CN106632342A - 2-naphthalenesulfonate of benzodiazepine derivative and crystal form and preparation methods thereof - Google Patents
2-naphthalenesulfonate of benzodiazepine derivative and crystal form and preparation methods thereof Download PDFInfo
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Abstract
The invention discloses 2-naphthalenesulfonate of benzodiazepine derivative and crystal form and preparation methods thereof. According to the invention, the crystal form of a compound shown in a formula (I) or 2-naphthalenesulfonate of the amorphous form compound shown in the formula (I), or the compound shown in the formula (I) and 2-naphthalenesulfonate are dissolved in a crystallization solvent, the material is cooled, crystallized, re-filtered for crystallization, and then washed and dried, and the 2-naphthalenesulfonate of the compound in the formula (I) or crystal form can be prepared, and the prepared 2-naphthalenesulfonate of the compound in the formula (I) or crystal form has the advantages of good stability, high purity and no toxicity, and can be better used for clinical treatment.
Description
Technical field
The invention belongs to chemicals preparation field, and in particular to benzodiazepineThe 2- naphthalene sulfonic acids of derivative
Salt and crystal formation and their preparation method.
Background technology
Formula (I) compound chemical entitled 3- [(4s) the bromo- 1- methyl -6- of -8- (2- pyridine radicals) -4H- imidazoles [l, 2-a] [l,
4] benzodiazepine- 4- bases] methyl propionate,
The compound contains carboxylate and benzodiazepine *Structure, be short-acting central nervous system (CNS,
Central Nervous System) inhibitor, it is in particular in tranquilizing soporific, antianxiety, of flaccid muscles and anti-
Convulsion effect.The compound can be additionally used in the intravenously administrable in clinical treatment, during such as performing the operation in hand
Preoperative calm, antianxiety and forgetting purposes；Conscious sedation during short-term diagnosis, operation or endoscopic procedure
It is calm；Before other anesthetic and anodyne is applied and/or while, as the induction for general anesthesia and
The component of maintenance；ICU calmness etc..But the compound is unstable, according to Chinese patent, Application No.
200780028964, patent name is《Short-acting benzodiazepineSalt and its polymorphic》Report, formula (I)
Free alkali be adapted only to the preservation of 5 DEG C of low temperature, under conditions of 40 DEG C/75% relative humidity (opening), store
Sample deliquescence, color yellowing shows that content is significantly reduced to orange relative to initial content
More than 7%.
As researcher constantly studies, it is believed that salt can be prepared into increase its chemical stability.
Tosilate, benzene sulfonate, the esilate of formula (I) compound are had reported now, wherein, it is right
Chemistry, the optical purity of toluene fulfonate 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 chemistry and optical purity.
NFV (nelfinavir mesilate) event that Europe in those early years occurs, let us is pacified for medicine
Full property pays special attention to；After European Union occurs for the event, the risk warning of small-molecular-weight sulfonic acid esters is have issued
File EMEA/44714/2008 is methanesulfonates, esilate, benzene sulfonate, right wherein specifically mention
The DNA alkylatings of tosylate and isethionic acid esters can cause mutagenic effect, carcinogenic effect and
Teratogenic effect.In view of in NFV (nelfinavir mesilate) event, Roche Holding Ag is in storage medicine mistake
Cheng Zhong, because the ethanol for cleaning holding vessel is remained in a large number, causes to react with methanesulfonic acid and generate severe overweight
Methanesulfonates, ultimately resulted in the potential safety hazard of the medicine, and recalled by EMEA compulsive requirements.Simultaneously
Also require that medicament research and development company should as far as possible avoid the small-molecular-weight to mentioning in above-mentioned file in drug development
Sulfonic acid 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 corresponding to three kinds of salt of existing formula (I) compound,
Benzene sulfonic acid, the ethyl sulfonic acid LD of itself50Toxicity is all bigger than normal, and toxicity test, rat difference mouth are done using rat
P-methyl benzenesulfonic acid, benzene sulfonic acid, ethyl sulfonic acid are taken, its LD50Respectively 2480mg/kg, 0.89mg/kg, 48mg/kg,
Therefore, develop purity height, good stability, the salt of avirulent formula (I) compound to be necessary.
The content of the invention
The invention provides a kind of benzodiazepineThe 2- naphthalene sulfonates of derivative and crystal formation and their preparation
Method, preparation method is simple, low cost, the benzodiazepine preparedThe 2- naphthalene sulfonates of derivative and
Crystal form purity is high, good stability, can use as active constituents of medicine, additionally, the LD of 2- naphthalene sulfonic acids50For
4440mg/kg, therefore the benzodiazepine preparedThe appropriate usage amount scope of the 2- naphthalene sulfonates of derivative
It is inside avirulent.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is：
The 2- naphthalene sulfonates of formula (I) compound：
Further, formula (I) compound and 2- naphthalene sulfonic acids stoicheiometry are 1:1, further, the salt is
Crystal salt.
Further, I crystal formation of the 2- naphthalene sulfonates of described formula (I) compound, is radiated using Cu-Ka,
Obtain the X-ray powder diffraction spectrogram represented with 2 θ angles, 6.3,11.8,17.7,19.0,19.4,
20.5th, there is characteristic peak at 21.7,22.2,22.8,23.3,23.9,25.9,27.9.
The preparation method of the 2- naphthalene sulfonic acids crystal salts of described formula (I) compound, comprises the following steps：
1) by crystal formation or the 2- naphthalene sulfonates of unformed formula (I) compound, or by formula (I) compound with
2- naphthalene sulfonic acids heating for dissolving in crystallization solvent, cooling, crystallization, wherein described crystallization solvent is for rudimentary organic
Solvent, water or their 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.
Further, in the preparation method of the 2- naphthalene sulfonic acids crystal salts of described formula (I) compound, formula (I)
The compound solvent used with the reaction of 2- naphthalene sulfonic acids is the mixed solvent of ethyl acetate and alcohols；Further,
Alcohols is methyl alcohol, ethanol, propyl alcohol or isopropanol.
Further, it is described in the preparation method of the 2- naphthalene sulfonic acids crystal salts of described formula (I) compound
Crystallization solvent be methyl alcohol, ethanol, propyl alcohol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate,
One or more in methyl tertiary butyl ether(MTBE), isopropyl ether, acetonitrile, N,N-dimethylformamide.
The preparation method of the crystal formation of 2- naphthalene sulfonates I of described formula (I) compound, including described formula (I)
The preparation process of the 2- naphthalene sulfonic acids crystal salts of compound, wherein described crystallization solvent is alcohols, ketone, second
One or more in acetoacetic ester, acetonitrile, water.
Further, it is described in the preparation method of the crystal formation of 2- naphthalene sulfonates I of described formula (I) compound
Crystallization solvent is the one kind in methyl alcohol, ethanol, isopropanol, acetone, butanone, ethyl acetate, acetonitrile, water
Or it is several.
The benzodiazepine that the present invention is providedThe 2- naphthalene sulfonates of derivative and crystal formation and their preparation side
Method, has the advantages that：Preparation method is simple, low cost, the 2- of the formula prepared (I) compound
Naphthalene sulfonate and its crystal form purity height, good stability, can use as active constituents of medicine.
Description of the drawings
Fig. 1 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 1；
Fig. 2 is the X-ray powder diffraction spectrum of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 1
Figure；
Fig. 3 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 2；
Fig. 4 is the X-ray powder diffraction spectrum of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 2
Figure.
Fig. 5 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 3；
Fig. 6 is the X-ray powder diffraction spectrum of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 3
Figure；
Fig. 7 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 4；
Fig. 8 is the X-ray powder diffraction spectrum of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 4
Figure；
Fig. 9 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 5；
Figure 10 is the X-ray powder diffraction of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 5
Spectrogram；
Figure 11 is the DSC spectrograms of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 6；
Figure 12 is the X-ray powder diffraction of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound in embodiment 6
Spectrogram.
Specific embodiment
Embodiment 1：The preparation of the 2- naphthalene sulfonates of formula (I) compound
Formula (I) compound 100mg (0.228mmol) is accurately weighed in 10mL single port bottles, 0.5mL is added
Ethyl acetate stirring makes it all dissolve, and then 47mg 2- naphthalene sulfonic acids (0.228mmol) is dissolved in into 0.25mL
In ethanol, and it is added drop-wise in the ethyl acetate solution of formula (I) compound, stirring and crystallizing, suction filtration, acetic acid second
Ester drip washing, 40 DEG C of drying under reduced pressure obtain the 2- naphthalene sulfonates of formula (I) compound, white solid 138mg, yield
94%.
The X-ray diffraction spectrogram of the crystallization is shown in accompanying drawing 2,6.3,11.8,17.7,19.0,19.4,20.5,
21.7th, have characteristic peak at 22.2,22.8,23.3,23.9,25.9,27.9, DSC collection of illustrative plates is shown in accompanying drawing 1,120 DEG C,
200 DEG C and 214 DEG C nearby have characteristic absorption peak, define the 2- naphthalene sulfonates I that the crystal formation is formula (I) compound
Crystal formation.
1H NMR (400MHz, MeOD) δ 8.54 (d, J=4.3Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=
7.9Hz, 1H), 8.03-7.98 (m, 2H), 7.93-7.84 (m, 4H), 7.78 (d, J=8.7Hz, 1H), 7.68
(d, J=2.2Hz, 1H), 7.58-7.51 (m, 3H), 7.43 (d, J=1.0Hz, 1H), 4.43 (dd, J=9.9,
4.2Hz, 1H), 3.68 (s, 3H), 2.86-2.54 (m, 5H), 2.47 (d, J=0.8Hz, 3H).
Embodiment 2：The preparation of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1, the round bottom for adding 25mL are burnt
In bottle, 8mL acetonitriles are added, be heated to reflux 10min, be completely dissolved solid, stop heating, while hot mistake
Filter, is cooled to room temperature crystallization overnight, and products therefrom overnight, obtains white solid 74mg in 40 DEG C of drying under reduced pressure,
Yield 74%.
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 crystallized sample
X-ray diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the 2- naphthalene sulfonic acids that product is formula (I) compound
The crystal formation of salt I.
Embodiment 3：The preparation of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
By the 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL,
Add mixed solution (volume ratio=5 of 6.0mL isopropyl alcohol and waters：1), 10min is heated to reflux, makes solid complete
CL, stops heating, filters while hot, is cooled to room temperature crystallization overnight, and products therefrom is dry in 40 DEG C of decompressions
It is dry overnight, obtain white solid 90mg, yield 90%.
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 crystallized sample
X-ray diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the 2- naphthalene sulfonic acids that product is formula (I) compound
The crystal formation of salt I.
Embodiment 4：The preparation of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
By the 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL,
Add mixed solution (volume ratio=1 of 15ml methyl alcohol and butanone：6), 10min is heated to reflux, makes solid complete
CL, stops heating, filters while hot, is cooled to room temperature crystallization overnight, and products therefrom is dry in 40 DEG C of decompressions
It is dry overnight, obtain white solid 87mg, yield 87%.
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 crystallized sample
X-ray diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the 2- naphthalene sulfonic acids that product is formula (I) compound
The crystal formation of salt I.
Embodiment 5：The preparation of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
By the 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL,
Add mixed solution (volume ratio=1 of 12mL ethanol and ethyl acetate：2), 10min is heated to reflux, is made solid
Body is completely dissolved, and stops heating, filters while hot, is cooled to room temperature crystallization overnight, and products therefrom subtracts at 40 DEG C
Pressure is dried overnight, and obtains white solid 93mg, yield 93%.
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 crystallized sample
X-ray diffraction spectrogram and DSC spectrograms Jing researchs are compared, and determine the 2- naphthalene sulfonic acids that product is formula (I) compound
The crystal formation of salt I.
Embodiment 6：The preparation of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
By the 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1, in adding the round-bottomed flask of 25mL,
Add mixed solution (volume ratio=3 of 4mL acetone and water：1), 10min is heated to reflux, makes solid completely molten
Solution, stop heating, filter while hot, be cooled to 4 DEG C of crystallizations overnight, products therefrom in 40 DEG C of drying under reduced pressure overnight,
Obtain white solid 76mg, yield 76%.
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 crystallized sample
X-ray diffraction spectrogram and DSC spectrograms Jing research compare, determine product be formula (I) compound 2- naphthalene sulphurs
The crystal formation of hydrochlorate I.
Embodiment 7：The 2- naphthalene sulfonate 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 different salt of formula (I) compound of table 1 compares
Note：Content (%) is calculated according to area normalization method
As it can be seen from table 1 in the aqueous solution under the 2- naphthalene sulfonate room temperatures of formula (I) compound of present invention offer
In stability it is very good, hence it is evident that better than the benzene sulfonate and p-methyl benzenesulfonic acid of formula (I) compound reported
Stability under salt room temperature in aqueous.
The stability of the 2- naphthalene sulfonates of formula (I) compound that the present invention is provided 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)
The benzene sulfonate of compound and tosilate increase respectively 0.08% and 0.10% within the time of 15h, and
The 2- naphthalene sulfonates of formula (I) compound that invention is provided are increasing by 0.04% within the time of 24h；
2. the benzene sulfonate of formula (I) compound is gone back with tosilate in addition to the growth of above-mentioned principal degradation impurity
Have other impurity with together increasing, and the 2- naphthalene sulfonates of formula (I) compound that the present invention is provided other are miscellaneous
Matter performance is extremely stable not to have significant change trend.
Embodiment 8：The purity and stability of the 2- naphthalene sulfonates of detection formula (I) compound
By the sample (sample is crude product, not purified) of the crystal formation of 2- naphthalene sulfonates I of formula (I) compound
It is open to divide placement, detect in heating (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%)
The stability of condition.Sample time is 5 days and 10 days, and HPLC detections purity is shown in Table 2.
The crystal form purity of 2- naphthalene sulfonates I detection of formula (I) compound under the different condition of table 2
Contrast 1：Application No. 200780028964, patent name is《Short-acting benzodiazepineSalt and its many
Crystal formation》, the crystallized sample surrounding altogether that benzene sulfonate is stored under 40 DEG C/75%RH of the report of 4 table of embodiment 10
And it is used for HPLC per seven days pipette samples, its purity is shown in Table 3：
The conclusion table of the crystallized sample of the benzene sulfonate of table 3 purity salt after the research of 4 peripheral stabilities
| Sample ID | Salt | T0 | T1 | T2 | T3 | T4 |
| LJC-039-037-1 | Benzene sulfonate | 97.1 | 97.3 | 97.4 | 96.7 | 96.7 |
Contrast 2：Application No. 201280003321.6, applies entitled《BenzodiazepineThe support of derivative
Western hydrochlorate and its polymorphic, their preparation method and purposes》The table 1 of middle embodiment 11 describes formula (I) chemical combination
The crystal form samples of tosilate I and IV of thing are open respectively to divide placement, investigate heating (40 DEG C, 60 DEG C),
The temperature stability of sample under the conditions of illumination (4500lux), high humidity (RH75%, RH92.5%), investigation takes
The sample time is 5 days and 10 days, and HPLC detections purity is shown in Table 4：
The stability of the crystal form samples of tosilate I and IV of formula (I) compound of table 4 compares
As can be seen from Table 2, (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) are heated
Each factor is nearly free from impact, explanation to the crystal formation of the 2- naphthalene sulfonates I (present invention) of formula (I) compound
The crystal formation of 2- naphthalene sulfonates I of formula (I) compound that the application is provided is under conditions of high temperature, high humidity, illumination
Purity is basically identical, shows fabulous stability.
From table 3 it can be seen that storing purity in the crystallized sample of benzene sulfonate, two weeks under 40 DEG C/75%RH
It is consistent, the crystallization of the benzene sulfonate that temperature, humidity are respectively higher than reported in about 97.1%, but the application
The condition of storage of sample, under the conditions of 60 DEG C, RH92.5%, purity is also consistent the sample in the present invention,
Its stability is substantially better than contrast 1.From table 4, it can be seen that the crystal formation of tosilate I of formula (I) compound exists
Under the conditions of 60 DEG C, high humidity (RH75%, RH90%) and illumination (4500lux), stability be not it is fine,
Stability of IV crystal formation under the conditions of 60 DEG C, high humidity (RH75%, RH90%) and illumination (4500lux) will
Better than formula (I) compound that I crystal formation, the especially stability under illumination condition are substantially provided than the present invention
The poor crystal form of 2- naphthalene sulfonates I.
Embodiment 9：The purity and stability of the 2- naphthalene sulfonates of detection formula (I) compound
The crystal form samples of 2- naphthalene sulfonates I of formula (I) compound respectively long-term (25 DEG C), accelerate (40 DEG C,
RH75% the study on the stability under the conditions of), the results are shown in Table 5：
The crystal form purity of 2- naphthalene sulfonates I of formula (I) compound is determined under the acceleration environment of table 5
Contrast：Application No. 201280003321.6, applies entitled《BenzodiazepineThe Tosi of derivative
Hydrochlorate and its polymorphic, their preparation method and purposes》The crystal formations of HR7056 I that 14 table of middle embodiment 4 is introduced
Study on the stability under the conditions of sample long-term (25 DEG C), acceleration (40 DEG C, RH75%), the results are shown in Table 6：
The crystal form samples of 6 HR7056 of table I accelerate for a long time the study on the stability of sample
Can be obtained by table 3, table 5, table 6, the present invention provide formula (I) compound the crystal formation of 2- naphthalene sulfonates I with
Application No. 200780028964, patent name is《Short-acting benzodiazepineSalt and its polymorphic》, implement
The crystallized sample stability data of the benzene sulfonate of the report of 4 table of example 10 is compared, formula (I) chemical combination that the present invention is provided
The crystal formation of 2- naphthalene sulfonates I of thing has a clear superiority；With Application No. 201280003321.6, apply entitled
《BenzodiazepineThe tosilate and its polymorphic of derivative, their preparation method and purposes》Middle reality
The stability data applied in the table 4 of example 14 is compared, and the present invention also has advantage.
Claims (10)
1. 2- naphthalene sulfonates of formula (I) compound：
2. 2- naphthalene sulfonates of formula (I) compound according to claim 1, it is characterised in that formula
(I) compound and 2- naphthalene sulfonic acids stoicheiometry are 1:1.
3. 2- naphthalene sulfonates of formula (I) compound according to claim 2, it is characterised in that should
Salt is crystal salt.
4. I crystal formation of the 2- naphthalene sulfonates of formula (I) compound according to claim 3, its feature
It is to be radiated using Cu-Ka, obtains the X-ray powder diffraction collection represented with 2 θ angles, 6.3,
11.8th, have at 17.7,19.0,19.4,20.5,21.7,22.2,22.8,23.3,23.9,25.9,27.9
Characteristic peak.
5. a kind of preparation method of the 2- naphthalene sulfonic acids crystal salts of formula as claimed in claim 3 (I) compound,
Comprise the following steps：
1) by crystal formation or the 2- naphthalene sulfonates of unformed formula (I) compound, or by formula (I) compound with
2- naphthalene sulfonic acids heating for dissolving in crystallization solvent, cooling, crystallization, wherein described crystallization solvent is for rudimentary organic
Solvent, water or their 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.
6. the preparation method of the 2- naphthalene sulfonic acids crystal salts of formula (I) compound according to claim 5,
Characterized in that, formula (I) compound and 2- naphthalene sulfonic acids reaction solvent used is the mixed of ethyl acetate and alcohols
Bonding solvent.
7. the preparation method of the 2- naphthalene sulfonic acids crystal salts of formula (I) compound according to right 6, formula (I)
The compound solvent used with the reaction of 2- naphthalene sulfonic acids is the mixed solvent of ethyl acetate and alcohols, it is characterised in that
Alcohols is methyl alcohol, ethanol, propyl alcohol or isopropanol.
8. the preparation method of the 2- naphthalene sulfonic acids crystal salts of formula (I) compound according to claim 5,
Characterized in that, described crystallization solvent is methyl alcohol, ethanol, propyl alcohol, isopropanol, acetone, butanone, second
In acetoacetic ester, butyl acetate, methyl tertiary butyl ether(MTBE), isopropyl ether, acetonitrile, N,N-dimethylformamide one
Plant or several.
9. a kind of preparation side of the crystal formation of 2- naphthalene sulfonates I of formula as claimed in claim 4 (I) compound
Method, including the step described in claim 5, it is characterised in that described crystallization solvent be alcohols, ketone,
One or more in ethyl acetate, acetonitrile, water.
10. the preparation of the crystal formation of 2- naphthalene sulfonates I for preparing formula (I) compound according to claim 9
Method, it is characterised in that described crystallization solvent is methyl alcohol, ethanol, isopropanol, acetone, butanone, second
One or more in acetoacetic ester, acetonitrile, water.
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| CN201510600942.8A Active 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 |
| 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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| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| US20100075955A1 (en) * | 2006-07-10 | 2010-03-25 | Gary Stuart Tilbrook | Short-acting benzodiazepine salts and their polymorphic forms |
| WO2013029431A1 (en) * | 2011-08-31 | 2013-03-07 | 江苏恒瑞医药股份有限公司 | Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof |
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| CN103230595B (en) * | 2013-05-05 | 2014-10-08 | 李友香 | Composition for treating mental diseases |
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| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| US20100075955A1 (en) * | 2006-07-10 | 2010-03-25 | Gary Stuart Tilbrook | Short-acting benzodiazepine salts and their polymorphic forms |
| WO2013029431A1 (en) * | 2011-08-31 | 2013-03-07 | 江苏恒瑞医药股份有限公司 | Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof |
| CN104768557A (en) * | 2012-08-31 | 2015-07-08 | Paion英国有限公司 | Method for administering hypnotic/sedative agent |
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| CN105130996A (en) | 2015-12-09 |
| CN105130996B (en) | 2017-05-03 |
| CN106380470A (en) | 2017-02-08 |
| CN106380470B (en) | 2019-03-19 |
| CN106632342B (en) | 2019-01-25 |
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