NO169228B - 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole - Google Patents
5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole Download PDFInfo
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- NO169228B NO169228B NO892008A NO892008A NO169228B NO 169228 B NO169228 B NO 169228B NO 892008 A NO892008 A NO 892008A NO 892008 A NO892008 A NO 892008A NO 169228 B NO169228 B NO 169228B
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- cyclopropyl
- oxadiazole
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- BGHGVAKKIBOJGS-UHFFFAOYSA-N 5-cyclopropyl-3-(isocyanomethyl)-1,2,4-oxadiazole Chemical compound [C-]#[N+]CC1=NOC(C2CC2)=N1 BGHGVAKKIBOJGS-UHFFFAOYSA-N 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- -1 11,13a-dihydro-9-oxo-9H-imidazo(1,5-a)pyrrolo(2,1-c)(1,4)benzodiazepine compound Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000004300 GABA-A Receptors Human genes 0.000 description 2
- 108090000839 GABA-A Receptors Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- ZSJUKDUHDOMINL-UHFFFAOYSA-N 3-(1H-1,2-benzodiazepin-3-yl)-1,2,4-oxadiazole Chemical class C1=CC2=CC=CC=C2NN=C1C=1N=CON=1 ZSJUKDUHDOMINL-UHFFFAOYSA-N 0.000 description 1
- YZIWCURGXWGKPE-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound N1=CN2C3=CC=CC=C3C(=O)N(C)CC2=C1C(N=1)=NOC=1C1CC1 YZIWCURGXWGKPE-UHFFFAOYSA-N 0.000 description 1
- XHBHKHBUALFEOU-UHFFFAOYSA-N 4,5-dihydroimidazo[1,5-a][1,4]benzodiazepin-6-one Chemical class O=C1NCC2=CN=CN2C2=CC=CC=C12 XHBHKHBUALFEOU-UHFFFAOYSA-N 0.000 description 1
- SADOJDRAQISFAK-UHFFFAOYSA-N 4-(1H-1,2-benzodiazepin-3-yl)oxadiazole Chemical class C1=CC2=CC=CC=C2NN=C1C1=CON=N1 SADOJDRAQISFAK-UHFFFAOYSA-N 0.000 description 1
- OUVUFAZUKYKNCJ-UHFFFAOYSA-N 4-imidazo[4,5-i][1,2]benzodiazepin-3-yloxadiazole Chemical class N=1N=C2C3=NC=NC3=CC=C2C=CC=1C1=CON=N1 OUVUFAZUKYKNCJ-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- BEGOWLXWPNPRSK-UHFFFAOYSA-N O1N=NC(=C1)C1=NC=CC=2C3=CC=CC=C3NC12 Chemical class O1N=NC(=C1)C1=NC=CC=2C3=CC=CC=C3NC12 BEGOWLXWPNPRSK-UHFFFAOYSA-N 0.000 description 1
- LTKUGDREISBAHW-UHFFFAOYSA-N O=C1N2CCCC2C2=CN=CN2C2=CC=CC=C12 Chemical class O=C1N2CCCC2C2=CN=CN2C2=CC=CC=C12 LTKUGDREISBAHW-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- LDDOSDVZPSGLFZ-UHFFFAOYSA-N ethyl cyclopropanecarboxylate Chemical compound CCOC(=O)C1CC1 LDDOSDVZPSGLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- OYPIXUZKTODLAC-UHFFFAOYSA-N n-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]formamide Chemical compound O=CNCC1=NOC(C2CC2)=N1 OYPIXUZKTODLAC-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Foreliggende oppfinnelse vedrører en ny 5-cyklopropyl-3-isocyanometyl-1,2,4-oksadiazol. The present invention relates to a new 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Den nye forbindelsen er nyttig for fremstillingen av oksadiazolylimidazo-benzodiazepinf orbindelser. De sistnevnte forbindelsene er nyttige i psykofarmasøytiske preparater, f.eks. for behandling av sykdommer i sentralnervesystemet, så som anti-konvulsive midler og anxiolytika. The new compound is useful for the preparation of oxadiazolylimidazo-benzodiazepine compounds. The latter compounds are useful in psychopharmaceutical preparations, e.g. for the treatment of diseases of the central nervous system, such as anticonvulsants and anxiolytics.
Det er velkjent (Squires, R.F. og Braestrup, C, Nature (London) 266, (1977) 732) at spesifikke seter i sentralnerve-systemene hos vertebrater viser en høy spesifikk affinitet for binding av 1,4- og 1,5-benzodiazepiner. Disse setene er betegnet benzodiazepinreseptorer. It is well known (Squires, R.F. and Braestrup, C, Nature (London) 266, (1977) 732) that specific sites in the central nervous systems of vertebrates show a high specific affinity for the binding of 1,4- and 1,5-benzodiazepines . These sites are termed benzodiazepine receptors.
Europeisk patentpublikasjon nr. 109.921 beskriver forbindelser som har den generelle formelen I: European Patent Publication No. 109,921 describes compounds having the general formula I:
hvori in which
R' er hydrogen, klor, fluor eller nitro på 7- eller 8-posisjonen, R' is hydrogen, chlorine, fluorine or nitro in the 7- or 8-position,
R<1> er hydrogen eller C^_3-alkyl, R<1> is hydrogen or C1-3-alkyl,
R<3> er en oksadiazolylgruppe som har formelen R<3> is an oxadiazolyl group having the formula
hvori in which
R'' er C-^-alkyl, R'' is C 1-6 alkyl,
A B er en gruppe som har formelen A B is a group that has the formula
hvori in which
R^ er hydrogen eller metyl og R 1 is hydrogen or methyl and
R''' er hydrogen eller klor. R''' is hydrogen or chlorine.
Europeisk patentpublikasjon nr. 109.921 beskriver videre at visse oksadiazolylbenzodiazepiner og oksadiazolylbeta-karboliner viser sterkere bindingsaffinitet for benzodia-zepinreseptorene enn alkylestrene av de tilsvarende syrene. European patent publication no. 109,921 further describes that certain oxadiazolylbenzodiazepines and oxadiazolylbeta-carbolines show stronger binding affinity for the benzodiazepine receptors than the alkyl esters of the corresponding acids.
Europeisk patentpublikasjon nr. 150.040 beskriver 1,2,4-oksadiazolylbenzodiazepinforbindelser som har formlene II og European Patent Publication No. 150,040 describes 1,2,4-oxadiazolylbenzodiazepine compounds having the formulas II and
III: III:
hvori in which
R<1> er alkyl, cykloalkyl, metoksymetyl, R<1> is alkyl, cycloalkyl, methoxymethyl,
R<3> er H, CH3 og R<3> is H, CH3 and
R<4> og R<5> er begge H eller halogen, hvori R<4> and R<5> are both H or halogen, wherein
hvori in which
R<1> er alkyl, cykloalkyl, CF3 eller metoksymetyl, R<1> is alkyl, cycloalkyl, CF3 or methoxymethyl,
R<4> og R<5> er begge H, halogen, CF3 og n er 2 eller 3. R<4> and R<5> are both H, halogen, CF3 and n is 2 or 3.
Forbindelsene beskrevet i eksemplene 2, 3, 16, 29, 32, 43, 44, 45, 49, 50, 51, 52, 53 og 56 i EP nr. 150.040 er 5,6-dihydro-6-okso-4H-imidazo (l,5-a)(l,4 )benzodiazepinforbind-elser (som har formel II ovenfor), mens forbindelsene beskrevet i eksemplene 1, 8, 9, 17, 18, 23 og 30 er 10,11,12,12a-tetrahydro-9-okso-9E-imidazo-( 1,5-a)aceto(2 , 1-c)(1,4)benzodiazepinforbindelser (som har formel III ovenfor) og forbindelsene beskrevet i eksemplene 4, 5, 6, 7, 10, 11, The compounds described in Examples 2, 3, 16, 29, 32, 43, 44, 45, 49, 50, 51, 52, 53 and 56 of EP No. 150,040 are 5,6-dihydro-6-oxo-4H-imidazo (1,5-a)(1,4)benzodiazepine compounds (having formula II above), while the compounds described in Examples 1, 8, 9, 17, 18, 23 and 30 are 10,11,12,12a- tetrahydro-9-oxo-9E-imidazo-(1,5-a)aceto(2,1-c)(1,4)benzodiazepine compounds (having formula III above) and the compounds described in Examples 4, 5, 6, 7 , 10, 11,
12, 13, 14, 15, 19, 20, 21, 22, 24, 25, 26, 27, 28, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 48, 54, 55, 57, 58 og 59 er 11,12,13,13a-tetrahydro-9-okso-9H-imidazo-(1,5-a)pyrrolo(2,1-c)(1,4 )benzodiazepinforbindelser (som også har formel III). 12, 13, 14, 15, 19, 20, 21, 22, 24, 25, 26, 27, 28, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 48, 54, 55, 57, 58 and 59 are 11,12,13,13a-tetrahydro-9-oxo-9H-imidazo-(1,5-a)pyrrolo(2,1-c)(1,4 ) benzodiazepine compounds (which also have formula III).
Endelig er forbindelsen beskrevet i eksempel 47 av EP 150-040 en 11,13a-dihydro-9-okso-9H-imidazo(l,5-a)pyrrolo(2, 1-c)(1,4)benzodiazepinforbindelse. Finally, the compound described in Example 47 of EP 150-040 is a 11,13a-dihydro-9-oxo-9H-imidazo(1,5-a)pyrrolo(2,1-c)(1,4)benzodiazepine compound.
Forbindelsene beskrevet i eksemplene 11, 15, 26 og 40 av EP The compounds described in Examples 11, 15, 26 and 40 of EP
150.040 er forbindelser av formel III hvori X er 1,2,4-oksadiazol-3-yl-gruppe og i forbindelsen beskrevet i eksempel 40 er X en 5-cyklopropyl-l,2,4-oksadiazol-3-yl-gruppe. 150,040 are compounds of formula III in which X is 1,2,4-oxadiazol-3-yl group and in the compound described in example 40 X is a 5-cyclopropyl-1,2,4-oxadiazol-3-yl group.
EP nr. 150.040 beskriver også en fremgangsmåte for fremstilling av forbindelser som har formlene II og III, denne fremgangsmåten innbefatter omsetning av en forbindelse som har formelen henholdsvis V og VI: EP No. 150,040 also describes a method for the preparation of compounds having the formulas II and III, this method includes reacting a compound having the formula V and VI respectively:
hvori R<4>, R^ og n har betydningene angitt ovenfor og Y er en avspaltbar gruppe, med en forbindelse av formelen CN-CE2-CO2R slik at det dannes en forbindelse av formel II eller III innbefattende en -CC^R-substituent ved 3-posisjonen, og omvandling av denne forbindelsen i flere trinn til det ønskede oksadiazolderivatet. wherein R<4>, R^ and n have the meanings given above and Y is a leaving group, with a compound of the formula CN-CE2-CO2R so as to form a compound of formula II or III including a -CC^R substituent at the 3-position, and converting this compound in several steps to the desired oxadiazole derivative.
Foreliggende oppfinnelse tilveiebringer en ny 5-cyklopropyl-3-isocyanometyl-l,2,4-oksadiazol, som er kjennetegnet ved at den har formelen: The present invention provides a new 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole, which is characterized by having the formula:
Forbindelsen ifølge oppfinnelsen er egnet for fremstillingen av 3-(5-cyklopropyl-l,2,4-oksadiazol-3-yl)-5,6-dihydro-5-metyl-6-okso-4H-imidazo(1,5-a)(l,4)-benzodiazepin med formelen VII: Følgelig kan forbindelsen av formel VII fremstilles ved å omsette forbindelsen ifølge oppfinnelsen med en forbindelse som har formelen VIII The compound according to the invention is suitable for the preparation of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5- a)(1,4)-benzodiazepine of the formula VII: Accordingly, the compound of the formula VII can be prepared by reacting the compound of the invention with a compound having the formula VIII
hvori Y er en avspaltbar gruppe. wherein Y is a leaving group.
Eksempler på egnede avspaltbare grupper for anvendelse i reaksjonene angitt ovenfor, er halogen, alkyltio, f.eks. metyltio, aralkyltio, N-nitrosoalkylamino, alkoksy, merkapto, -OP-(0)(OR)2 hvori R er lavere-alkyl eller -0P(0)(NR'R"), hvori R' og R" begge står for lavere alkyl eller fenyl, eller danner sammen med det nabostilte nitrogenatomet en hetero-cyklisk rest, så som morfolino, pyrrolidino, piperidino eller metylpiperazino. Examples of suitable cleavable groups for use in the reactions indicated above are halogen, alkylthio, e.g. methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -OP-(0)(OR)2 wherein R is lower-alkyl or -OP(0)(NR'R"), wherein R' and R" both stand for lower alkyl or phenyl, or together with the neighboring nitrogen atom forms a heterocyclic residue, such as morpholino, pyrrolidino, piperidino or methylpiperazino.
Omsetningen utføres fortrinnsvis under alkaliske betingelser, dvs. i nærvær av en base. Foretrukne baser er alkalimetall, f.eks. kalium eller natrium, alkoksider eller hydrider. Omsetningen bevirkes fortrinnsvis i nærvær av et organisk oppløsningsmiddel som ikke reagerer med reaktantene og reaksjonsproduktene under de herskende reaksjonsbetingelsene. Egnede oppløsningsmidler er vannfrie oppløsningsmidler og fortrinnsvis vannfrie aprotiske oppløsningsmidler så som dimetylformamid (DMF) eller lignende. Reaksjonstemperaturen hør være tilstrekkelig høy til å tillate reaksjonen å forløpe med en tilfredsstillende hastighet og uten uønsket for-sinkelse eller dekomponering, og et område på fra -40"C til 30°C er vanligvis velegnet. The reaction is preferably carried out under alkaline conditions, i.e. in the presence of a base. Preferred bases are alkali metal, e.g. potassium or sodium, alkoxides or hydrides. The reaction is preferably effected in the presence of an organic solvent which does not react with the reactants and reaction products under the prevailing reaction conditions. Suitable solvents are anhydrous solvents and preferably anhydrous aprotic solvents such as dimethylformamide (DMF) or the like. The reaction temperature should be sufficiently high to allow the reaction to proceed at a satisfactory rate and without undesirable retardation or decomposition, and a range of from -40°C to 30°C is usually suitable.
Oppfinnelsen skal i det følgende beskrives i større detalj under henvisning til det følgende eksempelet. In the following, the invention will be described in greater detail with reference to the following example.
Eksempel Example
a. Formvlaminometvl- karboksamidoksim a. Formylaminomethylcarboxamidoxime
0,55 mol nyfremstilt hydroksylamin oppløst i 370 ml metanol ble tilsatt til 53,6 g (0,638 mol) N-formylaminoacetonitril. Et isbad ble benyttet for å holde temperaturen under 20°C under tilsatsen. Oppløsningen fikk stå ved romtemperatur over natten, hvoretter den ble inndampet slik at man fikk forbindelsen i overskriften som bleke krystaller. 0.55 mol of freshly prepared hydroxylamine dissolved in 370 ml of methanol was added to 53.6 g (0.638 mol) of N-formylaminoacetonitrile. An ice bath was used to keep the temperature below 20°C during the addition. The solution was allowed to stand at room temperature overnight, after which it was evaporated to give the title compound as pale crystals.
Dekomponering 104-110°C. Decomposition 104-110°C.
b. 3- formylaminometyl- 5- cyklopropyl- l. 2. 4- oksadiazol En blanding av 35 ml etylcyklopropylkarboksylat, 30 g formylaminometyl-karboksamidoksim, 1 g natrium og 30 g nedknust molekylarsikt (4Å) ble oppvarmet under tilbakeløp i 300 ml absolutt EtOE i 8 timer, hvoretter ytterligere 1 g natrium ble tilsatt. Reaksjonsblandingen ble filtrert og filtratet ble inndampet. En mørk oljeformig rest ble dannet og den ble suspendert i 300 ml CEC13, filtrert, og filtratet ble inndampet slik at man fikk forbindelsen i overskriften som en olje. b. 3- formylaminomethyl- 5- cyclopropyl- 1. 2. 4- oxadiazole A mixture of 35 ml of ethyl cyclopropyl carboxylate, 30 g of formylaminomethyl-carboxamidoxime, 1 g of sodium and 30 g of crushed molecular sieve (4Å) was heated under reflux in 300 ml of absolute EtOE for 8 hours, after which another 1 g of sodium was added. The reaction mixture was filtered and the filtrate was evaporated. A dark oily residue formed and it was suspended in 300 ml of CEC13, filtered and the filtrate was evaporated to give the title compound as an oil.
E-NMR (60 MHz, CDC13) S (ppm): 1,2 (4 E, m) 2,8 (1 E, m), 4,5 (2 E, d, J=6 EZ), 7,8 (1 E, bred-NH), 8,2 (lE,s). c. 5- cyklopropyl- 3- isocyanometyl- l. 2, 4- oksadiazol En omrørt oppløsning av 5-cyklopropyl-3-formylaminometyl-1,2,4-oksadiazol (60 mmol) og trietylamin (176 mmol) i CH2CI2 (100 ml) ble dråpevis tilsatt POCI3 (60 mmol) ved 0"C, hvoretter en oppløsning av Na2C03 (60 mmol) i EtøO (50 ml) ble tilsatt. Blandingen ble oppvarmet til romtemperatur, hvoretter den organiske fasen ble separert, tørket og inndampet i vakuum. Resten ble behandlet med eter, dekantert og oppløsningen ble inndampet slik at man fikk forbindelsen i overskriften som en olje. E-NMR (60 MHz, CDC13) S (ppm): 1.2 (4 E, m) 2.8 (1 E, m), 4.5 (2 E, d, J=6 EZ), 7, 8 (1 E, broad-NH), 8.2 (lE,s). c. 5- cyclopropyl- 3- isocyanomethyl- 1. 2, 4- oxadiazole A stirred solution of 5-cyclopropyl-3-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2CI2 (100 ml) was added dropwise POCl3 (60 mmol) at 0"C, after which a solution of Na2CO3 (60 mmol) in Et2O (50 ml) was added. The mixture was warmed to room temperature, after which the organic phase was separated, dried and evaporated in vacuum The residue was treated with ether, decanted and the solution evaporated to give the title compound as an oil.
Oljen ble bearbeidet uten ytterligere rensing. The oil was processed without further purification.
IR, cm-<1>: 2160. IR, cm-<1>: 2160.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO892008A NO169228C (en) | 1985-05-17 | 1989-05-19 | 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK220485A DK220485D0 (en) | 1985-05-17 | 1985-05-17 | NEW OXADIAZOLYLIMIDAZOBENZODIAZEPINE DERIVATIVES AND PROCEDURES PREPARED THEREOF |
| DK365985A DK365985D0 (en) | 1985-08-12 | 1985-08-12 | NEW OXADIAZOLYLIMIDAZOBENZODIAZEPINE DERIVATIVES AND PROCEDURES PREPARED THEREOF |
| DK476985A DK476985D0 (en) | 1985-10-17 | 1985-10-17 | PROCEDURE FOR THE PREPARATION OF OXADIAZOLYL DERIVATIVES OF IMIDAZOBENZODIAZEPINES AND INTERMEDIATES FOR USING THE PROCEDURE |
| NO861954A NO163228C (en) | 1985-05-17 | 1986-05-16 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXADIAZOLYLIMIDAZOBENZODIAZEPIN CONNECTION. |
| NO892008A NO169228C (en) | 1985-05-17 | 1989-05-19 | 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO892008L NO892008L (en) | 1986-11-18 |
| NO892008D0 NO892008D0 (en) | 1989-05-19 |
| NO169228B true NO169228B (en) | 1992-02-17 |
| NO169228C NO169228C (en) | 1992-06-10 |
Family
ID=27512890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO892008A NO169228C (en) | 1985-05-17 | 1989-05-19 | 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO169228C (en) |
-
1989
- 1989-05-19 NO NO892008A patent/NO169228C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO169228C (en) | 1992-06-10 |
| NO892008D0 (en) | 1989-05-19 |
| NO892008L (en) | 1986-11-18 |
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