CN106749075A - Crystal formation of oxazolidone intermediate of Ah Nagqu ripple and preparation method thereof - Google Patents
Crystal formation of oxazolidone intermediate of Ah Nagqu ripple and preparation method thereof Download PDFInfo
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- CN106749075A CN106749075A CN201611049962.1A CN201611049962A CN106749075A CN 106749075 A CN106749075 A CN 106749075A CN 201611049962 A CN201611049962 A CN 201611049962A CN 106749075 A CN106749075 A CN 106749075A
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 239000013078 crystal Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000012065 filter cake Substances 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 3
- 239000000945 filler Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- 238000010792 warming Methods 0.000 abstract description 4
- 239000000377 silicon dioxide Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012452 mother liquor Substances 0.000 description 9
- OHIDCVTXTYVGRO-CDUCUWFYSA-N (4s,5r)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one Chemical group C[C@@H]1NC(=O)O[C@@H]1C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OHIDCVTXTYVGRO-CDUCUWFYSA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 2
- 229950004514 torcetrapib Drugs 0.000 description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- MZZLGJHLQGUVPN-HAWMADMCSA-N anacetrapib Chemical compound COC1=CC(F)=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1CN1C(=O)O[C@H](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)[C@@H]1C MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 description 1
- 229950000285 anacetrapib Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to Ah Nagqu ripple, and in particular to crystal formation of oxazolidone intermediate of a kind of Ah Nagqu ripple and preparation method thereof.The θ of angle of reflection 2 of the X-ray powder diffraction figure of the crystal formation of the oxazolidone intermediate of described Ah Nagqu ripple has characteristic peak at 4.36 °, 8.48 °, 11.28 °, 14.87 °, 15.65 °, 17.02 °, 18.78 °, 20.19 °, 22.70 °.Its preparation method is that the oxazolidone crude intermediate solvent of just Ah Nagqu ripple dissolves, then silica filler is used, the oxazolidone midbody solution of Ah Nagqu ripple is separated by TLC with solvent, normal heptane is added after concentration, it is warming up to backflow, until all dissolving, filtering is cooled to room temperature, continue stirring and crystallizing, filtered again, filter cake obtains the crystal formation of the oxazolidone intermediate of Ah Nagqu ripple through drying to constant weight.Preparation method of the present invention is simple and easy to apply, it is easy to accomplish.
Description
Technical Field
The invention relates to anatrove, in particular to a crystal form of an oxazolidinone intermediate of anatrove and a preparation method thereof.
Background
Anastrove is an orally active small molecule oxazolidinone selective CETP inhibitor developed by Merck, USA, and is used for treating atherosclerosis, coronary heart disease, etc. In view of the fact that this product has the same mechanism of action as Torcetrapib, researchers are concerned that Torcetrapib-like adverse reactions also occur in Anacetrapib. In order to explore the correlation between the action target point of the CETP inhibitor and adverse reactions, a series of researches are carried out by experimenters. The results indicate that adverse reactions of Torcetrapib are not associated with CETP inhibitors. Clinical studies with healthy volunteers and patients with hyperlipidemia show that anaqu can safely and effectively regulate the lipid levels of coronary heart disease and patients at high risk of coronary heart disease, and is tolerant to patients with adverse reactions. The chemical name of the oxazolidinone intermediate of anatrobove is (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
US20143033380, WO2006014357a1, TW201436862A, US2006014413a1, WO2007136672, and the like report methods for preparing oxazolidinone intermediates for the synthesis of anatrove, which are mainly prepared by reduction followed by cyclization of ketone a as an intermediate.
So far, no report on the crystal form of the oxazolidinone intermediate of anatrobove is found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a crystal form of an oxazolidinone intermediate of anatrobove, and simultaneously provides a simple and easy preparation method of the crystal form.
The crystal form of the oxazolidinone intermediate of anatrobove has a structural formula as follows:
the reflection angle 2 theta of an X-ray powder diffraction pattern of the crystal form has characteristic peaks at 4.36 degrees (100), 8.48 degrees (18.46), 11.28 degrees (23.65), 14.87 degrees (12.91), 15.65 degrees (13.02), 17.02 degrees (11.73), 18.78 degrees (23.35), 20.19 degrees (10.23) and 22.70 degrees (18.16).
The reflection angle 2 theta of the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 4.00 DEG (4.01), 7.44 DEG (4.27), 11.15 DEG (8.05), 13.09 DEG (2.35), 15.26 DEG (3.26), 15.39 DEG (2.98), 17.48 DEG (4.65), 21.56 DEG (2.61), 21.89 DEG (5.85), 22.42 DEG (4.09), 22.95 DEG (4.66), 23.42 DEG (3.40), 23.73 DEG (2.58), 23.82 DEG (4.09), 26.17 DEG (2.46) and 27.18 DEG (2.15).
In the two groups of crystal form data, the second group of characteristic peaks are complementary to the first group of characteristic peaks, and the parenthesized data are the relative intensities of spectral lines.
The preparation method of the crystal form of the oxazolidinone intermediate of the anatramadol comprises the steps of dissolving a crude product of the oxazolidinone intermediate of the anatramadol by using a solvent, then using silica gel filler, using a developing agent to separate an oxazolidinone intermediate solution of the anatramadol by TLC, adding n-heptane after concentration, heating to reflux until all the solution is dissolved, filtering, cooling to room temperature in an ice bath, continuing stirring for crystallization, filtering again, and drying a filter cake to constant weight to obtain the crystal form of the oxazolidinone intermediate of the anatramadol.
Wherein,
the solvent is ethyl acetate.
The developing agent is a mixed solvent of two of n-hexane, n-heptane, 60-90 petroleum ether, ethyl acetate or dichloromethane.
The silica gel is 50-400 meshes, and preferably 100-200 meshes.
The cooling mode is ice bath cooling.
The preparation method of the crude oxazolidinone intermediate of anatrobo is as follows:
mixing A, aluminum isopropoxide, isopropanol and toluene under the protection of nitrogen, heating to 50 ℃, stirring and reacting for 17 hours at 50 ℃, cooling to 25-30 ℃, adding potassium hydroxide, carrying out heat preservation reaction, detecting an end point by TLC, after the reaction is finished, dropwise adding hydrochloric acid, adjusting the pH to 3-4, stirring and crystallizing, filtering, and washing a filter cake to obtain a crude product of the oxazolidinone intermediate of anaqubo; wherein, the structural formula of A is as follows:
the equation for the crude oxazolidinone intermediate preparation of anatrobo is:
in conclusion, the beneficial effects of the invention are as follows:
the invention is a new crystal form of an oxazolidinone intermediate of anatrobove; the preparation method is simple and easy to implement and is easy to realize.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of an oxazolidinone intermediate crystalline form of anaatroban of example 1;
FIG. 2 is a differential scanning calorimetry chart of crystalline forms of oxazolidinone intermediates to anatramadol in example 1;
FIG. 3 is a thermogravimetric analysis of the crystalline form of the oxazolidinone intermediate of anaatroban in example 1.
Detailed Description
The present invention will be further described with reference to the following examples.
The structural formula of a referred to in the examples is:
example 1
A250 mL four-necked flask was charged with 5.73g of A, followed by 32mL of isopropanol and 48mL of toluene, and the nitrogen gas was replaced at room temperature for 0.5 h. Then 0.84g of aluminum isopropoxide was added while warming the mother liquor to 50 ℃, and then the reaction was stirred at 50 ℃ overnight. Cooling to 25 ℃ in a water bath, then adding 1.4g of potassium hydroxide into the mother liquor in batches, continuing the heat preservation reaction at 25 ℃, and detecting the end point by TLC. Then, 3mL of concentrated hydrochloric acid was added dropwise to the mother liquor, 30mL of water was added thereto, and the mixture was stirred at room temperature for crystallization for 1 hour. Filtration, washing of the filter cake with 100mL of purified water, and vacuum drying at 60 ℃ and 0.08MPa for 2h gave 4.2g of crude (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
The crude product obtained above was dissolved in 10mL of ethyl acetate. 50g of 50-100 mesh silica gel, 1000mL of 1:1 n-hexane and dichloromethane are weighed as developing agents. TLC extracted the target product solution and concentrated to give 3.65g of crude product. The crude product is then dissolved by heating to 80 ℃ with 50mL of n-heptane and, if not completely dissolved, additional n-heptane is added until all is dissolved. Hot filtering, and crystallizing the filter cake at 0 ℃ for 2 h. And (3) carrying out suction filtration, and carrying out vacuum drying on a filter cake at 60 ℃ and under 0.08MPa for 2h to constant weight to obtain 3.14g of (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
The crystal form is chemically pure, and through HPLC analysis, the normalized purity is more than or equal to 99.9 percent, the optical rotation is-103.3, the ee value is 99.54 percent, and the crystal form is white flaky crystal. In example 1, the X-ray powder diffraction Pattern (PXRD) of the crystalline form of (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one is shown in FIG. 1, the Differential Scanning Calorimetry (DSC) is shown in FIG. 2, and the thermogravimetric analysis (TGA) is shown in FIG. 3.
Example 2
A500 mL four-necked flask was charged with 16.81g of A, followed by 90mL of isopropanol and 110mL of toluene, and then purged with nitrogen at room temperature for 0.5 h. Then 2.45g of aluminum isopropoxide was added while warming the mother liquor to 50 ℃, and then the reaction was stirred at 50 ℃ overnight. Cooling to 30 ℃ in a water bath, then adding 4.17g of potassium hydroxide into the mother liquor in batches, continuing the heat preservation reaction at 30 ℃, and detecting the end point by TLC. Then 10mL of concentrated hydrochloric acid was added dropwise to the mother liquor, followed by addition of 90mL of water, and crystallization was carried out at room temperature for 1 hour with stirring. Filtration, washing of the filter cake with 100mL of purified water, and vacuum drying at 60 ℃ and 0.08MPa for 2h gave 15.54g of crude (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
The crude product obtained above was dissolved in 30mL of ethyl acetate. 200g of 100-200 mesh silica gel, 3000mL of 1:1 n-heptane and ethyl acetate are weighed as developing agents. TLC extracted the desired product solution and concentrated to yield 12.74g of crude product. The crude product was then dissolved by adding 150mL of n-heptane to 80 deg.C and, if not completely dissolved, additional n-heptane was added until all dissolved. Hot filtering, and crystallizing the filter cake at 0 ℃ for 2 h. And (3) carrying out suction filtration, and carrying out vacuum drying on a filter cake at 60 ℃ and under 0.08MPa for 2h to constant weight to obtain 10.53g of (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
Example 3
A500 mL four-necked flask was charged with 15.35g of A, followed by 80mL of isopropanol and 100mL of toluene, and the mixture was purged with nitrogen at room temperature for 0.5 h. Then 2.22g of aluminum isopropoxide was added while warming the mother liquor to 50 ℃ and then the reaction was stirred at 50 ℃ overnight. Cooling to 28 ℃ in a water bath, then adding 3.96g of potassium hydroxide into the mother liquor in batches, continuing the heat preservation reaction at 28 ℃, and detecting the end point by TLC. Then 9mL of concentrated hydrochloric acid was added dropwise to the mother liquor, and 80mL of water was added thereto, followed by crystallization under stirring at room temperature for 1 hour. Filtration, 100mL of purified water washing the filter cake, at 60 degrees C, 0.08MPa vacuum drying for 2h, 12.89g (4S,5R) -5- (3, 5-two (three methyl fluoride) phenyl) -4-methyl-1, 3-oxazolidin-2-ketone crude product.
The crude product obtained above was dissolved in 25mL of ethyl acetate. Weighing 180g of 300-400 mesh silica gel, 2500mL of 1:1 60-90 petroleum ether and ethyl acetate as developing agents. TLC extracted the desired product solution and concentrated to give 11.45g of crude product. The crude product was then dissolved by adding 100mL of n-heptane to 80 deg.C and, if not completely dissolved, additional n-heptane was added until all dissolved. Hot filtering, and crystallizing the filter cake at 0 ℃ for 2 h. Vacuum-filtering, and vacuum-drying the filter cake at 60 deg.C and 0.08MPa for 2h to constant weight to obtain 9.88g of (4S,5R) -5- (3, 5-bis (trifluoromethyl) phenyl) -4-methyl-1, 3-oxazolidin-2-one.
Claims (8)
1. A crystalline form of an oxazolidinone intermediate of anatrobove, characterized by: the reflection angle 2 theta of an X-ray powder diffraction pattern of the crystal form has characteristic peaks at 4.36 degrees, 8.48 degrees, 11.28 degrees, 14.87 degrees, 15.65 degrees, 17.02 degrees, 18.78 degrees, 20.19 degrees and 22.70 degrees.
2. A crystalline form of an oxazolidinone intermediate of anatrobove according to claim 1, wherein: the reflection angle 2 theta of the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 4.00 degrees, 7.44 degrees, 11.15 degrees, 13.09 degrees, 15.26 degrees, 15.39 degrees, 17.48 degrees, 21.56 degrees, 21.89 degrees, 22.42 degrees, 22.95 degrees, 23.42 degrees, 23.73 degrees, 23.82 degrees, 26.17 degrees and 27.18 degrees.
3. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobove according to claim 1 or 2, wherein: dissolving the crude product of the oxazolidinone intermediate of anatrove by using a solvent, then using silica gel filler, using a developing agent to separate an oxazolidinone intermediate solution of the anatrove by TLC, adding n-heptane after concentration, heating to reflux until the solution is completely dissolved, filtering, cooling to room temperature, continuously stirring for crystallization, filtering again, and drying a filter cake to constant weight to obtain the crystal form of the oxazolidinone intermediate of the anatrove.
4. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobo as defined in claim 3, wherein: the solvent was ethyl acetate.
5. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobo as defined in claim 3, wherein: the developing agent is a mixed solvent of two of n-hexane, n-heptane, 60-90 petroleum ether, ethyl acetate or dichloromethane.
6. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobo as defined in claim 3, wherein: the silica gel is 50-400 meshes.
7. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobo as defined in claim 3, wherein: the cooling mode is ice bath cooling.
8. A process for preparing a crystalline form of an oxazolidinone intermediate of anatrobo as defined in claim 3, wherein: the preparation method of the crude oxazolidinone intermediate of anatrobo is as follows: mixing A, aluminum isopropoxide, isopropanol and toluene under the protection of nitrogen, heating to 50 ℃, stirring and reacting for 17 hours at 50 ℃, cooling to 25-30 ℃, adding potassium hydroxide, carrying out heat preservation reaction, detecting an end point by TLC, after the reaction is finished, dropwise adding hydrochloric acid, adjusting the pH to 3-4, stirring and crystallizing, filtering, and washing a filter cake to obtain a crude product of the oxazolidinone intermediate of anaqubo; wherein, the structural formula of A is as follows:
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| CN111138375A (en) * | 2020-01-10 | 2020-05-12 | 阜阳欣奕华材料科技有限公司 | Chiral purification method of drug intermediate |
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2016
- 2016-11-24 CN CN201611049962.1A patent/CN106749075A/en active Pending
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