CN114478535B - Preparation method of crystal form Malun II of benzenesulfonic acid - Google Patents
Preparation method of crystal form Malun II of benzenesulfonic acid Download PDFInfo
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- CN114478535B CN114478535B CN202111232370.4A CN202111232370A CN114478535B CN 114478535 B CN114478535 B CN 114478535B CN 202111232370 A CN202111232370 A CN 202111232370A CN 114478535 B CN114478535 B CN 114478535B
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229940092714 benzenesulfonic acid Drugs 0.000 title claims abstract description 36
- 239000013078 crystal Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000012458 free base Substances 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 238000007605 air drying Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 6
- 229940077388 benzenesulfonate Drugs 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000004799 sedative–hypnotic effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- -1 2-pyridinyl Chemical group 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- VEFXTGTZJOWDOF-UHFFFAOYSA-N benzene;hydrate Chemical compound O.C1=CC=CC=C1 VEFXTGTZJOWDOF-UHFFFAOYSA-N 0.000 description 1
- ZTOFJEAQBPIGSV-UHFFFAOYSA-N benzenesulfonic acid methyl propanoate Chemical compound CCC(=O)OC.OS(=O)(=O)C1=CC=CC=C1 ZTOFJEAQBPIGSV-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a crystal form Malun II of benzenesulfonic acid, which comprises the following steps: 1) Dissolving the free base of the Rayleigh Malun in a first organic solvent to form a solution A, and dissolving the benzenesulfonic acid in a second organic solvent to form a solution B; 2) Adding the solution B into the solution A, and stirring to separate out solid; 3) Separating and drying the solid to obtain a crystal form II of the benzenesulfonic acid Rayleigh Malun; wherein the second organic solvent is acetonitrile. The method has high yield, the obtained II crystal form has high purity, less solvent residue, less impurities, safe used solvent and the process is suitable for industrialization.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a novel 3- [ (4S) -8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazole [1,2-a ]][1,4]Benzodiazepines-4-yl]A preparation method of a crystal form II of methyl propionate benzenesulfonate, which is commonly named as a preparation method of a crystal form II of benzenesulfonate Malun.
Background
One of the compounds disclosed in patent EP1183243 is the chemical name 3- [ (4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazo [1,2-a][1,4]Benzodiazepines-4-yl]Methyl propionate (Rate Malun), as shown in the following formula (I):
from the chemical structure, the compound belongs to benzodiazepineSedative hypnotics produce dose-related sedative hypnotics by interacting with gamma-aminobutyric acid (GABA) receptors in the central nervous system.
Such compounds are reported in European patent No. EP1183243 to be short acting CNS inhibitors with sedative hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. They are useful for intravenous administration in the following clinical treatment regimen: preoperative sedative, anxiolytic and amnestic uses such as during surgery; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; as a component of induction and maintenance of general anesthesia prior to and/or concurrent with administration of other anesthetics and analgesics; ICU sedation, and the like.
It is reported in patent CN101501019 that the free base stability of rayl Malun is poor, only suitable for storage at low temperatures of 5 ℃, but that samples stored at 40 ℃/75% relative humidity (open) are observed to deliquesce, change colour to yellow to orange and show a significant content reduction relative to the initial content. Thus, patent CN101501019 discloses the benzenesulfonate salt of rayl Malun, increasing its chemical stability. Its polymorphism is also disclosed: mainly form I, form II, form III and form IV exist. Wherein the I crystal form and the II crystal form are stable crystal forms.
According to the report of the prior patent application CN101501019, the preparation of the II crystal form is obtained by salifying the free base of the Rui Malun in methanol solution and the benzenesulfonic acid in ethanol solution, wherein the reaction temperature is 4 ℃.
Meanwhile, the patent reports that the crystal form II is obtained by crystallizing the benzenesulfonic acid Malun salt in the following solvent systems: ethanol/ethyl acetate, ethanol/methyl isobutyl ketone, ethanol/p-isopropyl benzene, dimethyl sulfoxide/1, 2-dichlorobenzene, acetonitrile/water, ethanol/1, 2-dichlorobenzene, ethanol/tetrachloroethylene, tetrahydrofuran/1, 2-dichlorobenzene, tetrahydrofuran/ethyl acetate, etc. are prepared under low temperature conditions.
The method needs to obtain the benzenesulfonate of the Rayleigh Malun first and then carry out crystal transformation to obtain the II crystal form. Complicated operation and lower overall yield.
It would therefore be of interest to develop a process for preparing the crystal form Malun II of benzenesulfonic acid which is stable and in high yield.
Disclosure of Invention
The invention mainly aims to provide a preparation method of a crystal form Malun II of benzenesulfonic acid, which comprises the following steps:
1) Dissolving the free base of the Rayleigh Malun in a first organic solvent to form a solution A, and dissolving the benzenesulfonic acid in a second organic solvent to form a solution B;
2) Adding the solution B into the solution A, and stirring to separate out solid;
3) Separating and drying the solid to obtain a crystal form Malun II of the benzenesulfonic acid; wherein the second organic solvent is acetonitrile.
Further, the molar ratio of the free base of the Rayleigh Malun to the benzenesulfonic acid was 1:1.
Further, the mass volume ratio of the free base of the Malun to the first solvent is 1:3-1:10 g/mL, preferably 1:5g/mL, and the mass ratio of the benzenesulfonic acid to the second solvent is 1:10-1:20 g/mL, preferably 1:14g/mL.
Further, the volume ratio of the first solvent to the second solvent is 1:1-3:1.
Further, the first organic solvent in the step 1) is selected from one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, diethyl ether, methyl tertiary butyl ether, isopropyl ether and acetone.
Further, the first organic solvent is selected from ethyl acetate, isopropyl acetate, methyl tertiary butyl ether or acetone.
Further, in the step 2), the solution B is slowly added into the solution A, and the temperature is controlled to be 0-10 ℃; the temperature of the stirred precipitated solid is 10-30 ℃.
Further, in the step 2), the crystallization time of stirring to precipitate the solid is 3 to 16 hours. Further, the separation in step 3) is filtration separation or centrifugal separation.
Further, the drying in the step 3) is selected from reduced pressure drying or forced air drying; the drying temperature is 40-60 ℃ and the drying time is 3-20 hours.
Further, the drying in the step 3) is reduced pressure drying, and the drying is carried out for 10 hours at the temperature of 40 ℃ under the vacuum degree of-0.080 MPa to-0.095 MPa.
The method is completed by one step of salifying the free base of the Rayleigh Malun and the benzenesulfonic acid and preparing the crystal form, and a crystal transformation step is not needed. The whole reaction is carried out at room temperature, the requirement on equipment is not high, the preparation method is simple and controllable, the yield is high, the used solvent is safe and has low toxicity, the method is suitable for industrial production, and the obtained II crystal form has high purity, less solvent residue and less impurities.
Drawings
FIG. 1 an X-ray powder diffraction (XRD) pattern of form II of the benzenesulfonic acid rayleigh Malun prepared in example 1;
FIG. 2 is a Differential Scanning Calorimetry (DSC) chart of crystalline form Malun II of benzenesulfonic acid prepared in example 1;
FIG. 3 is a High Performance Liquid Chromatography (HPLC) chart of the crystal form Malun II of the benzenesulfonic acid prepared in example 1;
FIG. 4 is an X-ray powder diffraction (XRD) pattern of the crystalline form Malun II of benzenesulfonic acid prepared in example 2;
FIG. 5 is a Differential Scanning Calorimetry (DSC) chart of crystalline form Malun II of benzenesulfonic acid prepared in example 2;
FIG. 6 is a High Performance Liquid (HPLC) chart of the form Malun II of benzenesulfonic acid prepared in example 2;
FIG. 7 is an X-ray powder diffraction (XRD) pattern of the crystalline form Malun II of benzenesulfonic acid prepared in example 3;
FIG. 8 is a Differential Scanning Calorimetry (DSC) chart of crystalline form Malun II of benzenesulfonic acid prepared in example 3;
FIG. 9 is a High Performance Liquid (HPLC) chart of the form Malun II of benzenesulfonic acid prepared in example 3;
figure 10 an X-powder diffraction (XRD) pattern of crystalline form Malun II of benzenesulfonic acid prepared in example 4;
figure 11 Differential Scanning Calorimetry (DSC) profile of crystalline form Malun II of benzenesulfonic acid prepared in example 4.
FIG. 12 is a High Performance Liquid Chromatography (HPLC) chart of the crystal form Malun II of benzenesulfonic acid prepared in example 4;
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
X-ray diffractometer:
conditions are as follows: tube voltage 40kV tube current 40mA start angle 3 DEG end angle 40 DEG step angle 0.02 DEG sample time 1s.
Differential scanning calorimeter:
conditions are as follows: heating at 25-250deg.C at 10deg.C/min.
EXAMPLE 1 preparation of the form Malun II of benzenesulfonate
1.0g of the compound free base of formula I is dissolved in 5ml of isopropyl acetate, then 0.361g of benzenesulfonic acid is dissolved in 5ml of acetonitrile, and is added dropwise to the isopropyl acetate solution of the compound free base of formula (I) at 0-10 ℃, then stirred and crystallized for 3 hours at 25 ℃, suction-filtered and dried under reduced pressure to obtain 1.25g of white solid, yield: 91.8%. Reduced pressure drying conditions: vacuum degree is-0.080 MPa to-0.095 MPa, and drying is carried out for 10 hours at 40 ℃. The X-ray powder diffraction pattern of the crystalline sample is shown in FIG. 1. The crystals have an X-ray powder diffraction pattern expressed in terms of 2 theta angle (interplanar spacing d value) and have characteristic peaks at 8.56 (10.32), 10.40 (8.498), 11.86 (7.456), 12.92 (6.846), 14.29 (6.191), 15.80 (5.604), 16.18 (5.474), and a DSC spectrum as shown in FIG. 2 and an initial melting temperature at 199.82 ℃. HPLC spectra are shown in FIG. 3, and the purity of Rayleigh Malun is 99.65%. The crystal form is a II crystal form.
EXAMPLE 2 preparation of the crystalline form of Benzenesulfonate Rayleigh Malun II
1.0g of the compound free base of the formula I is dissolved in 5ml of acetone, then 0.361g of benzenesulfonic acid is dissolved in 5ml of acetonitrile and is added dropwise into an acetone solution of the compound free base of the formula I at a temperature of between 0 and 10 ℃, then the mixture is stirred and crystallized for 5 hours at a temperature of 23 ℃, suction filtration and drying under reduced pressure are carried out to obtain 1.20g of white solid, and the yield is: 88.2%. Reduced pressure drying conditions: vacuum degree is-0.080 MPa to-0.095 MPa, and drying is carried out for 10 hours at 40 ℃. The X-ray powder diffraction pattern of this crystalline sample is shown in FIG. 4. The crystals have an X-ray powder diffraction pattern expressed in terms of 2 theta angle (interplanar spacing d value) at 8.58 (10.30), 10.28 (8.596), 11.86 (7.455), 12.94 (6.834), 14.26 (6.205), 15.80 (5.604), 16.18 (5.473) and a DSC spectrum as shown in FIG. 5, with an initial melting temperature at 199.73 ℃. HPLC spectra are shown in FIG. 6, and the purity of Rayleigh Malun is 99.96%. The crystal form is a II crystal form.
EXAMPLE 3 preparation of the crystalline form of Benzenesulfonate Rayleigh Malun II
1.0g of the free base of the compound of formula I is dissolved in 5ml of methyl tert-butyl ether, then 0.361g of benzenesulfonic acid is dissolved in 5ml of acetonitrile and added dropwise to an acetone solution of the free base of the compound of formula (I) at 0-10 ℃, stirred and crystallized at 25 ℃ for 8 hours, filtered off with suction, dried under reduced pressure to obtain 1.30g of white solid with a yield of 95.5%. Reduced pressure drying conditions: vacuum degree is-0.080 MPa to-0.095 MPa, and drying is carried out for 10 hours at 40 ℃. The X-ray powder diffraction pattern of this crystalline sample is shown in FIG. 7. The crystals have an X-ray powder diffraction pattern expressed in terms of 2 theta angle (interplanar spacing d value) at 8.56 (10.32), 10.40 (8.498), 11.84 (7.466), 12.94 (6.835), 14.26 (6.207), 15.80 (5.605), 16.18 (5.474), and a DSC spectrum as shown in FIG. 8, with an initial melting temperature at 200.66 ℃. HPLC spectra are shown in FIG. 9, and the purity of Rayleigh Malun is 99.93%. The crystal form is a II crystal form.
EXAMPLE 4 preparation of the crystalline form of Benzenesulfonate Rayleigh Malun II
1.0g of the free base of the compound of formula I is dissolved in 5ml of ethyl acetate, then 0.361g of benzenesulfonic acid is dissolved in 5ml of acetonitrile and is added dropwise to an acetone solution of the free base of the compound of formula (I) at 0-10 ℃, then stirred and crystallized at 26 ℃ for 10 hours, suction-filtered and dried under reduced pressure to obtain 1.27g of white solid with a yield of 93.3%. Reduced pressure drying conditions: vacuum degree is-0.080 MPa to-0.095 MPa, and drying is carried out for 10 hours at 40 ℃. The X-ray powder diffraction pattern of the crystalline sample is shown in FIG. 10. The crystals have an X-ray powder diffraction pattern expressed in terms of 2 theta angle (interplanar spacing d value) and have characteristic peaks at 8.58 (10.30), 10.32 (8.565), 11.90 (7.432), 12.96 (6.824), 14.26 (6.204), 15.82 (5.597), 16.22 (5.460), and DSC spectra as shown in FIG. 11, and have an initial melting temperature at 199.06 ℃. HPLC spectra are shown in FIG. 12, and the purity of Rayleigh Malun is 99.25%. The crystal form is a II crystal form.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions and methods of the invention without departing from the spirit or scope of the invention, and therefore, the invention embraces modifications and variations of the invention as fall within the scope of the claims and their equivalents.
Claims (6)
1. A method for preparing a crystal form Malun II of benzenesulfonic acid, which comprises the following steps:
1) Dissolving the free base of the Rayleigh Malun in a first organic solvent to form a solution A, and dissolving the benzenesulfonic acid in a second organic solvent to form a solution B; the first organic solvent is selected from ethyl acetate, isopropyl acetate, methyl tertiary butyl ether or acetone;
2) Slowly adding the solution B into the solution A, and controlling the temperature to be 0-10 ℃; the temperature of stirring to separate out solid is 10-30 ℃; the crystallization time of stirring to separate out the solid is 3-16 hours;
3) Separating and drying the solid to obtain a crystal form Malun II of the benzenesulfonic acid; wherein the second organic solvent is acetonitrile;
the molar ratio of the free base of the Rayleigh Malun to the benzenesulfonic acid is 1:1;
the mass volume ratio of the free base of the RED Malun to the first solvent is 1:3-1:10 g/mL, and the mass volume ratio of the benzenesulfonic acid to the second solvent is 1:10-1:20 g/mL.
2. The method of claim 1, wherein the mass to volume ratio of the free base of ray Malun to the first solvent is 1:5g/mL and the mass to volume ratio of benzenesulfonic acid to the second solvent is 1:14g/mL.
3. The method of claim 1, wherein the volume ratio of the first solvent to the second solvent is 1:1 to 3:1.
4. The method of claim 1, wherein the separation in step 3) is a filtration separation or a centrifugation separation.
5. The method according to claim 1, wherein the drying in step 3) is selected from the group consisting of reduced pressure drying and forced air drying; the drying temperature is 40-60 ℃ and the drying time is 3-20 hours.
6. The preparation method according to claim 5, wherein the drying in the step 3) is reduced pressure drying, and the drying is performed at 40 ℃ for 10 hours under vacuum of-0.080 MPa to-0.095 MPa.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011142967 | 2020-10-23 | ||
| CN2020111429675 | 2020-10-23 |
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| Publication Number | Publication Date |
|---|---|
| CN114478535A CN114478535A (en) | 2022-05-13 |
| CN114478535B true CN114478535B (en) | 2024-02-09 |
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