HRP20100019T1 - Kemijski postupak - Google Patents
Kemijski postupak Download PDFInfo
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- HRP20100019T1 HRP20100019T1 HR20100019T HRP20100019T HRP20100019T1 HR P20100019 T1 HRP20100019 T1 HR P20100019T1 HR 20100019 T HR20100019 T HR 20100019T HR P20100019 T HRP20100019 T HR P20100019T HR P20100019 T1 HRP20100019 T1 HR P20100019T1
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- 238000001311 chemical methods and process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 68
- 238000000034 method Methods 0.000 claims abstract 41
- 150000003839 salts Chemical class 0.000 claims abstract 20
- 239000002585 base Substances 0.000 claims abstract 17
- 239000002904 solvent Substances 0.000 claims abstract 16
- 239000000203 mixture Substances 0.000 claims abstract 14
- 239000012458 free base Substances 0.000 claims abstract 12
- 238000006243 chemical reaction Methods 0.000 claims abstract 9
- 239000012320 chlorinating reagent Substances 0.000 claims abstract 9
- 238000004519 manufacturing process Methods 0.000 claims abstract 7
- 238000011065 in-situ storage Methods 0.000 claims abstract 6
- 239000002253 acid Substances 0.000 claims abstract 5
- 125000006239 protecting group Chemical group 0.000 claims abstract 5
- 239000011541 reaction mixture Substances 0.000 claims abstract 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims abstract 3
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000010438 heat treatment Methods 0.000 claims abstract 2
- 238000003756 stirring Methods 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 6
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 claims 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 4
- XIHOMGRMQWNHHB-UHFFFAOYSA-N 4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-ol Chemical compound N1=CN=C2C=C(O)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F XIHOMGRMQWNHHB-UHFFFAOYSA-N 0.000 claims 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 239000006227 byproduct Substances 0.000 claims 3
- 239000003638 chemical reducing agent Substances 0.000 claims 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 3
- 239000008096 xylene Substances 0.000 claims 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 2
- 235000019253 formic acid Nutrition 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- -1 sulfonate ester Chemical class 0.000 claims 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical group C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- 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
Abstract
Postupak za proizvodnju spoja formule VI:gdje je R1 zaštitna skupina labilne kiselineiz spoja sa formulom VII: naznačen time, da navedeni postupak obuhvaća: (g) reakciju spoja formule VII sa prikladnim agensom za kloriranje u prisutnosti prikladne baze i prikladnog otapala, gdje se reakcija provodi uz: (g-1) dodavanje smjese spoja sa formulom VII i baze u otapalu u smjesu agensa za kloriranje u otapalu na temperaturi u rasponu od 60 do 90° C tijekom vremena od oko 60 min; ili (g-2) dodavanje agensa za kloriranje u smjesu spoja sa Formulom VII i baze u otapalu na sobnoj temperaturi tijekom perioda od oko 15 min, te tada pomoću grijanja reakcijske smjese tijekom perioda od oko 90 min na temperaturi u rasponu od 70 do 90° C i uz miješanje reakcijske smjese na istoj temperaturi od oko 1 h; ili (g-3) dodavanja agensa za kloriranje u mješavinu spoja sa formulom VII i baze u otapalu na temperaturi u rasponu od 60 do 110° C tijekom perioda od oko 15 min, radi dobivanja spoja sa Formulom VIII: i (h) reakciju spoja sa formulom VIII sa 4-bromo-2-fluoroanilinom in situ u prisutnosti otapala koje se koristi u koraku (g) sa svrhom dobivanja klorovodikove soli spoja sa formulom VI; i gdje spoj sa formulom VI, dobiven u obliku klorovodikove soli, može se konvertirati u slobodnu bazu ili u oblik neke alternativne soli, ako je potrebno.Patent sadrži još 27 patentnih zahtjeva.
Claims (28)
1. Postupak za proizvodnju spoja formule VI:
[image]
gdje je R1 zaštitna skupina labilne kiseline
iz spoja sa formulom VII:
[image]
naznačen time, da navedeni postupak obuhvaća:
(g) reakciju spoja formule VII sa prikladnim agensom za kloriranje u prisutnosti prikladne baze i prikladnog otapala, gdje se reakcija provodi uz:
(g-1) dodavanje smjese spoja sa formulom VII i baze u otapalu u smjesu agensa za kloriranje u otapalu na temperaturi u rasponu od 60 do 90° C tijekom vremena od oko 60 min; ili
(g-2) dodavanje agensa za kloriranje u smjesu spoja sa Formulom VII i baze u otapalu na sobnoj temperaturi tijekom perioda od oko 15 min, te tada pomoću grijanja reakcijske smjese tijekom perioda od oko 90 min na temperaturi u rasponu od 70 do 90° C i uz miješanje reakcijske smjese na istoj temperaturi od oko 1 h; ili
(g-3) dodavanja agensa za kloriranje u mješavinu spoja sa formulom VII i baze u otapalu na temperaturi u rasponu od 60 do 110° C tijekom perioda od oko 15 min, radi dobivanja spoja sa Formulom VIII:
[image]
i
(h) reakciju spoja sa formulom VIII sa 4-bromo-2-fluoroanilinom in situ u prisutnosti otapala koje se koristi u koraku (g) sa svrhom dobivanja klorovodikove soli spoja sa formulom VI;
i gdje spoj sa formulom VI, dobiven u obliku klorovodikove soli, može se konvertirati u slobodnu bazu ili u oblik neke alternativne soli, ako je potrebno.
2. Postupak prema zahtjevu 1, naznačen time, da se koraci (g) i (h), oba provode u toluenu.
3. Postupak prema zahtjevu 1 ili 2, naznačen time, da agens za kloriranje, koji se koristi u koraku (g) je fosforni oksiklorid.
4. Postupak u skladu sa jednim ili više od zahtjeva od 1 do 3, naznačen time, da je baza, koja se koristi u koraku (g) izabrana između trietilamina i N,N-diizopropiletilamina.
5. Postupak u skladu sa jednim ili više od zahtjeva od 1 do 4, naznačen time, da dodatno uključuje korak (i) za izoliranje spoja sa formulom VI.
6. Postupak za proizvodnju 7-hidroksi-4-(4-bromo-2-fluoroanilino)-6-metoksikinazolina, spoja sa formulom IX:
[image]
iz spoja sa formulom VII:
[image]
gdje je R1 zaštitna skupina labilne kiseline
naznačen time, da navedeni postupak obuhvaća korake pretvaranja spoja sa formulom VII u spoj sa formulom VI:
[image]
pomoću provođenja postupaka u skladu sa jednim ili više od zahtjeva od 1 do 4; i
(j) uklanjanja R1 sa spoja formule VI in situ u prisutnosti otapala koji se koristi u koracima (g) i (h) sa svrhom dobivanja spoja sa formulom IX ili njegove soli;
i gdje spoj formule IX, dobiven u obliku slobodne baze, može biti pretvoren u oblik soli, a spoj sa formule IX, dobiven u obliku soli, može biti pretvoren u slobodnu bazu ili u oblik alternativne soli, ako je potrebno.
7. Postupak prema zahtjevu 6, naznačen time, da R1 je benzil, a u koraku (j) se benzilna skupina odstranjuje in situ pomoću reakcije sa trifluorooctenom kiselinom na temperaturi u rasponu od 60 do 80° C.
8. Postupak prema zahtjevu 6, naznačen time, da R1 je benzil, a benzilna skupina se odstranjuje u prisutnosti trifluorooctene kiseline, a spoj formule IX se pretvara u trifluorooctenu kiselu sol pomoću dodavanja kalij hidroksida ili pomoću dodavanja natrij hidroksida i vode.
9. Postupak za proizvodnju 7-hidroksi-4-(4-bromo-2-fluoroanilino)-6-metoksikinazolina, spoja formule IX:
[image]
iz spoja sa formulom VII:
[image]
gdje je R1 zaštitna skupina labilne kiseline
naznačen time, da navedeni postupak obuhvaća korake pretvorbe spoja formule VII u spoj sa formulom VI:
[image]
pomoću provođenja postupaka prema zahtjevu 5; i
(k) odstranjivanja R1 iz spoja sa formulom VI sa svrhom dobivanja spoja sa formulom IX ili njegove soli;
i gdje spoj sa formulom IX, dobiven u obliku slobodne baze, može biti pretvoren u oblik soli, a spoj sa formulom IX, dobiven u obliku soli, može biti pretvoren u slobodnu bazu ili u oblik neke alternativne soli, ako je potrebno.
10. Postupak prema zahtjevu 9, naznačen time, da R1 je benzil, a u koraku (k) se benzilna skupina odstranjuje pomoću reakcije sa agensom pogodnim za hidrogenizaciju.
11. Postupak za proizvodnju 7-(1-tert-butoksikarbonil)piperidin-4-ilmetoksi)-4-(4-bromo-2-fluoroanilino)-6-metoksikinazolina, spoja sa formulom X:
[image]
iz spoja sa Formulom VII:
[image]
gdje je R1 zaštitna skupina labilne kiseline
naznačen time, da navedeni postupak obuhvaća korake pretvorbe spoja sa formulom VII u spoj sa formulom IX:
[image]
pomoću provođenja postupaka u skladu sa jednim ili više od zahtjeva od 6 do 9; i
(I) reakcije spoja sa formulom IX sa spojem sa formulom II:
[image]
u prisutnosti pogodne baze sa svrhom dobivanja spoja sa formulom X ili njegove soli;
i gdje spoj sa formulom X, dobiven u obliku slobodne baze, može biti pretvoren u oblik soli, a spoj sa formulom X, dobiven u obliku soli, može biti pretvoren u slobodnu bazu ili u oblik alternativne soli, ako je potrebno.
12. Postupak prema zahtjevu 11, naznačen time, da je baza koja se koristi u koraku (1) izabrana između natrij karbonata, kalij karbonata, natrij hidroksida i kalij hidroksida.
13. Postupak prema zahtjevu 11 ili 12, naznačen time, da dodatno uključuje korak (m) izoliranja spoja formule X.
14. Postupak za proizvodnju 7-(1-tert-butoksikarbonil)piperidin-4-ilmetoksi)-4-(4-bromo-2-fluoroanilino)-6-metoksikinazolina, spoja sa formulom X:
[image]
iz 7-hidroksi-4-(4-bromo-2-fluoroanilino)-6-metoksikinazolina, spoja sa Formulom IX:
[image]
naznačen time, da navedeni postupak obuhvaća:
(l) reakciju spoja sa formulom IX sa spojem sa formulom II:
[image]
uz prisutnost pogodne baze sa svrhom dobivanja spoja sa formulom X ili njegove soli; i
(m) izoliranja spoja sa formulom X pomoću:
(m-1) dodavanja vode i dozvoljavanja kristalizacije spoja sa formulom X, i sakupljanja spoja sa formulom X i pranja spoja formule X sa vodom, te nakon toga sa otapalom izabranim između etil acetata, butil acetata i acetonitrila na temperaturi u rasponu od 25 do 55° C; ili
(m-2) dodavanja vode i alkohola izabranog od metanola, etanola, izopropanola i n-propanola i dozvoljavanja kristalizacije spoja formule X, i sakupljanja spoja formulom X i pranja spoja sa formulom X sa mješavinom vode i alkohola izabranog od metanola, etanola, izopropanola i n-propanola, a nakon toga sa otapalom izabranim između etil acetata, butil acetata i acetonitrila na temperaturi u rasponu od 25 to 55° C;
i gdje spoj sa formulom X, dobiven u obliku slobodne baze, može biti pretvoren u oblik soli, a spoj sa formulom X, dobiven u obliku soli, može biti pretvoren u oblik slobodne baze ili u oblik neke alternativne soli, ako je potrebno.
15. Postupak prema zahtjevu 14, naznačen time, da baza koja se koristi u koraku (1) je izabrana između natrij karbonata i kalij karbonata.
16. Postupak u skladu sa jednim ili više od zahtjeva od 11 do 15, naznačen time, da spoj sa formulom II, koji se koristi u koraku (I), se priprema iz (C1-C6)alkil-4-piperidinkarboksilatnog spoja sa formulom III:
[image]
naznačen time, da navedeni postupak obuhvaća:
(a) reakciju (C1-C6)alkil-4-piperidinkarboksilatnog spoja sa formulom III sa di-tert-butil dikarbonatom u prisutnosti toluena ili ksilena sa svrhom dobivanja prve mješavine koja obuhvaća toluen ili ksilen, tert-butanol i spoj sa formulom IV:
[image]
(b) značajno odstranjivanje tert-butanola iz prve mješavine;
(c) reakciju spoja sa formulom IV sa prikladnim agensom za redukciju in situ u prisutnosti toluena ili ksilena sa svrhom dobivanja druge mješavine koja obuhvaća toluen, nus-produkte redukcije uključujući alkoholne nus-produkte i spoj sa formulom V:
[image]
(d) značajno odstranjivanje alkoholnih nus-produkata iz druge mješavine; i
(e) reakciju spoja formule V sa tosilkloridom in situ sa svrhom dobivanja sulfonatnog estera u prisutnosti prikladne baze i toluena sa svrhom dobivanja spoja sa formulom II.
17. Postupak prema zahtjevu 16, naznačen time, da (C1-C6)alkil-4-piperidinkarboksilat spoj sa formulom III je etil 4-piperidinkarboksilat.
18. Postupak prema zahtjevu 16 ili 17, naznačen time, da u koraku (c) redukcijski agens je izabran između natrij bi(2-metoksietoksi)aluminij hidrida, litij aluminij hidrida i diizobutilaluminij hidrida.
19. Postupak prema zahtjevu 18, naznačen time, da je u koraku (c) redukcijski agens natrij bi(2-metoksietoksi)aluminij hidrid.
20. Postupak u skladu sa jednim ili više od zahtjeva od 16 do 19, naznačen time, da je u koraku (e) baza trietilendiamin.
21. Postupak u skladu sa jednim ili više od zahtjeva od 16 do 20, naznačen time, da dodatno uključuje korak (f) za izoliranje spoja sa formulom II.
22. Postupak prema zahtjevu 21, naznačen time, da korak (f) obuhvaća kristalizaciju pomoću sustava otapala sa toluenom i izoheksanom.
23. Postupak za proizvodnju 4-(4-bromo-2-fluoroanilino)-6-metoksi-7-(1-metilpiperidin-4-ilmetoksi)kinazolina, ZD6474:
[image]
iz spoja sa formulom X:
[image]
naznačen time, da navedeni postupak obuhvaća:
(n) reakciju spoja formule X sa mravljom kiselinom i formaldehidom ili sa polimerom formaldehida sa svrhom nastajanja soli mravlje kiseline ZD6474;
(o) dodavanje inertnog organskog otapala i prikladne baze sa svrhom nastajanja slobodne baze ZD6474;
gdje ZD6474, dobiven u obliku slobodne baze, može biti pretvoren u farmaceutski prihvatljivu sol, ako je potrebno.
24. Postupak prema zahtjevu 23, naznačen time, da se korak (n) provodi u vodi na temperaturi u rasponu od 70 do 90° C.
25. Postupak prema zahtjevu 23 ili zahtjevom 24, naznačen time, da je inertno organsko otapalo, koje se koristi u koraku (o), izabrano između tetrahidrofurana, butironitrila i metanola.
26. Postupak u skladu sa jednim ili više od zahtjeva od 23 do 25, naznačen time, da je baza koja se koristi u koraku (o) izabrana između natrij hidroksida i kalij hidroksida.
27. Postupak u skladu sa jednim ili više od zahtjeva od 23 do 26, naznačen time, da se spoj formule X, koja se koristi u koraku (n), priprema u skladu sa postupkom koji odgovara opisima iz jednog ili više od zahtjeva od 1 do 16.
28. Postupak u skladu sa jednim ili više od zahtjeva od 23 do 27, naznačen time, da uključuje dodatno pročišćavanje ZD6474 u mješavini tetrahidrofurana, vode i butil acetata radi dobivanja kristalnog nevodenog oblika.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0519879.1A GB0519879D0 (en) | 2005-09-30 | 2005-09-30 | Chemical process |
| PCT/GB2006/003587 WO2007036713A2 (en) | 2005-09-30 | 2006-09-27 | Chemical process |
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| Publication Number | Publication Date |
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| HRP20100019T1 true HRP20100019T1 (hr) | 2010-02-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20100019T HRP20100019T1 (hr) | 2005-09-30 | 2010-01-11 | Kemijski postupak |
| HR20100620T HRP20100620T1 (hr) | 2005-09-30 | 2010-11-16 | Kemijski in situ postupak sulfoniranja |
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| Application Number | Title | Priority Date | Filing Date |
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| HR20100620T HRP20100620T1 (hr) | 2005-09-30 | 2010-11-16 | Kemijski in situ postupak sulfoniranja |
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| US (8) | US8163926B2 (hr) |
| EP (2) | EP2053048B8 (hr) |
| JP (2) | JP5213715B2 (hr) |
| KR (1) | KR101307641B1 (hr) |
| CN (3) | CN102503933B (hr) |
| AR (1) | AR055671A1 (hr) |
| AT (2) | ATE448218T1 (hr) |
| AU (1) | AU2006296367B2 (hr) |
| BR (1) | BRPI0616715A2 (hr) |
| CA (2) | CA2745829C (hr) |
| CY (2) | CY1110275T1 (hr) |
| DE (2) | DE602006017004D1 (hr) |
| DK (2) | DK1943240T3 (hr) |
| ES (2) | ES2350513T3 (hr) |
| GB (1) | GB0519879D0 (hr) |
| HK (2) | HK1122553A1 (hr) |
| HR (2) | HRP20100019T1 (hr) |
| IL (2) | IL190172A (hr) |
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| SG (1) | SG165416A1 (hr) |
| SI (2) | SI1943240T1 (hr) |
| TW (2) | TWI328580B (hr) |
| UY (1) | UY29824A1 (hr) |
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| EP1474420B1 (en) * | 2002-02-01 | 2012-03-14 | AstraZeneca AB | Quinazoline compounds |
| GB0519879D0 (en) * | 2005-09-30 | 2005-11-09 | Astrazeneca Ab | Chemical process |
| CL2007003158A1 (es) * | 2006-11-02 | 2008-05-16 | Astrazeneca Ab | Procedimiento de preparacion de compuestos derivados de quinazolina o sus sales farmaceuticamente aceptables; compuestos intermediarios; procedimiento de preparacion. |
| ES2547902T3 (es) * | 2011-09-01 | 2015-10-09 | Symrise Ag | Procedimiento para la preparación de derivados de indanona |
| KR20150043465A (ko) * | 2012-08-15 | 2015-04-22 | 글락소 그룹 리미티드 | 화학 공정 |
| CN104098544A (zh) * | 2013-04-07 | 2014-10-15 | 浙江九洲药物科技有限公司 | 一种凡德他尼的制备方法 |
| CN106397401B (zh) * | 2016-08-30 | 2018-11-13 | 山东罗欣药业集团股份有限公司 | 一种抗癌药物的晶体化合物及其制备方法 |
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| US4870083A (en) * | 1987-11-24 | 1989-09-26 | Merrell Dow Pharmaceuticals Inc. | 1,4-Disubstituted-piperidinyl compounds useful as analgesics and muscle relaxants |
| JP2829744B2 (ja) | 1989-05-31 | 1998-12-02 | 川研ファインケミカル株式会社 | ピペリジンカルボン酸類の製造方法 |
| WO1992006086A1 (en) | 1990-10-01 | 1992-04-16 | Janssen Pharmaceutica N.V. | Novel 4-piperidinylcarbonyl derivatives |
| CA2195129C (en) | 1991-03-28 | 2002-09-10 | Anabella Villalobos | Substituted piperidine intermediates for producing heterocyclic-cyclic amine derivatives capable of inhibiting cholinesterase |
| CA2102780C (en) | 1991-05-10 | 2007-01-09 | Alfred P. Spada | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
| US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
| CA2118117A1 (en) | 1993-02-18 | 1994-08-19 | Shigeki Fujiwara | Adenosine uptake inhibitor |
| JP3935199B2 (ja) * | 1993-05-26 | 2007-06-20 | シンテックス（ユー・エス・エイ）・インコーポレイテッド | 新規１−フェニルアルカノン５−ｈｔ▲４▼レセプターリガンド類 |
| DE4326344A1 (de) | 1993-08-05 | 1995-02-09 | Thomae Gmbh Dr K | Carbonamide, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| CA2180746A1 (en) | 1994-01-13 | 1995-07-20 | Raymond Baker | Gem-disubstituted azacyclic tachykinin antagonists |
| GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
| ES2169355T3 (es) | 1996-03-05 | 2002-07-01 | Astrazeneca Ab | Derivados de 4-anilinoquinazolina. |
| EP0954315A2 (en) | 1996-09-13 | 1999-11-10 | Sugen, Inc. | Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders |
| GB9718972D0 (en) * | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| ATE330954T1 (de) * | 1999-11-05 | 2006-07-15 | Astrazeneca Ab | Quinazolin-derivate als vegf-hemmer |
| GB0126879D0 (en) | 2001-11-08 | 2002-01-02 | Astrazeneca Ab | Combination therapy |
| ATE468339T1 (de) | 2001-12-20 | 2010-06-15 | Osi Pharm Inc | Pyrrolopyrimidin a2b selektive antagonistische verbindungen, deren synthese und verwendung |
| EP1474420B1 (en) | 2002-02-01 | 2012-03-14 | AstraZeneca AB | Quinazoline compounds |
| ATE533750T1 (de) | 2002-02-06 | 2011-12-15 | Ube Industries | Verfahren zur herstellung einer 4- aminochinazolinverbindung |
| GB0218526D0 (en) | 2002-08-09 | 2002-09-18 | Astrazeneca Ab | Combination therapy |
| EP1534287A1 (en) | 2002-08-09 | 2005-06-01 | Astrazeneca AB | Combination of zd6474, an inhibitor of the vascular endothelial growth factor receptor, with radiotherapy in the treatment of cancer |
| GB0223380D0 (en) | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
| WO2004071397A2 (en) | 2003-02-13 | 2004-08-26 | Astrazeneca Ab | Combination therapy of zd6474 with 5-fu or/and cpt-11 |
| DE602004028834D1 (de) | 2003-07-10 | 2010-10-07 | Astrazeneca Ab | Verwendung des chinazolin-derivats zd6474 in kombination mit platinverbindungen und optional ionisierender strahlung bei der behandlung von erkrankungen im zusammenhang mit angiogenese und/oder erhöhter gefässpermeabilität |
| GB0318423D0 (en) | 2003-08-06 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| GB0519879D0 (en) * | 2005-09-30 | 2005-11-09 | Astrazeneca Ab | Chemical process |
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