HRP20211816T1 - Postupak za pripravu [7-[[4-fenil-5-alkoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1h-imidazo[1,5-a]pirazin-2-l]alkila karboksilne kiseline - Google Patents
Postupak za pripravu [7-[[4-fenil-5-alkoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1h-imidazo[1,5-a]pirazin-2-l]alkila karboksilne kiseline Download PDFInfo
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- HRP20211816T1 HRP20211816T1 HRP20211816TT HRP20211816T HRP20211816T1 HR P20211816 T1 HRP20211816 T1 HR P20211816T1 HR P20211816T T HRP20211816T T HR P20211816TT HR P20211816 T HRP20211816 T HR P20211816T HR P20211816 T1 HRP20211816 T1 HR P20211816T1
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- 238000000034 method Methods 0.000 title claims 27
- -1 alkyl carboxylic acids Chemical class 0.000 title claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title claims 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 50
- 230000015572 biosynthetic process Effects 0.000 claims 26
- 239000002904 solvent Substances 0.000 claims 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 14
- 125000000217 alkyl group Chemical group 0.000 claims 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 10
- 239000002253 acid Substances 0.000 claims 10
- 239000003153 chemical reaction reagent Substances 0.000 claims 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 9
- 150000003839 salts Chemical class 0.000 claims 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims 7
- 239000012046 mixed solvent Substances 0.000 claims 7
- 235000011007 phosphoric acid Nutrition 0.000 claims 7
- 235000017550 sodium carbonate Nutrition 0.000 claims 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- 239000007864 aqueous solution Substances 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 claims 6
- 229910052736 halogen Inorganic materials 0.000 claims 6
- 150000002367 halogens Chemical class 0.000 claims 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 6
- 239000003960 organic solvent Substances 0.000 claims 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 5
- 239000012948 isocyanate Substances 0.000 claims 5
- 150000002513 isocyanates Chemical class 0.000 claims 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical group COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 4
- 229910015900 BF3 Inorganic materials 0.000 claims 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 4
- 239000004202 carbamide Substances 0.000 claims 4
- 235000015320 potassium carbonate Nutrition 0.000 claims 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 4
- 230000001681 protective effect Effects 0.000 claims 4
- 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 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical group C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 3
- 239000002841 Lewis acid Substances 0.000 claims 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims 3
- 235000019439 ethyl acetate Nutrition 0.000 claims 3
- 150000007517 lewis acids Chemical class 0.000 claims 3
- 239000012453 solvate Substances 0.000 claims 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims 2
- JEHUZVBIUCAMRZ-UHFFFAOYSA-N 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate Chemical compound O1P(O)(=O)OC2=CC=C(C=CC=C3)C3=C2C2=C1C=CC1=CC=CC=C21 JEHUZVBIUCAMRZ-UHFFFAOYSA-N 0.000 claims 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 2
- IGWHDMPTQKSDTL-JXOAFFINSA-N TMP Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IGWHDMPTQKSDTL-JXOAFFINSA-N 0.000 claims 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 claims 2
- 238000006460 hydrolysis reaction Methods 0.000 claims 2
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 claims 2
- 238000001953 recrystallisation Methods 0.000 claims 2
- 238000007363 ring formation reaction Methods 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims 2
- GIWQSPITLQVMSG-UHFFFAOYSA-N 1,2-dimethylimidazole Chemical compound CC1=NC=CN1C GIWQSPITLQVMSG-UHFFFAOYSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims 1
- BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 claims 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 claims 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- 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 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 claims 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims 1
- 229910009523 YCl3 Inorganic materials 0.000 claims 1
- 229910007339 Zn(OAc)2 Inorganic materials 0.000 claims 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 claims 1
- 150000004645 aluminates Chemical class 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical group ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical group ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 claims 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 claims 1
- 230000002829 reductive effect Effects 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 235000011149 sulphuric acid Nutrition 0.000 claims 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims 1
- PCMOZDDGXKIOLL-UHFFFAOYSA-K yttrium chloride Chemical compound [Cl-].[Cl-].[Cl-].[Y+3] PCMOZDDGXKIOLL-UHFFFAOYSA-K 0.000 claims 1
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 claims 1
- 239000011592 zinc chloride Substances 0.000 claims 1
- 235000005074 zinc chloride Nutrition 0.000 claims 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (24)
1. Postupak za pripravu spoja formule (I),
[image]
naznačen time, da
R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabranim od halogena i C1−6alkila;
R2 je C1-6alkil;
R3 je −CxH2x−;
x je 1, 2, 3, 4, 5, 6 ili 7,
ili njegova farmaceutski prihvatljiva sol ili dijastereomer,
koji se sastoji od sljedećih koraka:
korak a) formiranje izocijanata (III),
[image]
reakcijom spoja formule (II)
[image]
s trifosgenom,
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak b) formiranje uree (V) reakcijom dodavanja izocijanata (III) i spoja (IV)
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak c) formiranje spoja formule (VI) reakcijom ciklizacije uree (V),
[image]
pri čemu R3 je −CXH2X−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak d) formiranje spoja formule (VII) zaštitom spoja formule (VI),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak e) formiranje spoja formule (VIII) selektivnom redukcijom spoja formule (VII),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak f) formiranje spoja formule (IX) hidrolizom spoja formule (VIII),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak g) formiranje spoja formule (X) uklanjanjem zaštite spoja formule (IX),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak h) formiranje spoja formule (XIV) reakcijom poput Biginellijeve reagiranjem spojeva formula (XI), (XII) i (XIII)
[image]
kako bi se dobio spoj formule (XIV)
[image]
pri čemu R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabrana od halogena i C1−6alkila; R2 je C1−6alkil;
korak i) formiranje spoja formule (XVI) reakcijom spoja formule (XIV)
[image]
s organskom kiselinom (XV),
i prekristalizacija enantiomerne soli spoja formule (XVI) ili solvata,
[image]
pri čemu R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabrana od halogena i C1−6alkila; R2 je C1−6alkil; kiselina je D-(+)-DTTA, L-DTTA, L-vinska kiselina, D-DBTA, (+)-CSA, (S)-(+)-1,1’-binaftil-2,2’-diil vodikov fosfat ili (R)-(-)-1,1’-binaftil-2,2’-diil vodikov fosfat;
korak j) dobivanje enantiomernog spoja formule (XVII) iz njegove enantiomerne soli formule (XVI) ili solvata,
[image]
pri čemu R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabranih od halogena i C1−6alkila; R2 je C1−6alkil;
korak k) formiranje spoja formule (XVIII) reakcijom bromiranja spoja formule (XVII),
[image]
pri čemu R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabranih od halogena i C1−6alkila; R2 je C1−6alkil;
korak 1) formiranje spoja formule (I) reakcijom supstitucije spoja formule (XVIII) sa spojem formule (X),
[image]
pri čemu R1 je fenil, koji je nesupstituiran ili supstituiran s jednim, dva ili tri supstituenta neovisno odabrana od halogena i C1−6alkila; R2 je C1−6alkil; R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7.
2. Postupak prema patentnom zahtjevu 1, naznačen time, da R1 je klorofluorfenil ili metilklorofenil, R2 je metil ili etil, R3 je −CH2-C(CH3)2− ili njegova farmaceutski prihvatljiva sol ili dijastereomer.
3. Postupak prema patentnom zahtjevu 1 ili 2 za sintezu
[image]
ili
[image]
ili njegove farmaceutski prihvatljive soli ili dijastereomera.
4. Postupak pripreme spoja formule (X),
[image]
naznačen time, da
R3 je −CxH2x−;
x je 1, 2, 3, 4, 5, 6 ili 7,
ili njegova farmaceutski prihvatljiva sol, enantiomer ili dijastereomer,
koji se sastoji od jednog ili više sljedećih koraka:
korak a) formiranje izocijanata (III),
[image]
reakcijom spoja formule (II)
[image]
s trifosgenom,
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak b) formiranje uree (V) reakcijom dodavanja izocijanata (III) i spoja (IV)
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak c) stvaranje spoja formule (VI) reakcijom ciklizacije uree
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7;
korak d) formiranje spoja formule (VII) protekcijom spoja formule (VI),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak e) formiranje spoja formule (VIII) selektivnom redukcijom spoja formule (VII),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak f) formiranje spoja formule (IX) hidrolizom spoja formule (VIII),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7; R je C1−6alkil;
korak g) formiranje spoja formule (X) deprotekcijom spoja formule (IX),
[image]
pri čemu R3 je −CxH2x−; x je 1, 2, 3, 4, 5, 6 ili 7.
5. Postupak prema patentnom zahtjevu 4, naznačen time, da je R3 −CH2-C(CH3)2− ili njegova farmaceutski prihvatljiva sol ili dijastereomer.
6. Postupak prema patentnom zahtjevu 4 ili 5 za sintezu
[image]
ili njegove farmaceutski prihvatljive soli ili dijastereomera.
7. Postupak prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da se formiranje izocijanata (III) u koraku a) izvodi u prisutnosti baze u otapalu s fosgenskim reagensom, pri čemu je otapalo odabrano od 2-MeTHF, THF, IPAc, EA, toluena i DCM, posebice otapalo je DCM.
8. Postupak prema patentnom zahtjevu 7, naznačen time, da je baza odabrana između Na2CO3, NaHCO3, K2CO3, Na3PO4 i K3PO4, posebice baza je vodena otopina Na2CO3 u koncentraciji od 5 – 25 % mas. udjela Ili vodena otopina K2CO3 u koncentraciji od 5 – 30 % mas. udjela, prije svega baza je vodena otopina Na2CO3 u koncentraciji od 10 – 15 % mas. udjela.
9. Postupak prema patentnom zahtjevu 7 ili 8, naznačen time, da je fosgenski reagens odabran između fosgena, difosgena i trifosgena, posebice fosgenski reagens je trifosgen, pri čemu količina trifosgena je 0,34 – 1,0 ekv. spoja formule (II), posebice 0,34 – 0,45 ekv.
10. Postupak prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da se formiranje spoja formule (VI) u koraku c) izvodi u prisutnosti kiseline u organskom otapalu, pri čemu je otapalo odabrano od 2-MeTHF, IPAc, EA, toluena, DCM, metanola i etanola, posebice otapalo je etanol.
11. Postupak prema patentnom zahtjevu 10, naznačen time, da se kiselina bira između bor -trifluorid eterata, fosforne kiseline, sumporne kiseline, HBr i HCl, posebice kiselina je HCl, prije svega kiselina je koncentrirana HCl.
12. Postupak prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da se formiranje spoja formule (VII) u koraku d) izvodi u prisutnosti baze sa zaštitnim reagensom u otapalu, pri čemu je zaštitni reagens odabran od kloroformata i anhidrida, posebice zaštitni reagens je benzil kloroformat ili Boc anhidrid, prije svega zaštitni reagens je Boc anhidrid.
13. Postupak prema patentnom zahtjevu 12, naznačen time, da je otapalo odabrano između 2-MeTHF, THF, IPAc, EtOAc i DCM; posebice otapalo je THF ili 2-MeTHF.
14. Postupak prema patentnom zahtjevu 12 ili 13, naznačen time, da je baza odabrana između TEA, DIPEA, Na2CO3, NaHCO3, K2CO3, Na3PO4 i K3PO4; posebice baza je Na2CO3 ili NaHCO3; prije svega baza je vodena otopina Na2CO3 ili vodena otopina NaHCO3.
15. Postupak prema bilo kojem od patentnih zahtjeva 1 do 14, naznačen time, da se formiranje spoja formule (VIII) u koraku e) izvodi u prisutnosti katalitičke Lewisove kiseline i redukcijskog reagensa, pri čemu je katalitička Lewisova kiselina odabrana od InCl3, YCl3, ZnCl2, Zn(OAc)2 i BF3·Et2O; posebice Lewisova kiselina je BF3·Et2O, pri čemu količina BF3·Et2O je 0,05 – 1,1 ekv. spoja formule (VII), posebice 0,2 ekv.
16. Postupak prema patentnom zahtjevu 15, naznačen time, da je redukcijski reagens odabran između litij-aluminij hidrida, natrijeva dihidro-bis-(2-metoksietoksi)aluminata, bor dimetilsulfida, fenilsilana i kompleksa bor tetrahidrofurana; posebice reduktivni reagens je kompleks bor tetrahidrofurana, pri čemu količina kompleksa bor tetrahidrofurana je 1,6 – 5,0 ekv. spoja formule (VII), posebice 1,6 – 2,0 ekv.
17. Postupak prema bilo kojem od patentnih zahtjeva 1 do 16, naznačen time, da se spoj formule (IX) u koraku f) izolira postupkom obrade, pri čemu se postupak obrade sastoji od ekstrakcije organskim otapalom radi uklanjanja nečistoće, pri čemu je organsko otapalo odabrano od THF, EA, IPAc, MTBE i toluena, posebice organsko otapalo je IPAc.
18. Postupak prema bilo kojem od patentnih zahtjeva 1 do 17, naznačen time, da se formiranje spoja formule (X) u koraku g) izvodi u prisutnosti kiseline u otapalu, pri čemu se kiselina bira između TFA, fosforne kiseline, MSA, sumporne kiseline, HBr i HCl, posebice kiselina je HCl.
19. Postupak prema patentnom zahtjevu 18, naznačen time, da se otapalo bira između DCM, dioksana, EtOAc, IPAc, IPA, acetona, MIBK i miješanog otapala MIBK i acetona; posebice otapalo je MIBK.
20. Postupak prema patentnom zahtjevu 18 ili 19, naznačen time, da se spoj formule (X) u koraku g) izolira prekristalizacijom u otapalu, pri čemu se otapalo bira između acetonitrila, IPAc, MIBK, etanola, acetona, miješanog otapala acetona i metanola te miješanog otapala acetona i MIBK, posebice otapalo je aceton.
21. Postupak prema bilo kojem od patentnih zahtjeva 1 do 3 i 7 do 20, naznačen time, da se enantiomerna sol spoja formule (XVI) ili solvata u koraku i) prekristalizira u otapalu, pri čemu je otapalo odabrano od etanola, MIBK, IPAc, toluena i MTBE, posebice otapalo je etanol.
22. Postupak prema bilo kojem od patentnih zahtjeva 1 do 3 i 7 do 21, naznačen time, da se stvaranje spoja formule (I) u koraku 1) izvodi u prisutnosti baze, pri čemu se baza bira između TMP, DIPEA, TEA, tripropilamina, N,N-dicikloheksilmetilamina, DBU, NMM, 2,6-lutidina, 1-metilimidazola, 1,2-dimetilimidazola, tetra metilpiperidin-4-ola, Na2CO3, K2CO3, NaHCO3 i tris(2-hidroksiletil)amina; posebice baza je TMP ili tris(2-hidroksiletil)amin; a prije svega baza je tris(2-hidroksiletil)amin.
23. Postupak prema patentnom zahtjevu 22, naznačen time, da se spoj formule (I) pročišćava u koraku 1) kiselinsko-baznom obradom, pri čemu se kiselina korištena u kiselinsko-baznoj obradi bira između HCl, HBr, H2SO4, H3PO4, MSA, toluena sulfonske kiseline i kamfor sulfonske kiseline; posebice kiselina je H3PO4, pri čemu koncentracija vodene otopine H3PO4 odabrana je od 15 % mas. udjela do 60 % mas. udjela, posebice koncentracija vodene otopine H3PO4 je od 35 % mas. udjela do 40 % mas. udjela; količina H3PO4 je 5 – 25 ekv. spoja formule (XVII), posebice 10 – 15 ekv.
24. Postupak prema bilo kojem od patentnih zahtjeva 22 ili 23, naznačen time, da se spoj formule (I) rekristalizira u koraku 1) u organskom otapalu, pri čemu je organsko otapalo odabrano od IPA, etanola, EtOAc, IPAc, butila acetata, toluena, MIBK, miješanog otapala acetona i vode, miješanog otapala IPA i vode i miješanog otapala etanola i vode; posebice otapalo je miješano otapalo etanola i vode.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016074132 | 2016-02-19 | ||
| EP17705612.4A EP3416966B1 (en) | 2016-02-19 | 2017-02-16 | Process for the preparation of [7-[[4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1h-imidazo[1,5-a]pyrazin-2-yl]alkyl carboxylic acids |
| PCT/EP2017/053443 WO2017140750A1 (en) | 2016-02-19 | 2017-02-16 | Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1h-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid |
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| HRP20211816T1 true HRP20211816T1 (hr) | 2022-03-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| HRP20211816TT HRP20211816T1 (hr) | 2016-02-19 | 2017-02-16 | Postupak za pripravu [7-[[4-fenil-5-alkoksikarbonil-2-tiazol-2-il-1,4-dihidropirimidin-6-il]metil]-3-okso-5,6,8,8a-tetrahidro-1h-imidazo[1,5-a]pirazin-2-l]alkila karboksilne kiseline |
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| Country | Link |
|---|---|
| US (1) | US10927116B2 (hr) |
| EP (2) | EP3954691A1 (hr) |
| JP (1) | JP6672471B2 (hr) |
| KR (2) | KR102255228B1 (hr) |
| CN (1) | CN108718527B (hr) |
| AR (1) | AR107633A1 (hr) |
| AU (2) | AU2017219189B2 (hr) |
| CA (1) | CA3011650A1 (hr) |
| ES (1) | ES2899369T3 (hr) |
| HR (1) | HRP20211816T1 (hr) |
| IL (2) | IL260153B (hr) |
| MX (1) | MX2018009944A (hr) |
| PL (1) | PL3416966T3 (hr) |
| SG (2) | SG10202110927VA (hr) |
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| CA2935811C (en) * | 2014-03-07 | 2018-09-18 | F. Hoffmann-La Roche Ag | 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| US11142527B2 (en) | 2017-06-26 | 2021-10-12 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and uses thereof in medicine |
| AU2018291688B2 (en) | 2017-06-27 | 2022-02-03 | Janssen Pharmaceutica Nv | Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections |
| JP7202373B2 (ja) * | 2017-10-18 | 2023-01-11 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | ジヒドロピリミジン化合物、及び医薬におけるその使用 |
| TW201945003A (zh) | 2018-03-01 | 2019-12-01 | 愛爾蘭商健生科學愛爾蘭無限公司 | ２，４－二胺基喹唑啉衍生物及其醫學用途 |
| US11053235B2 (en) | 2018-08-09 | 2021-07-06 | Janssen Sciences Ireland Unlimited Company | Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases |
| TW202035412A (zh) * | 2018-12-20 | 2020-10-01 | 比利時商健生藥品公司 | 雜芳基二氫嘧啶衍生物和治療ｂ型肝炎感染之方法 |
| JP2022511819A (ja) * | 2018-12-20 | 2022-02-01 | ヤンセン ファーマシューティカ エヌ．ベー． | ヘテロアリールジヒドロピリミジン誘導体及びｂ型肝炎感染症を治療する方法 |
| CN113614088A (zh) * | 2019-03-25 | 2021-11-05 | 豪夫迈·罗氏有限公司 | Hbv核心蛋白变构修饰剂化合物的固体形式 |
| JP7532420B2 (ja) * | 2019-06-06 | 2024-08-13 | エフ． ホフマン－ラ ロシュ アーゲー | ４－フェニル－５－アルコキシカルボニル－２－チアゾール－２－イル－１，４－ジヒドロピリミジン－６－イル］メチル］－３－オキソ－５，６，８，８ａ－テトラヒドロ－１Ｈ－イミダゾ［１，５－ａ］ピラジン－２－イル］－カルボン酸を調製するための代替方法 |
| US20220241402A1 (en) | 2019-06-18 | 2022-08-04 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and quinazoline derivatives |
| EP4003355A4 (en) * | 2019-07-31 | 2023-07-26 | Janssen Sciences Ireland Unlimited Company | DIHYDROPYRIMIDE DERIVATIVES AND USES THEREOF IN THE TREATMENT OF HBV INFECTION OR HBV-INDUCED DISEASE |
| WO2021078221A1 (zh) * | 2019-10-24 | 2021-04-29 | 广东东阳光药业有限公司 | 二氢嘧啶类化合物及其在药物中的应用 |
| AU2021266084A1 (en) * | 2020-04-28 | 2022-10-20 | F. Hoffmann-La Roche Ag | Process for the preparation of a chiral piperazine-2-carboxylic acid |
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| DE10012823A1 (de) | 2000-03-16 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10125131A1 (de) | 2001-05-23 | 2002-12-05 | Bayer Ag | Verfahren zur Spaltung des Methyl 4-(2-chlor-4-fluorphenyl)-2-(3,5-difluor-2-pyridinyl)-6-methyl-1,4-dihydro-5-pyrmidincarboxylat-Racemats |
| CN100453542C (zh) | 2007-04-30 | 2009-01-21 | 广东东阳光药业有限公司 | 2-杂环取代的二氢嘧啶消旋化合物的拆分方法 |
| WO2010069147A1 (zh) | 2008-12-17 | 2010-06-24 | 张中能 | 二氢嘧啶类化合物、其组合物及其应用 |
| HUE034919T2 (en) | 2012-08-24 | 2018-03-28 | Sunshine Lake Pharma Co Ltd | 2,4,5,6-substituted 3,6-dihydropyrimidine derivatives such as hepatitis B virus (HBV) polymerase inhibitors, for example, for the treatment of chronic hepatitis |
| WO2014037480A1 (en) | 2012-09-10 | 2014-03-13 | F. Hoffmann-La Roche Ag | 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| JP6533217B2 (ja) | 2013-05-17 | 2019-06-19 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Ｂ型肝炎ウイルス感染症の治療および予防のための６−架橋ヘテロアリールジヒドロピリミジン類 |
| CA2935811C (en) | 2014-03-07 | 2018-09-18 | F. Hoffmann-La Roche Ag | 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| AR101319A1 (es) * | 2014-07-31 | 2016-12-07 | Hoffmann La Roche | Resolución quiral de los ésteres del ácido 4-aril-2-tiazol-2-il-1,4-dihidropirimidin-5-carboxílico |
| AR103222A1 (es) | 2014-12-23 | 2017-04-26 | Hoffmann La Roche | Procedimiento para la preparación de análogos de 4-fenil-5-alcoxicarbonil-2-tiazol-2-il-1,4-dihidropirimidina |
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- 2017-02-16 EP EP21193914.5A patent/EP3954691A1/en not_active Withdrawn
- 2017-02-16 ES ES17705612T patent/ES2899369T3/es active Active
- 2017-02-16 WO PCT/EP2017/053443 patent/WO2017140750A1/en active Application Filing
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- 2017-02-16 JP JP2018543245A patent/JP6672471B2/ja active Active
- 2017-02-16 KR KR1020217014633A patent/KR20210059801A/ko not_active Application Discontinuation
- 2017-02-16 CA CA3011650A patent/CA3011650A1/en active Pending
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- 2017-02-16 CN CN201780011960.XA patent/CN108718527B/zh active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| EP3416966A1 (en) | 2018-12-26 |
| CA3011650A1 (en) | 2017-08-24 |
| JP2019507144A (ja) | 2019-03-14 |
| KR20210059801A (ko) | 2021-05-25 |
| MX2018009944A (es) | 2018-11-09 |
| AU2017219189B2 (en) | 2021-04-01 |
| US10927116B2 (en) | 2021-02-23 |
| AU2017219189A1 (en) | 2018-06-28 |
| ES2899369T3 (es) | 2022-03-11 |
| KR20180104177A (ko) | 2018-09-19 |
| EP3954691A1 (en) | 2022-02-16 |
| AR107633A1 (es) | 2018-05-16 |
| SG10202110927VA (en) | 2021-11-29 |
| CN108718527A (zh) | 2018-10-30 |
| PL3416966T3 (pl) | 2022-01-17 |
| SI3416966T1 (sl) | 2022-01-31 |
| AU2021203860A1 (en) | 2021-07-08 |
| SG11201805595TA (en) | 2018-07-30 |
| KR102255228B1 (ko) | 2021-05-25 |
| IL260153B (en) | 2021-10-31 |
| BR112018016932A2 (pt) | 2019-01-08 |
| WO2017140750A1 (en) | 2017-08-24 |
| US20190010155A1 (en) | 2019-01-10 |
| JP6672471B2 (ja) | 2020-03-25 |
| IL286912A (en) | 2021-10-31 |
| EP3416966B1 (en) | 2021-09-29 |
| IL260153A (en) | 2018-07-31 |
| CN108718527B (zh) | 2022-06-28 |
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