CN105130996B - 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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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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 chemicalses preparation field, and in particular to a kind of benzodiazepineThe sulphur of 1,5- naphthalenes two of derivant
Hydrochlorate and crystal formation and their preparation method.
Background technology
Chemical entitled 3- [(4s) the bromo- 1- methyl -6- of -8- (2- the pyridine radicals) -4H- imidazoles [l, 2-a] of formula (I) compound
[l, 4] benzodiazepine- 4- bases] methyl propionate,
The compound contains carboxylate and benzodiazepineStructure, be short-acting central nervous system (CNS, Central
Nervous System) inhibitor, it is in particular in tranquilizing soporific, anxiety, of flaccid muscles and anticonvulsant action.The compound
Can be additionally used in the intravenously administrable in clinical treatment, during such as performing the operation in operation consent is calm, anxiety and forget purposes；
Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure；It is before other anesthetis and analgesic is applied and/or same
When, as the component of induction and maintenance for general anesthesia；ICU calmness etc..But the compound is unstable, it is adapted only to low
5 DEG C of preservations of temperature, under conditions of 40 DEG C/75% relative humidity (opening), the sample deliquescence of storage, color yellowing is to orange
Color, and show that content significantly reduces more than 7% relative to initial content.
As research worker is constantly studied, it is believed that salt can be prepared into increase its chemical stability.Now
Tosilate, benzene sulfonate, the esilate of formula (I) compound are reported, wherein, the chemistry of tosilate, light
Purity is slightly good, and the chemistry of remaining two kinds of salt, optical purity are all undesirable, and recrystallization process fails to significantly improve its change
Learn and optical purity.
NFV (nelfinavir mesilate) event that Europe in those early years occurs, let us is special for drug safety
Concern；After European Union occurs for the event, the risk warning file EMEA/44714/ of small-molecular-weight sulfonic acid esters is have issued
2008, wherein specifically mention, methanesulfonates, esilate, benzene sulfonate, p-toluenesulfonic esters and hydroxyethylsulfonic acid. esters
DNA alkylatings can cause mutagenic effect, carcinogenic effect and teratogenic effect.In view of NFV (nelfinavir mesilate) thing
In part, Roche Holding Ag storage pharmaceutical procedures in, due to clean holding vessel ethanol remain in a large number, cause with methanesulfonic acid reaction and
The methanesulfonates of severe overweight is generated, the potential safety hazard of the medicine has been ultimately resulted in, and is recalled by EMEA compulsive requirements.Simultaneously
Also require that medicament research and development company should as far as possible avoid the sulfonic acid of the small-molecular-weight to mentioning in above-mentioned file in drug development
Use, and should as far as possible select the acid group without latent gene toxicity.
In addition in addition to genotoxicity, p-methyl benzenesulfonic acid, benzenesulfonic acid corresponding to three kinds of salt of existing formula (I) compound,
The LD of ethyl sulfonic acid itself50Toxicity is all bigger than normal, does toxicity test using rat, rat distinguish oral p-methyl benzenesulfonic acid, benzenesulfonic acid,
Ethyl sulfonic acid, its LD50Respectively 2480mg/kg, 0.89mg/kg, 48mg/kg, therefore, exploitation purity height, good stability, avirulence
The salt of formula (I) compound be necessary.
The content of the invention
The invention provides a kind of benzodiazepineThe 1,5- napadisilates of derivant and crystal formation and their preparation
Method, preparation method simple possible, the low cost, the benzodiazepine preparedThe 1,5- napadisilates of derivant and crystalline substance
Type purity is high, good stability, can use as active constituents of medicine, additionally, the LD of 1,5- naphthalenedisulfonic acid50For 30000mg/kg,
Therefore the benzodiazepine preparedIt is avirulent in the range of the appropriate usage amount of the 1,5- napadisilates of derivant.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is：
The 1,5- napadisilates of formula (I) compound：
Further, the stoicheiometry of formula (I) compound and 1,5- naphthalenedisulfonic acid is 2:1, further, the salt is crystallization
Salt.
Further, I crystal formation of 1, the 5- napadisilates of described formula (I) compound, is radiated using Cu-Ka, is obtained
With the X-ray powder diffraction collection that 2 θ angles are represented, 7.9,11.9,14.6,14.9,15.9,17.4,18.3,19.0,
19.4th, at 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
There is characteristic peak.
The preparation method of 1, the 5- naphthalenedisulfonic acid crystal salt of described formula (I) compound, comprises the following steps：
1) by crystal formation or 1, the 5- napadisilates of unformed formula (I) compound, or by formula (I) compound and 1,5- naphthalene
Disulfonic acid heating for dissolving in crystallization solvent, cooling, crystallize, wherein described crystallization solvent be rudimentary organic solvent, water or
Their mixed solvent, described rudimentary organic solvent is alcohols of the carbon number less than 6, ketone, esters, ether solvent or second
Nitrile, N,N-dimethylformamide.
2) filtering for crystallizing and wash, be dried.
Further, in the preparation method of 1, the 5- naphthalenedisulfonic acid crystal salt of described formula (I) compound, formula (I) chemical combination
The thing solvent used with the reaction of 1,5- naphthalenedisulfonic acids is the mixed solvent of ethyl acetate and alcohols；Further, alcohols be methanol,
Ethanol, propanol or isopropanol.
Further, in the preparation method of 1, the 5- naphthalenedisulfonic acid crystal salt of described formula (I) compound, described crystallize
Solvent be methanol, ethanol, propanol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate, methyl tertiary butyl ether(MTBE), diisopropyl ether,
One or more in acetonitrile, N,N-dimethylformamide.
The preparation method of the crystal formation of 1,5- napadisilates I of described formula (I) compound, including described 1,5- naphthalenes two
The preparation process of sulfonic acid crystallization salt, wherein described crystallization solvent is alcohols, ketone, ethers, esters, acetonitrile, N, N- dimethyl
One or more in Methanamide, water.
Further, in the preparation method of the crystal formation of 1,5- napadisilates I of described formula (I) compound, described crystallize
Solvent be methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate, diisopropyl ether, methyl tertiary butyl ether(MTBE), acetonitrile,
One or more in N,N-dimethylformamide, water.
The benzodiazepine that the present invention is provided1, the 5- napadisilates of derivant and crystal formation and their preparation method,
Have the advantages that：Preparation method is simple, low cost, 1, the 5- napadisilates of the formula prepared (I) compound and its
Crystal form purity is high, good stability, can use as active constituents of medicine.
Description of the drawings
Fig. 1 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 1；
Fig. 2 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 1；
Fig. 3 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 2；
Fig. 4 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 2；
Fig. 5 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 3；
Fig. 6 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 3；
Fig. 7 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 4；
Fig. 8 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 4；
Fig. 9 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 5；
Figure 10 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 5；
Figure 11 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 6；
Figure 12 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 6；
Figure 13 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 7；
Figure 14 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 7；
Figure 15 is the DSC spectrograms of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 8；
Figure 16 is the X-ray powder diffraction spectrogram of the crystal formation of 1,5- napadisilates I of formula (I) compound in embodiment 8.
Figure 17 is the enlarged drawing of part A in Fig. 4；
Figure 18 is the enlarged drawing of part B in Fig. 8.
Specific embodiment
Embodiment 1：The preparation of the 1,5- napadisilates of formula (I) compound
Formula (I) compound 100mg (0.228mmol) is accurately weighed in 10mL single port bottles, adds 0.5mL ethyl acetate to stir
Mixing makes it all dissolve, and then 32mg 2- LOMAR PWA EINECS 246-676-2 (0.114mmol) is dissolved in 0.25mL ethanol, and is added drop-wise to formula (I) change
In the ethyl acetate solution of compound, stirring and crystallizing, sucking filtration, ethyl acetate drip washing, 40 DEG C of drying under reduced pressure obtain the 1 of formula (I) compound,
5- napadisilates, white solid 115mg, yield 87%.
The X-ray diffraction spectrogram of the crystallized sample is shown in accompanying drawing 2,7.9,11.9,14.6,14.9,15.9,17.4,
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、
29.2nd, there is characteristic peak at 30.1, DSC spectrograms are shown in accompanying drawing 1, have characteristic absorption peak near 260 DEG C, define the crystal formation for formula (I)
The crystal formation of 1,5- napadisilates I of compound.
1H NMR (400MHz, MeOD) δ 8.94 (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 the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 5mL, plus
Enter 3.0mL methanol, be heated to reflux 10min, be completely dissolved solid, stop heating, filtered while hot is cooled to 4 DEG C of crystallizes overnight,
Products therefrom overnight, obtains white solid 76mg, yield 76% in 40 DEG C of drying under reduced pressure.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 3, and X-ray diffraction spectrogram is shown in accompanying drawing 4.The X-ray of the crystallized sample is spread out
Penetrate spectrogram and DSC spectrograms Jing researchs are compared, determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 3：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL, plus
Enter mixed solution (volume ratio=5 of 6mL isopropyl alcohol and waters：1), 10min is heated to reflux, is completely dissolved solid, stop heating,
Filtered while hot, is cooled to room temperature crystallize overnight, and products therefrom overnight, obtains white solid 85mg, yield in 40 DEG C of drying under reduced pressure
85%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 5, and X-ray diffraction spectrogram is shown in accompanying drawing 6.The X-ray of the crystallized sample is spread out
Penetrate spectrogram and DSC spectrograms Jing researchs are compared, determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 4：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL, plus
Enter mixed solution (volume ratio=2 of 15mL diisopropyl ethers and N,N-dimethylformamide：1), 10min is heated to reflux, makes solid complete
CL, stops heating, and filtered while hot is cooled to room temperature crystallize overnight, and products therefrom overnight, obtains white in 40 DEG C of drying under reduced pressure
Color solid 88mg, yield 88%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 7, and X-ray diffraction spectrogram is shown in accompanying drawing 8.The X-ray of the crystallized sample is spread out
Penetrate spectrogram and DSC spectrograms Jing researchs are compared, determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 5：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 50mL, plus
Enter 18.0mL methanol with butyl acetate and mixed solution (volume ratio=1 of methyl tertiary butyl ether(MTBE)：4：4), 10min is heated to reflux,
Solid is completely dissolved, stops heating, filtered while hot is cooled to room temperature crystallize overnight, and products therefrom is in 40 DEG C of drying under reduced pressure mistakes
At night, obtain white solid 95mg, yield 95%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 9, and X-ray diffraction spectrogram is shown in accompanying drawing 10.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 6：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL, plus
Enter 10mL methanol with ethanol and mixed solution (volume ratio=2 of diisopropyl ether：1：2), 10min is heated to reflux, makes solid completely molten
Solution, stops heating, and filtered while hot is cooled to 4 DEG C of crystallizes overnight, and products therefrom overnight, obtains white solid in 40 DEG C of drying under reduced pressure
Body 81mg, yield 81%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 11, and X-ray diffraction spectrogram is shown in accompanying drawing 12.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 7：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL, plus
Enter mixed solution (volume ratio=1 of 15mL methanol and ethyl acetate：3), 10min is heated to reflux, is completely dissolved solid, stopped
Heating, filtered while hot is cooled to 4 DEG C of crystallizes overnight, and products therefrom overnight, obtains white solid 86mg in 40 DEG C of drying under reduced pressure,
Yield 86%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 13, and X-ray diffraction spectrogram is shown in accompanying drawing 14.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 8：The preparation of the crystal formation of 1,5- napadisilates I of formula (I) compound
By 1, the 5- napadisilate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL, plus
Enter 10mL methanol with butanone and mixed solution (volume ratio=1 of methyl tertiary butyl ether(MTBE)：2：2), 10min is heated to reflux, makes solid
It is completely dissolved, stops heating, filtered while hot is cooled to 4 DEG C of crystallizes overnight, and products therefrom overnight, is obtained in 40 DEG C of drying under reduced pressure
White solid 89mg, yield 89%.
The DSC spectrograms of the crystallized sample are shown in accompanying drawing 15, and X-ray diffraction spectrogram is shown in accompanying drawing 16.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the crystal formation of 1,5- napadisilates I that product is formula (I) compound.
Embodiment 9：The 1,5- napadisilate aqueous solution stability tests of formula (I) compound
Experiment condition：
Mobile phase：
A- phosphate buffers (0.025mol/L potassium dihydrogen phosphate aqueous solutions, with phosphorus acid for adjusting pH value for 3.5)
B- acetonitriles
Chromatographic column：Féraud door luna C18 (2) 4.6*250mm, 5 μm
Elution program：
| Time/min | A phases/% | B phases/% |
| 0 | 80 | 20 |
| 20 | 30 | 70 |
| 40 | 30 | 70 |
Column temperature：45℃
Detection wavelength：230nm
Sample introduction concentration：0.5mg/mL
Sample size：10μl
The stability of the different salt of formula (I) compound compares, and is shown in Table 1：
The stability of the salt of different formula (I) compounds of table 1 compares
Note：Content (%) is calculated according to area normalization method
Stability under the 1,5- napadisilate room temperatures of formula (I) compound that the present invention is provided in aqueous is very
It is good, hence it is evident that better than stablizing in aqueous under the benzene sulfonate and tosilate room temperature of formula (I) compound reported
Property.
The stability of the 1,5- napadisilates of formula (I) compound is mainly manifested in two aspects：
1. in the growth rate of principal degradation impurity that relative retention time (RRT) is 0.69 or so, formula (I) compound
Benzene sulfonate and tosilate increase by 0.08% and 0.10% respectively within the time of 15h, and formula (I) compound
1,5- napadisilates are increasing by 0.06% within the time of 24h；
2. the benzene sulfonate of formula (I) compound also has other with tosilate in addition to the growth of above-mentioned principal degradation impurity
Impurity is with together increasing, and the 1 of formula (I) compound of the present invention, and other impurity performances of 5- napadisilates are extremely stable equal
Without significant change trend.
Embodiment 10：The purity and stability of the 1,5- napadisilates of detection formula (I) compound
The sample (sample is crude product, not purified) of the crystal formation of 1,5- napadisilates I of formula (I) compound is open flat
Spread and put, detect that sample stablizes in heating (60 DEG C), illumination (4500lux), under the conditions of high humidity (RH75%, RH92.5%)
Property.Sample time is 5 days and 10 days, and HPLC detections purity is shown in Table 2.
The crystal form purity of 1,5- napadisilates I detection of formula (I) compound under the different condition of table 2
Contrast：Application No. 201280003321.6, applies entitled《BenzodiazepineThe tosilate of derivant and
Its polymorphic, their preparation method and purposes》The tosilate I and IV that the table 1 of middle embodiment 11 describes formula (I) compound is brilliant
Pattern product are open respectively to divide placement, investigate heating (40 DEG C, 60 DEG C), illumination (4500lux), high humidity (RH75%,
RH92.5% the temperature stability of sample under the conditions of), investigates sample time for 5 days and 10 days, and HPLC detections purity is shown in Table 3：
The stability of the crystal form samples of tosilate I and IV of formula (I) compound of table 3 compares
As can be seen from Table 2, (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) condition are heated to formula (I)
The crystal form samples stability influence of 1,5- napadisilates I of compound less, illustrates formula (I) compound 1,5- that the application is provided
The crystal formation of napadisilate I shows fabulous stability under conditions of high temperature, high humidity, illumination.
From table 3 it can be seen that in prior art formula (I) compound the crystal formation of tosilate I 60 DEG C, high humidity (RH75%,
RH92.5%) and under the conditions of illumination (4500lux), stability be not it is fine, IV crystal formation 60 DEG C, high humidity (RH75%,
RH90% the stability) and under the conditions of illumination (4500lux) is better than I crystal formation, but its stability, especially under illumination condition
Stability substantially than the present invention provide formula (I) compound the stability of crystal form of 1,5- napadisilates I it is poor.
Embodiment 11：The purity and stability of the 1,5- napadisilates of detection formula (I) compound
The crystal form samples of 1,5- napadisilates I of formula (I) compound respectively long-term (25 DEG C), accelerate (40 DEG C,
RH75% the study on the stability of sample, the results are shown in Table 4 under the conditions of).
The crystal form purity of 1,5- napadisilates I of formula (I) compound is determined under the acceleration environment of table 4
Contrast：Application No. 201280003321.6, applies entitled《BenzodiazepineThe tosilate of derivant and
Its polymorphic, their preparation method and purposes》Crystal form samples of HR7056 I long-term (25 DEG C) that 14 table of middle embodiment 4 is introduced, plus
Study on the stability under the conditions of fast (40 DEG C, RH75%), the results are shown in Table 5：
The crystal form samples of table 5,HR7,056 I accelerate for a long time the study on the stability of sample
Can be obtained by table 4 and table 5, the crystal formation of 1,5- napadisilates I and Application No. of formula (I) compound that the present invention is provided
201280003321.6, apply entitled《BenzodiazepineTosilate and its polymorphic, their the preparation side of derivant
Method and purposes》Stability data in the table 4 of middle embodiment 14 is compared, and the present invention has advantage.
Claims (5)
1. a kind of crystal formation of 1,5- napadisilates I of formula (I) compound, it is characterised in that：
The stoicheiometry 2 of formula (I) compound and 1,5- naphthalenedisulfonic acids in the 1,5- napadisilates of formula (I) compound:1；
I crystal formation of 1, the 5- napadisilates of formula (I) compound, is radiated using Cu-Ka, obtains the X- represented with 2 θ angles
Ray powder diffraction, 7.9,11.9,14.6,14.9,15.9,17.4,18.3,19.0,19.4,19.7,20.6,
20.9th, there is characteristic peak at 22.1,22.6,22.9,23.2,23.4,24.1,26.1,26.5,28.7,29.2,30.1.
2. a kind of preparation method of the crystal formation of 1,5- napadisilates I of formula as claimed in claim 1 (I) compound, including with
Lower step：
1) by crystal formation or 1, the 5- napadisilates of unformed formula (I) compound, or by formula (I) compound and the sulphur of 1,5- naphthalene two
Sour heating for dissolving in crystallization solvent, cooling, crystallize, wherein described crystallization solvent be rudimentary organic solvent, water or they
Mixed solvent, described rudimentary organic solvent be alcohols of the carbon number less than 6, ketone, esters, ether solvent or acetonitrile,
N,N-dimethylformamide；
2) filtering for crystallizing and wash, be dried.
3. the preparation method of the crystal formation of 1,5- napadisilates I of formula (I) compound according to claim 2, its feature exists
In formula (I) compound and the reaction of 1,5- naphthalenedisulfonic acid solvent used is the mixed solvent of ethyl acetate and alcohols.
4. the preparation method of the crystal formation of 1,5- napadisilates I of formula (I) compound according to claim 3, formula (I) is changed
Compound and the reaction of 1,5- naphthalenedisulfonic acid solvent used is the mixed solvent of ethyl acetate and alcohols, it is characterised in that alcohols is
Methanol, ethanol, propanol or isopropanol.
5. the preparation method of the crystal formation of 1,5- napadisilates I of formula (I) compound according to claim 2, its feature exists
In described crystallization solvent is methanol, ethanol, propanol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate, methyl- tert fourth
One or more in base ether, diisopropyl ether, acetonitrile, N,N-dimethylformamide.
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| CN201510600942.8A CN105130996B (en) | 2015-08-07 | 2015-09-18 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
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| CN108503644B (en) * | 2016-12-09 | 2019-06-14 | 成都倍特药业有限公司 | A kind of hydrobromate and its preparation method and application of benzodiazepine * derivative |
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| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| CN103230595A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Composition for treating mental diseases |
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| 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 |
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| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| CN104768557A (en) * | 2012-08-31 | 2015-07-08 | Paion英国有限公司 | Method for administering hypnotic/sedative agent |
| CN103230595A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Composition for treating mental diseases |
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