NO831622L - PROCEDURE FOR PREPARING 2- (4-SUBSTITUTED PIPERIDINO) 4-AMINO-6,7-DIMETOXYKINAZOLINE DERIVATIVES - Google Patents
PROCEDURE FOR PREPARING 2- (4-SUBSTITUTED PIPERIDINO) 4-AMINO-6,7-DIMETOXYKINAZOLINE DERIVATIVESInfo
- Publication number
- NO831622L NO831622L NO831622A NO831622A NO831622L NO 831622 L NO831622 L NO 831622L NO 831622 A NO831622 A NO 831622A NO 831622 A NO831622 A NO 831622A NO 831622 L NO831622 L NO 831622L
- Authority
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- Norway
- Prior art keywords
- formula
- compound
- compounds
- amino
- reacted
- Prior art date
Links
- -1 4-SUBSTITUTED PIPERIDINO Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 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 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- TUAHXRDDQSYUCY-UHFFFAOYSA-N cyclopentyl(piperidin-4-yl)methanol Chemical compound C1CNCCC1C(O)C1CCCC1 TUAHXRDDQSYUCY-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- SKBXVAOMEVOTGJ-UHFFFAOYSA-N xi-Pinol Chemical compound CC1=CCC2C(C)(C)OC1C2 SKBXVAOMEVOTGJ-UHFFFAOYSA-N 0.000 description 2
- NDJKRLGXVKYIGQ-UHFFFAOYSA-N 1-piperidin-4-ylethanol Chemical compound CC(O)C1CCNCC1 NDJKRLGXVKYIGQ-UHFFFAOYSA-N 0.000 description 1
- BJAYMNUBIULRMF-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzonitrile Chemical compound COC1=CC(N)=C(C#N)C=C1OC BJAYMNUBIULRMF-UHFFFAOYSA-N 0.000 description 1
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 description 1
- AFGXCIJBGLMDKI-UHFFFAOYSA-N 2-isothiocyanato-4,5-dimethoxybenzonitrile Chemical compound COC1=CC(N=C=S)=C(C#N)C=C1OC AFGXCIJBGLMDKI-UHFFFAOYSA-N 0.000 description 1
- DJJLZBAERKWDKG-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-phenylpiperidin-1-yl)quinazolin-4-amine Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCC1C1=CC=CC=C1 DJJLZBAERKWDKG-UHFFFAOYSA-N 0.000 description 1
- YQFGQRUVFDAPBW-UHFFFAOYSA-N C1=C(OC)C(OC)=CC(NC(=S)N2C(CCCC2)C(O)C2CCCC2)=C1C#N Chemical compound C1=C(OC)C(OC)=CC(NC(=S)N2C(CCCC2)C(O)C2CCCC2)=C1C#N YQFGQRUVFDAPBW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PNKLVCNYQMIOOW-UHFFFAOYSA-N [1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-yl]-cyclopentylmethanol;hydrochloride Chemical compound Cl.N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCC1C(O)C1CCCC1 PNKLVCNYQMIOOW-UHFFFAOYSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- OFFHOWWIQBWWQL-UHFFFAOYSA-N cyclohexyl(piperidin-4-yl)methanol Chemical compound C1CNCCC1C(O)C1CCCCC1 OFFHOWWIQBWWQL-UHFFFAOYSA-N 0.000 description 1
- WZJWFMLHYPEQQC-UHFFFAOYSA-N cyclopentyl(piperidin-4-yl)methanone Chemical compound C1CNCCC1C(=O)C1CCCC1 WZJWFMLHYPEQQC-UHFFFAOYSA-N 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VOZHYVXIZRHIIY-UHFFFAOYSA-N methyl n-cyano-n'-(3,4-dimethoxyphenyl)carbamimidothioate Chemical compound COC1=CC=C(N=C(NC#N)SC)C=C1OC VOZHYVXIZRHIIY-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
Description
Denne oppfinnelse angår en fremgangsmåte for fremstillingThis invention relates to a method for manufacturing
av 2-(4-substituert piperidino)-4-amino-6,7-dimetoksykinazoliner.of 2-(4-substituted piperidino)-4-amino-6,7-dimethoxyquinazolines.
Disse nye forbindelser har verdifulle farmakologiske egenskaper.These new compounds have valuable pharmacological properties.
Patenter FR 2 350 101 og FR 2 389 621 angår 2-(4-fenyl-piperidino)-4-amino-6,7-dimetoksykinazolin og tilsvarende for- Patents FR 2 350 101 and FR 2 389 621 relate to 2-(4-phenyl-piperidino)-4-amino-6,7-dimethoxyquinazoline and corresponding preparations
bindelser hvor fenylgruppen er substituert med en fluor- eller metoksygruppe. bonds where the phenyl group is substituted with a fluorine or methoxy group.
Ålment tilgjengelig ansøkning Fl 80 0481 angår 2-(4-alkyl-karbonylpiperidino)- og 2- (4-cykloalkylkarbonyl-piperidino)-4-amino-6,7-dimetoksykinazolin. Commonly Available Application Fl 80 0481 relates to 2-(4-alkylcarbonylpiperidino)- and 2-(4-cycloalkylcarbonylpiperidino)-4-amino-6,7-dimethoxyquinazoline.
Disse forbindelser senker blodtrykket.These compounds lower blood pressure.
Denne oppfinnelse angår fremstilling av forbindelser medThis invention relates to the preparation of compounds with
formelenthe formula
hvor R er cykloalkyl inneholdende 3 til 7 karbonatomer, alkenyl inneholdende 2 til 6 karbonatomer eller benzyl. where R is cycloalkyl containing 3 to 7 carbon atoms, alkenyl containing 2 to 6 carbon atoms or benzyl.
Forbindelsene med formel I fremstilles i henhold til opp-, finnelsen ved at The compounds of formula I are prepared according to the invention by
a) en forbindelse med formelena) a compound with the formula
omsettes med ammoniakk, ammoniumhalogenid, urinstoff eller reacted with ammonia, ammonium halide, urea or
urinstoff-hydrogenhalogenid, ellerurea hydrogen halide, or
b) en forbindelse med formelenb) a compound with the formula
hvor Z er en cyano- eller amidino-gruppe, omsettes med en where Z is a cyano or amidino group, is reacted with a
forbindelse med formelenconnection with the formula
hvor Z' er en cyano- eller amidino-gruppe, eller where Z' is a cyano or amidino group, or
c) en forbindelse med formelenc) a compound with the formula
hvor X er halogen så som klor, omsettes med en forbindelse med where X is halogen such as chlorine, is reacted with a compound with
formelenthe formula
eller or
d) en forbindelse med formelen d) a compound with the formula
omsettes med en forbindelse med formel VI, eller e) en karbonylforbindelse med formelen is reacted with a compound of formula VI, or e) a carbonyl compound of the formula
reduseres til den tilsvarende alkohol. is reduced to the corresponding alcohol.
Forbindelsene med formel II er verdifulle mellomprodukter for fremstilling av forbindelsene med formel I. The compounds of formula II are valuable intermediates for the preparation of the compounds of formula I.
Forbindelsene med formel I kan anvendes som farmasøytisk midler for behandling av hypertensjon. The compounds of formula I can be used as pharmaceutical agents for the treatment of hypertension.
Fremgangsmåtene a, b, c og d utføres som beskrevet iProcedures a, b, c and d are carried out as described in
Fl 80 0481. Forbindelsene med formel VI kan fremstilles fra de tilsvarende ketoner ved reduksjon. 4-(1-hydroksyetyl)piperidin er kjent fra J. Org. Chem. 31 (1976) 1732. Fl 80 0481. The compounds of formula VI can be prepared from the corresponding ketones by reduction. 4-(1-Hydroxyethyl)piperidine is known from J. Org. Chem. 31 (1976) 1732.
Metode e) reduksjonen utføres med hydrogen ved et trykkMethod e) the reduction is carried out with hydrogen at a pressure
på ca. 1 til 7 atmosfærer og ved ca. 20 til 100°C under anvendelse av vanlige hydrogeneringskatalysatorer så som palladium, platina eller nikkel. Andre reduksjonsmidler kan også anvendes, f.eks. natriumborhydrid eller aluminiumisopropoksyd. of approx. 1 to 7 atmospheres and at approx. 20 to 100°C using common hydrogenation catalysts such as palladium, platinum or nickel. Other reducing agents can also be used, e.g. sodium borohydride or aluminum isopropoxide.
Virkningen av forbindelsene, administrert peroralt, på spontan hypertensjon ble undersøkt hos rotter og sammenlignet med virkningen av forbindelsene beskrevet i Fl 80 0481. En dose på 0,5 pinol/rotte av forbindelsen ifølge eksempel 3 fremkalte en 30 mm Hg reduksjon av blodtrykket i løpet av 3 timer efter administreringen. Dette var mer enn med forbindelsene ifølge Fl 80 0481. The effect of the compounds, administered orally, on spontaneous hypertension was examined in rats and compared with the effect of the compounds described in Fl 80 0481. A dose of 0.5 pinol/rat of the compound of Example 3 produced a 30 mm Hg reduction in blood pressure during of 3 hours after administration. This was more than with the compounds according to Fl 80 0481.
Toksisiteten, for de nye forbindelsene er også noe lavereThe toxicity, for the new compounds, is also somewhat lower
enn for de kjente forbindelser.than for the known compounds.
De følgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.
Eksempel 1Example 1
1,3 g NaBH4i 15 ml vann settes ved 0°C til en oppløsning1.3 g of NaBH4 in 15 ml of water are added to a solution at 0°C
av 4,7 g (0,026 mol) 4-cyklopentylkarbonylpiperidin i 50 ml metanol. Denne blanding omrøres i 1 time ved 0°C og i 2 timer ved 20°C. Metanolen avdampes, vann tilsettes, og opp-løsningen ekstraheres med kloroform, og ekstrakten inndampes til tørrhet. 3,4 g 4-(1-hydroksy-l-cyklopentylmetyl)piperidin (VI) oppnås; sm.p. 123-5°C, utbytte 72%. of 4.7 g (0.026 mol) of 4-cyclopentylcarbonylpiperidine in 50 ml of methanol. This mixture is stirred for 1 hour at 0°C and for 2 hours at 20°C. The methanol is evaporated, water is added, and the solution is extracted with chloroform, and the extract is evaporated to dryness. 3.4 g of 4-(1-hydroxy-1-cyclopentylmethyl)piperidine (VI) are obtained; sm.p. 123-5°C, yield 72%.
2,9 g (0,016 mol) 4-(1-hydroksy-l-cyklopentylmety1)-piperidin i 25 ml etylacetat settes i små porsjoner ved 0-5°C 2.9 g (0.016 mol) of 4-(1-hydroxy-1-cyclopentylmethyl)-piperidine in 25 ml of ethyl acetate are placed in small portions at 0-5°C
til en oppløsning av 3,5 g (0,016 mol) 3,4-dimetoksy-6-isotio-cyanatobenzonitril i 25 ml etylacetat. Oppløsningen omrøres ved 0°C i 18 timer. Det oppnådde bunnfall filtreres, vaskes med kald etylacetat og tørres. 4,1 g 2-(4-(1-hydroksy-l-cyklopentyl-metyl) piperidino)tioformamido-4,5-dimetoksybenzonitril oppnås; sm.p. 196-200°C, utbytte 64%. to a solution of 3.5 g (0.016 mol) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile in 25 ml of ethyl acetate. The solution is stirred at 0°C for 18 hours. The precipitate obtained is filtered, washed with cold ethyl acetate and dried. 4.1 g of 2-(4-(1-hydroxy-1-cyclopentyl-methyl)piperidino)thioformamido-4,5-dimethoxybenzonitrile are obtained; sm.p. 196-200°C, yield 64%.
En oppløsning av 4,04 g (0,01 mol) 2-( -(1-hydroksy-l-cyklopentylmetyl) piperidino)tioformamido-4,5-dimetoksybenzonitril, 4,0 g metyljodid og 0,6 g kalsiumoksyd i 30 ml etylacetat oppvarmes langsomt til 60°C og holdes ved denne temperatur i 18 timer. Den avkjølte blanding filtreres, filtratet vaskes med fortynnet NaOH-oppløsning og vann og inndampes til tørrhet. 3,6 g metyl-N-(2-cyano-4,5-dimetoksyfenyl)-(4 -(1-hydroksy-l-cyklopentyl-metyl) piperidino)tioformamidat (II) oppnås; sm.p. 41-45°C, A solution of 4.04 g (0.01 mol) 2-( -(1-hydroxy-1-cyclopentylmethyl)piperidino)thioformamido-4,5-dimethoxybenzonitrile, 4.0 g methyl iodide and 0.6 g calcium oxide in 30 ml ethyl acetate is slowly heated to 60°C and kept at this temperature for 18 hours. The cooled mixture is filtered, the filtrate is washed with dilute NaOH solution and water and evaporated to dryness. 3.6 g of methyl N-(2-cyano-4,5-dimethoxyphenyl)-(4-(1-hydroxy-1-cyclopentylmethyl)piperidino)thioformamidate (II) are obtained; sm.p. 41-45°C,
utbytte 86%.yield 86%.
En oppløsning av 4,17 g (0,01 mol) metyl-N-(2-cyano-4,5-dimetoksyfenyl)-(4-(1-hydroksy-l-cyklopentylmetyl)-piperidino-tioformamidat og 15 g ammoniumklorid i 45 ml formamid oppvarmes og omrøres under nitrogenstrøm i 24 timer ved 120°C. Blandingen avkjøles, og vann tilsettes, fulgt av ekstraksjon med kloroform. Ekstrakten vaskes flere ganger med vann, og oppløsningsmidlet fjernes under redusert trykk. Residuet oppløses i aceton, og A solution of 4.17 g (0.01 mol) of methyl N-(2-cyano-4,5-dimethoxyphenyl)-(4-(1-hydroxy-1-cyclopentylmethyl)-piperidino-thioformamidate and 15 g of ammonium chloride in 45 mL of formamide is heated and stirred under nitrogen flow for 24 hours at 120°C. The mixture is cooled, and water is added, followed by extraction with chloroform. The extract is washed several times with water, and the solvent is removed under reduced pressure. The residue is dissolved in acetone, and
tørr HCl-gass føres inn i oppløsningen. 2,8 g 2-(4-(1-hydroksy-l-cyklopentylmetyl) piperidino)-4-amino-6,7-dimetoksykinazolin-hydroklorid oppnås; sm.p. 269-73°C, utbytte 66%. dry HCl gas is introduced into the solution. 2.8 g of 2-(4-(1-hydroxy-1-cyclopentylmethyl)piperidino)-4-amino-6,7-dimethoxyquinazoline hydrochloride are obtained; sm.p. 269-73°C, yield 66%.
Eksempel 2Example 2
Metode e: 1,2 g NaBH^i 10 ml vann settes i et isbad til en oppløsning av 4,35 g (0,01 mol) 2-(4-cykloheksylkarbonyl-piperidino)-4-amino-6,7-dimetoksy-kinazolin-hydroklorid og 20 ml 0,5N NaOH-oppløsning i 80 ml metanol. Oppløsningen om-røres i 1 time ved 0°C og i 18 timer ved 20°C. Noe av metanolen fjernes under redusert trykk, det dannede bunnfall frafiltreres, vaskes med vann og tørres. Produktet oppløses i aceton og ut-felles med gassformig HC1. 2-(4-hydroksy-l-cykloheksylmetyl)-piperidino)-4-amino-6,7-dimetoksykinazolin-hydroklorid oppnås; sm.p. 196-200°C. Method e: 1.2 g NaBH^ in 10 ml water is added to a solution of 4.35 g (0.01 mol) 2-(4-cyclohexylcarbonyl-piperidino)-4-amino-6,7-dimethoxy in an ice bath -quinazoline hydrochloride and 20 ml of 0.5N NaOH solution in 80 ml of methanol. The solution is stirred for 1 hour at 0°C and for 18 hours at 20°C. Some of the methanol is removed under reduced pressure, the precipitate formed is filtered off, washed with water and dried. The product is dissolved in acetone and precipitated with gaseous HCl. 2-(4-hydroxy-1-cyclohexylmethyl)-piperidino)-4-amino-6,7-dimethoxyquinazoline hydrochloride is obtained; sm.p. 196-200°C.
Metode b: 0,75 g (0,03 mol) natriumhydrid settes til en oppløsning av 1,78 g (0,01 mol) 2-amino-4,5-dimetoksybenzonitril og 2,38 g (0,01 mol) l-cyano-4-(1-hydroksy-l-cykloheksylmetyl)-piperidin i 25 ml tørr dimetylformamid. Oppløsningen oppvarmes under en nitrogenatmosfære i 5 timer ved 80 C, avkjøles, og vann tilsettes, og ekstraksjon foretas med kloroform. Opp-løsningsmidlet fjernes under redusert trykk. Residuet oppløses i aceton,, som tørr HCl-gass føres inn i. Det ønskede produkt oppnås. Method b: 0.75 g (0.03 mol) sodium hydride is added to a solution of 1.78 g (0.01 mol) 2-amino-4,5-dimethoxybenzonitrile and 2.38 g (0.01 mol) l -cyano-4-(1-hydroxy-1-cyclohexylmethyl)-piperidine in 25 ml of dry dimethylformamide. The solution is heated under a nitrogen atmosphere for 5 hours at 80 C, cooled, and water is added, and extraction is carried out with chloroform. The solvent is removed under reduced pressure. The residue is dissolved in acetone, into which dry HCl gas is introduced. The desired product is obtained.
Metode c: En oppløsning av 2,4 g (0,01 mol) 2-klor-4-amino-6,7-dimetoksykinazolin og 2,0 g (0,01 mol) 4-,(1-hydroksy-l-cykloheksylmetyl) piperidin i 30 ml isoamylalkohol tilbakeløps-behandles i 18 timer og avkjøles. Det utfelte produkt filtreres, vaskes med eter og tørres. Ønsket produkt oppnås. Method c: A solution of 2.4 g (0.01 mol) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 2.0 g (0.01 mol) of 4-,(1-hydroxy-l- cyclohexylmethyl) piperidine in 30 ml of isoamyl alcohol is refluxed for 18 hours and cooled. The precipitated product is filtered, washed with ether and dried. The desired product is achieved.
Metode d: En oppløsning av 2,5 g (0,01 mol) S-metyl-N-cyano-N'-(3,4-dimetoksyfenyl)isotiourinstoff og 3,0 g (0,01 mol) 4-(1-hydroksy-l-cykloheksylmetyl)piperidin i 35 ml diglykol-dimetyleter tilbakeløpsbehandles i 5 timer og avkjøles. Vann settes til blandingen, fulgt av ekstraksjon.med kloroform. Opp-løsningsmidlet avdampes fra ekstrakten, og residuet oppløses i aceton, som HCl-gass føres inn i. Ønsket produkt oppnås. Method d: A solution of 2.5 g (0.01 mol) S-methyl-N-cyano-N'-(3,4-dimethoxyphenyl)isothiourea and 3.0 g (0.01 mol) 4-(1 -hydroxy-1-cyclohexylmethyl)piperidine in 35 ml of diglycol dimethyl ether is refluxed for 5 hours and cooled. Water is added to the mixture, followed by extraction with chloroform. The solvent is evaporated from the extract, and the residue is dissolved in acetone, into which HCl gas is introduced. The desired product is obtained.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI812796 | 1981-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO831622L true NO831622L (en) | 1983-05-06 |
Family
ID=8514689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO831622A NO831622L (en) | 1981-09-09 | 1983-05-06 | PROCEDURE FOR PREPARING 2- (4-SUBSTITUTED PIPERIDINO) 4-AMINO-6,7-DIMETOXYKINAZOLINE DERIVATIVES |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0087456A1 (en) |
| JP (1) | JPS58501513A (en) |
| AU (1) | AU8906682A (en) |
| DK (1) | DK181083D0 (en) |
| ES (1) | ES515338A0 (en) |
| FI (1) | FI831585L (en) |
| IT (1) | IT1156319B (en) |
| NO (1) | NO831622L (en) |
| PT (1) | PT75525B (en) |
| WO (1) | WO1983000866A1 (en) |
| ZA (1) | ZA826596B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3517005A (en) * | 1967-10-26 | 1970-06-23 | Pfizer & Co C | Certain 2- and 4-substituted quinazolines |
| DK140695C (en) * | 1976-05-07 | 1980-05-12 | Synthelabo | ANALOGY PROCEDURE FOR PREPARING 2,4-DIAMINO-6,7-DIMETHOXYQUINAZOLINE DERIVATIVES OR ACID ADDITION SALTS |
| FR2389621A2 (en) * | 1977-05-05 | 1978-12-01 | Synthelabo | Antihypertensive 4-amino 2-piperidino-quinazoline(s) - prepd. from a 2-halo-quinazoline and a piperidine |
| IE800178L (en) * | 1979-01-31 | 1980-07-31 | Pfizer Ltd | Derivatives of 4-amino-2-piperidinoquinazoline |
| US4287341A (en) * | 1979-11-01 | 1981-09-01 | Pfizer Inc. | Alkoxy-substituted-6-chloro-quinazoline-2,4-diones |
| FI800481A (en) * | 1980-02-19 | 1981-08-20 | Orion Yhtymae Oy | FRAMEWORK FOR THE SUBSTANCES OF ACYLPIPERIDINER |
-
1982
- 1982-08-28 ES ES515338A patent/ES515338A0/en active Granted
- 1982-09-03 JP JP57502713A patent/JPS58501513A/en active Pending
- 1982-09-03 WO PCT/FI1982/000034 patent/WO1983000866A1/en not_active Application Discontinuation
- 1982-09-03 EP EP82902731A patent/EP0087456A1/en not_active Withdrawn
- 1982-09-03 AU AU89066/82A patent/AU8906682A/en not_active Abandoned
- 1982-09-08 PT PT75525A patent/PT75525B/en unknown
- 1982-09-08 ZA ZA826596A patent/ZA826596B/en unknown
- 1982-09-08 IT IT23168/82A patent/IT1156319B/en active
-
1983
- 1983-04-25 DK DK1810/83A patent/DK181083D0/en not_active Application Discontinuation
- 1983-05-06 NO NO831622A patent/NO831622L/en unknown
- 1983-05-09 FI FI831585A patent/FI831585L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA826596B (en) | 1983-11-30 |
| FI831585A0 (en) | 1983-05-09 |
| JPS58501513A (en) | 1983-09-08 |
| DK181083A (en) | 1983-04-25 |
| FI831585L (en) | 1983-05-09 |
| IT8223168A0 (en) | 1982-09-08 |
| IT1156319B (en) | 1987-02-04 |
| EP0087456A1 (en) | 1983-09-07 |
| DK181083D0 (en) | 1983-04-25 |
| PT75525B (en) | 1984-12-12 |
| AU8906682A (en) | 1983-03-28 |
| ES8405389A1 (en) | 1983-11-01 |
| ES515338A0 (en) | 1983-11-01 |
| PT75525A (en) | 1982-10-01 |
| WO1983000866A1 (en) | 1983-03-17 |
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