CN102964349A - Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application - Google Patents
Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application Download PDFInfo
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- 229950004288 tosilate Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000013078 crystal Substances 0.000 title claims description 54
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title description 2
- 238000002425 crystallisation Methods 0.000 claims abstract description 79
- 230000008025 crystallization Effects 0.000 claims abstract description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 46
- 230000015572 biosynthetic process Effects 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 235000019441 ethanol Nutrition 0.000 claims description 27
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 150000001298 alcohols Chemical class 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000001961 anticonvulsive agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 abstract description 5
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 abstract description 4
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 abstract description 3
- 229940017219 methyl propionate Drugs 0.000 abstract description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 150000001557 benzodiazepines Chemical class 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 44
- 239000007787 solid Substances 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 13
- 238000002441 X-ray diffraction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 8
- CYHWMBVXXDIZNZ-KRWDZBQOSA-N methyl 3-[(4s)-8-bromo-1-methyl-6-pyridin-2-yl-4h-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate Chemical compound N([C@H](C1=NC=C(C)N1C1=CC=C(Br)C=C11)CCC(=O)OC)=C1C1=CC=CC=N1 CYHWMBVXXDIZNZ-KRWDZBQOSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229950004245 remimazolam Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 5
- 229940077388 benzenesulfonate Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- 230000008925 spontaneous activity Effects 0.000 description 3
- 206010003084 Areflexia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229950007655 esilate Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to benzodiazepines
The tosilate and its polymorphic of derivative, their preparation method and purposes, especially 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
- 4- base] methyl propionate (I) tosilate polymorphic and its preparation method and application. The crystallization of obtained formula (I) the compound tosilate of the present invention, dissolvent residual is low, has good stability, and can be preferably applied to clinical treatment.
Description
Technical field
The present invention relates to 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
-4-yl] the tosilate polymorphic and its production and use of methyl propionate.
Background technology
The chemistry of formula (I) compound is called 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
-4-yl] methyl propionate,
Owing to contain carboxylicesters and benzodiazepine
Structure, patent EP1, this compounds of report is fugitive central nervous system (CNS, Central Nervous System) inhibitor in 183,243, has the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action.They can be used for the intravenously administrable in the following clinical treatment: such as calm before the operation in the intra-operative, anxiety with 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 component of inducing and keeping that is used for general anesthesia; ICU calmness etc., according to patent application CN101,501, report in 019, the free alkali of this compound is not very stable, only is suitable for 5 ℃ of preservations of low temperature, under the condition of 40 ℃/75% relative humidity (opening), the sample deliquescence that stores, the color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.So the salt of people's synthesis type (I) compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing patent application CN101,501,019 and US20,100,075,955 have reported respectively benzene sulfonate, the esilate of formula (I) compound, but the chemistry of institute's salify and optical purity are not very desirable, and recrystallization process also fails to improve significantly its chemistry and optical purity, because the chemistry of compound and the quality of optical purity, can directly have influence on compound as the steadiness of drug use and medicine, and the salt of therefore developing formula (I) compound of higher chemistry and optical purity just seems and extremely is necessary.Amazingly be, through research, the tosilate of our discoverable type (I) compound, although the same with benzene sulfonate and esilate, its crystallization exists polymorphic, but its toxicity is starkly lower than benzene sulfonate, the tosilate of same up-to-date style (I) compound also has how gratifying advantage, I crystal formation such as the tosilate of formula (I) compound of recrystallization in its water, have good chemistry and optical purity, thermostability and water-soluble, result of study shows that the stability of I type crystallization significantly is better than other crystal formation of salify gained.
Summary of the invention
The invention provides formula (I) compound
TosiHydrochlorate (being the tosilate of formula (I) compound).Preferably, the stoicheiometry of formula (I) compound and Tosi acid is 1: 1.Preferably, described tosilate is crystal salt.
The method that the purpose of this invention is to provide a kind of stable formula (I) compound tosilate and polymorphic thereof and prepare these crystal formations.
The tosilate of formula of the present invention (I) compound is to obtain easily, only needs formula (I) compound and Tosi acid are dissolved in respectively in the solvent, and the two is reacted, and can obtain the tosilate of formula (I) compound.When the two reacts in ethyl acetate/alcohol class system, as formula (I) compound is dissolved in ethyl acetate, Tosi acid is dissolved in methyl alcohol, make afterwards the two reaction, need not the recrystallization operation, crystallization can easily directly obtain the crystallization of IV type, and the chemical purity of product and optical purity are all very high.Aforementioned alcohols can be not limited to methyl alcohol, also can use other alcohol, such as ethanol, propyl alcohol, Virahol.
We have investigated the series of crystallization product that the tosilate of formula (I) compound obtains under different crystallization conditions, the gained crystallized product X-ray powder diffraction and DSC detection have been carried out, the tosilate of discoverable type (I) compound is under the crystallization condition of routine, there is polymorphic, becoming salt system (ethyl acetate/alcohol class) or recrystallization with this understanding, what all obtain is a kind of crystal formation, we are referred to as the IV crystal formation, the DSC collection of illustrative plates of the IV type crystallization among the application has charateristic avsorption band near being presented at 196 ℃ and 205 ℃, the X-ray powder diffraction as shown in Figure 7, use the Cu-Ka radiation, X-ray powder diffraction with 2 θ angles and spacing (d value) expression, wherein about 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56) have characteristic peak.
The compound of this IV crystal formation, recrystallization in water or moisture organic solvent can obtain a kind of crystal formation that has good stability, and we are called the crystallization of I type.The DSC collection of illustrative plates of I type crystallization is presented at the about 76 ℃ of vicinity of peak value among the application has blunt peak to exist, and this blunt peak just dewaters gradually since 32 ℃, is unsettled planar water, and this blunt peak can disappear after drying was processed; The DSC of I type crystallization is at about 152 ℃, 195 ℃ and 204 ℃ have charateristic avsorption band, the X-ray powder diffraction as shown in Figure 1, use the Cu-Ka radiation, X-ray powder diffraction with 2 θ angles and spacing (d value) expression, wherein about 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak.
Also find simultaneously the compound of IV crystal formation, at methyl alcohol, ethanol, Virahol, recrystallization in the single organic solvent such as acetone, all can generate the II crystal formation, recrystallization in above-mentioned system is found in research, although can well improve chemical purity, but do not improve its optical purity, the DSC collection of illustrative plates of II type crystallization is presented at about 196 ℃ and 205 ℃ among the application charateristic avsorption band, and the X-ray powder diffraction is used the Cu-Ka radiation as shown in Figure 3, X-ray powder diffraction with 2 θ angles and spacing (d value) expression, wherein about 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) characteristic peak is arranged.
The compound of IV crystal formation recrystallization in acetonitrile then obtains the III crystal formation.The DSC collection of illustrative plates of the III type crystallization among the application has charateristic avsorption band near being presented at about 195 ℃ and 206 ℃, the X-ray powder diffraction as shown in Figure 5, use the Cu-Ka radiation, X-ray powder diffraction with 2 θ angles and spacing (d value) expression, wherein 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.
The present invention prepares in the method for I, II, III, the crystallization of IV type, the crystal formation kind that can be used as formula (I) the compound tosilate of raw material use is not particularly limited, can use crystallization or the unformed solid of any crystal formation, the preparation method of formula of the present invention (I) compound tosilate I, II, III, the crystallization of IV type is:
Use some rudimentary organic solvent (alcohols that preferred carbon atom quantity is little, the while can volatilize, ketone, ester class isopolarity organic solvent), water or their mixing solutions as the solvent of crystallization; Preferred carbon atom quantity is less than 6 above-mentioned solvent; Make water or moisture organic solvent, can be stable obtain the I crystal formation, wherein said organic solvent refer to can be miscible with water organic solvent, as seen as long as contain the existence of water in the system, all can obtain the I crystal formation; With methyl alcohol, ethanol, Virahol, acetone and other organic solvent as recrystallisation solvent, can be stable obtain the II crystal formation; Do recrystallisation solvent with acetonitrile, can be stable obtain the III crystal formation; Salify or crystallization in ethyl acetate, alcohols system, all can be stable obtain the IV crystal formation.
Concrete, the method for preparation formula provided by the invention (I) compound tosilate crystallization may further comprise the steps:
1) with the tosilate of any crystal formation or unformed formula (I) compound, or with formula (I) compound and Tosi acid heating for dissolving in the crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or both mixed solvents, described rudimentary organic solvent is carbonatoms less than 6 alcohols, ketone, lipid solvent, is preferably methyl alcohol, ethanol, Virahol, acetone, acetonitrile, ethyl acetate or their mixed solvent;
2) filtering for crystallizing and washing, drying.
Further, preparation I crystal formation, described crystallization solvent is the aqueous solution of water or organic solvent; Be preferably water.
Preparation II crystal formation, described crystallization solvent is alcohols and ketone, is preferably in methyl alcohol, ethanol, Virahol, the acetone one or more.
Preparation III crystal formation, described crystallization solvent is acetonitrile.
Preparation IV crystal formation, described crystallization solvent is ethyl acetate and alcohols mixed solvent, wherein said alcohol is not particularly limited, and can be methyl alcohol, ethanol, propyl alcohol or Virahol, particular methanol.Also be not particularly limited for the two ratio of mixing of ethyl acetate and alcohols, the contriver has adopted the mixed solvent of various ratios to test, and can both obtain well the IV crystal formation.
The method of recrystallization is not particularly limited, and can carry out with common recrystallization working method.For example, can with raw material formula (I) compound tosilate in organic solvent, water or both mixed solvents, slowly cool off after the heating for dissolving and leave standstill crystallization, also can take stirring and crystallizing, after crystallization is finished, dry after filtration, can obtain needed crystallization.What need special instruction is, the I type crystallization of formula (I) compound tosilate, in water during recrystallization, its chemical purity and chiral purity all increase significantly, become the good stability of crystal formation, formula (I) the compound tosilate of II, III and IV crystal formation is stirred in water, can be converted to stable I type crystallization.The influence factor experimental result of I crystal formation shows that this stable crystal form is good, and dissolvent residual is low, can well use as active constituents of medicine.
Research is found, the I crystal formation of formula (I) compound tosilate, its moisture can be removed through super-dry, perhaps be controlled at below 1%, in the low situation of moisture controlled, the detection of DSC just no longer shows the existence of the blunt absorption peak of dehydration, but the characteristic absorbance of its X-RAY is consistent, and the result shows that crystal formation does not become.
Measure by differential scanning calorimeter (DSC), X-ray powder diffraction, formula (I) the compound tosilate xln that obtains has been carried out crystal formation research, simultaneously the dissolvent residual of gained crystallization detected, and tested the solubleness of tosilate in water and physiological saline, be about respectively 10mg/ml and 11mg/ml, similar to benzene sulfonate.
The residual solvent that does not contain or only contain lower aq according to the tosilate crystallization of formula (I) compound of method of the present invention preparation, meet the requirement of limiting the quantity of of the relevant pharmaceutical prod residual solvent of state-promulgated pharmacopoeia regulation, thereby I of the present invention, II, III, the crystallization of IV type can be used as the medicinal activity composition preferably.
Description of drawings
The X-ray powder diffraction of the tosilate I type crystallization (20110607) of Fig. 1 formula (I) compound.
The DSC spectrogram of the tosilate I type crystallization (20110607) of Fig. 2 formula (I) compound.
The X-ray powder diffraction of the tosilate II type crystallization (20110519) of Fig. 3 formula (I) compound.
The DSC spectrogram of the tosilate II type crystallization (20110519) of Fig. 4 formula (I) compound.
The X-ray powder diffraction of the tosilate III type crystallization (20110523-1) of Fig. 5 formula (I) compound.
The DSC spectrogram of the tosilate III type crystallization (20110523-1) of Fig. 6 formula (I) compound.
The X-ray powder diffraction of the tosilate IV type crystallization (20110530) of Fig. 7 formula (I) compound.
The DSC spectrogram of the tosilate IV type crystallization (20110530) of Fig. 8 formula (I) compound.
Embodiment
Explain in more detail the present invention below with reference to embodiment, embodiments of the invention only are used for technical scheme of the present invention is described, and non-limiting the spirit and scope of the invention.
Test used testing tool
1, DSC spectrum
Instrument model: Mettler Toledo DSC 1Stare
eSystem
Sweep gas: nitrogen
Temperature rise rate: 10.0 ℃/min
Temperature range: 40-250 ℃
2, x-ray diffraction pattern
Instrument model: D/Max-Bruker D8Focus X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha-ray
Scan mode: θ/2 θ, sweep limit: 2-40
O
Voltage: 40KV electric current: 40mA
Embodiment 1: salt synthetic:
Modus ponens (I) compound alkali is (according to patent US200,700,934,75A preparation) 1g is dissolved in the 6ml ethyl acetate, then 0.39g Tosi acid (equimolar ratio) is dissolved in the 1ml methyl alcohol, and be added drop-wise in the ethyl acetate solution of formula (I) compound alkali, stirring and crystallizing, suction filtration, drying under reduced pressure get the tosilate of formula (I) compound, white solid 0.94g, yield are 75.0%.HPLC:99.18%, optical purity: 99.87%.
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 50ml, add in the 20ml water, reflux 10min dissolves solid fully, stopped heating, filtered while hot, cooling crystallization, products therefrom spends the night at 45 ℃ of drying under reduced pressure, obtain white solid 0.64g, yield 64%.The X-ray diffraction spectrogram of this crystallized sample is seen Fig. 1.This crystallization is about 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak, and the DSC spectrogram is seen Fig. 2, at about 152.02 ℃, 195.05 ℃ and 204.49 ℃ charateristic avsorption band is arranged, defining this crystal formation is the I crystal formation.
Embodiment 3
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 10ml, among the isopropanol water solution 5.0ml of adding 50%, reflux is dissolved solid fully, stopped heating, cooling crystallization, products therefrom spends the night at 45 ℃ of drying under reduced pressure, obtain white solid 0.72g, yield 72%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is the I crystal formation.
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 50ml, add in the 30ml Virahol, reflux 10min dissolves solid fully, stopped heating, leave standstill crystallization, filter, resulting crystallization is spent the night at 45 ℃ of drying under reduced pressure, obtain white solid 0.67g, yield 67%.The X-ray diffraction spectrogram of this crystallized sample is seen Fig. 3.This crystallization is about 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) have characteristic peak.The DSC spectrogram is seen Fig. 4, at 195.71 ℃ and 205.44 ℃ charateristic avsorption band is arranged, and defining this crystal formation is the II crystal formation.
Embodiment 5
The tosilate 0.5g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 50ml, add the acetone of 15ml, reflux 10min dissolves solid fully, stopped heating, stirring and crystallizing is filtered, and resulting crystallization is spent the night at 45 ℃ of drying under reduced pressure, obtain white solid 0.81g, yield 81%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is the II crystal formation.
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 25ml, add in the 5.0ml acetonitrile, reflux 10min dissolves solid fully, stopped heating, leave standstill crystallization, filter, resulting crystallization is spent the night at 45 ℃ of drying under reduced pressure, obtain white solid 0.63g, yield 63%.The X-ray diffraction spectrogram of this crystallized sample is seen Fig. 5.This crystallization is about 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.The DSC spectrogram is seen Fig. 6, at 195.51 ℃ and 205.96 ℃ charateristic avsorption band is arranged, and defining this crystal formation is the III crystal formation.
Embodiment 7
The x-ray diffraction pattern of the tosilate sample of test implementation example 1 resulting formula (I) compound and DSC spectrum, the X-ray diffraction spectrogram is seen Fig. 7.This white solid is about 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56) have characteristic peak.The DSC spectrogram is seen Fig. 8, at 195.98 ℃ and 205.49 ℃ charateristic avsorption band is arranged, and defining this crystal formation is the IV crystal formation.
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 25ml, the mixing solutions (volume ratio=3: 1) that adds 5.0ml ethyl acetate and methyl alcohol, reflux is dissolved solid fully, and stopped heating leaves standstill crystallization, filter, resulting crystallization is spent the night at 45 ℃ of drying under reduced pressure, obtains white solid 0.35g, yield 35%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is the IV crystal formation.
Embodiment 9
The tosilate 1.0g of formula (I) compound will be obtained among the embodiment 1, add in the round-bottomed flask of 25ml, the mixing solutions (volume ratio=6: 1) that adds 20ml ethyl acetate and methyl alcohol, reflux is dissolved solid fully, and stopped heating leaves standstill crystallization, filter, resulting crystallization is spent the night at 45 ℃ of drying under reduced pressure, obtains white solid 0.21 gram, yield 21%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is the IV crystal formation.
Modus ponens (I) compound alkali 1g is (according to patent US200,700,934, the 75A preparation) is dissolved in the 6ml ethyl acetate, then 0.39g Tosi acid (equimolar ratio) is dissolved in the 1ml ethanol, and is added drop-wise in the ethyl acetate solution of formula (I) compound alkali, stirring and crystallizing, suction filtration, drying under reduced pressure get white solid 0.9g, and yield is 72.0%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is the IV crystal formation.
Embodiment 11
(this sample is without purification with the I type of above gained and IV crystal form samples, synthetic crude product) uncoveredly respectively divides placement, investigation is in low temperature, heating (40 ℃, 60 ℃), illumination (4500Lux), the stability of sample under high humidity (RH75%, the RH90%) condition.Investigating sample time is 5 days and 10 days, and HPLC detects purity and sees Table 1.
Study on the stability is the result show, formula (I) compound tosilate I type and IV type crystallized sample are under the condition of uncovered placement, through low temperature, heating (40 ℃, 60 ℃), illumination (4500Lux), stability under the conditions such as high humidity (RH75%, RH90%) is relatively found, illumination is very large on both impacts, sample need keep in Dark Place, and under the condition of low temperature, high temperature, high humidity, the stability of I type crystallization significantly is better than the sample of IV crystal formation.
The tosilate I of table 1, formula (I) compound and the stability of IV crystal form samples are relatively
Embodiment 12: the comparative experiments that the benzene sulfonate (calling CNS 7056 in the following text) of the tosilate (calling HR7056 in the following text) of formula (I) compound and formula (I) compound affects spontaneous activity in mice:
Single tail vein injection HR7056, CNS 7056 (2.5,5 and 7.5mg/kg, i.v.) and Normal group spontaneous activity in mice detailed data see Table 2.
Table 2, HR7056 and CNS7056 are on the impact of ICR spontaneous activity in mice
Embodiment 13:HR7056 and CNS7056 test the impact of ICR mouse righting reflex loss:
Single tail vein injection HR7056, CNS 7056 (15,30 and 60mg/kg, i.v.) and the impact experiment detailed data of Normal group mouse righting reflex see Table 3.
Table 3, HR7056 and CNS7056 are on the impact of ICR mouse righting reflex loss
HR7056I crystal form samples long-term (25 ℃), accelerate that (40 ℃, RH75%) study on the stability of sample under the condition the results are shown in Table 4.
Table 4, HR7056I crystal form samples are accelerated the study on the stability of sample for a long time
Upper table data presentation is compared with the stability data in 4 tables 10 of embodiment among the CN101501019A, and the present invention has clear superiority.
Claims (16)
1. the tosilate of formula (I) compound:
2. the tosilate of formula according to claim 1 (I) compound, the stoicheiometry of its Chinese style (I) compound and Tosi acid is 1: 1.
3. the tosilate of formula according to claim 2 (I) compound, wherein said salt is crystal salt.
4. the I type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using the Cu-Ka radiation, obtain the X-ray powder diffraction that represents with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 1, wherein about 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak.
5. the II type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using the Cu-Ka radiation, obtain the X-ray powder diffraction that represents with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 3, wherein about 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) characteristic peak is arranged.
6. the III type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using the Cu-Ka radiation, obtain the X-ray powder diffraction that represents with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 5, wherein about 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.
7. the IV type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using the Cu-Ka radiation, obtain the X-ray powder diffraction that represents with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 7, wherein about 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56), characteristic peak is arranged.
8. one kind prepares the according to claim 3 method of described crystal salt, and it comprises the steps:
1) with the tosilate of any crystal formation or unformed formula (I) compound, or with formula (I) compound and Tosi acid heating for dissolving in the crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or both mixed solvents, described rudimentary organic solvent is carbonatoms less than 6 alcohols, ketone, lipid solvent, is preferably methyl alcohol, ethanol, Virahol, acetone, acetonitrile, ethyl acetate or their mixed solvent;
2) filtering for crystallizing and washing, drying.
9. method for preparing I type as claimed in claim 4 crystallization, it comprises step claimed in claim 8, wherein said crystallization solvent is the aqueous solution of water or organic solvent; Be preferably water.
10. method for preparing II type according to claim 5 crystallization, it comprises step claimed in claim 8, wherein said crystallization solvent is alcohols and ketone, is preferably in methyl alcohol, ethanol, Virahol, the acetone one or more.
11. a method for preparing III type according to claim 6 crystallization, it comprises step claimed in claim 8, and wherein said crystallization solvent is acetonitrile.
12. method for preparing IV type according to claim 7 crystallization, it comprises step claimed in claim 8, wherein said crystallization solvent is the mixed solvent of ethyl acetate and alcohols, and wherein said alcohols is preferably methyl alcohol, ethanol, propyl alcohol or Virahol.
13. a method for preparing the tosilate of the described formula of claims 1 to 3 any one (I) compound, it comprises makes formula (I) compound and Tosi acid-respons.
14. method according to claim 13, wherein said reaction is carried out in solvent, and described solvent is the mixed solvent of ethyl acetate and alcohols, and described alcohols is preferably methyl alcohol, ethanol, propyl alcohol or Virahol.
15. a pharmaceutical composition, it contains according to claim 1 to the tosilate of the described formula of 3 any one (I) compound or according to claim 4 to crystallization and the pharmaceutically acceptable carrier of the tosilate of formula (I) compound of 7 any one.
16. according to claim 1 to the tosilate of the described formula of 3 any one (I) compound, according to claim 4 to crystallization or the pharmaceutical composition according to claim 15 of the tosilate of the described formula of 7 any one (I) compound calm in preparation, sleep peacefully, purposes in the anxiety, of flaccid muscles or anticonvulsant drug.
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| CN2011104568640A CN102964349A (en) | 2011-08-31 | 2011-12-23 | Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application |
| PCT/CN2012/078487 WO2013029431A1 (en) | 2011-08-31 | 2012-07-11 | Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof |
| CN201280003321.6A CN103221414B (en) | 2011-08-31 | 2012-07-11 | Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof |
| TW101126578A TWI607009B (en) | 2011-08-31 | 2012-07-24 | Tosylate of benzodiazepine derivatives and their crystalline polymorphic forms, preparation and pharmaceutical use thereof |
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| CN104146970A (en) * | 2013-05-05 | 2014-11-19 | 王元青 | Freeze-dried powder injection for treating mental disease |
| 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 |
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| GB9911152D0 (en) * | 1999-05-14 | 1999-07-14 | Glaxo Group Ltd | Short-acting benzodiazepines |
| ES2365402T3 (en) * | 2004-10-19 | 2011-10-04 | Glaxosmithkline Llc | BENZODIAZEPINE DERIVATIVES AS INHIBITORS OF ROCK KINASES. |
| GB0613692D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts |
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-
2011
- 2011-12-23 CN CN2011104568640A patent/CN102964349A/en active Pending
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2012
- 2012-07-11 WO PCT/CN2012/078487 patent/WO2013029431A1/en active Application Filing
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| CN103221414A (en) | 2013-07-24 |
| CN103221414B (en) | 2014-08-27 |
| TW201309704A (en) | 2013-03-01 |
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| TWI607009B (en) | 2017-12-01 |
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