG C, humidity 75%) water-content under high humidity environment for amine hydrochlorate monohydrate
| Storage period | Moisture KF value | Hydrate type |
| 0day | 3.6％ | Monohydrate |
| 4day | 9.70％ | Monohydrate |
| 15day | 9.85％ | Monohydrate |
| 30day | 10.03％ | Monohydrate |
Table 2 Ah examining is for the change of amine hydrochlorate trihydrate (60 DEG C, humidity < 40%) water-content in high temperature environments
| Storage period | Moisture KF value | Hydrate type |
| 0h | 10.03％ | Trihydrate |
| 5h | 6.54％ | Trihydrate |
| 18h | 4.30％ | Trihydrate |
| 20h | 3.30％ | Trihydrate |
Table 3 Ah examining be the change of (be exposed in air 25 DEG C, humidity > 40%) water-content under room temperature environment for amine hydrochlorate trihydrate
| Storage period | Moisture KF value | Hydrate type |
| 0day | 10.03％ | Trihydrate |
| 4day | 10.00％ | Trihydrate |
| 15day | 9.89％ | Trihydrate |
| 30day | 10.12％ | Trihydrate |
As can be seen from above table data, Ah examining is unstable under the high temperature conditions for amine hydrochlorate trihydrate.Preservation should be sealed at ambient temperature.And Ah examining is unstable under high humidity condition for amine hydrochlorate monohydrate, isolated air should be sealed and preserve at ambient temperature.
Embodiment 5 Oral Administration in Rats Ah examining is for the pharmacokinetics of amine hydrochlorate monohydrate I crystal and trihydrate I crystal
Tested raw material: Ah the examining of unit of the present invention synthesis replaces amine hydrochlorate trihydrate for amine hydrochlorate monohydrate and A Kao
Grouping administration
Select Wistar rat 40, be divided into 4 groups by body weight, often organize 10, male and female dual-purpose, fasting 16h, respectively select 2 groups of I crystal of oral administration gavage Ah examining for amine hydrochlorate monohydrate and I crystal of trihydrate respectively, dosage is 20mg/kg.Respectively after administration 0.5,1,2,4,6,8,12,18,24,36,48,60h eye socket gets blood, separation of serum ,-20 DEG C of preservations are to be measured.
Chromatographic condition
Stationary phase: DiamonsilTMC18 post, 10 μm, 250 × 4.6mm (I.D.), column temperature 30 DEG C.
Moving phase: methyl alcohol: water=70: 30, flow velocity: 1ml/min.
Determined wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
Blood sample treatments
Get rat blood serum 200 μ l, add interior mark (Ah examining is for amine 200 μ g/ml) 10 μ l, after mixing, add DMF (N, dinethylformamide) 200 μ l, vibration 10min, place 30 minutes, with the centrifugation 10min of 10000 turns/min, get supernatant liquor 20 μ l sample introduction.
Determination of plasma concentration
After bioassay standard curve, draw linear regression equation (y=ax+b).After the administration of mensuration rat, the ratio of blood sample gained peak area, calculates Plasma Concentration according to linear regression equation, and calculates medicine for parameter through 3P97 medicine for computation program.
Instrument
HPLC test macro: Shimadzu SPD-10AUV detector, Hi-TechP4000 high-pressure pump, LabAlliance-AS1000 automatic sampler, ANASTAR chromatographic working station.
HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai manufactures.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
Result of study
Note: in table, data are mean number ± standard deviation (n=6).
Conclusion: pharmacokinetic shows, the I crystal examined for amine hydrochlorate monohydrate of Oral Administration in Rats gavage 20mg/kg, from medicine for parameter, between the parameters of the I crystal of itself and hydrochloride trihydrate, there is some difference, but substantially all within the scope of the same order of magnitude, may be used for being developed to new medicine, and this Stability Analysis of Structures, absorption in animal body, eliminate basically identical.
Ah examining of the present invention shows higher biological activity, for Subsequent pharmacological exploitation provides broad space for the I crystal of amine hydrochlorate monohydrate in preparation treatment functional dyspepsia medicine.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (10)
1. prepare the method for Ah examining for the I crystal of amine hydrochlorate hydrate, it is characterized in that, comprising:
Ah examining is mixed with organic solvent for amine, to obtain containing first mixture of Ah examining for amine and organic solvent;
Salt-forming reaction is carried out, to obtain containing second mixture of Ah examining for amine hydrochlorate by adding into salt solvent in described first mixture;
Described second mixture is filtered, filter cake organic solvent washing, dry, to obtain containing three mixture of Ah examining for amine hydrochlorate crude product;
Described 3rd mixture is dissolved in moisture organic solvent, slow cooling crystallization after heating for dissolving, to obtain the 4 mixture of Ah examining for amine hydrochlorate hydrate crystal;
And be separated described crystal from described 4 mixture, and at 50 ~ 90 DEG C, be separated crystal is heated, so that Ah the examining described in obtaining is for the I crystal of amine hydrochlorate hydrate.
2. method according to claim 1, is characterized in that, described Ah examining for the I crystal of amine hydrochlorate hydrate for Ah examining is for amine hydrochlorate monohydrate.
3. method according to claim 1, it is characterized in that, described organic solvent is at least one being selected from methyl alcohol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, t-butyl methyl ether, methyltetrahydrofuran, at least one in particular methanol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, t-butyl methyl ether, the most preferably at least one of methyl alcohol, ethanol, Virahol.
4. method according to claim 1, is characterized in that, described one-tenth salt solvent is aqueous hydrochloric acid, and optionally, the concentration of described aqueous hydrochloric acid is 10 ~ 40% weight, and the concentration of preferred described aqueous hydrochloric acid is 30 ~ 40% weight.
5. method according to claim 1, is characterized in that, described salt-forming reaction temperature is 20 ~ 100 DEG C, preferably 30 ~ 80 DEG C, most preferably 40 ~ 60 DEG C.
6. method according to claim 5, it is characterized in that, in described moisture organic solvent, organic solvent is selected from least one in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, particular methanol, ethanol, Virahol, tetrahydrofuran (THF), the most preferably at least one of methyl alcohol, ethanol, Virahol
Optionally, in described moisture organic solvent, organic solvent accounts for 40% ~ 95% volume, and preferred organic solvent accounts for 60% ~ 90% volume.
7. Ah examining is for the I crystal of amine hydrochlorate hydrate, it is characterized in that, described Ah examining is prepared by the method described in any one of claim 1-6 for the I crystal of amine hydrochlorate hydrate, described Ah examining for the X-ray powder diffraction figure of the I crystal of amine hydrochlorate hydrate at 6.24 ° ± 0.2 °, 11.87 ° ± 0.2 °, 12.46 ° ± 0.2 °, 14.62 ° ± 0.2 °, 14.95 ° ± 0.2 °, 18.29 ° ± 0.2 °, 18.72 ° ± 0.2 °, 23.17 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.98 ° ± 0.2 °, there is X-ray diffraction peak in 28.61 ° ± 0.2 ° (2 θ).
8. according to claim 7 Ah examining for the I crystal of amine hydrochlorate hydrate, it is characterized in that, described Ah examining for the I crystal of amine hydrochlorate hydrate for Ah examining is for amine hydrochlorate monohydrate, described Ah examining has endotherm(ic)peak for amine hydrochlorate monohydrate at about 70 DEG C, and weightless 1.41%, be solvent and surface water, endotherm(ic)peak is had at 120.3-144.6 DEG C, weightless 3.75%, show that it contains a part water, 151.6-166.0 DEG C of fusing.
9. Ah examining, for the I crystal of amine hydrochlorate hydrate, is characterized in that according to claim 8, and described Ah examining is for containing described Ah the examining of at least 99.5% weight in amine hydrochlorate monohydrate for amine hydrochlorate monohydrate;
Optionally, containing compound shown in the formula I below 0.5% weight
Formula I.
10. Ah the examining described in any one of claim 7-9 is preparing the purposes in medicine for the I crystal of amine hydrochlorate hydrate, and described medicine is used for the treatment of functional dyspepsia.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107176934A (en) * | 2017-07-11 | 2017-09-19 | 湖南七纬科技有限公司 | One kind treats dyspeptic drug hydrate and preparation method thereof |
| CN107235928A (en) * | 2017-07-11 | 2017-10-10 | 湖南七纬科技有限公司 | It is a kind of to treat medical compounds of functional dyspepsia FD and preparation method thereof |
| CN107266389A (en) * | 2017-07-11 | 2017-10-20 | 湖南七纬科技有限公司 | It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof |
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| CN101006040A (en) * | 2004-08-23 | 2007-07-25 | 泽里新药工业株式会社 | Method for producing aminothiazole derivative and production intermediate |
| CN104447611A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Acotiamide compound |
| CN104447612A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Acotiamide hydrate crystal form and its preparation method and use |
| CN103896873A (en) * | 2013-10-23 | 2014-07-02 | 山东诚创医药技术开发有限公司 | Refining method for hydrochloride acid acotiamide |
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| CN107176934A (en) * | 2017-07-11 | 2017-09-19 | 湖南七纬科技有限公司 | One kind treats dyspeptic drug hydrate and preparation method thereof |
| CN107235928A (en) * | 2017-07-11 | 2017-10-10 | 湖南七纬科技有限公司 | It is a kind of to treat medical compounds of functional dyspepsia FD and preparation method thereof |
| CN107266389A (en) * | 2017-07-11 | 2017-10-20 | 湖南七纬科技有限公司 | It is a kind of to treat medicine times semihydrate of enterogastric diseases and preparation method thereof |
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