HRP20171535T1 - Sinteza 3-(5-amino-2-metil-4-oksokinazolin-3(4h)-il)piperidin-2,6-diona - Google Patents
Sinteza 3-(5-amino-2-metil-4-oksokinazolin-3(4h)-il)piperidin-2,6-diona Download PDFInfo
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- HRP20171535T1 HRP20171535T1 HRP20171535TT HRP20171535T HRP20171535T1 HR P20171535 T1 HRP20171535 T1 HR P20171535T1 HR P20171535T T HRP20171535T T HR P20171535TT HR P20171535 T HRP20171535 T HR P20171535T HR P20171535 T1 HRP20171535 T1 HR P20171535T1
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- Croatia
- Prior art keywords
- methyl
- dione
- nitro
- acid
- oxoquinazolin
- Prior art date
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- RSNPAKAFCAAMBH-UHFFFAOYSA-N 3-(5-amino-2-methyl-4-oxoquinazolin-3-yl)piperidine-2,6-dione Chemical compound CC1=NC2=CC=CC(N)=C2C(=O)N1C1CCC(=O)NC1=O RSNPAKAFCAAMBH-UHFFFAOYSA-N 0.000 title claims 5
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims 17
- 150000003839 salts Chemical class 0.000 claims 12
- 239000002904 solvent Substances 0.000 claims 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 10
- MMJSZIMFGHOSBC-UHFFFAOYSA-N 2-methyl-5-nitro-3,1-benzoxazin-4-one Chemical compound C1=CC([N+]([O-])=O)=C2C(=O)OC(C)=NC2=C1 MMJSZIMFGHOSBC-UHFFFAOYSA-N 0.000 claims 9
- NPWMTBZSRRLQNJ-UHFFFAOYSA-N pyroglutamine Chemical compound NC1CCC(=O)NC1=O NPWMTBZSRRLQNJ-UHFFFAOYSA-N 0.000 claims 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 7
- 125000000623 heterocyclic group Chemical group 0.000 claims 7
- 239000000203 mixture Substances 0.000 claims 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 claims 6
- 125000001072 heteroaryl group Chemical group 0.000 claims 6
- 239000000852 hydrogen donor Substances 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- 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 5
- 239000003054 catalyst Substances 0.000 claims 5
- 235000019253 formic acid Nutrition 0.000 claims 5
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 4
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 claims 4
- KHEXQYOPAOPUQQ-UHFFFAOYSA-N 3-(2-methyl-5-nitro-4-oxoquinazolin-3-yl)piperidine-2,6-dione Chemical compound CC1=NC2=CC=CC([N+]([O-])=O)=C2C(=O)N1C1CCC(=O)NC1=O KHEXQYOPAOPUQQ-UHFFFAOYSA-N 0.000 claims 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims 4
- 239000003153 chemical reaction reagent Substances 0.000 claims 4
- 230000021615 conjugation Effects 0.000 claims 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims 4
- 230000007062 hydrolysis Effects 0.000 claims 4
- 238000006460 hydrolysis reaction Methods 0.000 claims 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 4
- 239000012453 solvate Substances 0.000 claims 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 229910021205 NaH2PO2 Inorganic materials 0.000 claims 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims 3
- GGKYLHNARFFORH-UHFFFAOYSA-N 2-amino-6-nitrobenzoic acid Chemical compound NC1=CC=CC([N+]([O-])=O)=C1C(O)=O GGKYLHNARFFORH-UHFFFAOYSA-N 0.000 claims 2
- BVJRNKXVSYLNFD-UHFFFAOYSA-N 3-(5-amino-2-methyl-4-oxoquinazolin-3-yl)piperidine-2,6-dione;hydrochloride Chemical compound Cl.CC1=NC2=CC=CC(N)=C2C(=O)N1C1CCC(=O)NC1=O BVJRNKXVSYLNFD-UHFFFAOYSA-N 0.000 claims 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 2
- -1 C2-14 alkene Chemical class 0.000 claims 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- 229910019213 POCl3 Inorganic materials 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000003377 acid catalyst Substances 0.000 claims 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims 2
- 229910000071 diazene Inorganic materials 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 150000004677 hydrates Chemical class 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims 1
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical group Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 claims 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 1
- 239000012346 acetyl chloride Substances 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 235000010323 ascorbic acid Nutrition 0.000 claims 1
- 239000011668 ascorbic acid Substances 0.000 claims 1
- 229960005070 ascorbic acid Drugs 0.000 claims 1
- 150000001733 carboxylic acid esters Chemical class 0.000 claims 1
- 150000001734 carboxylic acid salts Chemical class 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 150000001925 cycloalkenes Chemical class 0.000 claims 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 claims 1
- 229940013688 formic acid Drugs 0.000 claims 1
- 150000002390 heteroarenes Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 229960000448 lactic acid Drugs 0.000 claims 1
- 229960002510 mandelic acid Drugs 0.000 claims 1
- 229940041616 menthol Drugs 0.000 claims 1
- ISSLESFGPVAXKC-UHFFFAOYSA-N n-[3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxoquinazolin-5-yl]formamide Chemical compound CC1=NC2=CC=CC(NC=O)=C2C(=O)N1C1CCC(=O)NC1=O ISSLESFGPVAXKC-UHFFFAOYSA-N 0.000 claims 1
- 229910000510 noble metal Inorganic materials 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 229910003445 palladium oxide Inorganic materials 0.000 claims 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 claims 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 229910052702 rhenium Inorganic materials 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- 235000017281 sodium acetate Nutrition 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 1
- 150000003505 terpenes Chemical class 0.000 claims 1
- 235000007586 terpenes Nutrition 0.000 claims 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Claims (17)
1. Postupak dobivanja 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona, ili njegovog enantiomera ili smjese njegovih enantiomera; ili njegove farmaceutski prihvatljive soli, solvata, hidrata ili polimorfa; naznačen time što se sastoji u koraku reduciranja 3-(2-metil-5-nitro-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona hidrogeniranjem prijenosom kako bi se dobilo 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-dion, ili njegov enantiomer ili smjesu njegovih enantiomera; ili njegovu farmaceutski prihvatljivu sol, solvat, hidrat ili polimorf.
2. Postupak u skladu s patentnim zahtjevom 1, naznačen time što se hidrogeniranje prijenosom provodi u prisutnosti donora vodika.
3. Postupak u skladu s patentnim zahtjevom 2, naznačen time što je donor vodika (i) C1-14 alkohol, C1-14 karboksilna kiselina, sol C1-14 karboksilne kiseline, ester C1-14 karboksilne kiseline, C2-14 alken, C3-14 cikloalken, C6-14 aren, heteroaren ili heterocikl, od kojih svaki može biti supstituiran s jednim ili više supstituenata Q; ili (ii) diazen, hidrazin, hidroksilamin ili NaH2PO2;
gdje se svaki supstituent Q neovisno bira iz skupine koju čine (a) okso, halogen, cijano, te nitro; (b) C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10 cikloalkil, C6-14 aril, C7-15 aralkil, heteroaril, te heterociklil, gdje svaki od može biti dodatno izborno supstituiran s jednim ili više supstituenata Qa; i (c) –C(O)Ra, –C(O)ORa, –C(O)NRbRc, –C(NRa)NRbRc, –ORa, –OC(O)Ra, –OC(O)ORa, –OC(O)NRbRc, –OC(=NRa)NRbRc, –OS(O)Ra, –OS(O)2Ra, –OS(O)NRbRc, –OS(O)2NRbRc, –NRbRc, –NRaC(O)Rd, –NRaC(O)ORd, –NRaC(O)NRbRc, –NRaC(=NRd)NRbRc, –NRaS(O)Rd, –NRaS(O)2Rd, –NRaS(O)NRbRc, –NRaS(O)2NRbRc, –P(O)RaRd, –P(O)(ORa)Rd, –P(O)(ORa)(ORd), –SRa, –S(O)Ra, -S(O)2Ra, –S(O)NRbRc, i –S(O)2NRbRc, gdje je svaki Ra, Rb, Rc i Rd neovisno (i) vodik; (ii) C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10 cikloalkil, C6-14 aril, C7-15 aralkil, heteroaril ili heterociklil, od kojih svaki može biti supstituiran s jednim ili više supstituenata Qa; ili (iii) Rb i Rc, zajedno s N atomom na kojeg su vezani, tvore heteroaril ili heterociklil, od kojih svaki može biti supstituiran s jednim ili više supstituenata Qa;
gdje se svaki supstituent Qa neovisno bira iz skupine koju čine (a) okso, cijano, halogen, te nitro; i (b) C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10 cikloalkil, C6-14 aril, C7-15 aralkil, heteroaril, te heterociklil; i (c) –C(O)Re, –C(O)ORe, –C(O)NRfRg, –C(NRe)NRfRg, -ORe, –OC(O)Re, –OC(O)ORe, –OC(O)NRfRg, –OC(=NRe)NRfRg, –OS(O)Re, –OS(O)2Re, –OS(O)NRfRg, –OS(O)2NRfRg, –NRfRg, –NReC(O)Rh, –NReC(O)ORh, –NReC(O)NRfRg, –NReC(=NRh)NRfRg, –NReS(O)Rh, –NReS(O)2Rh, –NReS(O)NRfRg, –NReS(O)2NRfRg, –P(O)ReRh, –P(O)(ORe)Rh, –P(O)(ORe)(ORh), –SRe, –S(O)Re, –S(O)2Re, –S(O)NRfRg, te –S(O)2NRfRg; gdje je svaki Re, Rf, Rg i Rh neovisno (i) vodik, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10 cikloalkil, C6-14 aril, C7-15 aralkil, heteroaril ili heterociklil; ili (ii) Rf i Rg, zajedno s N atomom na kojeg su vezani, tvore heteroaril ili heterociklil.
4. Postupak u skladu s patentnim zahtjevom 3, naznačen time što je donor vodika metanol, etanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, ciklopentanol, cikloheksanol, benzilalkohol, mentol, mravlja kiselina, mliječna kiselina, askorbinska kiselina, bademova kiselina, amonijev formijat, kalijev formijat, cikloheksadien, cikloheksen, 1-metilcikloheksen, tetralin, dihidrofuran, terpen, diazen, hidrazin, hidroksilamin ili NaH2PO2, ili njihova smjesa; ili
gdje je donor vodika mravlja kiselina, amonijev formijat, kalijev formijat, cikloheksen, 1-metilcikloheksen, NaH2PO2, ili njihova smjesa; ili
gdje je donor vodika C1-14 karboksilna kiselina.
5. Postupak u skladu s patentnim zahtjevom 4, naznačen time što je donor vodika mravlja kiselina; ili
gdje se molarni omjer između mravlje kiseline i 3-(2-metil-5-nitro-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona može kretati u rasponu od otprilike 1 do otprilike 100, ili se može kretati u rasponu od otprilike 15 do otprilike 25.
6. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time što se hidrogeniranje prijenosom provodi u prisutnosti katalizatora, po mogućnosti gdje je katalizator katalizator na bazi plemenitog metala, poželjnije gdje je katalizator paladij, paladijevo crnilo, paladij na ugljiku (Pd/C), paladijev oksid, ili Lindlarov katalizator; i/ili
gdje se hidrogeniranje prijenosom provodi u otapalu; po mogućnosti
gdje otapalo sadrži vodu, i/ili
gdje otapalo sadrži karboksilnu kiselinu,
gdje karboksilna kiselina može bit mravlja kiselina, i/ili gdje se hidrogeniranje prijenosom može provoditi na rasponu temperatura od otprilike 0 do otprilike 100 °C ili na rasponu temperatura od otprilike 10 do otprilike 60 °C.
7. Postupak u skladu s patentnim zahtjevom 6, naznačen time što otapalo sadrži karboksilnu kiselinu i vodu; gdje se volumni omjer između karboksilna kiselina i vode može kretati u rasponu od otprilike 0,1 do otprilike 10, ili od otprilike 1 do otprilike 5, ili je otprilike 1.
8. Postupak u skladu s bilo kojim od patentnih zahtjeva 5 do 7, naznačen time što se dobije N-(3-(2,6-dioksopiperidin-3-il)-2-metil-4-okso-3,4-dihidrokinazolin-5-il)formamid.
9. Postupak u skladu s patentnim zahtjevom 8, naznačen time što dodatno uključuje korak hidrolize N-(3-(2,6-dioksopiperidin-3-il)-2-metil-4-okso-3,4-dihidrokinazolin-5-il)formamida do 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona, ili njegovog enantiomera ili smjese njegovih enantiomera; ili njegove farmaceutski prihvatljive soli, solvata, hidrata ili polimorfa.
10. Postupak u skladu s patentnim zahtjevom 9, naznačen time što se hidrolizu provodi u prisutnosti kiselinskog katalizatora,
gdje kiselinski katalizator može biti klorovodik, i/ili
gdje se hidrolizu može provoditi u otapalu, po mogućnosti
gdje otapalo može sadržavati C1-6 alkohol, ili
gdje otapalo može sadržavati etanol; i/ili
gdje se hidrolizu može provoditi na rasponu temperatura od otprilike 50 do otprilike 120 °C, ili na rasponu temperatura od otprilike 65 do otprilike 85 °C.
11. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 10, naznačen time što dodatno uključuje korak reakcije 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, u uvjetima pogodnim za dobivanje 3-(2-metil-5-nitro-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona, prije koraka reduciranja 3-(2-metil-5-nitro-4-oksokinazolin-3(4H)-il)piperidin-2,6-diona.
12. Postupak u skladu s patentnim zahtjevom 11, naznačen time što se reakciju 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, provodi uz upotrebu soli 3-aminopiperidin-2,6-diona, po mogućnosti
gdje je sol 3-aminopiperidin-2,6-diona 3-aminopiperidin-2,6-dion-hidroklorid; i/ili
gdje se reakciju 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, provodi u prisutnosti baze; po mogućnosti
gdje je baza natrijev hidrogenkarbonat, natrijev karbonat, natrijev citrat, dihidrat, natrijev acetat, imidazol ili piridin; i/ili
gdje se reakciju 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, provodi u prisutnosti konjugacijskog reagensa; po mogućnosti
gdje konjugacijski reagens sadrži N-(3-dimetilaminopropil)-N′-etilkarbodiimid, PCl3, PCl5, ciklički anhidrid 1-propanfosfonske kiseline, acetanhidrid, fosfornu kiselinu, POCl3, ili smjesu POCl3 i vode; poželjnije
gdje je konjugacijski reagens ciklički anhidrid 1-propanfosfonske kiseline.
13. Postupak u skladu s patentnim zahtjevom 12, naznačen time što se molarni omjer između konjugacijskog reagensa i 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona kreće u rasponu od otprilike 1 do otprilike 10; ili se kreće u rasponu od otprilike 1 do otprilike 3; ili je otprilike 2; i/ili
gdje se reakciju 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, provodi u otapalu; po mogućnosti
gdje otapalo sadrži acetonitril ili amid; poželjnije gdje otapalo sadrži acetonitril, formamid, N,N-dimetilformamid, N,N-dimetilacetamid ili N-metilpirolidon; i/ili
gdje se reakciju 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju, provodi na rasponu temperatura od otprilike 0 do otprilike 150 °C ili od otprilike 60 do otprilike 100 °C.
14. Postupak u skladu s bilo kojim od patentnih zahtjeva 11 do 13, naznačen time što dodatno uključuje korak reakcije 2-amino-6-nitrobenzojeve kiseline s aktiviranom octenom kiselinom u otapalu kako bi se dobilo 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-on, prije reakcije 2-metil-5-nitro-4H-benzo[d][1,3]oksazin-4-ona s 3-aminopiperidin-2,6-dionom, ili njegovom solju; po mogućnosti
gdje je aktivirana octena kiselina acetil-klorid ili acetanhidrid.
15. Postupak u skladu s patentnim zahtjevom 14, naznačen time što se molarni omjer između aktivirane octene kiseline i 2-amino-6-nitrobenzojeve kiseline kreće u rasponu od otprilike 1 do otprilike 10, ili se kreće u rasponu od otprilike 1,5 do otprilike 2,5.
16. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 15, naznačen time što 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-dion, ili njegov enantiomer ili smjesa njegovih enantiomera; ili njegova farmaceutski prihvatljiva sol, solvat, hidrat ili polimorf, pripravljen ima čistoću koja nije manja od 95%, težinski.
17. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačen time što dodatno uključuje korak prekristaliziranja 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-dion-hidroklorida;
gdje 3-(5-amino-2-metil-4-oksokinazolin-3(4H)-il)piperidin-2,6-dion-hidroklorid može imati čistoću koja nije manja od 95%, težinski.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361818254P | 2013-05-01 | 2013-05-01 | |
| EP14728381.6A EP2991976B1 (en) | 2013-05-01 | 2014-04-30 | Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2,6-dione |
| PCT/US2014/036083 WO2014179416A1 (en) | 2013-05-01 | 2014-04-30 | Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2,6-dione |
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| Publication Number | Publication Date |
|---|---|
| HRP20171535T1 true HRP20171535T1 (hr) | 2017-11-17 |
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| HRP20171535TT HRP20171535T1 (hr) | 2013-05-01 | 2017-10-11 | Sinteza 3-(5-amino-2-metil-4-oksokinazolin-3(4h)-il)piperidin-2,6-diona |
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| Country | Link |
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| US (3) | US9067912B2 (hr) |
| EP (2) | EP2991976B1 (hr) |
| JP (2) | JP6490055B2 (hr) |
| KR (1) | KR20160003228A (hr) |
| CN (2) | CN107935994A (hr) |
| AR (1) | AR096165A1 (hr) |
| AU (2) | AU2014260011A1 (hr) |
| CA (1) | CA2910971A1 (hr) |
| CY (1) | CY1119525T1 (hr) |
| DK (1) | DK2991976T3 (hr) |
| ES (1) | ES2645944T3 (hr) |
| HR (1) | HRP20171535T1 (hr) |
| HU (1) | HUE034770T2 (hr) |
| LT (1) | LT2991976T (hr) |
| MX (1) | MX363652B (hr) |
| NZ (1) | NZ628322A (hr) |
| PH (1) | PH12015502477A1 (hr) |
| PL (1) | PL2991976T3 (hr) |
| PT (1) | PT2991976T (hr) |
| RS (1) | RS56565B1 (hr) |
| RU (1) | RU2015151359A (hr) |
| SG (1) | SG11201508836XA (hr) |
| SI (1) | SI2991976T1 (hr) |
| TW (1) | TW201536766A (hr) |
| WO (1) | WO2014179416A1 (hr) |
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| DK2420497T3 (en) | 2006-09-26 | 2016-03-07 | Celgene Corp | 5-substituted quinazolinone derivatives as anticancer agents |
| MX2013010360A (es) | 2011-03-11 | 2014-04-14 | Celgene Corp | Formas solidas sde 3-(5-amino-2-metil-4-oxo-4h-quinazolin-3-il)-pi peridin-2,6-diona, y sus composiciones farmaceuticas y usos. |
| ES2814952T3 (es) | 2012-09-04 | 2021-03-29 | Celgene Corp | Isotopólogos de 3-(5-amino-2-metil-4-oxoquinazolin-3(4H)-il) piperidina-2-6-diona y métodos de preparación de los mismos |
| US10973822B2 (en) | 2015-07-02 | 2021-04-13 | Celgene Corporation | Combination therapy for treatment of hematological cancers and solid tumors |
| CN106083622B (zh) * | 2016-06-16 | 2018-06-19 | 常州齐晖药业有限公司 | 一种甲苯咪唑中间体3,4-二氨基二苯甲酮的制备方法 |
| WO2018165142A1 (en) * | 2017-03-07 | 2018-09-13 | Celgene Corporation | Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses |
| CN113101295A (zh) * | 2020-03-20 | 2021-07-13 | 上海疆云医疗健康科技有限公司 | 二苯乙烯类似物在治疗糖尿病肾脏疾病中的用途 |
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| CN101528702A (zh) * | 2006-06-08 | 2009-09-09 | 阿雷生物药品公司 | 喹啉化合物和使用方法 |
| DK2420497T3 (en) * | 2006-09-26 | 2016-03-07 | Celgene Corp | 5-substituted quinazolinone derivatives as anticancer agents |
| CA2829592A1 (en) * | 2011-03-11 | 2012-09-20 | Celgene Corporation | Methods of treating cancer using 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione |
| MX2013010360A (es) * | 2011-03-11 | 2014-04-14 | Celgene Corp | Formas solidas sde 3-(5-amino-2-metil-4-oxo-4h-quinazolin-3-il)-pi peridin-2,6-diona, y sus composiciones farmaceuticas y usos. |
| ES2814952T3 (es) | 2012-09-04 | 2021-03-29 | Celgene Corp | Isotopólogos de 3-(5-amino-2-metil-4-oxoquinazolin-3(4H)-il) piperidina-2-6-diona y métodos de preparación de los mismos |
| US9540340B2 (en) * | 2013-01-14 | 2017-01-10 | Deuterx, Llc | 3-(5-substituted-4-oxoquinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives and compositions comprising and methods of using the same |
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- 2014-04-30 AU AU2014260011A patent/AU2014260011A1/en not_active Abandoned
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- 2014-04-30 WO PCT/US2014/036083 patent/WO2014179416A1/en active Application Filing
- 2014-04-30 EP EP17161076.9A patent/EP3199532A1/en not_active Withdrawn
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