CN115872919A - Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole - Google Patents
Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole Download PDFInfo
- Publication number
- CN115872919A CN115872919A CN202211698376.5A CN202211698376A CN115872919A CN 115872919 A CN115872919 A CN 115872919A CN 202211698376 A CN202211698376 A CN 202211698376A CN 115872919 A CN115872919 A CN 115872919A
- Authority
- CN
- China
- Prior art keywords
- toluenesulfonyl
- crystal form
- alanyloxy
- indole
- degrees
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 82
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 46
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 33
- 239000013078 crystal Substances 0.000 claims abstract description 129
- 230000001131 transforming effect Effects 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 61
- 239000002904 solvent Substances 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 48
- 238000001914 filtration Methods 0.000 claims description 34
- 238000001816 cooling Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 21
- 239000012141 concentrate Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- PCKPVGOLPKLUHR-UHFFFAOYSA-N indoxyl Chemical compound C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 14
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 8
- QQQCWVDPMPFUGF-ZDUSSCGKSA-N alpinetin Chemical compound C1([C@H]2OC=3C=C(O)C=C(C=3C(=O)C2)OC)=CC=CC=C1 QQQCWVDPMPFUGF-ZDUSSCGKSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000009466 transformation Effects 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 239000001433 sodium tartrate Substances 0.000 claims description 2
- 229960002167 sodium tartrate Drugs 0.000 claims description 2
- 235000011004 sodium tartrates Nutrition 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims 4
- 150000001348 alkyl chlorides Chemical class 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 30
- 239000012043 crude product Substances 0.000 abstract description 28
- 239000000047 product Substances 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000011426 transformation method Methods 0.000 abstract description 2
- 239000007864 aqueous solution Substances 0.000 description 13
- 150000001335 aliphatic alkanes Chemical class 0.000 description 12
- -1 indole ester Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Images
Classifications
-
- 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
Landscapes
- Indole Compounds (AREA)
Abstract
The invention provides a method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, belonging to the field of biological medicine. The method for transforming the 3- (N-tosyl-L-alanyloxy) indole comprises the following steps: a preparation method for converting an amorphous crude product into a crystal form I or a crystal form II; a preparation method for converting a mixed crystal form of the crystal form I and the crystal form II into the crystal form I or the crystal form II; a process for the preparation of form I converted to form II; a process for the preparation of form II converted to form I. The crystal transformation method can obtain single and high-purity crystal form products, and has the characteristics of high yield, high purity and suitability for industrial production and use.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a crystal transformation method of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole.
Background
3- (N-p-toluenesulfonyl-L-alanyloxy) -indole, abbreviated indole ester, british name: 3- (N-tosyl-L-alanyloxy) -indele, molecular formula: c 18 H 18 N 2 O 4 S, the structural formula is shown as the formula (1):
indole ester is an important raw material for detecting urine leucocyte, and the main technical problems of the prior application are as follows: due to different production methods, process conditions and processing processes, indole esters often have low-purity amorphous crude products, mixed crystal forms of crystal form I and crystal form II, single crystal form I or single crystal form II. Because the purity and the crystal form of the indole ester directly affect the stability, the sensitivity and the reaction rate of the indole ester, once the purity and the crystal form which are not targeted appear, the use of the indole ester is affected, and unnecessary loss is caused.
Therefore, how to overcome the defects of the prior art, the amorphous crude product, the mixed crystal form, the single crystal form I or the single crystal form II of the indole ester formed at present can be converted into any single crystal form of the high-purity crystal form I or the high-purity crystal form II, which is very important for the effective and full utilization of the indole ester, and is also a technical problem to be solved at present.
Disclosure of Invention
In view of the above, the invention provides a method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, which can obtain a single and high-purity crystal product, and has the characteristics of high yield, high purity and suitability for industrial production and use. The invention solves the technical problem that due to different production methods, process conditions and processing processes, the use of indole ester is influenced by the formed non-target purity and crystal form, so that unnecessary loss is caused.
The invention provides a method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, which comprises the following steps:
1) A process for the preparation of amorphous crude product converted into form I;
2) A process for the preparation of amorphous crude product converted into crystalline form II;
3) A preparation method for converting a mixed crystal form of a crystal form I and a crystal form II into a crystal form I;
4) A preparation method for converting a mixed crystal form of a crystal form I and a crystal form II into a crystal form II;
5) A process for the preparation of form I converted into form II;
6) A preparation method for converting the crystal form II into the crystal form I.
The invention provides a method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, which comprises the following steps:
(1) The preparation method of the amorphous crude product comprises the following steps:
(1-1) under the protection of inert gas, adding 3-hydroxyindole into an aprotic solvent according to the mass volume ratio of 1;
(1-2) adding an extraction solvent into a reaction concentrate, wherein the mass volume ratio of the reaction concentrate to the extraction solvent is 1; adding a drying agent, fully drying, filtering, collecting filtrate, and evaporating to remove the solvent to obtain an extraction concentrate;
(1-3) adding a decolorizing solvent into an extraction concentrate, wherein the mass volume ratio of the extraction concentrate to the decolorizing solvent is 1-1, stirring for dissolving, adding activated carbon, wherein the activated carbon is 5-30% of the mass of the extraction concentrate, stirring for 1-6 h at the temperature of 20-50 ℃ until the extract is decolorized to be colorless, filtering, collecting filtrate, and concentrating to obtain an amorphous crude product, wherein the reaction formula is shown as formula (2):
(2) A method for converting an amorphous crude product into a crystal form I or a crystal form II:
(2-1) preparation method for converting amorphous crude product into crystal form I:
(2-1-1) adding the amorphous crude product prepared in the step (1-3) into an ether solvent, wherein the mass volume ratio of the amorphous crude product to the ether solvent is 1-1;
(2-1-2) adding a product into a halogenated alkane solvent, wherein the mass volume ratio of the product to the halogenated alkane solvent is 1-2 to 1, heating, controlling the temperature and stirring for 1 to 6 hours at the temperature of 40 to 75 ℃, cooling to-20 ℃ at the speed of 1 to 5 ℃/min, stirring for 1 to 24 hours at a constant temperature, filtering, drying a filter cake in vacuum, and collecting to obtain a crystal form I;
(2-2) preparation method for converting amorphous crude product into crystal form II:
(2-2-1) adding the amorphous crude product prepared in the step (1-3) into an ether solvent, wherein the mass volume ratio of the amorphous crude product to the ether solvent is 1-1; heating and stirring for 1-6 h at the temperature of 40-80 ℃, cooling to 0 ℃ at the speed of 1-5 ℃/min, stirring for 1-24 h at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting a product;
(2-2-2) adding a product into an alcohol aqueous solution, wherein the mass volume ratio of the product to the alcohol aqueous solution is (1) - (5-1); heating and stirring for 1-6 h at the temperature of 50-80 ℃, preferably 55-75 ℃, cooling to-20 ℃ at the speed of 1-5 ℃/min, stirring for 1-24 h at constant temperature, filtering, drying a filter cake in vacuum, and collecting to obtain the crystal form II.
Preferably, the aprotic solvent in step (1-1) is any one of acetone, acetonitrile, dioxane and tetrahydrofuran;
the organic acid catalyst in the step (1-1) is any one of trifluoroacetic acid, citric acid or oxalic acid;
the organic base in the step (1-1) is at least one of pyridine and diisopropylethylamine;
the extraction solvent in the step (1-2) is any one of ethyl acetate, butyl acetate, dichloromethane and chloroform;
the weak acid in the step (1-2) is any one of acetic acid, citric acid, carbonic acid, tartaric acid, boric acid and ethylenediamine tetraacetic acid;
the weak base in the step (1-2) is any one of sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium borate;
the drying agent in the step (1-2) is any one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or a molecular sieve;
the decolorizing solvent in the step (1-3) is any one of diethyl ether, petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether or ethylene glycol dimethyl ether;
the ether solvent in the step (2-1-1) is any one of petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether and isobutyl ether;
the halogenated alkane solvent in the step (2-1-2) is a chlorinated alkane solvent, and the chlorinated alkane solvent is any one of dichloromethane, chloroform or carbon tetrachloride;
the ether solvent in the step (2-2-1) is any one of petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether and isobutyl ether;
the alcohol in the step (2-2-2) is any one of methanol, ethanol, propanol or isopropanol.
A method for the crystal transformation of 3- (N-tosyl-L-alanyloxy) indole, which comprises the following steps:
(1) The preparation method for converting the mixed crystal form of the crystal form I and the crystal form II into the crystal form I comprises the following steps:
(1-1) adding a mixed crystal form of a crystal form I and a crystal form II into an ether solvent, wherein the mass volume ratio of the mixed crystal form to the ether solvent is 1;
(1-2) adding a product into a halogenated alkane solvent, wherein the mass volume ratio of the product to the halogenated alkane solvent is 1-1;
(2) The preparation method for converting the mixed crystal form of the crystal form I and the crystal form II into the crystal form II comprises the following steps:
(2-1) adding a mixed crystal form of a crystal form I and a crystal form II into an ether solvent, wherein the mass volume ratio of the mixed crystal form to the ether solvent is 1;
(2-2) adding a product into an alcohol aqueous solution, wherein the mass volume ratio of the product to the alcohol aqueous solution is 1; heating, controlling the temperature, stirring and reacting at the temperature of 50-80 ℃, cooling to-20 ℃ at the speed of 1-5 ℃/min, stirring at the constant temperature for 1-24 h, filtering, drying a filter cake in vacuum, and collecting to obtain the crystal form II.
Preferably, the halogenated alkane solvent in the step (1-2) is a chlorinated alkane solvent, and the chlorinated alkane solvent is any one of dichloromethane, chloroform or carbon tetrachloride; the alcohol solvent in the step (2-2) is any one of methanol, ethanol, propanol or isopropanol.
A method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, comprising the following steps:
(1) The preparation method for converting the crystal form II into the crystal form I comprises the following steps:
(1-1) adding a crystal form II into an ether solvent, wherein the mass volume ratio of the crystal form II to the ether solvent is 1;
(1-2) adding a product into a halogenated alkane solvent, wherein the mass volume ratio of the product to the halogenated alkane solvent is 1;
(2) The preparation method for converting the crystal form I into the crystal form II comprises the following steps:
(2-1) adding a crystal form I into an ether solvent, wherein the mass volume ratio of the crystal form I to the ether solvent is 1;
(2-2) adding a product into an alcohol aqueous solution, wherein the mass volume ratio of the product to the alcohol aqueous solution is 1; heating, controlling the temperature, stirring and reacting for 1-6 h at the temperature of 50-80 ℃, cooling to-20 ℃ at the speed of 1-5 ℃/min, stirring for 1-24 h at constant temperature, filtering, drying a filter cake in vacuum, and collecting to obtain the crystal form II.
Preferably, the alkyl halide in the step (1-2) is any one of dichloromethane, chloroform or carbon tetrachloride; the alcohol in the step (2-2) is any one of methanol, ethanol, propanol or isopropanol.
Compared with the prior art, the invention has the following beneficial effects: the invention overcomes the defects of the prior art, converts the indole ester from the existing amorphous crude product, mixed crystal form, single crystal form I or single crystal form II into any single crystal form of high-purity crystal form I or crystal form II, and solves the technical problem that the existing indole ester can not be effectively and fully utilized. Meanwhile, the prepared crystal form I and crystal form II are subjected to X-RPD, DSC and IR characterization, and the reliability of the technical scheme is proved.
The invention discloses a 3- (N-p-toluenesulfonyl-L-alanyloxy) indole crystal form I and a 3- (N-p-toluenesulfonyl-L-alanyloxy) indole crystal form II, which are comprehensively characterized by means of X-ray powder diffraction spectrum (X-RPD), differential Scanning Calorimetry (DSC), infrared spectrum (IR) and the like.
The X-ray powder diffraction test instrument and the test conditions thereof related by the invention are as follows: a detection instrument, bruker d8 advanced diffractometer, germany; measurement conditions, target: copper; pipe pressure/pipe flow 40KV/40M; the scanning angle is 3-60 degrees; scanning step size 0.02 °; the scanning speed is 8 degrees/min; the radiation of Cu-K alpha is carried out,
the Differential Scanning Calorimetry (DSC) analysis test conditions related by the invention are as follows: the temperature rising procedure is 30-150 ℃,2 ℃/min;
the infrared spectrometer and the test conditions related by the invention are as follows: bruker 22; the operation method comprises the following steps: adopts KBr tablet pressing method, and the scanning range is 400-4000 cm -1 。
The purity related to the invention is detected by HPLC, and the specific HPLC detection conditions are as follows: a chromatographic column C18 packed column; the mobile phase is methanol-water gradient elution; the detection wavelength is 230nm; the flow rate is 1.0ml/min; the column temperature was 30 ℃.
1) X-ray powder diffraction results
Form I has characteristic absorption peaks at the following positions: 9.913 +/-0.2 degrees, 14.680 +/-0.2 degrees, 17.829 +/-0.2 degrees, 18.689 +/-0.2 degrees, 19.999 +/-0.2 degrees, 21.104 +/-0.2 degrees, 24.176 +/-0.2 degrees, 27.060 +/-0.2 degrees and 30.232 +/-0.2 degrees. The X-ray powder diffraction (X-RPD) pattern 2 theta data of the crystal form I is shown in a table 1, and the X-ray powder diffraction pattern is shown in a figure 1:
TABLE 1
Form II has characteristic absorption peaks at the following positions: 9.214 +/-0.2 degrees, 11.261 +/-0.2 degrees, 17.605 +/-0.2 degrees, 18.567 +/-0.2 degrees, 20.142 +/-0.2 degrees, 22.557 +/-0.2 degrees, 25.811 +/-0.2 degrees and 26.261 +/-0.2 degrees. The X-ray powder diffraction (X-RPD) pattern 2 theta data of the crystal form II is shown in a table 2, and the X-ray powder diffraction pattern is shown in a figure 4.
TABLE 2
2) Differential scanning calorimetry analysis results
The crystal form I has a first endothermic peak at 76-78 ℃ and a second endothermic peak at 103-105 ℃, and has a differential scanning calorimetry pattern substantially as shown in figure 2.
The maximum endothermic peak of the crystal form II in the range of 103-105 ℃ has a differential scanning calorimetry pattern shown in figure 5.
3) Results of infrared spectroscopic analysis
The crystal form I is 3340.55cm -1 、1748.20cm -1 、1455.38cm -1 、1427.19cm -1 、1382.28cm -1 、1327.72cm -1 、1305.05cm -1 、1263.01cm -1 、1232.65cm -1 、1167.45cm -1 、1126.25cm -1 、1090.31cm -1 、1071.56cm -1 、1035.39cm -1 、962.66cm -1 、890.64cm -1 、815.86cm -1 、744.50cm -1 、671.48cm -1 、564.85cm -1 、551.47cm -1 、491.94cm -1 、422.82cm -1 Has characteristic absorption peaks and has an infrared spectrum as shown in figure 3.
The crystal form II is 3401.45cm -1 ，3283.99cm -1 ，1747.98cm -1 ，1459.19cm -1 ，1429.79cm -1 ，1344.32cm -1 ，1315.98cm -1 ，1308.06cm -1 ，1290.86cm -1 ，1225.12cm -1 ，1193.49cm -1 ，1146.54cm -1 ，1089.49cm -1 ，1047.52cm -1 ，1014.20cm -1 ，973.21cm -1 ，815.83cm -1 ，737.24cm -1 ，711.95cm -1 ，671.01cm -1 ，589.59cm -1 ，576.08cm -1 ，553.20cm -1 Has characteristic absorption peak and infrared spectrum as shown in FIG. 6.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of form I;
FIG. 2 is a differential scanning calorimetry analysis of form I;
FIG. 3 is an infrared spectrum of form I;
FIG. 4 is an X-ray powder diffraction pattern of form II;
FIG. 5 is a differential scanning calorimetry analysis of form II;
fig. 6 is an infrared spectrum of the crystal form II.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The test methods or test methods described in the following examples are conventional methods unless otherwise specified; the starting materials and auxiliaries are, unless specified otherwise, either obtained from customary commercial sources or prepared in customary manner.
Example 1
A method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole comprises the following specific steps:
(1) The preparation method of the amorphous crude product comprises the following steps:
(1-1) under the protection of nitrogen, adding 7.0L of tetrahydrofuran into 1.332 kg (10 moL) of 3-hydroxyindole, stirring for dissolving, adding 2.4L (30 moL) of pyridine, adding 1.14L (10 moL) of trifluoroacetic acid, reducing the temperature of a system to 0 ℃, then slowly adding 3.926 kg (15 moL)/3.0L of N-p-toluenesulfonyl-L-alanyl chloride, continuously controlling the temperature to be below 10 ℃, reacting for 4 hours, and after the reaction is completed, evaporating the solvent to obtain a reaction concentrate;
(1-2) adding 15L of ethyl acetate into the reaction concentrate, stirring to dissolve, and washing with 5% citric acid aqueous solution for 3 times, 5L each time; washing with 5% sodium bicarbonate water solution for 3 times, 5L each time; washing with 10% sodium chloride water solution for 3 times, 5L each time; separating, reserving an ethyl acetate layer, adding 500 g of anhydrous sodium sulfate, drying for 5 hours, filtering, and evaporating to remove the solvent to obtain an extraction concentrate;
(1-3) adding 20L of diethyl ether into the extraction concentrate, stirring for dissolving, adding 300 g of activated carbon, decoloring for 2 hours, repeatedly decoloring for 3-4 times until the mixture is colorless, filtering, and concentrating to obtain 3.268 kg of an amorphous crude product, wherein the yield is 91.2 percent, and the purity is 97.89 percent;
(2) A method for converting an amorphous crude product into a crystal form I or a crystal form II:
(2-1) preparation method for converting amorphous crude product into crystal form I:
adding 200 g (purity of 97.89%) of amorphous crude product into 1200mL of petroleum ether, heating, controlling the temperature, stirring for 1 hour, slowly cooling, cooling to 1-5 ℃ per minute until the temperature reaches 0 ℃, stirring for 12 hours at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting; adding 800mL of dichloromethane, carrying out reflux reaction for 30 minutes, slowly cooling to 1 ℃ per minute, then cooling to-20 ℃, keeping for 24 hours until crystallization is complete, filtering, collecting a filter cake, and carrying out vacuum drying to obtain crystal form I,183.2 g, the yield is 91.6%, and the purity is 99.51%.
(2-2) preparation method for converting amorphous crude product into crystal form II:
adding 200 g of amorphous crude product (purity is 97.89%) into 1500mL of isopropyl ether, heating, controlling the temperature at 65 ℃, stirring for 6 hours, slowly cooling, cooling 1-5 ℃ per minute until the temperature reaches 0 ℃, stirring for 12 hours at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting; adding 800mL of 95% methanol aqueous solution, heating, controlling the temperature to be 70 ℃, stirring, reacting for 3 hours, slowly cooling to 1 ℃ per minute, cooling to-20 ℃, keeping for 24 hours until crystallization is complete, filtering, collecting filter cakes, and drying in vacuum to obtain 184.5 g of crystal form II, wherein the yield is 92.3%, and the purity is 99.33%.
Example 2
(1) The preparation method of the 3- (N-p-toluenesulfonyl-L-alanyloxy) indole from the mixed crystal form I and the crystal form II to the crystal form I is as follows:
taking 300 g (purity of 97.55%) of mixed crystal form I and crystal form II, adding the mixed crystal form I and crystal form II into 1500mL of n-propyl ether, heating, controlling the temperature to be 60 ℃, stirring for 4 hours, slowly cooling, cooling to be 1-5 ℃ per minute until the temperature reaches 0 ℃, stirring for 6 hours at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting; adding 1000mL of carbon tetrachloride, heating, controlling the temperature to be 75 ℃, stirring for 3 hours, slowly cooling, reducing the temperature by 1 ℃ per minute to-20 ℃, keeping for 18 hours until the crystallization is complete, filtering, collecting filter cakes, and drying in vacuum to obtain the crystal form I,271.5 g, the yield being 90.5% and the purity being 99.48%.
(2) The preparation method for converting the 3- (N-p-toluenesulfonyl-L-alanyloxy) indole from the mixed crystal form I and the crystal form II into the crystal form II comprises the following steps:
taking 300 g of mixed crystal form I and crystal form II (purity is 97.55%), adding the mixed crystal form I and crystal form II into 1500mL of n-propyl ether, heating, controlling the temperature to be 60 ℃, stirring for 4 hours, slowly cooling, cooling to 1-5 ℃ per minute until the temperature reaches 0 ℃, stirring for 6 hours at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting; adding 1500mL of 85% ethanol aqueous solution, heating, controlling the temperature to be 75 ℃, stirring for 3 hours, slowly cooling to 1 ℃ per minute, cooling to-20 ℃, keeping for 18 hours until crystallization is complete, filtering, collecting a filter cake, and drying in vacuum to obtain crystal form II,275.6 g, the yield of 91.9% and the purity of 99.42%.
Example 3
(1) Preparation of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole by converting crystal form II into crystal form I100 g (purity 98.11%) of crystal form II is added into 500mL of N-butyl ether, heated, controlled in temperature at 60 ℃, stirred for 6 hours, slowly cooled, cooled for 1-5 ℃ per minute until reaching 0 ℃, stirred for 12 hours at constant temperature until a large amount of powder is separated out, filtered, and the filter cake is dried in vacuum and collected; adding 400mL of chloroform, heating, controlling the temperature to be 75 ℃, stirring, reacting for 2 hours, slowly cooling, reducing the temperature by 1 ℃ per minute to-20 ℃, keeping for 10 hours until the crystallization is complete, filtering, collecting filter cakes, and drying in vacuum to obtain crystal form II,93.4 g, the yield of 93.4% and the purity of 99.93%;
(2) Preparation of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole from form I to form II
Taking 100 g of crystal form I (with the purity of 98.11%), adding the crystal form I into 600mL of isobutyl ether, heating, controlling the temperature at 60 ℃, stirring for 6 hours, slowly cooling, cooling 1-5 ℃ per minute until the temperature reaches 0 ℃, stirring for 12 hours at constant temperature until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting; adding 800mL of isopropanol% aqueous solution, heating, controlling the temperature to be 70 ℃, stirring, reacting for 4 hours, slowly cooling to 1 ℃ per minute, cooling to-20 ℃, keeping for 12 hours until crystallization is complete, filtering, collecting filter cakes, and drying in vacuum to obtain a crystal form II with 92.5 g, the yield of 92.5% and the purity of 99.97%.
The preparation method of the crystal form I in the example 3 comprises the following steps:
1) Preparation of a crude product: adding 133.2 g (1.0 moL) of 3-hydroxyindole into 600mL of tetrahydrofuran, stirring for dissolving, adding 237mL (3.0 moL) of pyridine, adding 114mL (1.0 moL) of trifluoroacetic acid, reducing the temperature of the system to 0 ℃, then slowly adding 287.9 g (1.1 moL) of N-p-toluenesulfonyl-L-alanyl chloride into 288mL of tetrahydrofuran, continuously controlling the temperature to be below 10 ℃, reacting for 1 hour, and after the reaction is completed, evaporating the solvent to obtain a reaction concentrate; adding 1500mL of ethyl acetate into the reaction concentrate, stirring to dissolve, and washing with 5% citric acid aqueous solution for 3 times, 500mL each time; washing with 10% sodium chloride water solution for 3 times, 500mL each time; washing 3 times with 5% sodium bicarbonate water solution, 500mL each time, separating liquid, reserving an ethyl acetate layer, adding 30 g of anhydrous sodium sulfate, drying for 5 hours, filtering, evaporating to remove the solvent, adding 2000mL of diethyl ether, stirring to dissolve, adding 30 g of activated carbon, decoloring for 30 minutes, repeatedly decoloring for 3-4 times until the solution is light clear, filtering, and concentrating to obtain 316.5 g of crude product, wherein the yield is 88.3%, and the purity is 97.23%;
2) Preparation of form I: and taking 316.5 g of the crude product in the previous step, adding 950mL of dichloromethane, heating to dissolve, cooling to room temperature, continuing to freeze overnight, crystallizing, filtering to obtain solid powder, recrystallizing in toluene for 1 time, filtering, collecting a filter cake, and drying in vacuum to obtain 289.6 g of white acicular crystals, which are the crystal form I.
The preparation method of the crystal form II in the example 3 comprises the following steps:
1) Preparation of a crude product: adding 133.2 g (1.0 moL) of 3-hydroxyindole into 500mL of tetrahydrofuran, stirring for dissolving, adding 79mL (1.0 moL) of pyridine, adding 171mL (1.5 moL) of trifluoroacetic acid, reducing the temperature of the system to 0 ℃, then slowly adding 261.7 g (1.0 moL) of N-p-toluenesulfonyl-L-alanyl chloride/261 mL of tetrahydrofuran, continuously controlling the temperature to be below 10 ℃, reacting for 3 hours, and after the reaction is completed, evaporating the solvent to obtain a reaction concentrate; adding 1500mL of ethyl acetate into the reaction concentrate, stirring to dissolve, and washing with 5% citric acid aqueous solution for 3 times, 500mL each time; washing with 10% sodium chloride water solution for 3 times, 500mL each time; washing 3 times with 5% sodium bicarbonate water solution, 500mL each time, separating liquid, reserving an ethyl acetate layer, adding 20 g of anhydrous sulfuric acid, drying for 5 hours, filtering, evaporating to remove the solvent, adding 2000mL of diethyl ether, stirring to dissolve, adding 20 g of activated carbon, decoloring for 30 minutes, repeatedly decoloring for 3-4 times until the solution is light clear, filtering, and concentrating to obtain 326.5 g of a crude product, wherein the yield is 91.1%, and the purity is 96.54%;
2) Preparation of form II: taking 326.5 g of the crude product in the last step, adding 1633mL of 90% ethanol aqueous solution, heating for dissolving, cooling to room temperature, continuously freezing overnight, crystallizing, and filtering to obtain solid powder; repeating the above process in toluene for 3-5 times, recrystallizing, filtering, collecting filter cake, vacuum drying to obtain 290.7 g of white flocculent powder, which is crystal form II.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, which comprises the following steps:
(1) Adding amorphous 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, a mixed crystal form of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole and a crystal form II of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole into an ether solvent, stirring and reacting for 1-6 h at the temperature of 40-80 ℃, cooling to 0 ℃ at the speed of 1-5 ℃/min, stirring at constant temperature for 1-24 h until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting to obtain an intermediate product;
(2) Adding the intermediate product into a haloalkane solvent, heating, controlling the temperature and stirring for 1-6 h at the temperature of 40-75 ℃, cooling to-20 ℃ at the speed of 1-5 ℃/min, stirring for 1-24 h at constant temperature, filtering, drying a filter cake in vacuum, and collecting to obtain a crystal form I with an X powder diffraction peak shown in the attached figure 1;
the crystalline form I has characteristic absorption peaks at the following positions using Cu-ka radiation, X-ray powder diffraction expressed in 2 Θ angles: 9.913 +/-0.2 degrees, 14.680 +/-0.2 degrees, 17.829 +/-0.2 degrees, 18.689 +/-0.2 degrees, 19.999 +/-0.2 degrees, 21.104 +/-0.2 degrees, 24.176 +/-0.2 degrees, 27.060 +/-0.2 degrees and 30.232 +/-0.2 degrees.
2. A method for the crystal transformation of 3- (N-tosyl-L-alanyloxy) indole, which is characterized by comprising the following steps:
(1) Adding amorphous 3- (N-p-toluenesulfonyl-L-alanyloxy) indole, a mixed crystal form of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole and a crystal form I of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole into an ether solvent, stirring and reacting for 1-6 h at the temperature of 40-80 ℃, cooling to 0 ℃ at the speed of 1-5 ℃/min, stirring at constant temperature for 1-24 h until a large amount of powder is separated out, filtering, drying a filter cake in vacuum, and collecting to obtain an intermediate product;
(2) Adding the intermediate product into an alcohol solution, heating, controlling the temperature and stirring for 1-6 h under the condition that the temperature is 50-80 ℃, cooling to-20 ℃ at the speed of 1-5 ℃/min, stirring for 1-24 h at constant temperature, filtering, drying a filter cake in vacuum, and collecting to obtain a crystal form II of the X powder diffraction peak shown in the attached figure 2;
the crystalline form II has characteristic absorption peaks at the following positions using Cu-ka radiation, X-ray powder diffraction expressed in 2 Θ angles: 9.214 +/-0.2 degrees, 11.261 +/-0.2 degrees, 17.605 +/-0.2 degrees, 18.567 +/-0.2 degrees, 20.142 +/-0.2 degrees, 22.557 +/-0.2 degrees, 25.811 +/-0.2 degrees and 26.261 +/-0.2 degrees.
3. The method for the transformation of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 1, wherein the amorphous 3- (N-p-toluenesulfonyl-L-alanyloxy) indole is prepared by the following steps:
(1-1) stirring and mixing 3-hydroxyindole and an aprotic solvent according to a mass volume ratio of 1; controlling the temperature to be 0 ℃, and adding an organic acid catalyst, wherein the molar ratio of the organic acid catalyst to the 3-hydroxyindole is (1); adding N-p-toluenesulfonyl-L-alanyl chloride, wherein the molar ratio of 3-hydroxyindole to N-p-toluenesulfonyl-L-alanyl chloride is 1-1;
(1-2) extracting treatment; adding an extraction solvent into a reaction concentrate, wherein the mass volume ratio of the reaction concentrate to the extraction solvent is 1-1; adding a drying agent for drying, filtering, collecting filtrate, and evaporating to remove the solvent to obtain an extraction concentrate;
(1-3) decoloring; adding a decolorizing solvent into an extraction concentrate, wherein the mass volume ratio of the extraction concentrate to the decolorizing solvent is 1-1, stirring for dissolving, adding activated carbon for heating, stirring and decolorizing, wherein the heating temperature is 20-50 ℃, the stirring time is 1-6 h, the adding amount of the activated carbon accounts for 5-30% of the mass of the extraction concentrate, filtering, collecting filtrate, and concentrating to obtain the amorphous 3- (N-p-toluenesulfonyl-L-alanyloxy) indole.
4. The process for the transformation of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 3, wherein the aprotic solvent used in step (1-1) is any one selected from the group consisting of acetone, acetonitrile, dioxane, and tetrahydrofuran;
the organic acid catalyst in the step (1-1) is any one of trifluoroacetic acid, citric acid or oxalic acid;
the organic base in the step (1-1) is at least one of pyridine and diisopropylethylamine;
the extraction solvent in the step (1-2) is any one of ethyl acetate, butyl acetate, dichloromethane and chloroform;
the weak acid in the step (1-2) is any one of acetic acid, citric acid, carbonic acid, tartaric acid, boric acid and ethylenediamine tetraacetic acid;
the weak base in the step (1-2) is any one of sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium borate;
the drying agent in the step (1-2) is any one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or a molecular sieve;
the decolorizing solvent in the step (1-3) is any one of diethyl ether, petroleum ether, n-propyl ether, isopropyl ether, n-butyl ether, isobutyl ether or ethylene glycol dimethyl ether.
5. The method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 1, wherein the ether solvent is any one of petroleum ether, N-propyl ether, isopropyl ether, N-butyl ether and isobutyl ether.
6. The method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 1, wherein the alkyl halide solvent is a chlorinated alkyl chloride solvent, and the chlorinated alkyl chloride solvent is any one of dichloromethane, chloroform, or carbon tetrachloride.
7. The method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 2, wherein the alcohol solution is any one of methanol, ethanol, propanol and isopropanol.
8. The method for transforming 3- (N-p-toluenesulfonyl-L-alanyloxy) indole according to claim 1, wherein the mixed crystal form of 3- (N-p-toluenesulfonyl-L-alanyloxy) indole is formed by mixing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole crystal form I and 3- (N-p-toluenesulfonyl-L-alanyloxy) indole crystal form II.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211698376.5A CN115872919A (en) | 2022-12-28 | 2022-12-28 | Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole |
| ZA2023/02944A ZA202302944B (en) | 2022-12-28 | 2023-02-28 | Crystal transformation method for 3-(n-tosyl-l-alanyloxy)-indole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211698376.5A CN115872919A (en) | 2022-12-28 | 2022-12-28 | Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115872919A true CN115872919A (en) | 2023-03-31 |
Family
ID=85755727
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211698376.5A Pending CN115872919A (en) | 2022-12-28 | 2022-12-28 | Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115872919A (en) |
| ZA (1) | ZA202302944B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1157984A2 (en) * | 2000-05-15 | 2001-11-28 | Bayer Corporation | Trypsin substrate and diagnostic device, and method of using same |
| JP2017184734A (en) * | 2016-03-30 | 2017-10-12 | 栄研化学株式会社 | Test strip for detecting esterase and/or protease |
| CN108956827A (en) * | 2018-06-04 | 2018-12-07 | 长春百纯和成医药科技有限公司 | A kind of method HPLC method analysis and prepare 3- (N- p-toluenesulfonyl-L- alanyl oxygroup) indoles and its enantiomter |
| CN109490519A (en) * | 2018-10-16 | 2019-03-19 | 迪瑞医疗科技股份有限公司 | A kind of leukocyte esterase Test paper and preparation method thereof |
| WO2021129589A1 (en) * | 2019-12-27 | 2021-07-01 | 广东东阳光药业有限公司 | New crystal form of kd-025 and preparation method therefor |
| EP3848708A1 (en) * | 2020-01-13 | 2021-07-14 | Roche Diagnostics GmbH | Reagent formulation for leukocyte test strip |
-
2022
- 2022-12-28 CN CN202211698376.5A patent/CN115872919A/en active Pending
-
2023
- 2023-02-28 ZA ZA2023/02944A patent/ZA202302944B/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1157984A2 (en) * | 2000-05-15 | 2001-11-28 | Bayer Corporation | Trypsin substrate and diagnostic device, and method of using same |
| JP2017184734A (en) * | 2016-03-30 | 2017-10-12 | 栄研化学株式会社 | Test strip for detecting esterase and/or protease |
| CN108956827A (en) * | 2018-06-04 | 2018-12-07 | 长春百纯和成医药科技有限公司 | A kind of method HPLC method analysis and prepare 3- (N- p-toluenesulfonyl-L- alanyl oxygroup) indoles and its enantiomter |
| CN109490519A (en) * | 2018-10-16 | 2019-03-19 | 迪瑞医疗科技股份有限公司 | A kind of leukocyte esterase Test paper and preparation method thereof |
| WO2021129589A1 (en) * | 2019-12-27 | 2021-07-01 | 广东东阳光药业有限公司 | New crystal form of kd-025 and preparation method therefor |
| EP3848708A1 (en) * | 2020-01-13 | 2021-07-14 | Roche Diagnostics GmbH | Reagent formulation for leukocyte test strip |
Non-Patent Citations (1)
| Title |
|---|
| 刘嘉;郑明;: "药物多晶型的研究进展", 西北药学杂志, vol. 32, no. 03, 10 May 2017 (2017-05-10), pages 394 - 396 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA202302944B (en) | 2023-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN116354939A (en) | Crystalline forms of a compound | |
| CN108026091B (en) | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and application thereof | |
| CN105646633B (en) | Method for preparing obeticholic acid type 1 | |
| CN102924434A (en) | Dexrabeprazole sodium monohydrate crystal form and preparation method thereof | |
| CN102924474B (en) | Preparation method of crystal form I of clopidogrel hydrogen sulfate | |
| CN116829549A (en) | 6- (cyclopropanecarboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) ３ ) Crystalline forms of pyridazine-3-carboxamide | |
| CN115872919A (en) | Method for crystallizing 3- (N-p-toluenesulfonyl-L-alanyloxy) indole | |
| CN112028896A (en) | Novel crystal form of acatinib and preparation method thereof | |
| WO2018176513A1 (en) | Crystal form of deuterated palbociclib and preparation method and use thereof | |
| CN115304608B (en) | Pyrazolopyrimidine ester compound crystal form and preparation method thereof | |
| CN115850286A (en) | Weibeigelong intermediate and preparation method thereof | |
| CN116410176A (en) | Violet Luo Zhongjian body and preparation method and application thereof | |
| CA3058886A1 (en) | Method for manufacturing diastereomer of citric acid derivative | |
| CN114008023B (en) | Crystal form of Sofos-piramide and preparation method thereof | |
| CN103172687A (en) | Nelarabine crystalline compound and preparation method thereof | |
| CN108558690B (en) | Crystal form of cycloserine esterified substance hydrochloride and preparation method thereof | |
| CN108570045B (en) | Crystal form of anisodamine hydrobromide, preparation method and pharmaceutical composition thereof | |
| CN116023320A (en) | 3- (N-p-toluenesulfonyl-L-alanyloxy) indole with polymorphic structure, and preparation method and application thereof | |
| CN106543074B (en) | One-dimensional chirality Cu (II) chain complex of one kind and the preparation method and application thereof | |
| CN113004281A (en) | Preparation method of entecavir intermediate | |
| CN111171001B (en) | Crystallization method of PARP inhibitor intermediate | |
| CN114075109B (en) | Preparation method of flurbiprofen axetil and prepared crystal form | |
| CN112409350B (en) | Preparation method of maleic acid atorvastatin crystal form C | |
| CN114920705B (en) | Preparation method and application of glipizide ester impurities | |
| CN113683607B (en) | Terilitine intermediate crystal form II and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |