HRP20120319T1 - Postupak za dobivanje dihidrokinazolina - Google Patents
Postupak za dobivanje dihidrokinazolina Download PDFInfo
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- HRP20120319T1 HRP20120319T1 HRP20120319TT HRP20120319T HRP20120319T1 HR P20120319 T1 HRP20120319 T1 HR P20120319T1 HR P20120319T T HRP20120319T T HR P20120319TT HR P20120319 T HRP20120319 T HR P20120319T HR P20120319 T1 HRP20120319 T1 HR P20120319T1
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- trifluoromethyl
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- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims 30
- 125000000217 alkyl group Chemical group 0.000 claims 12
- 229910052736 halogen Inorganic materials 0.000 claims 10
- 150000002367 halogens Chemical class 0.000 claims 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 9
- 125000003545 alkoxy group Chemical group 0.000 claims 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 9
- 229910052739 hydrogen Inorganic materials 0.000 claims 8
- 239000001257 hydrogen Substances 0.000 claims 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 8
- 125000004414 alkyl thio group Chemical group 0.000 claims 7
- -1 cyano, hydroxy, amino Chemical group 0.000 claims 7
- 125000001424 substituent group Chemical group 0.000 claims 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 125000003118 aryl group Chemical group 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 claims 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
- ZOBYBACEALCILX-UHFFFAOYSA-N methyl 2-[8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,4-dihydroquinazolin-4-yl]acetate Chemical compound O=C1NC2=C(F)C=CC=C2C(CC(=O)OC)N1C1=CC(C(F)(F)F)=CC=C1OC ZOBYBACEALCILX-UHFFFAOYSA-N 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 2
- HYPQVNLUKMOLIV-UHFFFAOYSA-N 1-(2-bromo-6-fluorophenyl)-3-[2-methoxy-5-(trifluoromethyl)phenyl]urea Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC(=O)NC1=C(F)C=CC=C1Br HYPQVNLUKMOLIV-UHFFFAOYSA-N 0.000 claims 1
- ISELQDXAOGXIAD-UHFFFAOYSA-N 1-(2-fluorophenyl)-3-[2-methoxy-5-(trifluoromethyl)phenyl]urea Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC(=O)NC1=CC=CC=C1F ISELQDXAOGXIAD-UHFFFAOYSA-N 0.000 claims 1
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 claims 1
- FWYSMLBETOMXAG-UHFFFAOYSA-N 2-[8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetic acid Chemical compound COC1=CC=CC(N2CCN(CC2)C=2N(C(CC(O)=O)C3=CC=CC(F)=C3N=2)C=2C(=CC=C(C=2)C(F)(F)F)OC)=C1 FWYSMLBETOMXAG-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 238000010931 ester hydrolysis Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- XBEUBXLFZSRSFE-RMKNXTFCSA-N methyl (e)-3-[3-fluoro-2-[[2-methoxy-5-(trifluoromethyl)phenyl]carbamoylamino]phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=CC(F)=C1NC(=O)NC1=CC(C(F)(F)F)=CC=C1OC XBEUBXLFZSRSFE-RMKNXTFCSA-N 0.000 claims 1
- DDWYVVLPVLTZIN-DEOSSOPVSA-N methyl 2-[(4s)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical class C=1C(C(F)(F)F)=CC=C(OC)C=1N([C@H](C1=CC=CC(F)=C1N=1)CC(=O)OC)C=1N(CC1)CCN1C1=CC=CC(OC)=C1 DDWYVVLPVLTZIN-DEOSSOPVSA-N 0.000 claims 1
- DDWYVVLPVLTZIN-UHFFFAOYSA-N methyl 2-[8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate Chemical compound N=1C2=C(F)C=CC=C2C(CC(=O)OC)N(C=2C(=CC=C(C=2)C(F)(F)F)OC)C=1N(CC1)CCN1C1=CC=CC(OC)=C1 DDWYVVLPVLTZIN-UHFFFAOYSA-N 0.000 claims 1
- 239000007800 oxidant agent Substances 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
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 150000003254 radicals Chemical group 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 241000701022 Cytomegalovirus Species 0.000 abstract 1
- 239000003443 antiviral agent Substances 0.000 abstract 1
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 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
-
- 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
-
- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
-
- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Oncology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Postupak za dobivanje spoja formule (I) gdjeAr predstavlja aril, pri čemu aril može biti supstituiran sa 1 do 3 supstituenta, gdje su supstituenti odabrani neovisno jedan od drugoga iz skupine koja sadrži alkil, alkoksi, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi, amino, alkilamino, aminokarbonil i nitro, pri čemu alkil može biti supstituiran sa 1 do 3 supstituenta, gdje su supstituenti odabrani neovisno jedan od drugoga iz skupine koja sadrži halogen, amino, alkilamino, hidroksi i aril, ili dva supstituenta na arilu, zajedno sa atomima ugljika na koje su vezani, formiraju 1,3-dioksolan, ciklopentanski prsten ili cikloheksanski prsten i proizvoljno prisutan treći supstituent je odabran neovisno od njih iz navedene skupine, R1 predstavlja vodik, amino, alkil, alkoksi, alkilamino, alkiltio, cijano, halogen, nitro ili trifluorometil, R2 predstavlja vodik, alkil, alkoksi, alkiltio, cijano, halogen, nitro ili trifluorometil, R3 predstavlja amino, alkil, alkoksi, alkilamino, alkiltio, cijano, halogen, nitro, trifluorometil, alkilsulfonil ili alkilaminosulfonililijedan od radikala R1, R2 i R3 predstavlja vodik, alkil, alkoksi, cijano, halogen, nitro ili trifluorometil i druga dva, zajedno sa atomima ugljika na koje su vezani, formiraju 1,3-dioksolan, ciklopentanski prsten ili cikloheksanski prsten, R4 predstavlja vodik ili alkil, R5 predstavlja vodik ili alkililiradikali R4 i R5 u piperazinskom prstenu su vezani na atome ugljika koji su direktno nasuprotni jedan prema drugom i formiraju metilenski most koji je proizvoljno supstituiran sa 1 do 2 metilne skupine, R6 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, aminokarbonil, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro, R7 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitroi R8 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro, sa hidrolizom estera spoja formule (II) gdjeAr, R1, R2, R3, R4, R5, R6, R7 i R8 imaju gore navedeno značenje, iR9 predstavlja C1-C4-alkil, Korištenjem baze ili kiseline, naznačen time da je spoj formule (II) dobiven sa reakcijom spoja formule (III) gdjeR1, R2, R3, R6, R7 i R8 imaju gore navedeno značenje, iR9 predstavlja C1-C4-alkil, u prisutnosti bazesa spojem formule (IV) gdjeAr, R4 i R5 imaju gore navedeno značenje. Patent sadrži još 10 patentnih zahtjeva.
Description
POSTUPAK ZA DOBIVANJE DIHIDROKINAZOLINA
Claims (11)
1. Postupak za dobivanje spoja formule (I)
[image]
gdje
Ar predstavlja aril, pri čemu aril može biti supstituiran sa 1 do 3 supstituenta, gdje su supstituenti odabrani neovisno jedan od drugoga iz skupine koja sadrži alkil, alkoksi, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi, amino, alkilamino, aminokarbonil i nitro,
pri čemu alkil može biti supstituiran sa 1 do 3 supstituenta, gdje su supstituenti odabrani neovisno jedan od drugoga iz skupine koja sadrži halogen, amino, alkilamino, hidroksi i aril,
ili dva supstituenta na arilu, zajedno sa atomima ugljika na koje su vezani, formiraju 1,3-dioksolan, ciklopentanski prsten ili cikloheksanski prsten i proizvoljno prisutan treći supstituent je odabran neovisno od njih iz navedene skupine,
R1 predstavlja vodik, amino, alkil, alkoksi, alkilamino, alkiltio, cijano, halogen, nitro ili trifluorometil,
R2 predstavlja vodik, alkil, alkoksi, alkiltio, cijano, halogen, nitro ili trifluorometil,
R3 predstavlja amino, alkil, alkoksi, alkilamino, alkiltio, cijano, halogen, nitro, trifluorometil, alkilsulfonil ili alkilaminosulfonil
ili
jedan od radikala R1, R2 i R3 predstavlja vodik, alkil, alkoksi, cijano, halogen, nitro ili trifluorometil i druga dva, zajedno sa atomima ugljika na koje su vezani, formiraju 1,3-dioksolan, ciklopentanski prsten ili cikloheksanski prsten,
R4 predstavlja vodik ili alkil,
R5 predstavlja vodik ili alkil
ili
radikali R4 i R5 u piperazinskom prstenu su vezani na atome ugljika koji su direktno nasuprotni jedan prema drugom i formiraju metilenski most koji je proizvoljno supstituiran sa 1 do 2 metilne skupine,
R6 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, aminokarbonil, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro,
R7 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro
i
R8 predstavlja vodik, alkil, alkoksi, alkiltio, formil, karboksi, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro,
sa hidrolizom estera spoja formule (II)
[image]
gdje
Ar, R1, R2, R3, R4, R5, R6, R7 i R8 imaju gore navedeno značenje, i
R9 predstavlja C1-C4-alkil,
K
orištenjem baze ili kiseline, naznačen time da je spoj formule (II) dobiven sa reakcijom spoja formule (III)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju gore navedeno značenje, i
R9 predstavlja C1-C4-alkil,
u prisutnosti baze
sa spojem formule (IV)
[image]
gdje
Ar, R4 i R5 imaju gore navedeno značenje.
2. Postupak prema zahtjevu 1, naznačen time da je spoj formule (III), kako je definirano u zahtjevu 1, dobiven pomoću reakcije spoja formule (V)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju značenje navedeno u zahtjevu 1, i
R9 predstavlja C1-C4-alkil,
sa fosfornim oksikloridom, fosfornim trikloridom ili fosfornim pentakloridom, u prisutnosti baze.
3. Postupak prema zahtjevu 2, naznačen time da je spoj formule (V), kako je definirano u zahtjevu 2, dobiven pomoću reakcije spoja formule (VI)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju značenje navedeno u zahtjevu 2,
sa spojem formule
[image]
gdje
R9 predstavlja C1-C4-alkil,
u prisutnosti paladijevog katalizatora i baze.
4. Postupak prema zahtjevu 2, naznačen time da je spoj formule (V), kako je definirano u zahtjevu 2, dobiven pomoću reakcije spoja formule (VII)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju značenje navedeno u zahtjevu 2,
u prvoj fazi sa spojem formule (IX) u octenoj kiselini u prisutnosti paladijevog katalizatora, oksidacijskog sredstva i kiseline da se dobije spoj formule (VIII)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju značenje navedeno u zahtjevu 2, i
R9 predstavlja C1-C4-alkil,
i u drugoj fazi sa bazom da se dobije spoj formule (V).
5. Postupak prema jednom od zahtjeva 1 do 4, naznačen time da spoj formule (I)
{8-fluoro-2-[4-(3-metoksifenil)piperazin-1-il]-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}octena kiselina je
[image]
spoj formule (II) je
metil {8-fluoro-2-[4-(3-metoksifenil)piperazin-1-il]-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetat
[image]
spoj formule (III) je
metil 2-kloro-8-fluoro-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetat
[image]
spoj formule (IV) je
1-(3-metoksifenil)piperazin
[image]
spoj formule (V) je
metil {8-fluoro-3-[2-metoksi-5-(trifluorometil)fenil]-2-okso-1,2,3,4-tetrahidrokinazolin-4-il}acetat
[image]
spoj formule (VI) je
N-(2-bromo-6-fluorofenil)-N'-[2-metoksi-5-(trifluorometil)fenil]urea
[image]
spoj formule (VII) je
N-(2-fluorofenil)-N'-[2-metoksi-5-(trifluorometil)fenil]urea
[image]
spoj formule (VIII) je
metil (2E)3-{3-fluoro-2-[({[2-metoksi-5-(trifluorometil)fenil]amino}karbonil)amino]fenil}akrilat
[image]
i
spoj formule (IX) je
metil akrilat
[image]
6. Postupak za razdvajanje enantiomera od(C1-C4)-alkil{8-fluoro-2-[4-(3-metoksifenil)piperazin-1-il]-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetata i izolaciju (C1-C4)-alkil(S)-{8-fluoro-2-[4-(3-metoksifenil)piperazin-1-il]-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetat, naznačen time da racemski ester je kristaliziran sa (2S,3S)-2,3-bis[(4-metilbenzoil)oksi]jantarnom kiselinom.
7. Metil (S)-{8-fluoro-2-[4-(3-metoksifenil)piperazin-1-il]-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetatna sol (2S,3S)-2,3-bis[(4-metilbenzoil)oksi] jantarne kiseline.
8. Spoj formule (III)
[image]
gdje
R1, R2, R3, R6, R7 i R8 imaju značenje navedeno u zahtjevu 1, i
R9 predstavlja C1-C4-alkil.
9. Spoj prema zahtjevu 8, naznačen time da spoj je metil 2-kloro-8-fluoro-3-[2-metoksi-5-(trifluorometil)fenil]-3,4-dihidrokinazolin-4-il}acetat
[image]
10. Spoj formule (V)
[image]
gdje
R1, R2, R3, R7 i R8 imaju značenje navedeno u zahtjevu 1,
R6 predstavlja alkil, alkoksi, alkiltio, formil, karboksi, aminokarbonil, alkilkarbonil, alkoksikarbonil, trifluorometil, halogen, cijano, hidroksi ili nitro,
i
R9 predstavlja C1-C4-alkil.
11. Spoj prema zahtjevu 10, naznačen time da spoj je metil {8-fluoro-3-[2-metoksi-5-(trifluorometil)fenil]-2-okso-1,2,3,4-tetrahidrokinazolin-4-il}acetat
[image]
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005027517A DE102005027517A1 (de) | 2005-06-15 | 2005-06-15 | Verfahren zur Herstellung von Dihydrochinazolinen |
| PCT/EP2006/005298 WO2006133822A1 (de) | 2005-06-15 | 2006-06-02 | Verfahren zur herstellung von dihydrochinazolinen |
Publications (1)
| Publication Number | Publication Date |
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| HRP20120319T1 true HRP20120319T1 (hr) | 2012-05-31 |
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| HRP20120319TT HRP20120319T1 (hr) | 2005-06-15 | 2012-04-12 | Postupak za dobivanje dihidrokinazolina |
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| Country | Link |
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| EP (1) | EP1893587B1 (hr) |
| JP (1) | JP5114391B2 (hr) |
| KR (1) | KR101355229B1 (hr) |
| CN (2) | CN101213180B (hr) |
| AT (1) | ATE542803T1 (hr) |
| AU (1) | AU2006257415B2 (hr) |
| BR (1) | BRPI0613277B1 (hr) |
| CA (1) | CA2611927C (hr) |
| DE (1) | DE102005027517A1 (hr) |
| DK (1) | DK1893587T3 (hr) |
| ES (1) | ES2383989T3 (hr) |
| HK (1) | HK1116185A1 (hr) |
| HR (1) | HRP20120319T1 (hr) |
| IL (1) | IL187586A (hr) |
| MX (1) | MX2007016040A (hr) |
| NO (1) | NO340521B1 (hr) |
| NZ (1) | NZ564325A (hr) |
| PL (1) | PL1893587T3 (hr) |
| PT (1) | PT1893587E (hr) |
| RU (1) | RU2419617C2 (hr) |
| SI (1) | SI1893587T1 (hr) |
| WO (1) | WO2006133822A1 (hr) |
| ZA (1) | ZA200710481B (hr) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10319612A1 (de) * | 2003-05-02 | 2004-11-18 | Bayer Healthcare Ag | Substituierte Dihydrochinazoline |
| DE10305785A1 (de) * | 2003-02-12 | 2004-08-26 | Bayer Healthcare Ag | Dihydrochinazoline |
| DE10320780A1 (de) * | 2003-05-09 | 2005-01-20 | Bayer Healthcare Ag | Heterocyclyl-substituierte Dihydrochinazoline |
| DE10352499A1 (de) * | 2003-11-11 | 2005-06-09 | Bayer Healthcare Ag | Substituierte Dihydrochinazoline II |
| DE102004022672A1 (de) * | 2004-05-07 | 2005-11-24 | Bayer Healthcare Ag | Substituierte Azachinazoline |
| DE102005027517A1 (de) | 2005-06-15 | 2006-12-21 | Bayer Healthcare Ag | Verfahren zur Herstellung von Dihydrochinazolinen |
| DE102012101673A1 (de) | 2012-02-29 | 2013-08-29 | Aicuris Gmbh & Co. Kg | Salze eines Dihydrochinazolinderivats |
| DE102012101680A1 (de) | 2012-02-29 | 2013-08-29 | Aicuris Gmbh & Co. Kg | Pharmazeutische Zubereitung enthaltend ein antiviral wirksames Dihydrochinazolinderivat |
| DE102012101659A1 (de) | 2012-02-29 | 2013-08-29 | Aicuris Gmbh & Co. Kg | Salze eines Dihydrochinazolinderivats |
| CN103232400B (zh) * | 2013-04-26 | 2015-01-21 | 苏州大学 | 一种制备喹唑啉-2-硫酮的方法 |
| AU2014283231B2 (en) * | 2013-06-19 | 2017-12-07 | Aicuris Anti-Infective Cures Gmbh | Amorphous Letermovir and solid pharmaceutical formulations thereof for oral administration |
| US9890128B2 (en) | 2013-12-12 | 2018-02-13 | Merck Sharp & Dohme Corp. | Process for making substituted quinazoline compounds |
| WO2016109360A1 (en) * | 2014-12-29 | 2016-07-07 | Auspex Pharmaceuticals, Inc. | Dihydroquinazoline inhibitors of viral terminase |
| US10392353B2 (en) | 2015-11-24 | 2019-08-27 | Merck Sharp & Dohme Corp. | Processes for making substituted quinazoline compounds using hydrogen bonding catalysts |
| CN111024861A (zh) * | 2019-12-31 | 2020-04-17 | 山东省药学科学院 | 一种莱特莫韦及含莱特莫韦的制剂中有关物质的检测方法 |
| UY39098A (es) | 2020-02-27 | 2021-09-30 | Aic246 Gmbh & Co Kg | 2-[(4s)-8-fluoro-2-[4-(3-metoxifenil)piperazin-1-il]-3-[2-metoxi-5- (trifluorometil)fenil]-4h-quinazolin-4-il] acetato de sodio monohidrato, su preparación y uso |
| AR121437A1 (es) | 2020-02-27 | 2022-06-08 | Aic246 Gmbh & Co Kg | Sal de potasio del ácido 2-[(4s)-8-fluoro-2-[4-(3-metoxifenil)piperazin-1-il]-3-[2-metoxi-5-(trifluorometil)fenil]-4h-quinazolin-4-il]acético |
| EP3906929A1 (en) | 2020-05-08 | 2021-11-10 | AiCuris GmbH & Co. KG | Letermovir for use in the prevention and the treatment of coronavirus infections |
| IT202000017617A1 (it) * | 2020-07-21 | 2022-01-21 | Olon Spa | Procedimento per la preparazione di un intermedio utilizzato nella sintesi del letermovir |
| CA3189271A1 (en) | 2020-08-17 | 2022-02-24 | Girij Pal Singh | A precipitation process for amorphous letermovir |
| CN115403528A (zh) * | 2021-05-27 | 2022-11-29 | 南京正大天晴制药有限公司 | 无定形3,4-二氢喹唑啉衍生物的制备方法 |
| WO2023185597A1 (zh) * | 2022-04-01 | 2023-10-05 | 上海迪赛诺化学制药有限公司 | 莱特莫韦中间体及其制备方法 |
| CN115322157B (zh) * | 2022-06-02 | 2023-12-05 | 浙江车头制药股份有限公司 | 来特莫韦中间体化合物及其制备方法和应用 |
| CN115677539B (zh) * | 2022-11-01 | 2023-10-24 | 南京工业大学 | 一种温和条件下钴催化脲基导向芳烃的高选择性单烯基化的方法 |
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|---|---|---|---|---|
| US5854245A (en) | 1996-06-28 | 1998-12-29 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| IL137922A0 (en) | 1998-02-17 | 2001-10-31 | Tularik Inc | Anti-viral pyrimidine derivatives |
| US6730682B2 (en) | 2000-07-12 | 2004-05-04 | Pharmacia & Upjohn Company | Heterocycle carboxamides as antiviral agents |
| WO2002010169A1 (en) | 2000-07-31 | 2002-02-07 | F. Hoffmann-La Roche Ag | Piperazine derivatives |
| EP1201765A3 (en) | 2000-10-16 | 2003-08-27 | Axxima Pharmaceuticals Aktiengesellschaft | Cellular kinases involved in cytomegalovirus infection and their inhibition |
| DE10251914A1 (de) | 2002-11-08 | 2004-05-19 | Bayer Ag | Substituierte Chinazoline |
| DE10319612A1 (de) * | 2003-05-02 | 2004-11-18 | Bayer Healthcare Ag | Substituierte Dihydrochinazoline |
| DE10305785A1 (de) * | 2003-02-12 | 2004-08-26 | Bayer Healthcare Ag | Dihydrochinazoline |
| DE10320780A1 (de) | 2003-05-09 | 2005-01-20 | Bayer Healthcare Ag | Heterocyclyl-substituierte Dihydrochinazoline |
| DE10352499A1 (de) | 2003-11-11 | 2005-06-09 | Bayer Healthcare Ag | Substituierte Dihydrochinazoline II |
| KR100610731B1 (ko) | 2004-02-24 | 2006-08-09 | 한국과학기술연구원 | Ｔ-형 칼슘 채널 차단제로서 유용한 ３,４-디히드로퀴나졸린유도체 및 그의 제조 방법 |
| DE102004022672A1 (de) | 2004-05-07 | 2005-11-24 | Bayer Healthcare Ag | Substituierte Azachinazoline |
| US8518959B2 (en) | 2005-01-25 | 2013-08-27 | Prolexys Pharmaceuticals, Inc. | Quinoxaline derivatives as antitumor agents |
| DE102005027517A1 (de) | 2005-06-15 | 2006-12-21 | Bayer Healthcare Ag | Verfahren zur Herstellung von Dihydrochinazolinen |
| MX2008000885A (es) | 2005-07-21 | 2008-03-18 | Hoffmann La Roche | Compuestos de pirido[2,3-d]pirimidin-2,4-diamina como inhibidores de la proteina tirosina fosfatasa 1b. |
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2005
- 2005-06-15 DE DE102005027517A patent/DE102005027517A1/de not_active Withdrawn
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2006
- 2006-06-02 BR BRPI0613277-4A patent/BRPI0613277B1/pt active IP Right Grant
- 2006-06-02 NZ NZ564325A patent/NZ564325A/en unknown
- 2006-06-02 EP EP06743106A patent/EP1893587B1/de active Active
- 2006-06-02 PL PL06743106T patent/PL1893587T3/pl unknown
- 2006-06-02 ES ES06743106T patent/ES2383989T3/es active Active
- 2006-06-02 AT AT06743106T patent/ATE542803T1/de active
- 2006-06-02 CN CN2006800211044A patent/CN101213180B/zh active Active
- 2006-06-02 US US11/922,280 patent/US8084604B2/en active Active
- 2006-06-02 CN CN2010102197919A patent/CN101863843B/zh active Active
- 2006-06-02 AU AU2006257415A patent/AU2006257415B2/en active Active
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- 2006-06-02 KR KR1020087000996A patent/KR101355229B1/ko active IP Right Grant
- 2006-06-02 RU RU2007147955/04A patent/RU2419617C2/ru active
- 2006-06-02 CA CA2611927A patent/CA2611927C/en active Active
- 2006-06-02 ZA ZA200710481A patent/ZA200710481B/xx unknown
- 2006-06-02 WO PCT/EP2006/005298 patent/WO2006133822A1/de active Application Filing
- 2006-06-02 SI SI200631321T patent/SI1893587T1/sl unknown
- 2006-06-02 MX MX2007016040A patent/MX2007016040A/es active IP Right Grant
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- 2011-11-30 US US13/308,418 patent/US8372972B2/en active Active
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