NO861122L - NEW PYRIDONE DERIVATIVES. - Google Patents
NEW PYRIDONE DERIVATIVES.Info
- Publication number
- NO861122L NO861122L NO861122A NO861122A NO861122L NO 861122 L NO861122 L NO 861122L NO 861122 A NO861122 A NO 861122A NO 861122 A NO861122 A NO 861122A NO 861122 L NO861122 L NO 861122L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- pyrrolo
- compound
- pyrido
- pyrid
- Prior art date
Links
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 36
- 239000000460 chlorine Substances 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000001540 azides Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- CKRFUWCHGXXAJY-UHFFFAOYSA-N 1-(1h-pyrrolo[3,2-b]pyridin-2-yl)ethanone Chemical compound C1=CC=C2NC(C(=O)C)=CC2=N1 CKRFUWCHGXXAJY-UHFFFAOYSA-N 0.000 claims description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000006264 debenzylation reaction Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000013081 microcrystal Substances 0.000 description 5
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- -1 alkyl radical Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 2
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001448862 Croton Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101150030755 Ocln gene Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- QLZHNIAADXEJJP-UHFFFAOYSA-N Phenylphosphonic acid Chemical compound OP(O)(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QOHMWDJIBGVPIF-UHFFFAOYSA-N n',n'-diethylpropane-1,3-diamine Chemical compound CCN(CC)CCCN QOHMWDJIBGVPIF-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Description
Oppfinnelsen gjelder nye derivater av 5-H pyrido(3<1>,4<1>:4,5)-pyrrolo(3,2-c)pyrid-l-oner, fremgangsmåte for å fremstille dem og deres bruk som utgangsforbindelser i syntese ved fremstilling av forbindelser som er nyttige i den farmasøytiske industri. The invention relates to new derivatives of 5-H pyrido(3<1>,4<1>:4,5)-pyrrolo(3,2-c)pyrid-l-ones, process for preparing them and their use as starting compounds in synthesis in the production of compounds useful in the pharmaceutical industry.
De nye derivatene i oppfinnelsen tilsvarer den følgendeThe new derivatives in the invention correspond to the following
formelformula
hvori X betegner hydrogen eller klor, R-^ betegner hydrogen, en lavere alkyl- eller benzyl-gruppe. wherein X denotes hydrogen or chlorine, R-^ denotes hydrogen, a lower alkyl or benzyl group.
Oppfinnelsen gjelder også de tautomere former der de eksis-terer . The invention also applies to the tautomeric forms where they exist.
Ved lavere alkylradikal menes en rett eller forgrenet C^~C4~mettet hydrokarbonkjede. By lower alkyl radical is meant a straight or branched C^~C4~ saturated hydrocarbon chain.
Disse derivatene er utgangsforbindelser ved fremstillingThese derivatives are starting compounds during manufacture
av nye forbindelser med formelof new compounds of formula
hvori n betegner et helt tall fra 2 til 4, R_ og R3er begge uavhengig av hverandre hydrogen, en lavere alkyl- eller hydroksy-alkyl-gruppe, og betegner hydrogen eller et lavere alkyl- wherein n represents an integer from 2 to 4, R_ and R3 are both independently hydrogen, a lower alkyl or hydroxyalkyl group, and represent hydrogen or a lower alkyl
radikal .radical.
De nye forbindelser med formel A er utstyrt med interessante antitumoregenskaper, og de er nyttige i terapi. De er emne for den franske anmeldelse nr. 85.04872 registrert på samme dag. The new compounds of formula A are endowed with interesting antitumor properties and are useful in therapy. They are the subject of the French notification No. 85.04872 registered on the same day.
Oppfinnelsen gjelder også fremgangsmåte for fremstillingen av forbindelsene med formel (I) ovenfor,karakterisert ved: a) oksydasjon av 2-(1-hydroksyetyl)-4-klor-l-H-pyrrolo- (3,2-c)pyridin substituert i 1-posisjon, med formel The invention also applies to methods for the preparation of the compounds of formula (I) above, characterized by: a) oxidation of 2-(1-hydroxyethyl)-4-chloro-1-H-pyrrolo- (3,2-c)pyridine substituted in the 1-position, with formula
hvori R<1>^er en lavere alkyl- eller benzyl-gruppe, til 2-acetyl- pyrrolo-pyridin som tilsvarer formelen wherein R<1>^ is a lower alkyl or benzyl group, to 2-acetyl- pyrrolo-pyridine corresponding to the formula
hvor R<1>^er som i formel (II) where R<1>^ is as in formula (II)
b) overføring av forbindelsen med formel (III) ved en Wittig-Horner-reaksjon til 3-(pyrrolo-2-pyridyl)krotonat tilsvarende formel b) transfer of the compound of formula (III) by a Wittig-Horner reaction to 3-(pyrrolo-2-pyridyl)crotonate corresponding to formula
hvori R^ er som i formel (II) wherein R^ is as in formula (II)
c) forsåpning av esteren med formel IV som er dannet, slik at det dannes den tilsvarende 3-^4-klor-l-H-pyrrolo-(3,2-c)2-pyridylJkrotonsyre med formel c) saponification of the ester of formula IV which is formed, so that the corresponding 3-4-chloro-1-H-pyrrolo-(3,2-c)2-pyridyl-crotonic acid of formula
hvor R<1>^er som i formel II where R<1>^ is as in formula II
4°) overføring av forbindelsen med formel V til et azid med formel 4°) transfer of the compound of formula V to an azide of formula
hvori R1-^ er som i formel II, wherein R 1 -^ is as in formula II,
5°) ringdannelsen av azidet med formel VI slik at det dannes en forbindelse med formel I, der X er klor, 5°) the ring formation of the azide of formula VI so that a compound of formula I is formed, where X is chlorine,
hvori R'^ betegner en alkyl- eller benzyl-gruppe, og deretter ettersom tilfellet måtte kreve, 6°) ved hydrogenering, dannelse av forbindelsen med formel r, X betegner hydrogen wherein R'^ denotes an alkyl or benzyl group, and then as the case may require, 6°) by hydrogenation, forming the compound of formula r, X denotes hydrogen
hvori R'^betegner en lavere alkyl- eller benzyl-gruppe. wherein R' represents a lower alkyl or benzyl group.
Denne forbindelsen kan brukes direkte for å oppnå forbindelsene med formel (A) hvori R^betegner en lavere alkylgruppe. Den vil bli debenzylert om det er ønsket for å oppnå intermediatet med formel I hvori X og R-^begge representerer hydrogen; This compound can be used directly to obtain the compounds of formula (A) in which R₁ denotes a lower alkyl group. It will be debenzylated if desired to obtain the intermediate of formula I wherein X and R-^ both represent hydrogen;
med hensikt å fremstille forbindelsene med formel (A) hvori R^betegner hydrogen. with the intention of preparing the compounds of formula (A) in which R^ denotes hydrogen.
Alkoholene med formel II, utgangspunktet i fremstillingen, fremstilles fra 4-klor-l-H-pyrrolo-(3,2-c)-pyridiner substituert i 1-posisjon ved fremgangsmåten som er beskrevet av E. Bisagni et Coll. (Tétrahedron, 39, 1777-1781, (1983)), imidlertid med bruk av dietyleter som oppløsningsmiddel i det tilfelle der substituenten er en benzylgruppe. The alcohols of formula II, the starting point in the preparation, are prepared from 4-chloro-1-H-pyrrolo-(3,2-c)-pyridines substituted in the 1-position by the method described by E. Bisagni et Coll. (Tétrahedron, 39, 1777-1781, (1983)), however with the use of diethyl ether as solvent in the case where the substituent is a benzyl group.
Oksyderingen av alkoholene til acetylerte derivater med formel (III) utføres med mangandioksyd i et klorert oppløsnings-middel, med tilbakeløp. The oxidation of the alcohols to acetylated derivatives of formula (III) is carried out with manganese dioxide in a chlorinated solvent, with reflux.
Overføringen til krotonesteren med formel (IV) skjer vedThe transfer to the croton ester of formula (IV) takes place by
å omsette derivatet med formel (III) i oppløsning i et inert oppløsningsmiddel såsom 1,2-dimetoksyetan, ved en temperatur mellom 0°C og 90°C, med etyldietylfosfonoacetat på forhånd gjort basisk med natriumhydrid. En cis-trans-blanding av etylesteren av krotonsyre med formel (IV) dannes. reacting the derivative of formula (III) in solution in an inert solvent such as 1,2-dimethoxyethane, at a temperature between 0°C and 90°C, with ethyldiethylphosphonoacetate previously made basic with sodium hydride. A cis-trans mixture of the ethyl ester of crotonic acid of formula (IV) is formed.
Denne esteren forsåpes direkte til 3-(4-klor-l-H-pyrrolo-(3, 2-c)-'2-pyrridyl) krotonsyre med formel (V). This ester is saponified directly to 3-(4-chloro-1-H-pyrrolo-(3,2-c)-'2-pyrridyl) crotonic acid of formula (V).
Denne syren overføres til et blandet anhydrid i acetonopp-løsning, ved innvirkning av etylklorkarbonat ved lav temperatur i nærvær av et tertiært alifatisk amin, deretter til et azid med formel (VI) ved innvirkning av natriumnitrid i vandig opp-løsning ved lav temperatur. This acid is transferred to a mixed anhydride in acetone solution, by the action of ethyl chlorocarbonate at low temperature in the presence of a tertiary aliphatic amine, then to an azide of formula (VI) by the action of sodium nitride in aqueous solution at low temperature.
Azidet i oppløsning i et inert oppløsningsmiddel såsom difenyleter gjøres ringformet ved oppvarming til høy temperatur i nærvær av et tertiært alifatisk amin med høyt kokepunkt, såsom tributylamin. Således fremkommer forbindelser med formel (I) hvori X betegner klor og R^ er en lavere alkyl- eller benzyl-gruppe. The azide in solution in an inert solvent such as diphenyl ether is cyclized by heating to a high temperature in the presence of a high boiling tertiary aliphatic amine such as tributylamine. Compounds of formula (I) are thus produced in which X denotes chlorine and R 1 is a lower alkyl or benzyl group.
Ved hydrogenering, ved omgivelsenes temperatur og trykk,During hydrogenation, at ambient temperature and pressure,
i nærvær av en katalysator såsom palladisert trekull, fremkommer forbindelser med formel (I) hvori X betegner hydrogen og R^fremdeles er en lavere alkyl- eller benzyl-gruppe. in the presence of a catalyst such as palladated charcoal, compounds of formula (I) are produced in which X denotes hydrogen and R is still a lower alkyl or benzyl group.
For å oppnå forbindelsene med formel (I) hvori R^betegner hydrogen, utsettes forbindelsene hvori R^betegner en benzyl-gruppe, for debenzylering: denne reaksjonen skjer ved innvirkning av natrium i flytende ammoniakk. To obtain the compounds of formula (I) in which R^ denotes hydrogen, the compounds in which R^ denotes a benzyl group are subjected to debenzylation: this reaction takes place by the action of sodium in liquid ammonia.
De følgende eksempler er gitt som ikke-begrensende eksempel på den foreliggende oppfinnelse. The following examples are given as non-limiting examples of the present invention.
EKSEMPEL 1 EXAMPLE 1
9-Klor-4 ,5-dimetyl-2-H, 5-H-pyrido- ( 3' , 4 11: 4 , 5) -pyrrolo-(3,2-c)-pyrid-l-on 9-Chloro-4,5-dimethyl-2-H,5-H-pyrido-(3',41:4,5)-pyrrolo-(3,2-c)-pyrid-1-one
(X = C1-R1=CH3)-derivat nr. 1(X = C1-R1=CH3) derivative #1
<54>a) l-metyl-2-acetyl-4-klor-l-H-pyrrolo-(3,2-c)-pyridin (derivat med formel (III) <54>a) 1-methyl-2-acetyl-4-chloro-1-H-pyrrolo-(3,2-c)-pyridine (derivative of formula (III)
4-Klor-l-metyl-2-(1-hydroksyetyl)-1-H-pyrrolo-(3,2-c)-pyridin (lg) løses opp i 30 ml kloroform. 8 g Mangandioksyd tilsettes, deretter varmes reaksjonsblandingen under røring, opp til til-bakeløp i 2 2 timer. Etter avkjøling og filtrering dampes opp-løsningen inn under vakuum og resten omkrystalliseres i etanol. 0,780 g av det ønskede produkt fremkommer. 4-Chloro-1-methyl-2-(1-hydroxyethyl)-1-H-pyrrolo-(3,2-c)-pyridine (Ig) is dissolved in 30 ml of chloroform. 8 g of manganese dioxide are added, then the reaction mixture is heated with stirring, up to reflux for 2 2 hours. After cooling and filtering, the solution is evaporated under vacuum and the residue is recrystallized in ethanol. 0.780 g of the desired product is obtained.
Utbytte: 78%, sm.pkt. = 215-216°C.Yield: 78%, sm.pt. = 215-216°C.
Ber. for C1()HgClN20 = C, 57,55; H, 4,32; N, 13,43; Cl, 17,03; Funnet: C, 57,42; H, 4,29; N, 13,31; Cl, 16,73 Pray. for C1(HgClN2O) = C, 57.55; H, 4.32; N, 13.43; Cl, 17.03; Found: C, 57.42; H, 4.29; N, 13.31; Cl, 16.73
H b) 3-[l-metyl-4-klor-l-H-pyrrolo-(3,2-c)-2-pyridyl] krotonat (derivat med formel (IV)- cis-trans-blanding). H b) 3-[1-methyl-4-chloro-1-H-pyrrolo-(3,2-c)-2-pyridyl]crotonate (derivative with formula (IV)- cis-trans mixture).
Til en suspensjon av natriumhydrid (1,34 g, 50% i olje, 28 mmol) i 100 ml 1,2-dimetoksyetan tilsettes 6,3 g (28 mmol) etyldietyl-fosfonacetat i oppløsning i 90 ml 1,2-dimetoksyetan destillert over kalsiumhydrid. Etter 3 timer ved 0°C under røring, tilsettes 4,17 g av det tidligere fremstilte keton med formel (III) i suspensjon i 100 ml 1,2-dimetoksyetan, gradvis. Reaksjonsblandingen får stå 2 timer ved 0°C, 18 timer ved romtempe-ratur, varmes deretter til tilbakeløp i 4 timer. Etter inndamping av oppløsningsmidlet helles blandingen i vann, ekstraheres med metylenklorid og ved at dette dampes bort, samles detønskede produkt i form av en olje. To a suspension of sodium hydride (1.34 g, 50% in oil, 28 mmol) in 100 ml of 1,2-dimethoxyethane is added 6.3 g (28 mmol) of ethyl diethyl phosphonoacetate in solution in 90 ml of distilled 1,2-dimethoxyethane over calcium hydride. After 3 hours at 0°C with stirring, 4.17 g of the previously prepared ketone of formula (III) in suspension in 100 ml of 1,2-dimethoxyethane are gradually added. The reaction mixture is allowed to stand for 2 hours at 0°C, 18 hours at room temperature, then heated to reflux for 4 hours. After evaporation of the solvent, the mixture is poured into water, extracted with methylene chloride and by this being evaporated, the desired product is collected in the form of an oil.
c) 3-l-metyl-4-klor-l-H-pyrrolo-(3,2-c)-2-pyridylkroton-syre (derivat med formel (V) cis-trans-blanding) c) 3-1-methyl-4-chloro-1-H-pyrrolo-(3,2-c)-2-pyridylcrotonic acid (derivative of formula (V) cis-trans mixture)
Esteren som ble dannet i det foregående trinn løses opp i 50The ester formed in the previous step is dissolved in 50
ml etanol avkjølt til 0°C. Deretter tilsettes sakte en oppløs-ning av natriumhydroksyd (4,57 g, 4 ekvivalenter) i 5 ml vann og 50 ml alkohol avkjølt til 0°C. Etter 48 timer ved 0°C, dampes etanolen bort under redusert trykk for å unngå oppvarming, og resten, løst opp i 200 ml isvann, ekstraheres tre ganger med 100 ml metylenklorid. Vannfasen surgjøres med eddiksyre og røres 1 time ved 0°C. Den ønskede forbindelse, 4,7 g, samles ved filtrering. ml of ethanol cooled to 0°C. A solution of sodium hydroxide (4.57 g, 4 equivalents) in 5 ml of water and 50 ml of alcohol cooled to 0°C is then slowly added. After 48 hours at 0°C, the ethanol is evaporated under reduced pressure to avoid heating, and the residue, dissolved in 200 ml of ice water, is extracted three times with 100 ml of methylene chloride. The water phase is acidified with acetic acid and stirred for 1 hour at 0°C. The desired compound, 4.7 g, is collected by filtration.
Utbytte: 9 3,8% - Sm.pkt. = 244°C-246°C med dekomponering Ber.for ci2HnclN2°2:C'57'50'H'4'42?N>11,17; Cl, 14,14 Funnet: C, 57,16; H, 4,14; N, 11,01; Cl, 14,16. Dividend: 9 3.8% - Sm.pt. = 244°C-246°C with decomposition Ber.for ci2HnclN2°2:C'57'50'H'4'42?N>11.17; Cl, 14.14 Found: C, 57.16; H, 4.14; N, 11.01; Cl, 14,16.
NMR: ( (CD3) 2S0) ; 5: 3,42 (d, 3H, CH3~C=) ; 3,65 (s,3H, N-CH3) ; 5,31 og 5,48 (2s, 1H-C=CH- cis-trans-blanding); 6,44(s, 1H, H-3); 7,35(d, 1H, H7J6_7= 5,5Hz); 7,83(d,lH, H-6). NMR: ((CD 3 ) 2 SO ); 5: 3.42 (d, 3H, CH3~C=); 3.65 (s, 3H, N-CH 3 ); 5.31 and 5.48 (2s, 1H-C=CH-cis-trans mixture); 6.44(s, 1H, H-3); 7.35(d, 1H, H7J6_7= 5.5Hz); 7.83 (d, 1H, H-6).
x d) azidderivat med formel (VI)x d) azide derivative of formula (VI)
Oppløsningen av syren som tidligere var dannet (4,7g,The solution of the acid previously formed (4.7g,
18 mmol) i 30 ml aceton og 2,9 ml trietylamin avkjøles til18 mmol) in 30 ml of acetone and 2.9 ml of triethylamine is cooled to
-10°C og sakte tilsettes en oppløsning av 2 ml etylklorkarbonat i 30 ml aceton, mens temperaturen holdes på -10°C. Etter 1 times røring ved den samme temperatur, tilsettes natriumnitrid (1,77 g) oppløst i et minimum av vann, gradvis, og blandingen som holdes under -5°C røres i 2 timer. Acetonet dampes bort under redusert trykk mens vannbadet holdes under 10°C, resten taes opp igjen i 200 ml vann og ekstraheres umiddelbart med metylenklorid. -10°C and a solution of 2 ml of ethyl chlorocarbonate in 30 ml of acetone is slowly added, while the temperature is kept at -10°C. After stirring for 1 hour at the same temperature, sodium nitride (1.77 g) dissolved in a minimum of water is added gradually, and the mixture, which is kept below -5°C, is stirred for 2 hours. The acetone is evaporated under reduced pressure while the water bath is kept below 10°C, the residue is taken up again in 200 ml of water and extracted immediately with methylene chloride.
Den organiske fasen tørres over natriumsulfat og filtreres deretter. Ved inndamping til tørrhet under redusert trykk ved vanlig temperatur fremkommer det ønskede derivat. The organic phase is dried over sodium sulfate and then filtered. Evaporation to dryness under reduced pressure at ordinary temperature gives the desired derivative.
M e) 4,5-Dimetyl-9-klor-2-H,5-H-pyrido-(3',4' :4,5)-pyrrolo-(3,2-c)-pyrid-l-on (derivat med formel (I)) M e) 4,5-Dimethyl-9-chloro-2-H,5-H-pyrido-(3',4':4,5)-pyrrolo-(3,2-c)-pyrid-1-one (derivative of formula (I))
Azidet som er dannet i det foregående trinn, løses opp i difenyleter varmet opp til 35°C-40°C og tilsettes i små porsjo-ner til en blanding av 80 ml difenyleter og 4,4 ml tributylamin, oppvarmet og holdt ved 2 30-235°C under god røring. Etter endt tilsetning holdes blandingen i 10 minutter ved 230-240°C, deretter avkjøles den og tilsettes 400 ml lettbensin. The azide formed in the previous step is dissolved in diphenyl ether heated to 35°C-40°C and added in small portions to a mixture of 80 ml of diphenyl ether and 4.4 ml of tributylamine, heated and kept at 2 30 -235°C with good stirring. After the addition is complete, the mixture is kept for 10 minutes at 230-240°C, then it is cooled and 400 ml light petrol is added.
Det faste stoff som er dannet, filtreres fra, vaskes med lettbensin og taes opp igjen i 30 ml kokende etanol. The solid that is formed is filtered off, washed with light petrol and taken up again in 30 ml of boiling ethanol.
Produktet som er uoppløselig i kald tilstand, filtreres fra og tørres og gir farveløse nåler. The product, which is insoluble in the cold state, is filtered off and dried to give colorless needles.
På denne måten samles 2,2 g av det ønskede produkt med et utbytte på 4 7% med hensyn til syren med formel (V). In this way, 2.2 g of the desired product are collected with a yield of 47% with respect to the acid of formula (V).
Smelting: usmeltelig ved 260°C<*>.Melting: infusible at 260°C<*>.
Ber. for C12H10<C>lN3O:C,58,19; H, 4,07; N, 16,96; Cl, 14,34; Funnet: C, 57,95; H, 3,86; N, 16,75; Cl, 14,34 Pray. for C12H10<C>1N3O: C, 58.19; H, 4.07; N, 16.96; Cl, 14.34; Found: C, 57.95; H, 3.86; N, 16.75; Cl, 14.34
NMR: H1((CD3)2<S>O); 6: l,56(s,3H, CH3~4); 3,13(s, 3H, N-CH3); 6,24(s, 1H, H-3); 6,73(d,lH, H-6, J6_?=6Hz); 7,26(d,lH,H-7); 10,36(s, 1H, N-H). NMR: H1((CD3)2<S>O); 6: 1.56 (s, 3H, CH 3 ~ 4 ); 3.13(s, 3H, N-CH3); 6.24(s, 1H, H-3); 6.73(d, 1H, H-6, J6_?=6Hz); 7.26 (d,1H,H-7); 10.36(s, 1H, N-H).
EKSEMPEL 2 EXAMPLE 2
9-Klor-4-metyl-5-benzyl-2-H,5-H-pyrido(3',4<*>:4,5)pyrrolo-(3,2-c)-pyrid-l-on (X = Cl, R = benzyl) derivat nr. 2. 9-Chloro-4-methyl-5-benzyl-2-H,5-H-pyrido(3',4<*>:4,5)pyrrolo-(3,2-c)-pyrid-1-one ( X = Cl, R = benzyl) derivative #2.
K a) l-Benzyl-2-acetyl-4-klor-l-H-pyrrolo(3,2-c)-pyridin (derivat med formel (III)) K a) 1-Benzyl-2-acetyl-4-chloro-1-H-pyrrolo(3,2-c)-pyridine (derivative of formula (III))
11,3 g l-benzyl-2-(1-hydroksyetyl)-4-klor-l-H-pyrrolo-(3,2-c)pyridin løses opp i 600 ml kokende kloroform. Gradvis tilsettes 120 g mangandioksyd og blandingen varmes til tilbake-løp i 18 timer under røring. Etter tilsetning av 14 g mangandioksyd og 2 timers oppvarming med tilbakeløp til alkoholen er forsvunnet, filtreres mangandioksydet fra, vaskes med varm kloroform og oppløsningsmidlet dampes bort. Ved omkrystalli-sering av resten i etanol, oppnås 8,6 g av det ønskede derivat. Utbytte: 76,6%, sm.pkt. = 136°C. 11.3 g of 1-benzyl-2-(1-hydroxyethyl)-4-chloro-1-H-pyrrolo-(3,2-c)pyridine are dissolved in 600 ml of boiling chloroform. 120 g of manganese dioxide are gradually added and the mixture is heated to reflux for 18 hours while stirring. After adding 14 g of manganese dioxide and heating at reflux for 2 hours until the alcohol has disappeared, the manganese dioxide is filtered off, washed with hot chloroform and the solvent is evaporated. By recrystallization of the residue in ethanol, 8.6 g of the desired derivative is obtained. Yield: 76.6%, sm.pt. = 136°C.
Ber. for C,,H,oClN0„: C, 67,49; H 4,6; N, 9,84; Cl, 12,45Pray. for C 1 , H 2 oClN 0 2 : C, 67.49; H 4.6; N, 9.84; Cl, 12.45
lb 1j zlb 1j z
Funnet: C, 67,21; H, 4,39; N, 12; Cl, 12,75 Found: C, 67.21; H, 4.39; N, 12; Cl, 12.75
NMRE1((CD3)2SO), : 2,68(s, 3H, -CO-CH3); 5,88(s, 2H, -CH2~); NMRE1((CD3)2SO), : 2.68(s, 3H, -CO-CH3); 5.88 (s, 2H, -CH 2 ~ );
7,05-7,32(m, 5H, -6gH5); 7,66(q, 1H, H-7, J3_ 7= 0,8Hz); 7.05-7.32 (m, 5H, -6gH5); 7.66(q, 1H, H-7, J3_7= 0.8Hz);
7,76(d, 1H, H-3); 8,17(d, 1H, H-6) 7.76 (d, 1H, H-3); 8.17(d, 1H, H-6)
K b) 1-(Benzyl-4-klor-l-H-pyrrolo-(3,2-c)-2-pyridylkroton-syre (derivat med formél (V)) K b) 1-(Benzyl-4-chloro-1-H-pyrrolo-(3,2-c)-2-pyridylcrotonic acid (derivative with formula (V))
På samme måte som i eksempel 1, tilsettes det til en suspensjon av natriumhydrid (2,36 g 50% i olje) i 50 ml dimetoksyetan, 12,12 g (54 mmol) etyldietylfosfonoacetat i oppløsning i 90 ml dimetoksyetan og 7 g (25 mmol) av forbindelsen med formel (III) som tidligere er dannet, i oppløsning i 160 ml dimetoksyetan, og reaksjonsblandingen får stå ved omgivelsenes temperatur i 48 timer. In the same way as in example 1, to a suspension of sodium hydride (2.36 g 50% in oil) in 50 ml of dimethoxyethane, 12.12 g (54 mmol) of ethyl diethylphosphonoacetate in solution in 90 ml of dimethoxyethane and 7 g (25 mmol) of the compound of formula (III) which was previously formed, in solution in 160 ml of dimethoxyethane, and the reaction mixture is allowed to stand at ambient temperature for 48 hours.
Etter at oppløsningsmidlet er dampet bort, dekomponering med etanol, ekstraksjon med metylenklorid, forsåpning av residuet fra inndampingen med overskudd av kaliumhydroksyd (5,6 g) After the solvent has evaporated, decomposition with ethanol, extraction with methylene chloride, saponification of the residue from the evaporation with excess potassium hydroxide (5.6 g)
i vandig alkoholmedium og surgjøring med eddiksyre, filtreres det faste stoff som fremkommer fra og tørres og gir 7,9 g (98%) av den ønskede syre, i cis-trans-blanding. in aqueous alcohol medium and acidifying with acetic acid, the resulting solid is filtered and dried to give 7.9 g (98%) of the desired acid, in a cis-trans mixture.
Sm.pkt. 170°C.Sm.pt. 170°C.
Ber.for C18H15C1N2°2: C'66' 16' H'4'63'' N'8'57?Cl, 10,85 Funnet: C, 65,86; H, 4,81; N, 8,35; Cl, 11,08 Ber. for C18H15C1N2°2: C'66' 16' H'4'63'' N'8'57?Cl, 10.85 Found: C, 65.86; H, 4.81; N, 8.35; Cl, 11.08
<*>c) 9-Klor-4-metyl-5-benzyl-2-H,5-H-pyrido-(3<1>,4':4,5)-pyrrolo-(3,2-c)-pyrid-l-on (derivat med formel (I)) <*>c) 9-Chloro-4-methyl-5-benzyl-2-H,5-H-pyrido-(3<1>,4':4,5)-pyrrolo-(3,2-c) -pyrid-l-one (derivative of formula (I))
Denne forbindelse ble fremstilt via azidet ved fremgangsmåten beskrevet i eksempel 1. This compound was prepared via the azide by the method described in example 1.
Ved å gå ut fra 7,9 g av syren med formel (V), ble det opp-nådd etter rensing ved koking i dioksan, 2,8 g farveløse mikrokrystaller av derivatet med formel (I). Starting from 7.9 g of the acid of formula (V), 2.8 g of colorless microcrystals of the derivative of formula (I) were obtained after purification by boiling in dioxane.
Utbytte: 35,7%, sm.pkt. = usmeltelig til 260°C.Dividend: 35.7%, sm.pt. = infusible to 260°C.
Ber. for ClgH14ClN30: C, 66,77; H, 4,36; N, 12,98; Cl, 10,98 Funnet: 66,52; H, 4,57; N, 12,69; Cl, 10,69 Pray. for ClgH 14 ClN 3 O: C, 66.77; H, 4.36; N, 12.98; Cl, 10.98 Found: 66.52; H, 4.57; N, 12.69; Cl, 10.69
EKSEMPEL 3 EXAMPLE 3
4,5-Dimetyl-2-H,5-H-pyrido-(3',4':4,5)-pyrrolo-(3,2-c)-pyrid-l-on (X = H, R-^CH^) derivat nr. 3 4,5-Dimethyl-2-H,5-H-pyrido-(3',4':4,5)-pyrrolo-(3,2-c)-pyrid-1-one (X = H, R- ^CH^) derivative No. 3
Derivat nr. 1, 9-klor-4 , 5-dimetyl-2-H, 5-H-pyrido- ( 3 1 ,4 ':4,5) - pyrrolo-(3,2-c)-pyrid-l-on (X = H, R^=CH3) (10 mmol) anbringes i en trehalset kolbe på 1 liter, som inneholder 500 ml etanol, Derivative No. 1, 9-chloro-4,5-dimethyl-2-H,5-H-pyrido-(31,4':4,5)-pyrrolo-(3,2-c)-pyrid-1 -on (X = H, R^=CH3) (10 mmol) is placed in a three-necked 1 liter flask containing 500 ml of ethanol,
7,5 ml trietylamin og 700 mg 10% palladisert trekull, og røres under hydrogenatmosfære ved normalt trykk og ved omgivelsenes temperatur i omtrent 2 timer. Katalysatoren filtreres fra, 7.5 ml of triethylamine and 700 mg of 10% palladium charcoal, and stirred under a hydrogen atmosphere at normal pressure and at ambient temperature for approximately 2 hours. The catalyst is filtered off,
vaskes flere ganger med kokende etanol og oppløsningsmidlet dampes bort. Resten taes opp igjen i 200 ml IN natriumhydroksyd-oppløsning, filtreres kald og omkrystalliseres i etanol og gir farveløse mikrokrystaller av den ønskede hydratiserte forbindelse . washed several times with boiling ethanol and the solvent evaporated. The residue is taken up again in 200 ml of 1N sodium hydroxide solution, filtered cold and recrystallized in ethanol to give colorless microcrystals of the desired hydrated compound.
Utbytte: 88%, sm.pkt. usmeltelig til 260°C.Yield: 88%, sm.pt. infusible to 260°C.
Ber. for<C>12H11<N>3<O>.H20 = C, 62,34; H, 5,63; N, 18,18; Pray. for <C>12H11<N>3<O>.H2O = C, 62.34; H, 5.63; N, 18.18;
Funnet: C, 62,37; H, 18,07Found: C, 62.37; H, 18.07
NMR: E1 ((CD3)2SO); 6: 2,57(s, 3H, CH3~4); 4,14(s, 3H, N-CH3); 7,23(s, 1H, H-3); 7,7(d, 1H, H-6, J6_7= 6Hz); 8,49(d, 1H, H-7); 9,21(s, 1H, NH-2); 9,36 (s, 1H, H-9) NMR: E1 ((CD3)2SO); 6: 2.57(s, 3H, CH3~4); 4.14(s, 3H, N-CH3); 7.23(s, 1H, H-3); 7.7(d, 1H, H-6, J6_7 = 6Hz); 8.49 (d, 1H, H-7); 9.21(s, 1H, NH-2); 9.36 (p, 1H, H-9)
EKSEMPEL 4EXAMPLE 4
4-Metyl-5-benzyl-2-H,5-H-pyrido-(31,4': 4,5)-pyrrolo-(3,2-c)-pyrid-l-on (X = H, R = benzyl) derivat nr. 4 4-Methyl-5-benzyl-2-H,5-H-pyrido-(31,4':4,5)-pyrrolo-(3,2-c)-pyrid-1-one (X = H, R = benzyl) derivative No. 4
Denne forbindelsen ble fremstilt fra derivat nr. 2, 9-klor-4-metyl-5-benzyl-2-H,5-H-pyrido-(3<1>,4<1>:4,5)-pyrrolo-(3,2-c)-pyrid-l-on, ved den samme fremgangsmåte som i eksempel 3. Utbytte: 92%, sm.pkt. usmeltelig til 260°C. This compound was prepared from derivative No. 2, 9-chloro-4-methyl-5-benzyl-2-H,5-H-pyrido-(3<1>,4<1>:4,5)-pyrrolo- (3,2-c)-pyrid-1-one, by the same method as in example 3. Yield: 92%, m.p. infusible to 260°C.
Ber.for Cl<gH>15<N>3<0>.1,5 H20 : C, 68,35; H, 5,7; N, 13,29 Ber. for Cl<gH>15<N>3<O>.1.5 H2O: C, 68.35; H, 5.7; N, 13.29
Funnet: C, 68,13; H, 6,24; N, 12,75 Found: C, 68.13; H, 6.24; N, 12.75
NMR: H1((CD3)2SO) ; 6: 2,3 (s, 3H, CH3) ; 5,88 (s, 2H, CH2) ; 6,88-7,3(m, 5H, -C6H5); 7,63 (q, 1H, H-6, Jg_7=5,6 Hz, Jg_9=0, 9Hz); 8,43(d, 1H, H-7); 9,41 (d, 1H, H-9); ll,43(s, lH,NH-2) NMR: H1((CD3)2SO) ; 6: 2.3 (s, 3H, CH3); 5.88 (s, 2H, CH 2 ); 6.88-7.3 (m, 5H, -C 6 H 5 ); 7.63 (q, 1H, H-6, Jg_7=5.6Hz, Jg_9=0.9Hz); 8.43(d, 1H, H-7); 9.41 (d, 1H, H-9); 11.43(s, 1H,NH-2)
EKSEMPEL 5 EXAMPLE 5
4-Mety1-2-H,5-H-pyrido-(3<1>,4<1>:4,5)-pyrrolo-(3,2-c)-pyrid-l-on (X = H, R1= H) derivat nr. 5. 4-Methy1-2-H,5-H-pyrido-(3<1>,4<1>:4,5)-pyrrolo-(3,2-c)-pyrid-1-one (X = H, R1= H) derivative No. 5.
I en trehalset kolbe på 500 ml nedsenket i et kjølebad ved In a three-necked flask of 500 ml immersed in a cooling bath at
-70°C og ovenpå den anbragt en spiral med aceton og tørris, utstyrt med magnetrører, fylles gradvis 250 ml flytende ammoniakk og deretter tilsettes 1,18 g av derivat nr. 4, 4-metyl-5-benzyl-2-H,5-H-pyrido-(3<1>,4':4,5)-pyrrolo-(3,2-c)-pyrid-l-on. Det hele blir rørt ved -34°C, natrium tilsettes i små stykker inntil den blå farven holder seg mer enn 30 minutter etter siste tilsetning. Etter ytterligere én time ved ammoniakks tilbakeløps-temperatur, blir blandingen avfarvet ved tilsetning av ammonium-klorid og får stå for å tillate ammoniakken å fordampe. Det faste residu taes opp igjen i omkring 30 ml isvann, filtreres -70°C and on top of it a spiral with acetone and dry ice, equipped with a magnetic stirrer, is gradually filled with 250 ml of liquid ammonia and then 1.18 g of derivative no. 4, 4-methyl-5-benzyl-2-H, is added. 5-H-pyrido-(3<1>,4':4,5)-pyrrolo-(3,2-c)-pyrid-1-one. The whole thing is stirred at -34°C, sodium is added in small pieces until the blue color persists more than 30 minutes after the last addition. After an additional hour at the ammonia reflux temperature, the mixture is decolorized by the addition of ammonium chloride and allowed to stand to allow the ammonia to evaporate. The solid residue is taken up again in about 30 ml of ice water, filtered
og omkrystalliseres i etanol. 500 mg farveløse mikrokrystaller and recrystallized in ethanol. 500 mg colorless microcrystals
samles.gather.
Utbytte: 56,4%, sm.pkt. = 270°C.Yield: 56.4%, sm.pt. = 270°C.
Ber.for Ci;LHgN3O.H20 : C, 60,82; H, 5,10; N, 19,35Ber. for Ci;LHgN 3 O.H 2 O : C, 60.82; H, 5.10; Sun, 19.35
Funnet: C, 60,81; H, 5,11; N, 19,43 Found: C, 60.81; H, 5.11; N, 19.43
NMR H1((CD3)2SO) ; 6: 2,29(d, 3H, CH3"4): 7,21(d, 1H, H-3, J3-CH3-4 = 1Hz); 7,49(q, 1H, H-6, J6_?=5,8 Hz, Jg_9=lHz); 8,38(d, 1H, H-7); 9,26(d, 1H, H-9); ll,10(s, 1H, NH-5); NMR H1((CD3)2SO) ; 6: 2.29(d, 3H, CH3"4): 7.21(d, 1H, H-3, J3-CH3-4 = 1Hz); 7.49(q, 1H, H-6, J6_? =5.8 Hz, Jg_9=1Hz); 8.38(d, 1H, H-7); 9.26(d, 1H, H-9); 11.10(s, 1H, NH-5);
12(s, 1H, NH-2)12(s, 1H, NH-2)
Derivatene som nettopp er beskrevet, tjener etter klorering i 1-posisjon som utgangsforbindelser ved fremstilling av forbindelser med formel A, i henhold til følgende reaksjonsdiagram: The derivatives just described serve, after chlorination in the 1-position, as starting compounds in the preparation of compounds of formula A, according to the following reaction diagram:
For å illustrere fremgangsmåten i oppfinnelsen, er det nedenfor beskrevet fremstillingen av (a-dietylamino)-l-propylamin-4,5-dimetyl-5-H-pyrido- [3',41:4,5] -pyrrolo-[3,2-c]-pyridin (forbindelse med formel A) ut fra 4,5-dimetyl-2-H,5-H-pyrido-C.3 1 , 4 ': 4 , 5]-pyrrolo- (3 , 2-c) -pyrid-l-on (derivat nr. 3 med formel To illustrate the method of the invention, the preparation of (α-diethylamino)-1-propylamine-4,5-dimethyl-5-H-pyrido-[3',41:4,5]-pyrrolo-[3 ,2-c]-pyridine (compound of formula A) from 4,5-dimethyl-2-H,5-H-pyrido-C.3 1 , 4 ': 4 , 5]-pyrrolo-(3 , 2 -c) -pyrid-l-one (derivative no. 3 with formula
I) IN)
500 mg av derivatet nr. 3 (2,5 mmol) og 25 ml av dikloridet av 500 mg of derivative No. 3 (2.5 mmol) and 25 ml of the dichloride of
fenylfosfonsyre varmes på et oljebad ved 170°C under røring i 68 timer og overskuddet av diklorid dampes bort ved 130°C ved 2 mm Hg. 12 0 ml vann tilsettes til resten og blandingen varmes til koking og filtreres deretter. Det uoppløselige vaskes med 40 ml kokende vann og filtratet gjøres alkalisk og kaldt ved tilsetning av ammoniakk. Bunnfallet som dannes filtreres fra, tørres og omkrystalliseres i xylen og gir 450 mg farveløse mikrokrystaller av l-klor-4-metyl-5-H-pyrido-[3',4<1>:4,5]-pyrrolo- [3,2-c]-pyridin. phenylphosphonic acid is heated in an oil bath at 170°C with stirring for 68 hours and the excess of dichloride is evaporated off at 130°C at 2 mm Hg. 120 ml of water is added to the residue and the mixture is heated to boiling and then filtered. The insoluble matter is washed with 40 ml of boiling water and the filtrate is made alkaline and cold by adding ammonia. The precipitate that forms is filtered off, dried and recrystallized in xylene to give 450 mg of colorless microcrystals of 1-chloro-4-methyl-5-H-pyrido-[3',4<1>:4,5]-pyrrolo- [3 ,2-c]-pyridine.
Utbytte: 82,3%; sm.pkt. = usmeltelig til 270°C .Yield: 82.3%; sm.pt. = infusible to 270°C.
250 mg av forbindelsen (1,02 mmol) i 15 ml dietylaminopropylamin varmes opp under røring i. 24 timer og overskuddet av amin dampes bort på vannbad ved 80°C under 1 mm Hg trykk. Residuet taes opp igjen i 100 ml IN natriumhydroksyd-oppløsning og ekstraheres med metylenklorid. Etter inndamping, kromatograferes produktet på en aluminiumoksydkolonne med utvasking med blandingen metylenklorid-etanol 9/1. Fraksjonene som inneholder det rene hovedprodukt samles og dampes inn til tørrhet. Resten taes opp igjen i etanol mettet med saltsyre og inndampes igjen til tørrhet. Den faste resten vaskes to ganger med 10 ml aceton, krystalliserer i n-butanol, filtreres, vaskes tre ganger med 10 ml aceton, taes opp igjen i 10 ml av det samme oppløsnings-middel, filtreres og tørres, og gir 340 mg farveløse mikrokrystaller som tilsvarer trihydrogenkloridtrihydrat av den ønskede forbindelse med formel A. Denne forbindelsen svetter mot 130°C og sublimerer fra 200°C. 250 mg of the compound (1.02 mmol) in 15 ml of diethylaminopropylamine are heated with stirring for 24 hours and the excess of amine is evaporated on a water bath at 80°C under 1 mm Hg pressure. The residue is taken up again in 100 ml of IN sodium hydroxide solution and extracted with methylene chloride. After evaporation, the product is chromatographed on an alumina column with elution with the mixture methylene chloride-ethanol 9/1. The fractions containing the pure main product are collected and evaporated to dryness. The residue is taken up again in ethanol saturated with hydrochloric acid and evaporated again to dryness. The solid residue is washed twice with 10 ml of acetone, crystallized in n-butanol, filtered, washed three times with 10 ml of acetone, taken up again in 10 ml of the same solvent, filtered and dried, yielding 340 mg of colorless microcrystals which corresponds to trihydrogen chloride trihydrate of the desired compound of formula A. This compound sweats towards 130°C and sublimes from 200°C.
Ber.for CigH27N5.3HC1.3H20:C, 46,73; H, 7,37; N, 14,33; Cl,21,80. Funnet: C, 46,48; H, 7,81; N, 13,88; Cl, 22,08. Ber. for C 12 H 27 N 5 .3HCl .3H 2 O: C, 46.73; H, 7.37; N, 14.33; Cl, 21.80. Found: C, 46.48; H, 7.81; N, 13.88; Cl, 22.08.
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8504870A FR2579206B1 (en) | 1985-03-22 | 1985-03-22 | NOVEL 5-H PYRIDO (3 ', 4': 4,5) (PYRROLO 3,2-C) PYRIDONES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS SYNTHESIS INTERMEDIATES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO861122L true NO861122L (en) | 1986-09-23 |
Family
ID=9317787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO861122A NO861122L (en) | 1985-03-22 | 1986-03-21 | NEW PYRIDONE DERIVATIVES. |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0199618A1 (en) |
| JP (1) | JPS61267581A (en) |
| KR (1) | KR860007260A (en) |
| DK (1) | DK133086A (en) |
| FI (1) | FI861215A (en) |
| FR (1) | FR2579206B1 (en) |
| GR (1) | GR860749B (en) |
| IL (1) | IL78162A0 (en) |
| NO (1) | NO861122L (en) |
| PT (1) | PT82242B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2061891T3 (en) * | 1988-11-16 | 1994-12-16 | Nippon Kayaku Kk | CRYSTALS OF ETHOPOSIDE-2-DIMETHYLAMINE COMPOSITE DIHYDROCHLORIDE DIHYDRATE AND A PROCEDURE FOR ITS PRODUCTION. |
| WO2005111042A1 (en) | 2004-05-03 | 2005-11-24 | Janssen Pharmaceutica N.V. | Novel indole derivatives as selective androgen receptor modulators (sarms) |
-
1985
- 1985-03-22 FR FR8504870A patent/FR2579206B1/en not_active Expired
-
1986
- 1986-03-14 IL IL78162A patent/IL78162A0/en unknown
- 1986-03-18 KR KR1019860002052A patent/KR860007260A/en not_active Application Discontinuation
- 1986-03-20 GR GR860749A patent/GR860749B/en unknown
- 1986-03-21 PT PT82242A patent/PT82242B/en unknown
- 1986-03-21 EP EP86400603A patent/EP0199618A1/en not_active Withdrawn
- 1986-03-21 NO NO861122A patent/NO861122L/en unknown
- 1986-03-21 FI FI861215A patent/FI861215A/en not_active Application Discontinuation
- 1986-03-21 DK DK133086A patent/DK133086A/en not_active Application Discontinuation
- 1986-03-22 JP JP61064667A patent/JPS61267581A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DK133086A (en) | 1986-09-23 |
| JPS61267581A (en) | 1986-11-27 |
| PT82242A (en) | 1986-04-01 |
| IL78162A0 (en) | 1986-07-31 |
| FI861215A0 (en) | 1986-03-21 |
| KR860007260A (en) | 1986-10-10 |
| FR2579206A1 (en) | 1986-09-26 |
| PT82242B (en) | 1987-08-17 |
| EP0199618A1 (en) | 1986-10-29 |
| DK133086D0 (en) | 1986-03-21 |
| FI861215A (en) | 1986-09-23 |
| FR2579206B1 (en) | 1987-05-07 |
| GR860749B (en) | 1986-07-21 |
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