CN117105953A - A crystal form of AM-2822 and preparation method thereof - Google Patents
A crystal form of AM-2822 and preparation method thereof Download PDFInfo
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- CN117105953A CN117105953A CN202210528049.9A CN202210528049A CN117105953A CN 117105953 A CN117105953 A CN 117105953A CN 202210528049 A CN202210528049 A CN 202210528049A CN 117105953 A CN117105953 A CN 117105953A
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- 239000013078 crystal Substances 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 13
- 230000005855 radiation Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000012043 crude product Substances 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000002386 leaching Methods 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 5
- 238000000855 fermentation Methods 0.000 claims description 5
- 230000004151 fermentation Effects 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 230000001747 exhibiting effect Effects 0.000 claims description 4
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000013076 target substance Substances 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 241001052560 Thallis Species 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000204098 Saccharothrix Species 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
- 101710175516 14 kDa zinc-binding protein Proteins 0.000 description 1
- 241000187362 Actinomadura Species 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000235342 Saccharomycetes Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000187762 Streptomyces actuosus Species 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an A crystal form of AM-2822 and a preparation method thereof, wherein the A crystal form has an X-ray powder diffraction pattern which is obtained by utilizing CuK alpha radiation and shows peaks at 6.9021 +/-0.2 DEG, 8.3723 +/-0.2 DEG, 10.7519 +/-0.2 DEG, 12.6875 +/-0.2 DEG, 14.3895 +/-0.2 DEG, 16.7386 +/-0.2 DEG, 18.3335 +/-0.2 DEG, 19.3081 +/-0.2 DEG, 20.9472 +/-0.2 DEG and 25.4186 +/-0.2 DEG of a 2 theta angle position. The crystal form provided by the invention has the advantages of good stability, small hygroscopicity, simple preparation method and low cost, meets the requirements of medicine, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of industrial microorganisms, and relates to a crystal form of AM-2822 and a preparation method thereof.
Background
AM-2822 (hereinafter STS, structure shown in formula I) was isolated from Saccharothrix staurosporeus AM-2282 fermentation products by Japanese scholars S.QMURA et al in 1977, and was subsequently described in Streptomyces Streptomyces hygroscopicus, streptomyces actuosus of the family Actinomyces; saccharothrix genus; STS was also obtained from fermentation products of bacteria belonging to the genus Actinomadura and Nocarda. The chemical structural formula of STS is shown below:
in 1986 STS was found to be a very potent inhibitor of protein kinases (ic50=1 to 20nmol/L, IC50 value refers to the concentration of inhibitor at which 50% inhibition is achieved). STS is a broad spectrum, non-specific protein kinase C inhibitor that potently inhibits protein kinase C and most other kinases including tyrosine protein kinases. The compound can directly inhibit the activity of topoisomerase II by blocking the transfer of phosphodiester bonds from DNA to activated tyrosine sites, can be used for resisting a plurality of infectious diseases caused by yeasts and fungi, inhibiting cell proliferation, inducing apoptosis, abrogating cell cycle checkpoints, inhibiting vascular proliferation and the like, has extremely strong anti-tumor activity, and has an average IC50 of 0.016 mug/ml for 12 human tumor cells clinically. The antibacterial spectrum of the antibacterial agent is various mould, saccharomycetes and the like, and has no obvious effect on bacteria.
Different crystal forms of the same drug often cause the difference of stability and solubility of the drug, and can cause the difference of dissolution and bioavailability of the drug, thereby affecting the absorption and utilization of the drug in vivo and further causing the difference of the curative effect of the drug. In addition, the subsequent process can be determined by the characteristics of the crystal forms of the medicines, so that the equivalence of the medicines among the batches of the production is effectively ensured. Thus, screening of the crystalline form is critical for subsequent drug development.
At present, no report exists on the AM-2822 crystal form, so that the comprehensive system of polymorphic screening is necessary to select a crystal form suitable for development.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects in the prior art and providing the A crystal form of AM-2822 and the preparation method thereof, and the A crystal form provided by the invention has the advantages of good stability, small hygroscopicity, simple preparation method and low cost, meets the requirements of medicines, and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
a crystalline form of AM-2822 having an X-ray powder diffraction pattern obtained using cukα radiation and exhibiting peaks at 2θ angular positions 6.9021 ±0.2°,8.3723 ±0.2°,10.7519 ±0.2°,12.6875 ±0.2°,14.3895 ±0.2°,16.7386 ±0.2°,18.3335 ±0.2°,19.3081 ±0.2°,20.9472 ±0.2° and 25.4186 ±0.2°, the AM-2822 having the structural formula shown in formula I:
in the present invention, the measurement of the 2θ angle value uses the cukα light source with a precision of ±0.2°, and therefore, the above-mentioned taken 2θ angle value is allowed to have a reasonable error range of ±0.2 °.
Preferably, the crystalline form also has an X-ray powder diffraction pattern exhibiting peaks at 2θ angular positions 6.3835 ±0.2°,13.1064 ±0.2°,16.1879 ±0.2°,19.8428 ±0.2° and 26.2645 ±0.2°.
Preferably, the crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
Preferably, the crystalline form has a crystalline form at 1674.21cm -1 ，1396.46cm -1 ，1280.73cm -1 And 746.54cm -1 The infrared spectrum of the characteristic absorption peak is shown.
Preferably, the crystalline form has an infrared spectrum as shown in fig. 2.
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for the preparation of form a of AM-2822 as described above comprising the steps of:
(1) Leaching AM-2822 producing thalli with an organic solvent under alkaline conditions, and concentrating to obtain a concentrated solution;
(2) Filtering the concentrated solution under an acidic condition to obtain filtrate;
(3) Extracting the filtrate with an organic solvent under alkaline conditions to obtain an extract;
(4) Concentrating the extract, and performing silica gel column chromatography to obtain the target product.
Preferably, the organic solvent in step (1) is methanol.
Preferably, the alkaline condition in the step (1) is that the pH is 10-13.
Preferably, the alkaline conditions are adjusted to a pH of 10-13, more preferably to a pH of 12, using ammonia in step (1).
Preferably, the acidic condition in step (2) is a pH of 2 to 4.
Preferably, the acidic condition pH is adjusted to 2-4 in step (2) with dilute hydrochloric acid, more preferably pH 3.
Preferably, the alkaline condition in step (3) is a pH of 10 to 13, more preferably a pH of 12.
Preferably, the organic solvent in the step (3) is ethyl acetate.
Preferably, the silica gel column chromatography in the step (4) uses chloroform-methanol mixed solution with the volume ratio of 100:1-100:20.
Preferably, the AM-2822 producing strain in step (1) is obtained by filtering a fermentation broth of the AM-2822 producing strain.
Preferably, the preparation method further comprises concentrating the target substance to obtain a crude product, recrystallizing the crude product to obtain wet crystals, and drying the wet crystals to obtain AM-2822 crystals.
Preferably, the recrystallization of the crude product comprises: dissolving the crude product with polar solvent at 5-70deg.C, more preferably at 45-65deg.C, crystallizing at-20-40deg.C, more preferably at 2-8deg.C for 2-16 hr, more preferably at 2-8 hr, cooling to crystallize or concentrating to 20-100g/L, and naturally cooling to crystallize.
Further preferably, the polar solvent is one or more selected from methanol, ethanol, acetone, acetonitrile, isopropanol, ethyl acetate and butyl acetate.
Preferably, the polar solvent is used in an amount of 20 to 500ml of polar solvent per gram of crude product, more preferably, the polar solvent is used in an amount of 100 to 200ml of polar solvent per gram of crude product.
Preferably, the drying is vacuum drying and/or air drying, the temperature is controlled at 30-70 ℃, and the drying time is 2-16h.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the prior art does not disclose an AM-2822 crystal form, and the invention creatively finds an advantageous crystal form;
2. the crystal form provided by the invention has good stability, the purity of the crystal with the purity of 99.42% is detected to be 99.39% after the crystal is dried for 18 hours at 80 ℃, no obvious degradation occurs, and the comparison of HPLC (high performance liquid chromatography) patterns before and after high temperature drying is shown in figures 4 and 5;
3. the crystal form provided by the invention has lower hygroscopicity, meets the medicinal requirement, can well avoid crystal transformation in the process of medicine storage and development, has low requirement on storage conditions, is convenient for long-term storage, greatly reduces the cost in material storage and quality control, has strong economic value, and is suitable for industrial production;
4. the A crystal form of the compound shown in the formula I has advantages in aspects of physical properties, preparation processing performance, bioavailability and the like, such as at least one of melting point, solubility, hygroscopicity, purification effect, stability, adhesiveness, compressibility, flowability, in-vivo and in-vitro dissolution, bioavailability and the like.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern for form AM-2822A of the invention;
FIG. 2 is an Infrared (IR) spectrum of the AM-2822A crystal form of the invention;
FIG. 3 is an HPLC chart of AM-2822A crystal form obtained in example 2;
FIG. 4 is an HPLC chart of AM-2822 wet crystal obtained in example 5;
FIG. 5 is an HPLC chart after 18h of drying at example 6AM-2822 80 ℃.
Detailed Description
In order to make the technical scheme and the beneficial effects of the invention more obvious and understandable, the following detailed description is given by way of example only with reference to the accompanying drawings. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which specific conditions are not noted in the examples below, generally follows conventional experimental conditions. The reagents and materials used in the present invention are commercially available unless otherwise specified.
Example 1
Preparation of AM-2822 crude product
Filtering 1L of fermentation liquor of AM-2822 producing bacteria to obtain 0.25kg of mycelium residues (AM-2822 producing bacteria), adding 1L of methanol, regulating the pH value to 12.0 by ammonia water, stirring and leaching at normal temperature for 2 hours, then filtering with 300-mesh filter cloth in vacuum, and leaching the bacteria again by 0.8L of methanol to obtain secondary leaching liquor. Combining the two leaching solutions, and vacuum concentrating at 60deg.C under reduced pressure to remove methanol in the filtrate to obtain concentrated solution.
The concentrated solution is regulated to pH 3 by dilute hydrochloric acid, the filtrate is obtained by filtering after stirring, the sediment obtained by filtering is added with the dilute hydrochloric acid with pH 3 again, and the operation is repeated. All filtrates were combined, pH was adjusted to 12.0 with ammonia water, then extracted twice with 300ml of ethyl acetate, respectively, all the extracts were combined, dehydrated by adding 30g of anhydrous sodium sulfate, and concentrated under vacuum at 60℃under reduced pressure to remove ethyl acetate to give a pale yellow oil.
Dissolving the light yellow oily substance with ethyl acetate, performing silica gel column chromatography, eluting with chloroform-methanol mixed solution with volume ratio of 100:2 as eluent, separating and collecting in bottle, mixing the collected eluates containing target substance, and vacuum concentrating to obtain light yellow powdery AM-2822 crude product 1.23g.
Example 2
Taking 3g of crude product, adding 900ml of methanol, heating, stirring and dissolving at 60 ℃, filtering by using a 0.45um organic filter membrane, concentrating the filtrate to 150ml under vacuum and reduced pressure at 60 ℃, slowly cooling to 5 ℃, stirring and crystallizing for 5 hours, filtering by suction and leaching by using a small amount of methanol to obtain white wet crystals, and finally heating and drying the wet crystals under vacuum degree of-0.9 MPa at 60 ℃ for 6 hours to obtain high-purity AM-2822 crystals. The HPLC pattern is shown in FIG. 3, the XRPD pattern is the same as in FIG. 1, and the IR pattern is the same as in FIG. 2.
Example 3
4.6g of crude product are taken and 300ml of methanol are added: the mixed solvent of ethyl acetate=1:1 (volume ratio) is heated and stirred at 65 ℃ for dissolution, 0.45um organic filter membrane is filtered, the filtrate is concentrated to 50ml under vacuum and reduced pressure at 60 ℃, the temperature is slowly reduced to 8 ℃, stirring and crystallization are carried out for 4 hours, suction filtration is carried out, a small amount of methanol is used for leaching, white wet crystals are obtained, and finally the wet crystals are dried in a hot air circulation oven at 60 ℃ for 5 hours, thus obtaining AM-2822 crystals with high purity. The product is A crystal form through X-ray powder diffraction detection.
Example 4
Adding 6.5g of crude product into 500ml of ethyl acetate, heating, stirring and dissolving at 65 ℃, filtering with a 0.45um organic filter membrane, slowly cooling the filtrate to 5 ℃, stirring and crystallizing for 2 hours, filtering with suction and leaching with a small amount of ethyl acetate to obtain white wet crystals, and finally drying the wet crystals in a hot air circulation oven at 60 ℃ for 3 hours to obtain high-purity AM-2822 crystals. The product is A crystal form through X-ray powder diffraction detection.
Example 5
Adding 400ml of ethyl acetate into 2.8g of crude product, heating, stirring and dissolving at 65 ℃, filtering with 0.45um organic filter membrane, concentrating the filtrate to 100ml under vacuum and reduced pressure at 60 ℃, stirring and crystallizing at 20 ℃ for 2h, filtering and leaching with a small amount of methanol to obtain white wet crystals, and finally heating and drying the wet crystals under vacuum at-0.9 MPa and 50 ℃ for 5h to obtain high-purity AM-2822 crystals. The product is A crystal form through X-ray powder diffraction detection.
Example 6
The crystals of AM-2822 of example 5 were dried in vacuo at 80℃for 18h. Through detection and comparison of HPLC patterns, the purity of the AM-2822 crystal is compared with that before high temperature drying, the purity of the crystal with the purity of 99.42 percent is detected to be 99.39 percent after the crystal is dried for 18 hours at the temperature of 80 ℃, no obvious degradation occurs, and the comparison of the HPLC patterns before and after high temperature drying is shown in figures 4 and 5.
It should be understood that the above examples are illustrative and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may be made in the above embodiments without departing from the scope of the disclosure. Likewise, the individual features of the above embodiments can also be combined arbitrarily to form further embodiments of the invention which may not be explicitly described. Therefore, the above examples merely represent several embodiments of the present invention and do not limit the scope of protection of the patent of the present invention.
Claims (10)
1. Form a of AM-2822 having an X-ray powder diffraction pattern obtained using cukα radiation and exhibiting peaks at 2Θ angular positions 6.9021 ±0.2 °,8.3723 ±0.2°,10.7519 ±0.2°,12.6875 ±0.2°,14.3895 ±0.2°,16.7386 ±0.2°,18.3335 ±0.2°,19.3081 ±0.2°,20.9472 ±0.2° and 25.4186 ±0.2°, said AM-2822 having the structural formula shown below:
2. form a of AM-2822 according to claim 1, further having an X-ray powder diffraction pattern exhibiting peaks at 2Θ angular positions 6.3835 ± 0.2 °,13.1064 ± 0.2 °,16.1879 ± 0.2 °,19.8428 ± 0.2 ° and 26.2645 ± 0.2 °, having an X-ray powder diffraction pattern as shown in fig. 1.
3. Form a of AM-2822 as claimed in claim 1, having a crystal form a of at 1674.21cm -1 ，1396.46cm -1 ，1280.73cm -1 And 746.54cm -1 An infrared spectrum showing characteristic absorption peaks, having an infrared spectrum as shown in fig. 2.
4. A process for the preparation of form a of AM-2822 as claimed in any one of claims 1 to 3, wherein: the method comprises the following steps:
(1) Leaching AM-2822 producing thalli with an organic solvent under alkaline conditions, and concentrating to obtain a concentrated solution;
(2) Filtering the concentrated solution under an acidic condition to obtain filtrate;
(3) Extracting the filtrate with an organic solvent under alkaline conditions to obtain an extract;
(4) Concentrating the extract, and performing silica gel column chromatography to obtain the target product.
5. The method for preparing the A crystal form of AM-2822 according to claim 4, wherein: the organic solvent in the step (1) is methanol;
preferably, the alkaline condition in the step (1) is that the pH is 10-13;
preferably, the alkaline condition in the step (1) is adjusted by ammonia water;
preferably, the acidic condition in step (2) is a pH of 2 to 4;
preferably, the acidic condition in step (2) is adjusted with dilute hydrochloric acid;
preferably, the alkaline condition in the step (3) is that the pH is 10-13;
preferably, the organic solvent in the step (3) is ethyl acetate.
6. The method for preparing the A crystal form of AM-2822 according to claim 4, wherein: the silica gel column chromatography in the step (4) uses chloroform-methanol mixed solution with the volume ratio of 100:1-100:20.
7. The method for preparing the A crystal form of AM-2822 according to claim 4, wherein: the AM-2822 producing strain in the step (1) is obtained by filtering fermentation liquor of the AM-2822 producing strain.
8. The method for preparing the A crystal form of AM-2822 according to claim 4, wherein: the method also comprises the steps of concentrating the target substance separated by silica gel column chromatography to obtain a crude product, recrystallizing the crude product to obtain wet crystals, and drying the wet crystals to obtain AM-2822 crystals.
9. The process for the preparation of form a of AM-2822 as claimed in claim 8, wherein: the recrystallization of the crude product specifically comprises: stirring and dissolving the crude product with polar solvent at 5-70deg.C, cooling to crystallize or concentrating to 20-100g/L, and naturally cooling to crystallize, wherein the temperature during crystallization is controlled at-20-40deg.C, and the crystallization time is 2-16 hr.
10. The process for the preparation of form a of AM-2822 as claimed in claim 9, wherein: the polar solvent is one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, ethyl acetate and butyl acetate;
preferably, the polar solvent is used in an amount of 20-500ml of polar solvent per gram of crude product.
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| CN202210528049.9A Pending CN117105953A (en) | 2022-05-16 | 2022-05-16 | A crystal form of AM-2822 and preparation method thereof |
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| CN (1) | CN117105953A (en) |
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