JP2016523899A - Novel crystalline form of gefitinib and process for its production - Google Patents
Novel crystalline form of gefitinib and process for its production Download PDFInfo
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- JP2016523899A JP2016523899A JP2016523636A JP2016523636A JP2016523899A JP 2016523899 A JP2016523899 A JP 2016523899A JP 2016523636 A JP2016523636 A JP 2016523636A JP 2016523636 A JP2016523636 A JP 2016523636A JP 2016523899 A JP2016523899 A JP 2016523899A
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- gefitinib
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- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 111
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 111
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title abstract description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000007787 solid Substances 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- QUINXWLATMJDQF-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine;hydrochloride Chemical group Cl.C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 QUINXWLATMJDQF-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims 2
- 239000013078 crystal Substances 0.000 abstract description 69
- -1 4- (3′-chloro-4′-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline compound Chemical class 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000012453 solvate Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 150000008064 anhydrides Chemical class 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- OHAYARNLYSPHOJ-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine;dihydrochloride Chemical compound Cl.Cl.C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 OHAYARNLYSPHOJ-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000004684 trihydrates Chemical class 0.000 description 4
- WCABKKDNOBDPHC-UHFFFAOYSA-N 4-[3-(4-chloro-7-methoxyquinazolin-6-yl)oxypropyl]morpholine Chemical compound COC1=CC2=NC=NC(Cl)=C2C=C1OCCCN1CCOCC1 WCABKKDNOBDPHC-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZRECPFOSZXDFDT-UHFFFAOYSA-N 1-decylpyrrolidin-2-one Chemical compound CCCCCCCCCCN1CCCC1=O ZRECPFOSZXDFDT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 150000004924 Gefitinib derivatives Chemical class 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WPPOGHDFAVQKLN-UHFFFAOYSA-N N-Octyl-2-pyrrolidone Chemical compound CCCCCCCCN1CCCC1=O WPPOGHDFAVQKLN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
【課題】ゲフィチニブの新規な結晶形およびその製造方法を提供する。【解決手段】本発明は、ゲフィチニブとして知られている4−(3’−クロロ−4’−フルオロアニリノ)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン化合物の新規な結晶形、およびその製造方法を提供する。【選択図】図1A novel crystal form of gefitinib and a method for producing the same are provided. The present invention provides a novel crystalline form of a 4- (3′-chloro-4′-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline compound known as gefitinib, And a method for manufacturing the same. [Selection] Figure 1
Description
本発明は、無溶媒和物および無水和物の形でも安定し、高純度で得ることが可能であるうえ、薬学的に利用可能である、ゲフィチニブ(gefitinib)の新規な結晶形およびその製造方法に関する。より具体的には、本発明の新規な結晶形は、無溶媒和物および無水物の形であるので、結晶形に含まれている有機溶媒により人体に弊害を及ぼすおそれがなく、製造工程が経済的・環境調和的であり、量産が容易である。前記ゲフィチニブの化学名は4−(3’−クロロ−4’−フルオロアニリノ)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリンであって、その構造は下記化学式Iのとおりである。
[化学式I]
The present invention is a novel crystalline form of gefitinib, which is stable in solvate-free and anhydrous forms, can be obtained with high purity, and is pharmaceutically usable, and a process for producing the same About. More specifically, since the novel crystalline form of the present invention is a solvate-free and anhydrous form, there is no risk of harmful effects on the human body due to the organic solvent contained in the crystalline form. Economical and environmentally harmonious and easy to mass-produce. The chemical name of the gefitinib is 4- (3′-chloro-4′-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, and its structure is shown in the following chemical formula I.
[Formula I]
ゲフィチニブは、癌細胞の上皮成長因子受容体(epidermal growth factor receptor、EGFR)を抑制する抗がん剤であって、癌細胞の成長に関与するシグナルを遮断することにより、抗がん治療効果を示す抗がん剤である。肺癌は組織型によって小細胞肺癌(small cell lung cancer)と非小細胞肺癌(non−small cell lung cancer)に分けられるが、ゲフィチニブは特に非小細胞肺癌の治療に有用である。 Gefitinib is an anticancer agent that suppresses epidermal growth factor receptor (EGFR) of cancer cells, and has an anticancer therapeutic effect by blocking signals involved in the growth of cancer cells. It is an anticancer agent to be shown. Lung cancer is classified into small cell lung cancer and non-small cell lung cancer according to tissue type, but gefitinib is particularly useful for the treatment of non-small cell lung cancer.
国際公開第2006/090413号では、公知のゲフィチニブの結晶形を次のとおり分類している。
(i)結晶形−1:無水和物
(ii)結晶形−2:MeOH溶媒和物
(iii)結晶形−3:DMSO溶媒和物
(iv)結晶形−5:三水和物
In WO 2006/090413, the known crystal forms of gefitinib are classified as follows.
(I) Crystal form-1: Anhydrous (ii) Crystal form-2: MeOH solvate (iii) Crystal form-3: DMSO solvate (iv) Crystal form-5: Trihydrate
結晶形−2は、国際公開第2003/072108号(対応の韓国登録特許第1002374号)の実施例2で製造された形態であって、メタノールにゲフィチニブを溶解して還流・冷却する過程を経た結晶形である。結晶形−2のメタノール含量は約3.45w/w%である。 Crystalline Form-2 is a form produced in Example 2 of WO2003 / 072108 (corresponding Korean Registered Patent No. 10000234), which has undergone a process of refluxing and cooling by dissolving gefitinib in methanol. Crystal form. Crystalline-2 has a methanol content of about 3.45 w / w%.
結晶形−3は、国際公開第2003/072108号の実施例1で製造された形態であって、酢酸エチルおよびジメチルスルホキシド(DMSO)にゲフィチニブを75℃で溶解し、濾過・冷却する過程を経た結晶形である。結晶形−3のDMSO含量は約14.88w/w%である。 Crystalline Form-3 is the form produced in Example 1 of International Publication No. WO2003 / 072108, which was obtained by dissolving gefitinib in ethyl acetate and dimethyl sulfoxide (DMSO) at 75 ° C., followed by filtration and cooling. Crystal form. The DMSO content of crystal form-3 is about 14.88 w / w%.
しかし、ICH(International conference on Harmonization)のガイドライン(欧州薬局方サプリメント(European Pharmacopoeia Supplement)1999、セクション5.4を参照)によれば、活性物質、賦形剤および医薬品中の残留溶媒レベルは、MeOHが最大0.3w/w%、およびDMSOが最大0.5w/w%であると提示されている。しかし、結晶形−2のMeOH含量はおよそ11.5倍であり、結晶形−3のDMSO含量はおよそ30倍であるから、これらの結晶形は薬学的に利用可能ではない。 However, according to International Conference on Harmonization (ICH) guidelines (see European Pharmacopoeia Supplement 1999, section 5.4), residual solvent levels in active substances, excipients and pharmaceuticals are Is up to 0.3 w / w% and DMSO is up to 0.5 w / w%. However, since the MeOH content of crystal form-2 is approximately 11.5 times and the DMSO content of crystal form-3 is approximately 30 times, these crystal forms are not pharmaceutically available.
結晶形−5は、国際公開第2003/072108号の実施例7で製造された形態であって、ゲフィチニブにイソプロピルアルコールと水を添加し、撹拌・加熱・還流して溶解する過程を経た結晶形である。結晶形−5の含水率は約23w/w%であり、室温で24時間放置した場合、含水率は約10.6w/w%に減少し、理論的な三水和物の含水率10.78w/w%に到達する。ところが、この含水率は、48時間放置した場合には4.30w/w%、7日間放置した場合には2.4w/w%に低下してしまう。よって、結晶形−5は安定していない。 Crystal form-5 is the form manufactured in Example 7 of WO2003 / 072108, and is a crystal form that has been subjected to a process of adding isopropyl alcohol and water to gefitinib and dissolving it by stirring, heating, and refluxing. It is. The water content of crystal form-5 is about 23 w / w%, and when left at room temperature for 24 hours, the water content decreases to about 10.6 w / w% and the theoretical trihydrate water content is 10. 78w / w% is reached. However, the moisture content decreases to 4.30 w / w% when left for 48 hours and to 2.4 w / w% when left for 7 days. Therefore, crystal form-5 is not stable.
国際公開第2006/090413号は、前記結晶形−5の三水和物よりも安定したゲフィチニブの結晶形−6であるゲフィチニブ一水和物について開示している。
本発明の結晶形は、無溶媒和物および無水物の形であるので、結晶形に含まれている有機溶媒により人体に弊害を及ぼすおそれがなく、製造工程が経済的・環境調和的であり、量産がより容易である。
WO 2006/090413 discloses gefitinib monohydrate which is gefitinib crystal form-6 which is more stable than the crystal form-5 trihydrate.
Since the crystal form of the present invention is in the form of a solvate or an anhydride, there is no risk of harm to the human body due to the organic solvent contained in the crystal form, and the production process is economical and environmentally harmonious. , Mass production is easier.
ゲフィチニブの現在まで知られている唯一の無溶媒和物結晶形は、結晶形−1である。 The only solvate crystal form known to date of gefitinib is crystal form-1.
国際公開第1996/033980号の実施例1では、ゲフィチニブをカラムクロマトグラフィーで精製して得た後、トルエンで再結晶化するときに生成される物質について、119〜120℃の融点を有するとだけ記述されており、その他のいかなる物理的性質も記載されていない。このため、国際公開第2003/072108号では、当時得られた形態がゲフィチニブの新規な結晶形ではなく、準安定(metastable)な無水和物多形であると看做した。しかし、国際公開第2006/090413号では、前記国際公開第1996/033980号の実施例1と同じ条件で生成された結晶形は結晶形−1であって、その融点が194〜198℃であり、無水和物結晶多形の準安定な形態は存在しないと記載されている。また、無溶媒和物、無水和物の唯一の結晶形は結晶形−1だけであると記載することで、国際公開第2003/072108号の内容に反証している。 In Example 1 of WO 1996/033980, gefitinib is obtained by purifying by column chromatography and then the substance produced when recrystallizing with toluene has only a melting point of 119-120 ° C. It is described and does not describe any other physical properties. For this reason, International Publication No. 2003/072108 considered that the form obtained at that time was not a novel crystal form of gefitinib but a metastable anhydrous polymorph. However, in International Publication No. 2006/090413, the crystal form produced under the same conditions as Example 1 of International Publication No. 1996/033980 is Crystal Form-1, and its melting point is 194-198 ° C. , The metastable form of the anhydrate crystal polymorph is described as absent. Further, it is disproved to the contents of International Publication No. 2003/072108 by stating that the only crystal form of the solvate and anhydride is only crystal form-1.
上記の特許文献からも分かるように、薬学的に利用可能であるうえ、安定性が高く、高純度で得ることが可能な無溶媒和物および無水和物のゲフィチニブの結晶形−1を製造することが難しいとともに、再現性よくゲフィチニブの結晶形−1を製造することが難しいという問題があった。 As can be seen from the above patent documents, solvate-free and anhydrous gefitinib crystal form-1 which is pharmaceutically usable, highly stable and obtainable with high purity is produced. In addition, it is difficult to produce crystal form-1 of gefitinib with good reproducibility.
したがって、経済的で、環境に優しい無溶媒和物及び無水和物の形で長期間安定し、高純度で得ることが可能であるうえ、薬学的に利用可能であるゲフィチニブ結晶形の製造が求められている。 Therefore, there is a demand for the production of gefitinib crystal form that is economical and environmentally friendly and can be obtained for a long period of time in the form of solvate-free and anhydride-free hydrates and with high purity. It has been.
本発明の目的は、無溶媒和物及び無水和物の形でも安定し、高純度で得ることが可能であるうえ、薬学的に安全に利用可能であるゲフィチニブの新規な結晶形を提供することにある。本発明の結晶形は、無溶媒和物および無水物の形であるので、結晶形に含まれている有機溶媒により人体に弊害を及ぼすおそれがなく、製造工程が経済的・環境調和的であり、量産が容易である。
本発明の他の目的は、ゲフィチニブの新規な結晶形を高純度および高収率で製造する方法を提供することにある。
The object of the present invention is to provide a novel crystalline form of gefitinib that is stable even in the form of solvates and anhydrides, can be obtained with high purity, and can be used pharmaceutically safely. It is in. Since the crystal form of the present invention is in the form of a solvate or an anhydride, there is no risk of harm to the human body due to the organic solvent contained in the crystal form, and the production process is economical and environmentally harmonious. Easy to mass-produce.
Another object of the present invention is to provide a process for producing a novel crystalline form of gefitinib with high purity and high yield.
上記課題を達成するために、本発明はゲフィチニブの新規な結晶形を提供する。前記新規な結晶形は無溶媒和物および無水和物の形を呈する。
本発明のゲフィチニブの新規な結晶形は、Cu−Kα放射線を使用する粉末X線回折分析において、2θ回折角が6.45±0.2°、8.20±0.2°、11.32±0.2°、12.90±0.2°、14.02±0.2°の回折パターンを有する。
前記結晶形ゲフィチニブの無水和物は、好ましくは、[図1]の粉末X線回折スペクトルのピークを示す。
また、前記結晶形ゲフィチニブの無水和物は、昇温速度が10℃/minである場合、194.8℃でDSC(Differential Scanning Calorimetry)吸熱転移を示す。
但し、前記DSC吸熱転移値は、本発明の結晶形の純度によって異なり、例えば、約194℃〜約196℃の範囲内の値を有し得る。
In order to achieve the above object, the present invention provides a novel crystalline form of gefitinib. The novel crystalline form takes the form of solvates and anhydrides.
The novel crystalline form of gefitinib of the present invention has a 2θ diffraction angle of 6.45 ± 0.2 °, 8.20 ± 0.2 °, 11.32 in powder X-ray diffraction analysis using Cu—Kα radiation. It has diffraction patterns of ± 0.2 °, 12.90 ± 0.2 °, and 14.02 ± 0.2 °.
The crystalline gefitinib anhydrate preferably exhibits a powder X-ray diffraction spectrum peak of FIG.
In addition, the crystalline gefitinib anhydrate exhibits a DSC (Differential Scanning Calorimetry) endothermic transition at 194.8 ° C. when the heating rate is 10 ° C./min.
However, the DSC endothermic transition value depends on the purity of the crystalline form of the present invention, and may have a value in the range of about 194 ° C. to about 196 ° C., for example.
本発明は、ゲフィチニブの新規な結晶形を製造する方法を提供する。
本発明に係る方法では、ゲフィチニブまたはその塩を、水と、アセトン、ブタノン、イソプロパノール、アセトニトリルおよびテトラヒドロフランの中から選ばれた少なくとも1種の有機溶媒を用いて結晶化して、新規結晶形を得ることができる。
本発明の方法によれば、前記ゲフィチニブ1重量に対して水を0.3〜2重量部で含むことができる。
前記有機溶媒は、好ましくはアセトンである。本発明の方法によれば、前記有機溶媒がアセトンである場合、前記水とアセトンとの体積比は1:3〜10であり、好ましくは1:5である。
本発明に係る方法によれば、前記出発物質であるゲフィチニブまたはその塩は、ゲフィチニブの無水結晶形、ゲフィチニブの水和物またはゲフィチニブの塩酸塩であり得る。
The present invention provides a method for producing a novel crystalline form of gefitinib.
In the method according to the present invention, gefitinib or a salt thereof is crystallized using water and at least one organic solvent selected from acetone, butanone, isopropanol, acetonitrile, and tetrahydrofuran to obtain a novel crystal form. Can do.
According to the method of the present invention, 0.3 to 2 parts by weight of water may be included with respect to 1 weight of the gefitinib.
The organic solvent is preferably acetone. According to the method of the present invention, when the organic solvent is acetone, the volume ratio of water to acetone is 1: 3 to 10, preferably 1: 5.
According to the method of the present invention, the starting material gefitinib or a salt thereof may be an anhydrous crystalline form of gefitinib, a hydrate of gefitinib or a hydrochloride of gefitinib.
本発明に係るゲフィチニブの新規結晶形の製造方法は、
ゲフィチニブまたはその塩を水に溶解させてゲフィチニブの湿体を得る第1段階と、
前記ゲフィチニブの湿体にアセトンを加える第2段階とを含むことができる。
本発明の方法において、前記第1段階の湿体を得る段階は、
前記ゲフィチニブまたはその塩を水に溶解させた後、固体を得る段階と、
前記固体を水で洗浄して、湿体を得る段階とを含む。
ゲフィチニブまたはその塩を精製水に溶解させ、冷却して得られた固体は、ゲフィチニブの水和物であり、好ましくはゲフィチニブの三水和物である。
The method for producing a novel crystalline form of gefitinib according to the present invention is as follows:
A first step of dissolving gefitinib or a salt thereof in water to obtain a wet body of gefitinib;
A second step of adding acetone to the gefitinib wet body.
In the method of the present invention, the step of obtaining the first stage wet body comprises:
Obtaining a solid after dissolving said gefitinib or salt thereof in water;
Washing the solid with water to obtain a wet body.
The solid obtained by dissolving gefitinib or a salt thereof in purified water and cooling is a hydrate of gefitinib, preferably gefitinib trihydrate.
本発明において、前記ゲフィチニブの塩を精製水に溶解させ、濾過した後、塩基を添加してpHを調節した濾過液を冷却して、固体を得ることができる。
本発明において、前記固体を水で洗浄すると、前記固体よりも水分含量の増加した湿体が得られる。したがって、本発明において、前記「湿体」は、ゲフィチニブ三水和物よりも水分含量が高い。例えば、前記湿体の水分含量は、湿体の総重量に対して約25〜50w/w%であり、好ましくは約30〜45w/w%、より好ましくは35〜40w/w%である。前記湿体に含まれる水分としては、結晶水および吸着水の両方を含むことができる。
In the present invention, the gefitinib salt can be dissolved in purified water and filtered, and then the filtrate adjusted to pH by adding a base can be cooled to obtain a solid.
In the present invention, when the solid is washed with water, a wet body having a moisture content higher than that of the solid is obtained. Therefore, in the present invention, the “wet body” has a higher water content than gefitinib trihydrate. For example, the moisture content of the wet body is about 25-50 w / w%, preferably about 30-45 w / w%, more preferably 35-40 w / w%, based on the total weight of the wet body. The moisture contained in the wet body can include both crystal water and adsorbed water.
本発明の方法において、前記新規ゲフィチニブの新規結晶形の製造時に、出発物質としてゲフィチニブの塩酸塩を使用することができ、好ましくは、ゲフィチニブの二塩酸塩を使用する。このようにゲフィチニブの塩酸塩、好ましくは二塩酸塩を使用する場合、前記ゲフィチニブの塩酸塩を溶解させ、これを濾過し、前記濾過液に塩基性物質を滴加してpHを11〜13に調節した後、冷却して水和物タイプの固体を得ることができる。ここで、前記塩基性物質は、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、およびこれらの水溶液から選ばれる少なくとも1種であり、好ましくは水酸化ナトリウム水溶液である。 In the method of the present invention, gefitinib hydrochloride can be used as a starting material in the production of the novel crystalline form of the novel gefitinib, preferably gefitinib dihydrochloride is used. Thus, when gefitinib hydrochloride, preferably dihydrochloride, is used, the gefitinib hydrochloride is dissolved, filtered, and a basic substance is added dropwise to the filtrate to adjust the pH to 11-13. After conditioning, it can be cooled to obtain a hydrate type solid. Here, the basic substance is at least one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, and an aqueous solution thereof, preferably Sodium hydroxide aqueous solution.
本発明の方法によれば、前記第2段階の前記湿体にアセトンを加える段階では、前記第1段階を経て製造された湿体にアセトンを加え、攪拌してスラリーを形成し、これを濾過して洗浄した後、減圧乾燥してゲフィチニブの新規結晶形を得ることができる。
前記第2段階で、前記攪拌は、約10℃〜約30℃で行うことができ、好ましくは約20℃で行う。
前記第2段階で、前記洗浄は、アセトンを用いて行うことができる。
前記第2段階で、前記乾燥は、真空乾燥または減圧乾燥で行うことができる。
前記乾燥は、約50℃〜約60℃で行うことができ、好ましくは約50℃で行う。
According to the method of the present invention, in the step of adding acetone to the wet body in the second stage, acetone is added to the wet body manufactured through the first stage and stirred to form a slurry, which is filtered. After washing, it is dried under reduced pressure to obtain a new crystalline form of gefitinib.
In the second stage, the stirring may be performed at about 10 ° C. to about 30 ° C., preferably about 20 ° C.
In the second step, the cleaning may be performed using acetone.
In the second step, the drying may be performed by vacuum drying or reduced pressure drying.
The drying can be performed at about 50 ° C. to about 60 ° C., preferably about 50 ° C.
本発明に係るゲフィチニブの新規結晶形の製造方法は、
a)ゲフィチニブ結晶形に溶媒を加えて固体を得る第1段階と、
b)前記固体を乾燥させる第2段階とを含む。
The method for producing a novel crystalline form of gefitinib according to the present invention is as follows:
a) a first stage of adding a solvent to the gefitinib crystal form to obtain a solid;
b) a second stage of drying the solid.
前記ゲフィチニブの新規結晶形の製造方法において、前記ゲフィチニブの結晶形は、ゲフィチニブの結晶形1、ゲフィチニブの結晶形2、ゲフィチニブの結晶形3、ゲフィチニブの結晶形5、ゲフィチニブの結晶形6またはこれらの混合物であり、好ましくはゲフィチニブの結晶形1である。 In the method for producing a novel crystal form of gefitinib, the crystal form of gefitinib is gefitinib crystal form 1, gefitinib crystal form 2, gefitinib crystal form 3, gefitinib crystal form 5, gefitinib crystal form 6 or these A mixture, preferably crystalline form 1 of gefitinib.
前記ゲフィチニブの新規結晶形の製造方法において、前記第1段階の溶媒は、水、アセトン、ブタノン、イソプロパノール、アセトニトリル、テトラヒドロフラン、またはこれらの混合物であり、好ましくは、前記溶媒は、水およびアセトンを含む混合溶媒である。
前記ゲフィチニブの結晶形を水およびアセトンを含む混合溶媒に加えると、スラリーを形成することができ、これを濾過して洗浄することにより、固体を得ることができる。
前記溶媒として、水とアセトンとの混合物を使用する場合、前記混合物は、ゲフィチニブ1重量部に対して水を約0.1〜約2重量部で含むものであり得る。好ましくは、前記混合溶媒は、ゲフィチニブ1重量部に対して水を約0.3重量部〜約1.5重量部、より好ましくは約0.5〜約1.0重量部、さらにより好ましくは約1.0重量部で含む。
前記溶媒として、水とアセトンとの混合物を使用する場合、前記混合溶媒は水1体積に対してアセトン5〜10体積で含むものであり得る。前記混合溶媒は、好ましくは水1体積に対してアセトン約5体積を含むことができる。
In the method for producing a novel crystalline form of gefitinib, the first-stage solvent is water, acetone, butanone, isopropanol, acetonitrile, tetrahydrofuran, or a mixture thereof, and preferably the solvent includes water and acetone. It is a mixed solvent.
When the crystal form of gefitinib is added to a mixed solvent containing water and acetone, a slurry can be formed, and a solid can be obtained by filtration and washing.
When a mixture of water and acetone is used as the solvent, the mixture may include about 0.1 to about 2 parts by weight of water with respect to 1 part by weight of gefitinib. Preferably, the mixed solvent is about 0.3 to about 1.5 parts by weight, more preferably about 0.5 to about 1.0 parts by weight, and even more preferably about 1 part by weight of gefitinib. About 1.0 part by weight.
When a mixture of water and acetone is used as the solvent, the mixed solvent may contain 5 to 10 volumes of acetone with respect to 1 volume of water. The mixed solvent may include about 5 volumes of acetone with respect to 1 volume of water.
前記ゲフィチニブの新規結晶形の製造方法において、前記第2段階では、前記第1段階の固体を得た後、洗浄し、乾燥してゲフィチニブの新規結晶形を得ることができる。
前記第2段階における洗浄は、アセトンを用いて行うことができる。
前記第2段階における乾燥は、真空乾燥または減圧乾燥により行うことができる。前記乾燥は、約50℃ 〜約60℃で行うことができ、好ましくは約50℃で行う。
In the method for producing a novel crystalline form of gefitinib, in the second stage, after obtaining the solid of the first stage, it can be washed and dried to obtain a novel crystalline form of gefitinib.
The washing in the second stage can be performed using acetone.
The drying in the second stage can be performed by vacuum drying or reduced pressure drying. The drying can be performed at about 50 ° C. to about 60 ° C., preferably about 50 ° C.
本発明はゲフィチニブの結晶形1の製造方法を提供する。本発明に係るゲフィチニブの結晶形1の製造方法は、
a)本発明のゲフィチニブの新規結晶形に溶媒を加えて固体を得る段階と、
b)前記固体を乾燥させる段階とを含む。
The present invention provides a process for preparing gefitinib crystal form 1. The method for producing gefitinib crystal form 1 according to the present invention comprises:
a) adding a solvent to the novel crystalline form of gefitinib of the present invention to obtain a solid;
b) drying the solid.
前記溶媒は、精製水、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、イソブタノール、t−ブタノール、シクロヘキサノール、テトラヒドロフルフリルアルコール、エチレングリコール、グリセロール、酢酸メチル、酢酸エチル、乳酸エチル、ブチロラクトン、炭酸エチレン、炭酸プロピレン、アセトニトリル、ジメチルスルホキシド、ジメチルホルムアミド、ジメチルアセトアミド、N−メチル−2−ピロリドン、N−オクチル−2−ピロリドン、N−デシル−2−ピロリドン、アセトン、ブタノン、メチルイソブチルケトン、メチルプロピルケトン、アセトフェノン、シクロヘキサノン、塩化メチレン、トリクロロメタン、トリクロロエタン、テトラヒドロフラン、ジエチルエーテル、1,2−ジメトキシエタン、ジオキサン、メチル−第3級−ブチルエーテル、エタノールアミン、ピリジン、クロロベンゼン、トルエン、キシレンおよびテトラメチル尿素の中から選ばれる少なくとも1種の有機溶媒であり、好ましくはアセトンである。 The solvent is purified water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, cyclohexanol, tetrahydrofurfuryl alcohol, ethylene glycol, glycerol, methyl acetate, ethyl acetate, ethyl lactate, butyrolactone, ethylene carbonate. , Propylene carbonate, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, N-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, acetone, butanone, methyl isobutyl ketone, methyl propyl ketone , Acetophenone, cyclohexanone, methylene chloride, trichloromethane, trichloroethane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane Emissions, dioxane, methyl - tertiary - an ether, ethanolamine, pyridine, chlorobenzene, at least one organic solvent selected from toluene, in xylene and tetramethyl urea, preferably acetone.
本発明のゲフィチニブの新規な結晶形に溶媒を加える場合、スラリーが形成され、別途の冷却段階がなくても、濾過および洗浄による結晶の析出が可能である。
前記ゲフィチニブの結晶形に溶媒を加え、濾過して固体を得る段階では、溶媒を加えた後、濾過する前に、攪拌過程を経ることができる。
前記攪拌は、約10〜約30℃で行うことができ、好ましくは約20℃で行う。
本発明の製造方法において、出発物質であるゲフィチニブ、その二塩酸塩および反応試薬としては、いずれも、市販されているものを購入して使用することができる。
When a solvent is added to the novel crystalline form of gefitinib of the present invention, a slurry is formed and crystals can be precipitated by filtration and washing without a separate cooling step.
In the step of adding a solvent to the crystalline form of gefitinib and obtaining a solid by filtration, a stirring process can be performed after adding the solvent and before filtering.
The stirring can be performed at about 10 to about 30 ° C., preferably about 20 ° C.
In the production method of the present invention, commercially available gefitinib, its dihydrochloride salt and reaction reagent can all be purchased and used.
本発明に係るゲフィチニブの新規な結晶形は、無溶媒和物および無水和物の形でも安定し、高純度で得ることが可能であるうえ、薬学的に利用可能である。本発明の結晶形は、無溶媒和物および無水物の形であるので、結晶形に含まれている有機溶媒により人体に弊害を及ぼすおそれがなく、製造工程が経済的・環境調和的であり、量産が容易である。
また、本発明の製造方法は、ゲフィチニブの新規な結晶形を高純度および高収率で得ることができる。
The novel crystal form of gefitinib according to the present invention is stable even in a solvate-free and anhydrous form, can be obtained with high purity, and can be used pharmaceutically. Since the crystal form of the present invention is in the form of a solvate or an anhydride, there is no risk of harm to the human body due to the organic solvent contained in the crystal form, and the production process is economical and environmentally harmonious. Easy to mass-produce.
In addition, the production method of the present invention can obtain a novel crystal form of gefitinib with high purity and high yield.
以下、製造例および実施例を挙げて、本発明をより具体的に説明する。これらの製造例および実施例は、本発明を説明するためのもので、本発明の範囲を限定するものではない。 Hereinafter, the present invention will be described more specifically with reference to production examples and examples. These production examples and examples are for explaining the present invention and do not limit the scope of the present invention.
下記水分測定は次の機械および条件で行った。この水分測定では、KF(Karl Fisher)法、Metrohm 787 KF Titrino機器およびHYDRANAL−Composite 5試液(Fluka社から購入)を使用した。 The following moisture measurements were performed on the following machines and conditions. In this moisture measurement, KF (Karl Fisher) method, Metrohm 787 KF Titrino instrument and HYDRANAL-Composite 5 reagent (purchased from Fluka) were used.
下記生成物の確認データは次の機械および条件で測定した。
1)1H−NMR
機器名:VARIAN 400MHz
2)融点(M.P)
機器名:BUCHI Melting Point B−545
測定方法:185℃まで昇温した後、分あたりの昇温速度:1℃/minで測定する。
3)純度測定のための液体クロマトグラフィー(HPLC)
Confirmation data for the following products were measured on the following machines and conditions.
1) 1 H-NMR
Device name: VARIAN 400MHz
2) Melting point (MP)
Device name: BUCHI Melting Point B-545
Measuring method: After heating up to 185 ° C., measurement is performed at a heating rate of 1 ° C./min per minute.
3) Liquid chromatography (HPLC) for purity measurement
4)粉末X線回折スペクトルの機械および条件
−製造社:Bruker(ドイツ)
−モデル:D8 Focus
−Kβ remover:Niフィルター
−電圧kV:40
−電流mA:40
−スキャン範囲:2〜40deg.
−スキャン速度:10.0deg./min
−インクリメント(increment):0.02deg.
−発散スリット幅(Divergence Slit width):0.6mm
−空気散乱スリット(Air scatter slit):3mm
−検出器(Detector):LynxEye Detector(line detector)
5)DSC(示差走査熱量)機器および条件
−製造社:TA Instruments
−モデル:Q−1000
−昇温速度:10℃/min
4) Machine and conditions for powder X-ray diffraction spectrum-Manufacturer: Bruker (Germany)
-Model: D8 Focus
-Kβ remover: Ni filter-Voltage kV: 40
-Current mA: 40
Scan range: 2-40 deg.
-Scanning speed: 10.0 deg. / Min
-Increment: 0.02 deg.
-Divergence slit width: 0.6 mm
-Air scatter slit: 3 mm
-Detector: LynxEye Detector (line detector)
5) DSC (Differential Scanning Calorimetry) equipment and conditions-Manufacturer: TA Instruments
-Model: Q-1000
-Temperature increase rate: 10 ° C / min
本発明に係るゲフィチニブの無水和物の製造方法を反応式で図式化すると、次のとおりである。
[反応式I]
The method for producing an anhydrous gefitinib according to the present invention is schematically represented by the following reaction formula.
[Reaction Formula I]
<製造例1>4−クロロ−7−メトキシ−6−(3−モルホリン−4−イルプロポキシ)キナゾリン(化学式III)の製造
7−メトキシ−6−(3−モルホリン−4−イルプロポキシ)キナゾリン−4(3H)−オン200g、ジクロロメタン2000mL、N,N−ジメチルホルムアミド200mLおよびアセトニトリル200mLの反応混合物にオキシ塩化リン(POCl3)192gを入れ、40〜45℃で3時間撹拌して反応物を製造した。
前記で製造された反応物を−10〜0℃に冷却し、25%炭酸カリウム水溶液をゆっくりと滴加して、pHが6〜8となるようにした。その後、層を分離し、有機層を水で2回洗浄した。有機層を無水硫酸マグネシウムと活性炭で処理した後、濾過して濃縮し、イソプロパノール2000mLを加えて再結晶した。生成された固体を濾過し、50℃で減圧乾燥して、4−クロロ−7−メトキシ−6−(3−モルモルホリン−4−イルプロポキシ)キナゾリン171gを得た(収率80.3%)。
1H NMR(DMSO-d6) δ 8.87(s, 1H), 7.45(s, 1H), 7.38(s, 1H), 4.24(t, 2H), 4.01(s, 3H), 3.58(m, 4H), 2.46(m, 2H), 2.38 (m, 4H), 1.98(m, 2H)
<Production Example 1> Production of 4-chloro-7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline (Chemical Formula III) 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline- 192 g of phosphorus oxychloride (POCl 3 ) was added to a reaction mixture of 200 g of 4 (3H) -one, 2000 mL of dichloromethane, 200 mL of N, N-dimethylformamide and 200 mL of acetonitrile, and stirred at 40 to 45 ° C. for 3 hours to produce a reaction product. did.
The reaction product prepared above was cooled to −10 to 0 ° C., and a 25% aqueous potassium carbonate solution was slowly added dropwise to adjust the pH to 6 to 8. The layers were then separated and the organic layer was washed twice with water. The organic layer was treated with anhydrous magnesium sulfate and activated carbon, filtered and concentrated, and recrystallized by adding 2000 mL of isopropanol. The produced solid was filtered and dried under reduced pressure at 50 ° C. to obtain 171 g of 4-chloro-7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline (yield 80.3%). .
1 H NMR (DMSO-d 6 ) δ 8.87 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.24 (t, 2H), 4.01 (s, 3H), 3.58 (m, 4H ), 2.46 (m, 2H), 2.38 (m, 4H), 1.98 (m, 2H)
<製造例2>ゲフィチニブ二塩酸塩(化学式IV)の製造
4−クロロ−7−メトキシ−6−(3−モルホリン−4−イルプロポキシ)キナゾリン150g、3−クロロ−4−フルオロアニリン96.9gおよびメタノール3000mLの反応混合物に、35%c−HCl37mLをゆっくりと滴加し、20℃で1時間攪拌した。生成した固体を濾過し、メタノールで洗浄した。濾過して得た固体をメタノールで2時間65℃で還流攪拌した後、20℃に冷却して結晶を濾過し、メタノールで洗浄した後、50℃で減圧乾燥してゲフィチニブ二塩酸塩215gを得た(収率93.3%、純度99.9%)。
1H NMR(DMSO-d6) δ11.79(s, 1H), 10.96(s, 1H), 8.87(s, 1H), 8.63(s, 1H), 8.10(dd, 1H), 7.83(m, 1H), 7.54(t, 1H), 7.40(s, 1H), 4.40(t, 2H), 4.00(s, 3H), 3.97(d, 2H), 3.82(t, 2H), 3.50(d, 2H), 3.32(d, 2H), 3.12(m, 2H), 2.33(m, 2H)
X線粉末回折の2θ値:約6.00、7.49、8.07、9.59、14.99、15.31°
<Production Example 2> Production of gefitinib dihydrochloride (chemical formula IV) 4-chloro-7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline 150 g, 3-chloro-4-fluoroaniline 96.9 g and To a reaction mixture of 3000 mL of methanol, 37 mL of 35% c-HCl was slowly added dropwise and stirred at 20 ° C. for 1 hour. The resulting solid was filtered and washed with methanol. The solid obtained after filtration was refluxed and stirred with methanol at 65 ° C. for 2 hours, then cooled to 20 ° C., the crystal was filtered, washed with methanol, and dried under reduced pressure at 50 ° C. to obtain 215 g of gefitinib dihydrochloride. (Yield 93.3%, Purity 99.9%).
1 H NMR (DMSO-d 6 ) δ 11.79 (s, 1H), 10.96 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.10 (dd, 1H), 7.83 (m, 1H), 7.54 (t, 1H), 7.40 (s, 1H), 4.40 (t, 2H), 4.00 (s, 3H), 3.97 (d, 2H), 3.82 (t, 2H), 3.50 (d, 2H ), 3.32 (d, 2H), 3.12 (m, 2H), 2.33 (m, 2H)
X-ray powder diffraction 2θ value: about 6.00, 7.49, 8.07, 9.59, 14.99, 15.31 °
<実施例1>ゲフィチニブ(化学式I)の新規な結晶形の製造
ゲフィチニブ二塩酸塩200gを精製水3000mLに入れ、60〜70℃で溶解させて濾過した。濾過液に10%水酸化ナトリウム水溶液を60〜70℃でゆっくりと滴加して、pHが11〜13となるように調節した。pH調節された濾過液を60〜70℃で1時間攪拌した後、30℃に冷却し、30分間攪拌した。析出した結晶を濾過し、精製水で洗浄した。濾過して洗浄することにより、三水和物より水分含量が高いため、水分含量約35〜40重量%のゲフィチニブの湿体を得た。得られた湿体にアセトン1000mLを加え、20℃で2時間撹拌した後、濾過し、アセトンで洗浄した。50〜60℃で減圧乾燥して、ゲフィチニブの新規な結晶形156gを得た(収率90.7%、純度99.9%、水分0.6%)。
融点:約194℃
1H NMR(DMSO-d6) δ 9.56(s, 1H), 8.50(s, 1H), 8.11(dd, 1H), 7.81(s, 1H), 7.78(m, 1H), 7.44(t, 1H), 7.20(s, 1H), 4.18(t, 2H), 3.94(s, 3H), 3.58(m, 4H), 2.50(m, 2H), 2.40(m, 4 H), 2.00(m, 2H)
X線粉末回折の2θ値:約6.45、8.20、11.32、12.90、14.02°
<Example 1> Production of a novel crystal form of gefitinib (chemical formula I) 200 g of gefitinib dihydrochloride was placed in 3000 mL of purified water, dissolved at 60 to 70 ° C and filtered. A 10% aqueous sodium hydroxide solution was slowly added dropwise to the filtrate at 60 to 70 ° C. to adjust the pH to 11 to 13. The pH-adjusted filtrate was stirred at 60 to 70 ° C. for 1 hour, then cooled to 30 ° C. and stirred for 30 minutes. The precipitated crystals were filtered and washed with purified water. By filtering and washing, the wet content of gefitinib having a water content of about 35 to 40% by weight was obtained because the water content was higher than that of the trihydrate. To the obtained wet body, 1000 mL of acetone was added, stirred at 20 ° C. for 2 hours, filtered, and washed with acetone. After drying under reduced pressure at 50-60 ° C., 156 g of a new crystalline form of gefitinib was obtained (yield 90.7%, purity 99.9%, moisture 0.6%).
Melting point: about 194 ° C
1 H NMR (DMSO-d 6 ) δ 9.56 (s, 1H), 8.50 (s, 1H), 8.11 (dd, 1H), 7.81 (s, 1H), 7.78 (m, 1H), 7.44 (t, 1H ), 7.20 (s, 1H), 4.18 (t, 2H), 3.94 (s, 3H), 3.58 (m, 4H), 2.50 (m, 2H), 2.40 (m, 4H), 2.00 (m, 2H )
2θ value of X-ray powder diffraction: about 6.45, 8.20, 11.32, 12.90, 14.02 °
<実施例2>結晶形−1から新規な結晶形への転換工程
10gのゲフィチニブ結晶形−1を水10mLとアセトン50mLとの混合溶媒に投入し、20℃で2時間撹拌した。これを濾過し、アセトン20mLで洗浄した後、50〜60℃で減圧乾燥して、ゲフィチニブの新規な結晶形9.5gを得た(水分:0.16%)。
X線粉末回折の2θ値:約6.45、8.20、11.32、12.90、14.02°
Example 2 Conversion Step from Crystal Form-1 to Novel Crystal Form 10 g of gefitinib crystal form-1 was put into a mixed solvent of 10 mL of water and 50 mL of acetone and stirred at 20 ° C. for 2 hours. This was filtered, washed with 20 mL of acetone, and then dried under reduced pressure at 50 to 60 ° C. to obtain 9.5 g of a novel crystalline form of gefitinib (water content: 0.16%).
2θ value of X-ray powder diffraction: about 6.45, 8.20, 11.32, 12.90, 14.02 °
<実施例3>結晶形−1から新規な結晶形への転換工程
10gのゲフィチニブ結晶形−1を水5mLとアセトン50mLとの混合溶媒に投入し、20℃で2時間撹拌した。これを濾過し、アセトン20mLで洗浄した後、50〜60℃で減圧乾燥して、ゲフィチニブの新規な結晶形9.6gを得た(水分:0.24%)。
X線粉末回折の2θ値:約6.45、8.20、11.32、12.90、14.02°
Example 3 Conversion Step from Crystal Form-1 to Novel Crystal Form 10 g of gefitinib crystal form-1 was put into a mixed solvent of 5 mL of water and 50 mL of acetone and stirred at 20 ° C. for 2 hours. This was filtered, washed with 20 mL of acetone, and then dried under reduced pressure at 50 to 60 ° C. to obtain 9.6 g of a novel crystal form of gefitinib (water content: 0.24%).
2θ value of X-ray powder diffraction: about 6.45, 8.20, 11.32, 12.90, 14.02 °
<実施例4>新規な結晶形からゲフィチニブ結晶形−1への転換工程
実施例3で得たゲフィチニブ100g(新規結晶形)をアセトン500mLに投入し、20℃で2時間撹拌した。これを濾過し、アセトン100mLで洗浄した後、50〜60℃で減圧乾燥して、結晶形−1のゲフィチニブ96.9gを得た(水分:0.15%)。
融点:約194℃
X線粉末回折の2θ値:約7.15、11.28、15.89、19.39、24.35、26.41°
<Example 4> Step of conversion from novel crystal form to gefitinib crystal form-1 100 g (new crystal form) of gefitinib obtained in Example 3 was added to 500 mL of acetone and stirred at 20 ° C for 2 hours. This was filtered, washed with 100 mL of acetone, and then dried under reduced pressure at 50 to 60 ° C. to obtain 96.9 g of gefitinib of crystal form-1 (water content: 0.15%).
Melting point: about 194 ° C
2θ value of X-ray powder diffraction: about 7.15, 11.28, 15.89, 19.39, 24.35, 26.41 °
本発明に係るゲフィチニブの新規な結晶形は、無溶媒和物及び無水和物の形でも安定し、高純度で得ることが可能であるうえ、薬学的に利用可能である。本発明の結晶形は、無溶媒和物および無水物の形であるので、結晶形に含まれている有機溶媒により人体に弊害を及ぼすおそれがなく、製造工程が経済的・環境調和的であり、量産が容易である。
また、本発明の製造方法は、ゲフィチニブの新規な結晶形を高純度および高収率で得ることができるので、有用に使用可能である。
The novel crystalline form of gefitinib according to the present invention is stable even in a solvate-free and anhydrous form, can be obtained with high purity, and can be used pharmaceutically. Since the crystal form of the present invention is in the form of a solvate or an anhydride, there is no risk of harm to the human body due to the organic solvent contained in the crystal form, and the production process is economical and environmentally harmonious. Easy to mass-produce.
Further, the production method of the present invention can be used effectively because a novel crystal form of gefitinib can be obtained with high purity and high yield.
Claims (15)
前記ゲフィチニブの湿体にアセトンを加える段階とを含む、ゲフィチニブの結晶形を製造する方法。 Dissolving gefitinib or a salt thereof in water to obtain a wet body of gefitinib;
Adding acetone to the gefitinib wet body to produce a crystalline form of gefitinib.
前記懸濁液を濾過して固体を得る段階と、
前記固体を乾燥する段階とを含んでなる、ゲフィチニブの結晶形を製造する方法。 Injecting water and acetone into gefitinib or a salt thereof to produce a suspension;
Filtering the suspension to obtain a solid;
Drying said solid, comprising producing a crystalline form of gefitinib.
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