CN106316943A - Refining method of bedaquiline fumarate crystal form compound - Google Patents
Refining method of bedaquiline fumarate crystal form compound Download PDFInfo
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- CN106316943A CN106316943A CN201610599009.8A CN201610599009A CN106316943A CN 106316943 A CN106316943 A CN 106316943A CN 201610599009 A CN201610599009 A CN 201610599009A CN 106316943 A CN106316943 A CN 106316943A
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- purification
- quinoline
- fumaric acid
- form compound
- organic solvent
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 239000013078 crystal Substances 0.000 title abstract description 13
- 229960001137 bedaquiline fumarate Drugs 0.000 title abstract 6
- ZLVSPMRFRHMMOY-WWCCMVHESA-N bedaquiline fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 ZLVSPMRFRHMMOY-WWCCMVHESA-N 0.000 title abstract 6
- 238000007670 refining Methods 0.000 title abstract 5
- 239000007787 solid Substances 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000009413 insulation Methods 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 88
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 75
- 235000015170 shellfish Nutrition 0.000 claims description 42
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 38
- 239000001530 fumaric acid Substances 0.000 claims description 37
- 230000008569 process Effects 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000000047 product Substances 0.000 abstract description 8
- 238000001914 filtration Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000005352 clarification Methods 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical group C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- -1 biaryl quinolin class Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005059 dormancy Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of drug synthesis research and relates to a refining method of a bedaquiline fumarate crystal form compound. The refining method comprises mixing a bedaquiline fumarate crude product and an organic solvent, carrying out heating dissolved clarification, filtration and thermal insulation until solids are precipitated, then carrying out cooling crystallization, carrying out solid-liquid separation and carrying out drying to obtain the bedaquiline fumarate crystal form compound. The refining method can satisfy refining demands of different sources of bedaquiline fumarate crude products, can stably produce the bedaquiline fumarate crystal form compound with high purity, can utilize the low toxicity organic solvent, has a high product yield, can be operated simply and can be industrialized easily.
Description
Technical field
The invention belongs to pharmaceutical synthesis research field, be specifically related to a kind of fumaric acid and reach the refined side of quinoline crystal-form compound
Method.
Background technology
Fumaric acid shellfish reaches quinoline chemical structural formula and is shown below, and chemical name is (1R, 2S)-1-(6-bromo-2-methoxy
Base-3-quinolyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol fumarate.
Fumaric acid shellfish reaches quinoline and is belonging to biaryl quinolin class antibiotic, mycobacterium tuberculosis is belonged to antibacterial, mainly makees
It is adenosine triphosphate (ATP) synzyme of suppression mycobacterium tuberculosis by mechanism, blocks the energy supply of antibacterial.To common and resistance to
The M. tuberculosis strains of medicine (including Drug-fast case) all has equal bactericidal activity, resistance to without intersecting with existing antituberculotics
Medicine, and the most effective to dormancy bacterium.
Fumaric acid shellfish reaches quinoline principal agent molecular structure shellfish and reaches quinoline and report in compound patent CN03817713.7, and
Experimental example reports optics mixing shellfish and reaches the preparation method of quinoline；Report by 1-naphthalene second in patent CN200680017475.5
Ketone is prepared DL shellfish through Mannich reaction, condensation reaction and is reached quinoline and split through R-dinaphthol phosphate ester, free obtain optical purity
Shellfish reach the preparation method of quinoline；Patent CN200780044808.8 is reported in and isopropanol is reached quinoline by fumaric acid with shellfish becomes
The method that fumaric acid shellfish reaches quinoline prepared by salt.Drug crystal forms is the key factor of pharmaceutical preparation, affects Drug safety and has
Effect property.
In FDA evaluates report, only mention at present fumaric acid shellfish reach quinoline there is polymorphism, and clearly state this change
Compound only has the crystal formation of a kind of stable existence.Cannot meeting separate sources fumaric acid shellfish in the method for current report, to reach quinoline thick
The refined demand of product.
It is thus desirable to develop a kind of fumaric acid shellfish to reach the process for purification of quinoline crystal-form compound to meet the richness of separate sources
Horse acid shellfish reaches the refined demand of quinoline.The fumaric acid shellfish of this patent report reaches crystal formation prepared by quinoline crystal-form compound preparation method
Consistent with the crystal formation of preparation in patent CN200780044808.8.This patent provides more fumaric acid shellfish to reach quinoline crystal formation chemical combination
The preparation method of thing, the fumaric acid shellfish that can meet separate sources reaches the refined demand of quinoline, and the crystal-form compound of preparation is same
Crystal formation and purity are high, and yield is high, and quality meets requirements for pharmaceuticals.Reacted literature search repeatedly, prepares fumaric acid shellfish without other and reaches
The preparation method of quinoline crystal-form compound.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of fumaric acid shellfish and reach the process for purification of quinoline crystal-form compound,
The method can stably obtain fumaric acid shellfish and reach quinoline crystal-form compound, and crystal form purity is high, and product yield is high, uses hypotoxic
Organic solvent, the method is easy and simple to handle simultaneously, easy industrialized production.
For achieving the above object, the technical scheme is that
A kind of fumaric acid shellfish reaches the process for purification of quinoline crystal-form compound, and the step of described process for purification is: by fumaric acid
Shellfish reaches quinoline crude product and mixes with organic solvent, adds thermosol clear, filters, and insulation separates out cooling crystallize after solid, dry after solid-liquid separation
Dry, obtain fumaric acid shellfish and reach quinoline crystal-form compound.
Described fumaric acid shellfish reaches quinoline chemical structural formula and is shown below:
Further, described fumaric acid shellfish reaches the mass volume ratio of quinoline crude product and organic solvent is 1:5～1:50g/ml.Matter
Amount volume ratio is conducive to removal and the raising of product yield of impurity in prescribed limit.
Further, described organic solvent is the organic solvent of one or more mixing in addition to single isopropanol.
Further, adding the clear temperature of thermosol described in is 40～120 DEG C.Boiling point according to solvent for use arranges solution temperature to be had
It is beneficial to reduction and the raising of yield of solvent usage amount.
Preferred as one, filtered while hot is wanted in described filtration.Filtered while hot is to prevent temperature from reducing, impurity and object one
Play precipitation to be filtered off, reduce the loss of goal object.
Preferred as one, described in add thermosol clear during with stirring, the time of described stirring is 0.5～1.5 hour.
Further, insulation separates out the temperature of solid is 30～60 DEG C；The temperature of described cooling crystallize is-10～20 DEG C.First
Insulation separates out solid crystallize of lowering the temperature again and is possible to prevent the too fast precipitation of product and forms solvate and change product crystal formation, simultaneously crystallize
The regulation of temperature range advantageously ensures that product purity and yield.
Preferred as one, the time that described insulation separates out solid is 0.5～2.5 hour, the time of described cooling crystallize
It it is 0.5～4.5 hour.
Further, described organic solvent includes alcohols, esters, ketone, ethers, hydro carbons, dimethylformamide, dimethyl second
Amide.
Further, described alcohols be methanol, ethanol, normal propyl alcohol, n-butyl alcohol, the tert-butyl alcohol one or more.
Further, one or more during described esters is the acetate esters of C1～C4.
Further, described ketone be acetone, butanone, methyl iso-butyl ketone (MIBK) one or more.
Further, described ethers be methyl tert-butyl ether, diisopropyl ether, dioxane, oxolane one or more；Described
Hydro carbons be toluene, dichloromethane, C6～C10 alkane one or more.
The beneficial effects of the present invention is:
1) the fumaric acid shellfish that the present invention provides reaches the process for purification of quinoline crystal-form compound, can meet separate sources richness horse
Acid shellfish reaches the refined demand of quinoline crude product.
2) the method can stably obtain fumaric acid shellfish and reaches quinoline crystal-form compound, and the crystal form purity obtained is high, uses low
The organic solvent of toxicity, product yield is high, and the method is easy and simple to handle simultaneously, easy industrialized production.
Accompanying drawing explanation
Fig. 1 is that embodiment 1 prepares fumaric acid shellfish and reaches the XRD figure of quinoline crystal-form compound.
Fig. 2 is that embodiment 2 prepares fumaric acid shellfish and reaches the XRD figure of quinoline crystal-form compound.
Fig. 3 is that embodiment 3 prepares fumaric acid shellfish and reaches the XRD figure of quinoline crystal-form compound.
Fig. 4 is that embodiment 4 prepares fumaric acid shellfish and reaches the XRD figure of quinoline crystal-form compound.
Fig. 5 is that embodiment 5 prepares fumaric acid shellfish and reaches the XRD figure of quinoline crystal-form compound.
Detailed description of the invention
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.Unreceipted tool in preferred embodiment
The experimental technique of concrete conditions in the establishment of a specific crime, generally according to normal condition, illustrated embodiment is to preferably say present disclosure
Bright, but be not that present disclosure is only limitted to illustrated embodiment.So those of ordinary skill in the art are according to foregoing invention
Content carries out nonessential improvement and adjustment to embodiment, still falls within protection scope of the present invention.
The spectrogram of following example is prepared by following condition:
Instrument: Holland's PANalytical Multifunctional powder X-ray diffractometer
Test condition: CuK α radiates, graphite monochromator, tube voltage 40kV, tube current 40mA, 2 θ sweep limitss 4-60 °, speed
Degree is 3 °/point, and scanning step is 0.02 °.
Embodiment 1
2.0g fumaric acid shellfish is reached quinoline crude product and 50ml isobutyl acetate and adds in reaction bulb, temperature rising reflux, molten clearly, take out
Filter, mother solution separates out solid, insulated and stirred 1 hour in 40～50 DEG C of stirrings, is cooled to 0～10 DEG C of stirring and crystallizing 1 hour, sucking filtration,
Being dried, obtain 1.6g solid, yield is 80%, and Fig. 1 is shown in by XRD detection collection of illustrative plates.
Embodiment 2
2.0g fumaric acid shellfish reaches quinoline crude product add in reaction bulb with 30ml hexone, is warming up to backflow,
Molten clearly, sucking filtration, mother solution in 50～60 DEG C stirring separate out solids, insulated and stirred 1 hour, be cooled to 0～10 DEG C of stirring and crystallizing 1 little
Time, sucking filtration, it is dried, obtains 1.5g solid, yield is 75%, and Fig. 2 is shown in by XRD detection collection of illustrative plates.
Embodiment 3
2.0g fumaric acid shellfish reaches quinoline crude product and 20ml n-butyl alcohol add in reaction bulb, is warming up to backflow, molten clearly, take out
Filter, mother solution separates out solid, insulated and stirred 1 hour in 50～60 DEG C of stirrings, is cooled to 0～10 DEG C of stirring and crystallizing 1 hour, sucking filtration,
Being dried, obtain 1.2g solid, yield is 60%, and Fig. 3 is shown in by XRD detection collection of illustrative plates.
Embodiment 4
2.0g fumaric acid shellfish reaches quinoline crude product and 6ml dichloromethane add in reaction bulb, is warming up to backflow, molten clearly, take out
Filter, drips 10ml methyl tertiary butyl ether(MTBE), insulated and stirred 1 hour, is cooled to 0～10 DEG C of stirring and crystallizing 1 hour, takes out under reflux temperature
Filter, is dried, obtains 1.6g solid, and yield is 80%, and Fig. 4 is shown in by XRD detection collection of illustrative plates.
Embodiment 5
2.0g fumaric acid shellfish reaches quinoline crude product and 40ml isopropanol add in reaction bulb, is warming up to backflow, molten clearly, take out
Filter, 40～50 DEG C of insulated and stirred 1 hour, it is cooled to 0～5 DEG C of stirring and crystallizing 1 hour, sucking filtration, it is dried, obtains 1.6g solid, yield
Being 80%, Fig. 5 is shown in by XRD detection collection of illustrative plates.
Finally illustrating, above example is only in order to illustrate technical scheme and unrestricted, although with reference to relatively
The present invention has been described in detail by good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent, and without deviating from objective and the scope of technical solution of the present invention, it all should be contained at this
In the middle of the right of invention.
Claims (10)
1. fumaric acid shellfish reaches the process for purification of quinoline crystal-form compound, it is characterised in that fumaric acid shellfish is reached quinoline crude product and had
Machine solvent mixes, and adds thermosol clear, filters, crystallize of lowering the temperature after insulation precipitation solid, is dried, obtains fumaric acid shellfish and reach quinoline after solid-liquid separation
Quinoline crystal-form compound.
Process for purification the most according to claim 1, it is characterised in that described fumaric acid shellfish reaches quinoline crude product and organic solvent
Mass volume ratio be 1:5～1:50g/ml.
Process for purification the most according to claim 1, it is characterised in that described organic solvent is in addition to single isopropanol
The organic solvent of one or more mixing.
Process for purification the most according to claim 1, it is characterised in that described in add the clear temperature of thermosol be 40～120 DEG C.
Process for purification the most according to claim 1, it is characterised in that it is 30～60 DEG C that insulation separates out the temperature of solid；Institute
The temperature stating cooling crystallize is-10～20 DEG C.
Process for purification the most according to claim 3, it is characterised in that described organic solvent include alcohols, esters, ketone,
Ethers, hydro carbons, dimethylformamide, dimethyl acetylamide.
Process for purification the most according to claim 6, it is characterised in that described alcohols is methanol, ethanol, normal propyl alcohol, positive fourth
Alcohol, the tert-butyl alcohol one or more.
Process for purification the most according to claim 6, it is characterised in that described esters is in the acetate esters of C1～C4
Plant or multiple.
Process for purification the most according to claim 6, it is characterised in that described ketone is acetone, butanone, methyl iso-butyl ketone (MIBK)
One or more.
Process for purification the most according to claim 6, it is characterised in that described ethers be methyl tert-butyl ether, diisopropyl ether, two
Oxygen six ring, oxolane one or more；Described hydro carbons be toluene, dichloromethane, C6～C10 alkane one or more.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349898A (en) * | 2015-10-20 | 2018-07-31 | 浙江海正药业股份有限公司 | Fumaric acid shellfish reaches the crystal form and preparation method thereof of quinoline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547904A (en) * | 2006-12-05 | 2009-09-30 | 詹森药业有限公司 | Fumarate salt of (alpha S, beta R) -6-bromo-alpha- [ 2- (dimethylamino) ethyl ] -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol |
| WO2016027253A1 (en) * | 2014-08-21 | 2016-02-25 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as rip1 kinase inhibitors as medicaments |
| WO2016058564A1 (en) * | 2014-10-16 | 2016-04-21 | Zentiva, K.S. | Salts of bedaquiline |
-
2016
- 2016-07-27 CN CN201610599009.8A patent/CN106316943A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547904A (en) * | 2006-12-05 | 2009-09-30 | 詹森药业有限公司 | Fumarate salt of (alpha S, beta R) -6-bromo-alpha- [ 2- (dimethylamino) ethyl ] -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol |
| WO2016027253A1 (en) * | 2014-08-21 | 2016-02-25 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as rip1 kinase inhibitors as medicaments |
| WO2016058564A1 (en) * | 2014-10-16 | 2016-04-21 | Zentiva, K.S. | Salts of bedaquiline |
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| CN108349898A (en) * | 2015-10-20 | 2018-07-31 | 浙江海正药业股份有限公司 | Fumaric acid shellfish reaches the crystal form and preparation method thereof of quinoline |
| CN108349898B (en) * | 2015-10-20 | 2021-03-23 | 浙江海正药业股份有限公司 | Crystal form of bedaquiline fumarate and preparation method thereof |
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