CN105130996A - 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form - Google Patents
1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form Download PDFInfo
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Abstract
The invention discloses 1,5-naphthalenedisulfonate and crystal form of a benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form. 1,5-naphthalenedisulfonate of a crystal-form or amorphous compound represented in the formula (I) or the compound represented in the formula (I) and 1,5-naphthalene disulfonic acid are heated and dissolved in a crystallization solvent for cooling and crystallization and then are filtered, crystalized, washed and dried, and 1, 5-naphthalene sulfonate or the crystal form of the compound represented in the formula (I) is prepared. The prepared 1, 5-naphthalene sulfonate or the crystal form of the compound represented in the formula (I) has good stability and high purity, is free of toxicity and can be used for clinical treatment better.
Description
Technical field
The invention belongs to chemicals preparation field, be specifically related to a kind of benzodiazepine
1,5-napadisilate of derivative and crystal formation and their preparation method.
Background technology
The chemistry of formula (I) compound is called 3-[the bromo-1-methyl of (4s)-8--6-(2-pyridyl)-4H-imidazoles [l, 2-a] [l, 4] benzodiazepine
-4-base] methyl propionate,
This compound contains carboxylicesters and benzodiazepine
structure, be fugitive central nervous system (CNS, CentralNervousSystem) inhibitor, be in particular in tranquilizing soporific, anxiety, of flaccid muscles and anticonvulsant action.This compound also can be used for the intravenously administrable in clinical treatment, as calm in the operation consent in intra-operative, anxiety and forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other narcotic and pain killer and/or simultaneously, as the induction of general anesthesia and the component of maintenance; ICU is calm.But this compound is unstable, only be suitable for low temperature 5 DEG C preservation, under the condition of 40 DEG C/75% relative humidity (opening), the sample deliquescence of storage, color yellowing to orange, and significantly reduces more than 7% relative to initial content display content.
Along with researchist constantly studies, think and can be prepared salify to increase its chemical stability.Tosilate, benzene sulfonate, the esilate of formula (I) compound are reported now, wherein, the chemistry of tosilate, optical purity are slightly well, chemistry, the optical purity of all the other two kinds of salt are all undesirable, and recrystallization process failing improves its chemistry and optical purity significantly.
NFV (nelfinavir mesilate) event that Europe in those early years occurs, let us is for drug safety special concern; After European Union occurs for this event, have issued the risk warning file EMEA/44714/2008 of small-molecular-weight sulfonic acid esters, wherein clearly mention, the DNA alkylating of methanesulfonates, esilate, benzene sulfonate, p-toluenesulfonic esters and isethionic acid ester class can cause mutagenic effect, carcinogenic effect and teratogenic effect.In view of in NFV (nelfinavir mesilate) event, Roche Holding Ag is depositing in pharmaceutical procedures, because the ethanol cleaning hold-up vessel remains in a large number, cause reacting with methylsulfonic acid and creating the methanesulfonates of severe overweight, finally result in the potential safety hazard of this medicine, and recalled by EMEA mandatory requirement.Also require that medicament research and development company should avoid the use of the sulfonic acid to the small-molecular-weight mentioned in above-mentioned file in drug development simultaneously as far as possible, and the acid group not having latent gene toxicity should be selected as far as possible.
In addition except genotoxicity, the LD of the tosic acid corresponding to existing formula (I) compound three kinds of salt, Phenylsulfonic acid, ethyl sulfonic acid itself
50toxicity is all bigger than normal, and adopt rat to do toxicity test, rat is oral tosic acid, Phenylsulfonic acid, ethyl sulfonic acid respectively, its LD
50be respectively 2480mg/kg, 0.89mg/kg, 48mg/kg, therefore, high, good stability, avirulent formula (I) compound the salt of exploitation purity is necessary.
Summary of the invention
The invention provides a kind of benzodiazepine
1,5-napadisilate of derivative and crystal formation and their preparation method, this preparation method's simple possible, cost are low, the benzodiazepine prepared
1,5-napadisilate of derivative and crystal form purity is high, good stability, can be used as active constituents of medicine and uses, in addition, and the LD of 1,5-naphthalene disulfonic acid
50for 30000mg/kg, the benzodiazepine therefore prepared
avirulent within the scope of the usage quantity that 1,5-napadisilate of derivative is suitable.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
1,5-napadisilate of formula (I) compound:
Further, the stoicheiometry of formula (I) compound and 1,5-naphthalene disulfonic acid is 2:1, and further, this salt is crystal salt.
Further, 1 of described formula (I) compound, I crystal formation of 5-napadisilate, use Cu-Ka radiation, obtain the X-ray powder diffraction represented with 2 θ angles, have characteristic peak at 7.9,11.9,14.6,14.9,15.9,17.4,18.3,19.0,19.4,19.7,20.6,20.9,22.1,22.6,22.9,23.2,23.4,24.1,26.1,26.5,28.7,29.2,30.1 places.
The preparation method of 1,5-naphthalene disulfonic acid crystal salt of described formula (I) compound, comprises the following steps:
1) by 1 of crystal formation or unformed formula (I) compound, 5 ?napadisilate, or by formula (I) compound and 1,5 ?naphthalene disulfonic acid heating for dissolving in crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or their mixed solvent, described rudimentary organic solvent be carbonatoms be less than 6 alcohols, ketone, ester class, ether solvent or acetonitrile, DMF.
2) filtering for crystallizing and wash, dry.
Further, in the preparation method of 1,5-naphthalene disulfonic acid crystal salt of described formula (I) compound, the solvent that formula (I) compound and 1,5-naphthalene disulfonic acid react used is the mixed solvent of ethyl acetate and alcohols; Further, alcohols is methyl alcohol, ethanol, propyl alcohol or Virahol.
Further, 1 of described formula (I) compound, in the preparation method of 5-naphthalene disulfonic acid crystal salt, described crystallization solvent is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, butanone, ethyl acetate, butylacetate, methyl tertiary butyl ether, isopropyl ether, acetonitrile, DMF.
1 of described formula (I) compound, the preparation method of 5-napadisilate I crystal formation, comprise described 1, the preparation process of 5-naphthalene disulfonic acid crystal salt, wherein said crystallization solvent is one or more in alcohols, ketone, ethers, ester class, acetonitrile, DMF, water.
Further, 1 of described formula (I) compound, in the preparation method of 5-napadisilate I crystal formation, described crystallization solvent is one or more in methyl alcohol, ethanol, Virahol, acetone, butanone, ethyl acetate, butylacetate, isopropyl ether, methyl tertiary butyl ether, acetonitrile, DMF, water.
Benzodiazepine provided by the invention
1 of derivative, 5-napadisilate and crystal formation and their preparation method, have following beneficial effect: preparation method is simple, cost is low, 1 of formula (I) compound prepared, 5-napadisilate and crystal form purity is high, good stability, can be used as active constituents of medicine and uses.
Accompanying drawing explanation
Fig. 1 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 1 Chinese style (I) compound;
Fig. 2 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 1 Chinese style (I) compound;
Fig. 3 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 2 Chinese style (I) compound;
Fig. 4 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 2 Chinese style (I) compound;
Fig. 5 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 3 Chinese style (I) compound;
Fig. 6 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 3 Chinese style (I) compound;
Fig. 7 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 4 Chinese style (I) compound;
Fig. 8 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 4 Chinese style (I) compound;
Fig. 9 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 5 Chinese style (I) compound;
Figure 10 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 5 Chinese style (I) compound;
Figure 11 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 6 Chinese style (I) compound;
Figure 12 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 6 Chinese style (I) compound;
Figure 13 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 7 Chinese style (I) compound;
Figure 14 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 7 Chinese style (I) compound;
Figure 15 is the DSC spectrogram of 1,5-napadisilate I crystal formation of embodiment 8 Chinese style (I) compound;
Figure 16 is the X-ray powder diffractogram of 1,5-napadisilate I crystal formation of embodiment 8 Chinese style (I) compound.
Figure 17 is the enlarged view of part A in Fig. 4;
Figure 18 is the enlarged view of part B in Fig. 8.
Embodiment
Embodiment 1: the preparation of 1,5-napadisilate of formula (I) compound
Formula (I) compound 100mg (0.228mmol) is accurately taken in 10mL single port bottle, adding the stirring of 0.5mL ethyl acetate makes it all dissolve, then 32mg2-naphthene sulfonic acid (0.114mmol) is dissolved in 0.25mL ethanol, and be added drop-wise in the ethyl acetate solution of formula (I) compound, stirring and crystallizing, suction filtration, ethyl acetate drip washing, 40 DEG C of drying under reduced pressure obtain 1 of formula (I) compound, 5-napadisilate, white solid 115mg, yield 87%.
The X-ray diffraction spectrogram of this crystallized sample is shown in accompanying drawing 2, characteristic peak is had at 7.9,11.9,14.6,14.9,15.9,17.4,18.3,19.0,19.4,19.7,20.6,20.9,22.1,22.6,22.9,23.2,23.4,24.1,26.1,26.5,28.7,29.2,30.1 places, DSC spectrogram is shown in accompanying drawing 1, charateristic avsorption band is had near 260 DEG C, define 1,5-napadisilate I crystal formation that this crystal formation is formula (I) compound.
1HNMR(400MHz,MeOD)δ8.94(d,J＝8.8Hz,1H),8.53(d,J＝4.4Hz,1H),8.15–8.10(m,2H),8.02–7.94(m,2H),7.70(dd,J＝18.9,5.5Hz,2H),7.55–7.50(m,2H),7.34(d,J＝1.0Hz,1H),4.41(dd,J＝10.0,4.1Hz,1H),3.68(s,3H),2.883–2.52(m,4H),2.41(d,J＝0.8Hz,3H).
Embodiment 2: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 5mL, adds 3.0mL methyl alcohol, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to 4 DEG C of crystallizatioies to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 76mg, yield 76%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 3, and X-ray diffraction spectrogram is shown in accompanying drawing 4.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 3: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 25mL, adds the mixing solutions (volume ratio=5:1) of 6mL isopropyl alcohol and water, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to room temperature crystallization to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 85mg, yield 85%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 5, and X-ray diffraction spectrogram is shown in accompanying drawing 6.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 4: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1,5-napadisilate 100mg of formula (I) compound in embodiment 1, add in the round-bottomed flask of 25mL, add 15mL isopropyl ether and N, the mixing solutions (volume ratio=2:1) of dinethylformamide, reflux 10min, makes solid dissolve completely, stop heating, filtered while hot, is cooled to room temperature crystallization and spends the night, and products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtain white solid 88mg, yield 88%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 7, and X-ray diffraction spectrogram is shown in accompanying drawing 8.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 5: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 50mL, adds the mixing solutions (volume ratio=1:4:4) of 18.0mL methyl alcohol and butylacetate and methyl tertiary butyl ether, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to room temperature crystallization to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 95mg, yield 95%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 9, and X-ray diffraction spectrogram is shown in accompanying drawing 10.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 6: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 25mL, adds the mixing solutions (volume ratio=2:1:2) of 10mL methyl alcohol and ethanol and isopropyl ether, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to 4 DEG C of crystallizatioies to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 81mg, yield 81%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 11, and X-ray diffraction spectrogram is shown in accompanying drawing 12.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 7: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 25mL, adds the mixing solutions (volume ratio=1:3) of 15mL methyl alcohol and ethyl acetate, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to 4 DEG C of crystallizatioies to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 86mg, yield 86%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 13, and X-ray diffraction spectrogram is shown in accompanying drawing 14.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 8: the preparation of 1,5-napadisilate I crystal formation of formula (I) compound
By 1 of formula (I) compound in embodiment 1,5-napadisilate 100mg, adds in the round-bottomed flask of 25mL, adds the mixing solutions (volume ratio=1:2:2) of 10mL methyl alcohol and butanone and methyl tertiary butyl ether, reflux 10min, solid is dissolved completely, stops heating, filtered while hot, be cooled to 4 DEG C of crystallizatioies to spend the night, products therefrom spends the night at 40 DEG C of drying under reduced pressure, obtains white solid 89mg, yield 89%.
The DSC spectrogram of this crystallized sample is shown in accompanying drawing 15, and X-ray diffraction spectrogram is shown in accompanying drawing 16.The X-ray diffraction spectrogram of this crystallized sample and the comparison after deliberation of DSC spectrogram, determine that product is 1,5-napadisilate I crystal formation of formula (I) compound.
Embodiment 9: 1,5-napadisilate aqueous solution stability test of formula (I) compound
Experiment condition:
Moving phase:
A-phosphate buffered saline buffer (0.025mol/L potassium dihydrogen phosphate aqueous solution is 3.5 by phosphoric acid adjust ph)
B-acetonitrile
Chromatographic column: Féraud door lunaC18 (2) 4.6*250mm, 5 μm
Elution program:
| Time/min | A phase/% | B phase/% |
| 0 | 80 | 20 |
| 20 | 30 | 70 |
| 40 | 30 | 70 |
Column temperature: 45 DEG C
Determined wavelength: 230nm
Sample introduction concentration: 0.5mg/mL
Sample size: 10 μ l
The stability of the different salt of formula (I) compound compares, in table 1:
The stability of the table 1 not salt of cotype (I) compound compares
Note: calculate content (%) according to area normalization method
1 of formula provided by the invention (I) compound, under 5-napadisilate room temperature, stability is in aqueous very good, is obviously better than stability in aqueous under the benzene sulfonate of formula (I) compound reported and tosilate room temperature.
The stability main manifestations of 1,5-napadisilate of formula (I) compound is both ways:
1. in relative retention time (RRT) be about 0.69 the rate of growth of principal degradation impurity on, benzene sulfonate and the tosilate of formula (I) compound increase by 0.08% and 0.10% respectively within the time of 15h, and 1,5-napadisilate of formula (I) compound increases by 0.06% within the time reaching 24h;
2. the benzene sulfonate of formula (I) compound and tosilate also have other impurity with together increasing except above-mentioned principal degradation impurity increases, and other impurity of 1,5-napadisilate of formula of the present invention (I) compound shows, and extreme is stable does not all have considerable change trend.
Embodiment 10: the purity and the stability that detect 1,5-napadisilate of formula (I) compound
By 1 of formula (I) compound, (this sample is crude product to the sample of 5-napadisilate I crystal formation, without purification) uncoveredly divide placement, detect the stability of sample under heating (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) condition.Sample time is 5 days and 10 days, and HPLC detects purity in table 2.
1,5-napadisilate I crystal form purity of table 2 different condition following formula (I) compound detects
Contrast: application number is 201280003321.6, application name is called " benzodiazepine
the tosilate of derivative and polymorphic, their preparation method and purposes " in embodiment 11 table 1 describe that tosilate I and IV crystal form samples of formula (I) compound is uncovered respectively divides placement, investigate the warm stability of sample under heating (40 DEG C, 60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) condition, investigating sample time is 5 days and 10 days, and HPLC detects purity in table 3:
The stability of tosilate I and IV crystal form samples of table 3 formula (I) compound compares
As can be seen from Table 2, heating (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) condition are to 1 of formula (I) compound, 5-napadisilate I crystal form samples stability influence is little, illustrate that formula (I) compound 1,5-napadisilate I crystal formation that the application provides all shows fabulous stability under the condition of high temperature, high humidity, illumination.
As can be seen from Table 3, tosilate I crystal formation of prior art Chinese style (I) compound 60 DEG C, under high humidity (RH75%, RH92.5%) and illumination (4500lux) condition, stability is not fine, IV crystal formation 60 DEG C, stability under high humidity (RH75%, RH90%) and illumination (4500lux) condition is better than I crystal formation, but its stability, especially the stability under illumination condition is obviously poor than 1,5-napadisilate I stability of crystal form of formula provided by the invention (I) compound.
Embodiment 11: the purity and the stability that detect 1,5-napadisilate of formula (I) compound
1,5-napadisilate I crystal form samples of formula (I) compound at long-term (25 DEG C), the study on the stability accelerating sample under (40 DEG C, RH75%) condition, the results are shown in Table 4 respectively.
1,5-napadisilate I crystal form purity of table 4 acceleration environment following formula (I) compound measures
Contrast: application number is 201280003321.6, application name is called " benzodiazepine
the tosilate of derivative and polymorphic, their preparation method and purposes " in embodiment 14 table 4 introduce HR7056 I crystal form samples long-term (25 DEG C), accelerate (40 DEG C, RH75%) study on the stability under condition, the results are shown in Table 5:
Table 5,HR7,056 I crystal form samples accelerates the study on the stability of sample for a long time
Can be obtained by table 4 and table 5,1,5-napadisilate I crystal formation of formula provided by the invention (I) compound and application number are 201280003321.6, and application name is called " benzodiazepine
the tosilate of derivative and polymorphic, their preparation method and purposes " in stability data in embodiment 14 table 4 compare, the present invention has advantage.
Claims (10)
1. 1,5-napadisilate of formula (I) compound:
2. 1,5-napadisilate of formula according to claim 1 (I) compound, is characterized in that, the stoicheiometry of formula (I) compound and 1,5-naphthalene disulfonic acid is 2:1.
3. 1,5-napadisilate of formula according to claim 2 (I) compound, is characterized in that, this salt is crystal salt.
4. formula according to claim 3 (I) compound 1, I crystal formation of 5-napadisilate, it is characterized in that, use Cu-Ka radiation, obtain the X-ray powder diffraction represented with 2 θ angles, have characteristic peak at 7.9,11.9,14.6,14.9,15.9,17.4,18.3,19.0,19.4,19.7,20.6,20.9,22.1,22.6,22.9,23.2,23.4,24.1,26.1,26.5,28.7,29.2,30.1 places.
5. the preparation method of 1,5-naphthalene disulfonic acid crystal salt of formula as claimed in claim 3 (I) compound, comprises the following steps:
1) by 1 of crystal formation or unformed formula (I) compound, 5 ?napadisilate, or by formula (I) compound and 1,5 ?naphthalene disulfonic acid heating for dissolving in crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or their mixed solvent, described rudimentary organic solvent be carbonatoms be less than 6 alcohols, ketone, ester class, ether solvent or acetonitrile, DMF.
2) filtering for crystallizing and wash, dry.
6. the preparation method of 1,5-naphthalene disulfonic acid crystal salt of formula according to claim 5 (I) compound, is characterized in that, the solvent that formula (I) compound and 1,5-naphthalene disulfonic acid react used is the mixed solvent of ethyl acetate and alcohols.
7. 1 of formula (I) compound according to right 6, the preparation method of 5-naphthalene disulfonic acid crystal salt, formula (I) compound and 1, the solvent that 5-naphthalene disulfonic acid reacts used is the mixed solvent of ethyl acetate and alcohols, it is characterized in that, alcohols is methyl alcohol, ethanol, propyl alcohol or Virahol.
8. formula according to claim 5 (I) compound 1, the preparation method of 5-naphthalene disulfonic acid crystal salt, it is characterized in that, described crystallization solvent is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, butanone, ethyl acetate, butylacetate, methyl tertiary butyl ether, isopropyl ether, acetonitrile, DMF.
9. formula (I) compound as described in claims 41, the preparation method of 5-napadisilate I crystal formation, comprise step according to claim 5, it is characterized in that, described crystallization solvent is one or more in alcohols, ketone, ethers, ester class, acetonitrile, DMF, water.
10. preparation formula according to claim 9 (I) compound 1, the preparation method of 5-napadisilate I crystal formation, it is characterized in that, described crystallization solvent is one or more in methyl alcohol, ethanol, Virahol, acetone, butanone, ethyl acetate, butylacetate, isopropyl ether, methyl tertiary butyl ether, acetonitrile, DMF, water.
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| CN107266452A (en) * | 2016-04-08 | 2017-10-20 | 四川科伦药物研究院有限公司 | The salt and its crystal form, preparation method and purposes of benzodiazepine * derivatives |
| CN108503644A (en) * | 2016-12-09 | 2018-09-07 | 成都倍特药业有限公司 | A kind of hydrobromate and its preparation method and application of benzodiazepine * derivatives |
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| WO2018148361A1 (en) * | 2017-02-09 | 2018-08-16 | Watson Laboratories Inc. | Process for the preparation of remimazolam and solid state forms of remimazolam salts |
| CN112209932B (en) * | 2019-07-12 | 2023-03-24 | 成都倍特药业股份有限公司 | New solid form of compound hydrobromide, preparation method and application thereof |
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| WO1995001964A1 (en) * | 1993-07-06 | 1995-01-19 | Yamanouchi Pharmaceutical Co., Ltd. | Novel crystal of benzodiazepine derivative |
| GB0613693D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts (3) |
| GB0613692D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts |
| CN101274290B (en) * | 2007-03-30 | 2011-04-20 | 中国石油天然气股份有限公司 | Late transition metal catalyst and preparation method and application thereof |
| CN102964349A (en) * | 2011-08-31 | 2013-03-13 | 江苏恒瑞医药股份有限公司 | Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application |
| JP6199869B2 (en) * | 2012-08-31 | 2017-09-20 | パイオン ユーケー リミティド | Administration of hypnotic sedatives |
| CN103230595B (en) * | 2013-05-05 | 2014-10-08 | 李友香 | Composition for treating mental diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266452A (en) * | 2016-04-08 | 2017-10-20 | 四川科伦药物研究院有限公司 | The salt and its crystal form, preparation method and purposes of benzodiazepine * derivatives |
| CN110511224A (en) * | 2016-04-08 | 2019-11-29 | 四川科伦药物研究院有限公司 | The salt and its crystal form, preparation method and purposes of benzodiazepine * derivative |
| CN108503644A (en) * | 2016-12-09 | 2018-09-07 | 成都倍特药业有限公司 | A kind of hydrobromate and its preparation method and application of benzodiazepine * derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106632342A (en) | 2017-05-10 |
| CN105130996B (en) | 2017-05-03 |
| CN106380470A (en) | 2017-02-08 |
| CN106380470B (en) | 2019-03-19 |
| CN106632342B (en) | 2019-01-25 |
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