DK158352B - Fremgangsmaade til fremstilling af 6,7-dimethoxy-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolinhydrochlorid - Google Patents
Fremgangsmaade til fremstilling af 6,7-dimethoxy-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolinhydrochlorid Download PDFInfo
- Publication number
- DK158352B DK158352B DK042680A DK42680A DK158352B DK 158352 B DK158352 B DK 158352B DK 042680 A DK042680 A DK 042680A DK 42680 A DK42680 A DK 42680A DK 158352 B DK158352 B DK 158352B
- Authority
- DK
- Denmark
- Prior art keywords
- furoyl
- piperazinyl
- dimethoxy
- hydrochloride
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 17
- -1 4- (2-FUROYL) -1-PIPERAZINYL Chemical class 0.000 title description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 230000003276 anti-hypertensive effect Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- 229960001289 prazosin Drugs 0.000 description 7
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 229960002386 prazosin hydrochloride Drugs 0.000 description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- MXWBCRALMDQINL-UHFFFAOYSA-N n-(2-cyano-4,5-dimethoxyphenyl)-4-(furan-2-carbonyl)-n-methylpiperazine-1-carbothioamide Chemical compound C1=C(OC)C(OC)=CC(C#N)=C1N(C)C(=S)N1CCN(C(=O)C=2OC=CC=2)CC1 MXWBCRALMDQINL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
i
DK 158352B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-l-piperazi-nyl]kinazolinhydrochlorid, også kaldet prazosinhydrochlorid med antihypertensiv virkning, hvilken forbindelse har formlen 5 αΐ30\ N /-V .0 ' jQfrNwN-c°\j 10 CH3° 1 1^2 ' HC1 hvorved der gennemføres en intramolekylær ringslutning af methyl-N-(3,4-dimethoxy-6-cyanphenyl)-[4-(2-furoyl)-1-piperazi nyl]thi oforma-midat med formlen 15 CH-0 N=C-N F ~ c0 "if ^ - XK ·
CH3Cr ^ CN
Forskellige, tidligere kendte fremgangsmåder til fremstilling af 25 prazosin er beskrevet i US patentskrift nr. 3.511.836, DE offentliggørelsesskrift nr. 24 57 911 og NL patentansøgning nr. 7206067.
Der er imidlertid mange tekniske besværligheder forbundet med den praktiske udøvelse af disse kendte fremgangsmåder. Desuden er 30 udbyttet ved disse fremgangsmåder temmelig lavt, og oprensningen af den opnåede forbindelse er besværlig. Ved den i svensk fremlæggelsesskrift nr. 435.284 beskrevne fremgangsmåde til fremstilling af prazosin har man i betydelig grad kunnet reducere de forstyrrende faktorer, der optræder ved de nævnte, tidligere fremgangsmåder, og 35 samtidig opnået et bedre udbytte.
Ved fremgangsmåden ifølge SE nr. 435.284 til fremstilling af prazosin udføres ringslutningen til dannelse af kinazolinringen intramo-lekylært under anvendelse af methyl-N-(3,4-dimethoxy-6-cyanphenyl)-
DK 158352B
2 [4-(2-furoyl)-l-piperazinyl]thioformamidat med den nedenstående formel II som udgangsmateriale. Denne forbindelse omsættes med ammoniak i formamid i nærvær af en basisk katalysator, såsom natriumamid, ifølge følgende reaktionsskema: 5
/-\ O
CH,0 = C - N N - CO \
Prazosin
Udbyttet af prazosin ved denne fremgangsmåde beløber sig til 40-50% råprodukt med en renhedsgrad på 95-97%. Produktet bør derefter yder-15 ligere omdannes til hydrochloridet, som udgør det egentlige lægemiddel, samt omkrystalliseres et antal gange inden man opnår den som lægemiddel krævede renhedsgrad (99,7-99,8%). Det totale udbytte falder herved til ca. 35%.
20 Det har nu overraskende vist sig, at udbyttet af prazosin og samtidigt produktets renhed i betragtelig grad kan forbedres, samt at fremstillings- og oprensningmetoderne kan forenkles, hvis man ved ovennævnte reaktion til ringslutning af methyl-N-(3,4-dimethoxy-6-cyanphenyl)-[4-(2-furoyl)-1-pi perazi nyl]thi oformami dat i følge den 25 foreliggende opfindelse anvender et stort overskud ammoniumchlorid i stedet for ammoniakgas.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at forbindelsen med formlen II ved en temperatur på fra 100 til 140°C, fortrins-30 vis 120°C, omsættes med et stort overskud af ammoniumchlorid i et polært opløsningsmiddel, f.eks. formamid.
Til udøvelsen af reaktionen kræves slet ikke nogen basisk katalysator (natriumamid eller lignende). Ved reaktionen dannes desuden 35 direkte det ønskede prazosinhydrochlorid i højt udbytte (93-95%). Råproduktet har endog en meget højere renhedsgrad, dvs. ca. 99,5%.
Gennem en eneste omkrystallisation af dette råprodukt opnås den krævede renhedsgrad (99,7-99,8%). Det totale udbytte herved er 85-86%.
DK 158352B
3
Ved fremgangsmåden til fremstilling af prazosinhydrochlorid ifølge den foreliggende opfindelse opnår man således en meget betydelig forbedring i forhold til de hidtil kendte fremgangsmåder. Den praktiske gennemførelse af reaktionen, isolering samt oprensning af 5 produktet bliver væsentligt enklere end tidligere. Desuden eliminerer man anvendelse af det i større mængder svært håndterlige natriumamid.
Ved anvendelse af ammoniak og natriumamid sker reaktionen i alkalisk 10 miljø, hvorved der som følge af det som opløsningsmiddel anvendte formamids indvirkning sker en vis substitution af den i prazosin-molekylet indgående furoylgruppe med en formylgruppe. Derimod er ammoniumchloridopløsning svagt sur, og derfor sker der næppe overhovedet den nævnte om-acylering. Dette er en fordel, da en fuld-15 stændig fjernelse af nævnte, i små mængder forekommende forbindelse har vist sig at være besværlig i praksis.
Det som udgangsmateriale anvendte methyl-N-(3,4-dimethoxy-6-cyan-phenyl)-[4-(2-furoyl)-l-piperazinyl]thioformamidat med formlen (II) 20 kan fremstilles med et udbytte på 70 til 75% ved at omsætte 3,4-di-methoxy-6-[4-(2-furoyl)-l-piperazinylthiocarbamido]benzoenitril med methyliodid ved den i svensk fremlæggelsesskrift nr. 435.284 beskrevne fremgangsmåde.
25 Følgende eksempel illustrerer opfindelsen.
EKSEMPEL
6.7-Dimethoxv-4-amino-2-r4-(2-furovl)-l-Diperazinvnkinazolinhvdro-30 chlorid 275 g (0,66 mol) methyl-N-(3,4-dimethoxy-6-cyanphenyl)-[4-(2-furo-yl)-l-piperazinyl]thioformamidat opløstes i 3000 ml formamid, og under omrøring tilsattes 1375 g (25,7 mol) ammoniumchlorid. Reak-35 tionsblandingen opvarmedes derefter under omrøring i 15 til 20 timer ved 120°C under samtidig tilledning af nitrogen til fjernelse af den fremkomne methanthiol (kan absorberes i natriumhypochloritopløsning). Det dannede prazosinhydrochlorid udkrystalliserer lidt efter lidt fra reaktionsblandingen. Efter afslutning af reaktionen
DK 158352B
4 til sattes 3 til 4 kg is. Produktet filtreredes, vaskedes med koldt vand og acetone samt tørredes. Udbytte 254-259 g (93-95%). Renhedsgrad 99,5% (HPLC). Produktet omkrystalliseredes fra ca. 10 liter vand-ethanol-blanding (15:50). Udbytte 232-235 g (85-86%).
5 Renhedsgrad 99,7-99,8% (HPLC). Produktets IR-, NMR- og massespektre er identiske med modsvarende spektre for prazosinhydrochlorid, som er fremstillet ved de tidligere nævnte, fra litteraturen kendte fremgangsmåder.
10 15 20 25 30 35
Claims (3)
1. Fremgangsmåde til fremstilling af 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]ki nazolinhydrochlorid med antihypertensiv 5 virkning, hvilken forbindelse har formlen 01,0 \ ^ N / ^ A 10 Λ CH.,0 1
3 NH2 * HCl hvorved der gennemføres en intramolekylær ringslutning af methyl-N-(3,4-dimethoxy-6-cyanphenyl)-[4-(2-furoyl)-l-piperazinyl]thioforma-15 midat med formlen CH.O N = C — N U - CO -ζ' )
20 SCH3 ^^ '- 11 CH 0/^Ns>//Ns CN 25 kendetegnet ved, at forbindelsen med formlen II ved en temperatur på fra 100 til 140eC, fortrinsvis 120°C, omsættes med et stort overskud af ammoniumchlorid i et polært opløsningsmiddel, f.eks. formamid. 30
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at der anvendes 30 til 40 mol NH^Cl pr. mol af forbindelsen med formlen II.
3. Fremgangsmåde ifølge krav 1 eller 2, kendetegnet 35 ved, at reaktionen gennemføres med en reaktionstid på fra 15 til 20 timer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI790320A FI67699C (fi) | 1979-01-31 | 1979-01-31 | Foerfarande foer framstaellning av 6,7-dimetoxi-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolinhydroklorid med blodtryckssaenkande verkan |
| FI790320 | 1979-01-31 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK42680A DK42680A (da) | 1980-08-01 |
| DK158352B true DK158352B (da) | 1990-05-07 |
| DK158352C DK158352C (da) | 1990-10-08 |
Family
ID=8512343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK042680A DK158352C (da) | 1979-01-31 | 1980-01-31 | Fremgangsmaade til fremstilling af 6,7-dimethoxy-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolinhydrochlorid |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4271300A (da) |
| JP (1) | JPS55104280A (da) |
| AT (1) | AT374475B (da) |
| BE (1) | BE881297A (da) |
| CA (1) | CA1128945A (da) |
| CH (1) | CH644605A5 (da) |
| CS (1) | CS214692B2 (da) |
| DD (1) | DD148952A1 (da) |
| DE (1) | DE3002553A1 (da) |
| DK (1) | DK158352C (da) |
| FI (1) | FI67699C (da) |
| FR (1) | FR2447920A1 (da) |
| GB (1) | GB2041932B (da) |
| HU (1) | HU181016B (da) |
| NL (1) | NL190701C (da) |
| NO (1) | NO152298C (da) |
| PL (1) | PL126994B1 (da) |
| SE (1) | SE430692B (da) |
| SU (1) | SU900812A3 (da) |
| YU (1) | YU41498B (da) |
| ZA (1) | ZA80501B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI70411C (fi) * | 1980-12-29 | 1986-09-19 | Pfizer | Foerfarande foer framstaellning av nya antihypertensiva 4-amino-6,7-dimetoxi-2-piperazinokinazolin derivat |
| FI79107C (fi) * | 1984-06-25 | 1989-11-10 | Orion Yhtymae Oy | Foerfarande foer framstaellning av stabil -form av prazosinhydroklorid. |
| US4601897A (en) * | 1985-11-06 | 1986-07-22 | Pfizer Inc. | Prazosin-pirbuterol combination for bronchodilation |
| AT384218B (de) * | 1985-12-04 | 1987-10-12 | Gerot Pharmazeutika | Verfahren zur herstellung von neuen chinazolin-derivaten |
| YU70890A (en) * | 1989-04-21 | 1992-05-28 | Egyt Gyogyszervegyeszeti Gyar | Process for obtaining quinazoline derivatives |
| CA2077252C (en) * | 1992-08-31 | 2001-04-10 | Khashayar Karimian | Methods of making ureas and guanidines, and intermediates therefor |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3511836A (en) * | 1967-12-13 | 1970-05-12 | Pfizer & Co C | 2,4,6,7-tetra substituted quinazolines |
| GB1390015A (en) * | 1971-05-07 | 1975-04-09 | Koninklijke Pharma Fab Nv | 4-amino-quinazoline compounds |
| US3935213A (en) * | 1973-12-05 | 1976-01-27 | Pfizer Inc. | Process for hypotensive 4-amino-2-(piperazin-1-yl) quinazoline derivatives |
| US4092315A (en) * | 1976-03-01 | 1978-05-30 | Pfizer Inc. | Novel crystalline forms of prazosin hydrochloride |
| FI58124C (fi) * | 1976-12-15 | 1980-12-10 | Orion Yhtymae Oy | Ny mellanprodukt 3,4-dimetoxi-6-(4-(2-furoyl)-1-piperazinyltiokarbamido)-bensonitril foer framstaellning av 6,7-dimetoxi-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolin med blodtryckssaenkande verkan |
| FI58125C (fi) * | 1976-12-15 | 1985-01-02 | Orion Yhtymae Oy | Foerfarande foer framstaellning av 6,7-dimetoxi-4-amino-2-(4-(2-furoyl)-1-piperazinyl)kinazolin med blodtryckssaenkande vekan |
-
1979
- 1979-01-31 FI FI790320A patent/FI67699C/fi not_active IP Right Cessation
- 1979-12-27 NO NO794279A patent/NO152298C/no unknown
-
1980
- 1980-01-09 CA CA343,361A patent/CA1128945A/en not_active Expired
- 1980-01-09 CH CH12180A patent/CH644605A5/de not_active IP Right Cessation
- 1980-01-09 US US06/110,589 patent/US4271300A/en not_active Expired - Lifetime
- 1980-01-10 YU YU58/80A patent/YU41498B/xx unknown
- 1980-01-15 AT AT0019580A patent/AT374475B/de not_active IP Right Cessation
- 1980-01-16 NL NL8000289A patent/NL190701C/xx not_active IP Right Cessation
- 1980-01-23 BE BE0/199070A patent/BE881297A/fr not_active IP Right Cessation
- 1980-01-25 DE DE19803002553 patent/DE3002553A1/de active Granted
- 1980-01-28 ZA ZA00800501A patent/ZA80501B/xx unknown
- 1980-01-28 CS CS80588A patent/CS214692B2/cs unknown
- 1980-01-29 GB GB8002903A patent/GB2041932B/en not_active Expired
- 1980-01-29 HU HU8080182A patent/HU181016B/hu not_active IP Right Cessation
- 1980-01-30 SU SU802874898A patent/SU900812A3/ru active
- 1980-01-30 PL PL1980221684A patent/PL126994B1/pl unknown
- 1980-01-30 JP JP1081580A patent/JPS55104280A/ja active Granted
- 1980-01-30 FR FR8001991A patent/FR2447920A1/fr active Granted
- 1980-01-31 DD DD80218776A patent/DD148952A1/de not_active IP Right Cessation
- 1980-01-31 DK DK042680A patent/DK158352C/da not_active IP Right Cessation
- 1980-01-31 SE SE8000777A patent/SE430692B/sv unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU181016B (en) | 1983-05-30 |
| CS214692B2 (en) | 1982-05-28 |
| NO152298C (no) | 1985-09-04 |
| GB2041932B (en) | 1982-10-27 |
| DD148952A1 (de) | 1981-06-17 |
| FI790320A7 (fi) | 1980-08-01 |
| CA1128945A (en) | 1982-08-03 |
| ATA19580A (de) | 1983-09-15 |
| NL8000289A (nl) | 1980-08-04 |
| DK158352C (da) | 1990-10-08 |
| SE430692B (sv) | 1983-12-05 |
| NO794279L (no) | 1980-08-01 |
| DE3002553C2 (da) | 1988-10-27 |
| JPS55104280A (en) | 1980-08-09 |
| YU41498B (en) | 1987-08-31 |
| DK42680A (da) | 1980-08-01 |
| NL190701C (nl) | 1994-07-01 |
| BE881297A (fr) | 1980-05-16 |
| FR2447920A1 (fr) | 1980-08-29 |
| NL190701B (nl) | 1994-02-01 |
| SU900812A3 (ru) | 1982-01-23 |
| FR2447920B1 (da) | 1982-12-03 |
| NO152298B (no) | 1985-05-28 |
| AT374475B (de) | 1984-04-25 |
| YU5880A (en) | 1983-02-28 |
| ZA80501B (en) | 1981-02-25 |
| GB2041932A (en) | 1980-09-17 |
| CH644605A5 (de) | 1984-08-15 |
| PL221684A1 (da) | 1980-10-20 |
| SE8000777L (sv) | 1980-08-01 |
| US4271300A (en) | 1981-06-02 |
| JPS6310955B2 (da) | 1988-03-10 |
| PL126994B1 (en) | 1983-09-30 |
| DE3002553A1 (de) | 1980-08-07 |
| FI67699B (fi) | 1985-01-31 |
| FI67699C (fi) | 1985-05-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |