NO125820B - - Google Patents
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- NO125820B NO125820B NO70255A NO25570A NO125820B NO 125820 B NO125820 B NO 125820B NO 70255 A NO70255 A NO 70255A NO 25570 A NO25570 A NO 25570A NO 125820 B NO125820 B NO 125820B
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- Prior art keywords
- pyrimido
- pyrimidine
- bis
- reaction
- groups
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- 238000000034 method Methods 0.000 claims description 32
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims description 13
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 12
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- CBFFOLYONILLBG-UHFFFAOYSA-N (4,8-dichloro-6-chlorooxysulfanylpyrimido[5,4-d]pyrimidin-2-yl)sulfanyl hypochlorite Chemical compound ClC=1C2=C(N=C(N1)SOCl)C(=NC(=N2)SOCl)Cl CBFFOLYONILLBG-UHFFFAOYSA-N 0.000 claims 1
- HNTHPSUIOUUVCO-UHFFFAOYSA-N 2,6-bis(sulfanylidene)-1,5-dihydropyrimido[5,4-d]pyrimidine-4,8-dione Chemical compound N1C(=S)NC(=O)C2=C1C(=O)NC(=S)N2 HNTHPSUIOUUVCO-UHFFFAOYSA-N 0.000 claims 1
- LNLNOSAYOUJYGD-UHFFFAOYSA-N 4,8-di(piperidin-1-yl)-2,6-bis(piperidin-1-yloxysulfanyl)pyrimido[5,4-d]pyrimidine Chemical compound N1(CCCCC1)C=1C2=C(N=C(N1)SON1CCCCC1)C(=NC(=N2)SON2CCCCC2)N2CCCCC2 LNLNOSAYOUJYGD-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- 229960002768 dipyridamole Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- -1 chlorosulfeno groups Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Fremgangsmåte ved fremstilling av 2,6-bis-(diethanol-amino)-4,8-dipiperidino-pyrimido-[5,4-dJ-pyrimidin. Process for the preparation of 2,6-bis-(diethanol-amino)-4,8-dipiperidino-pyrimido-[5,4-dJ-pyrimidine.
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av 2,6-bis-(diethanolamino) -1+,8-dipiperidino-pyrimido-[5,U—d]-pyrimidin (d.v.s, dipyridamol), som er verdifull som vaso-dilator for hjertepulsårene. Nærmere bestemt angår oppfinnelsen en ny fremgangsmåte ved fremstilling av dipyridamol, som går ut på å overfore Lt-,8-dihydroxy-2,6-dimercapto-pyrimido-[ 5 A"d J"Pyri~ midin til <1>+,8-diklor-2,6-bis-(klorsulfeno)-pyrimido-[5,^-d]-pyrimidin ved omsetning med fosforpentaklorid, overfore M-,8-diklor-2,6-bis-(klorsulfeno)-pyrimido-[5A-^]-pyrimidinet til ^,8-di-piperidino-2,6-bis-(piperidinosulfeno)-pyrimido-[5]-pyrimidin ved omsetning med piperidin, overfore Lt-,8-diperidino-2,6-bis-(piperidinosulfeno)-pyrimido-[5,<1>+-<3]-pyrimidinet til 2,6-bis-(klorsulfonyl)-^,8-dipiperidino-pyrimido-f 5]-pyrimidin ved be-handling med klorid og deretter overfore 2,6-bis-(klorsulfonyl)-lf,8-dipiperidino-pyrimido-[5,M~d]-pyrimidinet til 2 ,(p-bis-(di-ethanolamino)-^,8-dipiperidino-pyrimido-[5,^-d]-pyrimidin ved omsetning med diethanolamin. The present invention relates to a new process for the production of 2,6-bis-(diethanolamino)-1+,8-dipiperidino-pyrimido-[5,U—d]-pyrimidine (i.e., dipyridamole), which is valuable as a vasodilator for the heart arteries. More specifically, the invention relates to a new process for the production of dipyridamole, which consists in transferring Lt-,8-dihydroxy-2,6-dimercapto-pyrimido-[5 A"d J"pyrimidine to <1>+,8 -dichloro-2,6-bis-(chlorosulfeno)-pyrimido-[5,^-d]-pyrimidine by reaction with phosphorus pentachloride, transfer M-,8-dichloro-2,6-bis-(chlorosulfeno)-pyrimido-[ the 5A-^]-pyrimidine to ^,8-di-piperidino-2,6-bis-(piperidinosulfeno)-pyrimido-[5]-pyrimidine by reaction with piperidine, transfer Lt-,8-diperidino-2,6-bis -(piperidinosulfeno)-pyrimido-[5,<1>+-<3]-pyrimidine to 2,6-bis-(chlorosulfonyl)-^,8-dipiperidino-pyrimido-f 5]-pyrimidine by treatment with chloride and then transferring the 2,6-bis-(chlorosulfonyl)-1,8-dipiperidino-pyrimido-[5,M~d]-pyrimidine to 2,(p-bis-(di-ethanolamino)-2,8-dipiperidino- pyrimido-[5,^-d]-pyrimidine by reaction with diethanolamine.
For fremstilling av dipyridamol er det fra tysk patentskrift nr. 1.116.676 kjent en fremgangsmåte ved hvilken et 2,<*>+,6,8-tetra-halogen-pyrimido-[5,^-d]-pyrimidin, som kan fremstilles ved halo-genering av 2, h,6,8-tetrahydroxy-pyrimldo-[5,^-d]-pyrimidin, be-nyttes som utgangsmateriale, idet dettes halogenatomer erstattes med piperidingrupper og diethanolaminogrupper. Ved denne kjente fremgangsmåte erstattes forst halogenatomene i 2,^-,6,8-tetrahalo-gen-pyrimido-[5 A-d]-pyrimidinets h- og 8-stillinger med piperidino-grupper ved omsetning med piperidin ved lav temperatur, hvoretter halogenatomene i 2- og 6-stillingene erstattes med diethanolaminogrupper ved omsetning med diethanolamin ved forhoyet temperatur, idet det trekkes fordel av at pyrimido-[ 5A-d J-pyrimidinenes h- og 8-stillinger har storre reaktivitet enn 2- og 6-stillingene. I hen-hold til denne kjente fremgangsmåte fåes imidlertid dipyridamol i et utbytte av hoyst 30 %, beregnet på 2 ,>+,6,8-tetrahydroxy-pyrimido-[ 5 ,*+-d ]-pyrimidinet. For the production of dipyridamole, a method is known from German patent document no. 1,116,676 by which a 2,<*>+,6,8-tetra-halo-pyrimido-[5,^-d]-pyrimidine, which can be prepared by halogenation of 2,h,6,8-tetrahydroxy-pyrimldo-[5,^-d]-pyrimidine, is used as starting material, its halogen atoms being replaced by piperidine groups and diethanolamino groups. In this known method, the halogen atoms in the h- and 8-positions of the 2,^-,6,8-tetrahalo-pyrimido-[5 A-d]-pyrimidine are first replaced with piperidino groups by reaction with piperidine at low temperature, after which the halogen atoms in The 2- and 6-positions are replaced with diethanolamino groups by reaction with diethanolamine at elevated temperature, taking advantage of the fact that the h- and 8-positions of pyrimido-[5A-d J-pyrimidines have greater reactivity than the 2- and 6-positions. According to this known method, however, dipyridamole is obtained in a yield of at most 30%, calculated on the 2,>+,6,8-tetrahydroxy-pyrimido-[5,*+-d]-pyrimidine.
Videre er det fra tysk patentskrift nr. 1.151.806 kjent en fremgangsmåte hvor det anvendes en forbindelse erholdt ut fra et 2,Lt-,6,8-tetrahalogen-pyrimido-[5A-d]-pyrimidin ved å erstatte forst de meget reaktive halogenatomer i h- og 8-stillingene med usubstituerte eller substituerte mercapto- eller hydroxylgrupper ved omsetning med lav temperatur og deretter halogenatomene i 2- Furthermore, a method is known from German patent document no. 1,151,806 in which a compound obtained from a 2,Lt-,6,8-tetrahalo-pyrimido-[5A-d]-pyrimidine is used by first replacing the highly reactive halogen atoms in the h- and 8-positions with unsubstituted or substituted mercapto or hydroxyl groups by low-temperature reaction and then the halogen atoms in the 2-
og 6-stillingene med diethanolaminogrupper ved omsetning av diethanolamin ved forhoyet temperatur, anvendes som utgangsmateriale, og de ovennevnte grupper i h- og 8-stillingene erstattes med piperi-dinogrupper ved omsetning med piperidin ved en temperatur hoyere enn nevnte forhoyede temperatur. Denne fremgangsmåte er imidlertid mindre fordelaktig enn fremgangsmåten ifolge tysk patentskrift nr. 1.116.676, idet den foruten å gi lavt utbytte også er bundet til den hbye temperatur. and the 6-positions with diethanolamino groups by reaction of diethanolamine at an elevated temperature are used as starting material, and the above-mentioned groups in the h- and 8-positions are replaced with piperidino groups by reaction with piperidine at a temperature higher than said elevated temperature. This method is, however, less advantageous than the method according to German patent document No. 1,116,676, since, in addition to giving a low yield, it is also bound to the high temperature.
Det er riktignok så at tysk patentskrift nr. 1.151.806 be-skriver reaksjoner for å erstatte usubstituerte eller substituerte mercapto- eller hydroxylgrupper o.s.v., som er bundet direkte til pyrimido-[ 5A-d]-pyrimidinringen i 2-, h-, 6- og 8-stillingene, med amingrupper, men bortsett fra i det ovennevnte spesielle tilfelle kan disse reaksjoner neppe anvendes i praksis for fremstilling av dipyridamol når den ovennevnte spesifikke kombinasjon av substi-tuenter i 2-, h-, 6- og 8-stillingene og aminer er nodvendig. Eksempelvis dannes dipyridamol ikke dersom 2,6-bis-(alkylmercapto)-1+,8-dipiperidino-pyrimido-[5,If-d]-pyrimidin, som fåes ut fra 2,6-bis-(alkylmercapto)-M-,8-dihydroxy-pyrimido-[5, h- å]-pyrimidin ved klorering og påfolgende omsetning med piperidin, anvendes som utgangsmateriale og omsettes med diethanolamin ved hoy temperatur. Dette skyldes formodentlig at pyrimido-[5d]-pyrimidiners h- og 8-stillinger er mer reaktive enn 2- og 6-stillingene og dertil at reaksjonen for utskiftning av alkylmercaptogrupper i 2- og 6-stillingene med diethanolaminogrupper forloper tungt. Dersom reaksjonen fremtvinges ved okning av reaksjonstemperaturen, vil også piperidinogruppene i h- og 8-stillingene skiftes ut med diethanolaminogrupper, og sluttproduktet vil også eventuelt spaltes. It is true that German patent document No. 1,151,806 describes reactions to replace unsubstituted or substituted mercapto or hydroxyl groups, etc., which are bound directly to the pyrimido-[5A-d]-pyrimidine ring in the 2-, h-, 6 - and 8-positions, with amine groups, but except in the above-mentioned special case, these reactions can hardly be used in practice for the production of dipyridamole when the above-mentioned specific combination of substituents in the 2-, h-, 6- and 8-positions and amines are required. For example, dipyridamole is not formed if 2,6-bis-(alkylmercapto)-1+,8-dipiperidino-pyrimido-[5,If-d]-pyrimidine, which is obtained from 2,6-bis-(alkylmercapto)-M- ,8-dihydroxy-pyrimido-[5, h- å]-pyrimidine by chlorination and subsequent reaction with piperidine, is used as starting material and reacted with diethanolamine at high temperature. This is presumably due to pyrimido-[5d]-pyrimidines' h- and 8-positions being more reactive than the 2- and 6-positions and to the fact that the reaction for replacement of alkyl mercapto groups in the 2- and 6-positions with diethanolamino groups is difficult. If the reaction is forced by increasing the reaction temperature, the piperidino groups in the h- and 8-positions will also be replaced by diethanolamino groups, and the end product will also possibly be split.
Man har derfor ansett den fra tysk patentskrift nr. 1.116.676 kjente fremgangsmåte for fremstilling av dipyridamol ut fra 2,W,-6,8-tetrahydroxy-pyrimido-[5,<1>+-d]-pyrimidin for å være den mest fordelaktige. Denne fremgangsmåte loser imidlertid ikke problemet med å fremstille dipyridamol til lave omkostninger. The method for producing dipyridamole from 2,W,-6,8-tetrahydroxy-pyrimido-[5,<1>+-d]-pyrimidine, known from German patent document no. 1,116,676, has therefore been considered to be the most beneficial. However, this method does not solve the problem of producing dipyridamole at low cost.
Dette problem er nu blitt lost. Det har således nu vist seg at man ved å anvende som utgangsmateriale M-,8-dihydroxy-2,6-di-mercapto-pyrimido-[5,V-d]-pyrimidin (se tysk patentskrift nr. 1.093.801), som på samme måte som 2,<l>+,6,8-tetrahydroxy-pyrimido-[5,^-d]-pyrimidin kan fremstilles til lave omkostninger, kan fremstille dipyridamol i industriell målestokk i et såpass godt utbytte som hO % eller mer. This problem has now been solved. It has thus now been shown that by using as starting material M-,8-dihydroxy-2,6-di-mercapto-pyrimido-[5,V-d]-pyrimidine (see German patent document no. 1,093,801), which on the same way that 2,<l>+,6,8-tetrahydroxy-pyrimido-[5,^-d]-pyrimidine can be prepared at low cost, dipyridamole can be prepared on an industrial scale in a yield as good as hO% or more.
Fremgangsmåten ifolge oppfinnelsen kan representeres ved de folgende reaksjonsligninger: The method according to the invention can be represented by the following reaction equations:
De karakteristiske trekk ved fremgangsmåten ifolge oppfinnelsen beskrives i det nedenstående. The characteristic features of the method according to the invention are described below.
Det er kjent at når M-,6,8-trihydroxy-2-mercapto-pyrimido-[5A-d]-pyrimidin, d.v.s. et pyrimido-[5,*+-d]-pyrimidin med hydro-xyl- og mercaptosubstituenter som forbindelsen av formel (I), omsettes med fosforpentaklorid, utskiftes bare hydroxylgruppene med kloratomer, mens mercaptogruppen forblir uendret. Derved fåes H-,6,8-triklor-2-mercapto-pyrimido-[5,^-d]-pyrimidin (jfr. eksempel 12 i tysk patentskrift nr. 1.116.676). I lys av denne lære kunne man ikke forutse noen overforing av mercaptogrupper til klorsul-fenogrupper ved klorering som i det fbrste trinn av fremgangsmåten ifolge oppfinnelsen. It is known that when M-,6,8-trihydroxy-2-mercapto-pyrimido-[5A-d]-pyrimidine, i.e. a pyrimido-[5,*+-d]-pyrimidine with hydroxyl and mercapto substituents like the compound of formula (I) is reacted with phosphorus pentachloride, only the hydroxyl groups are replaced by chlorine atoms, while the mercapto group remains unchanged. This gives H-,6,8-trichloro-2-mercapto-pyrimido-[5,^-d]-pyrimidine (cf. example 12 in German patent document no. 1,116,676). In light of this teaching, one could not foresee any conversion of mercapto groups to chlorosulfeno groups by chlorination as in the first step of the method according to the invention.
Videre har en reaksjon som den som utgjor det tredje trinn av fremgangsmåten ifolge oppfinnelsen, hvor piperidinosulfeno-gruppene i forbindelse (III), som er et slags syreamid, overfores til -klorsulfonylgrupper ved samtidig oxydasjon og klorering under innvirkning av klor, hittil vært ukjent. Det tredje trinn utgjor således et av de mest karakteristiske trekk ved fremgangsmåten ifolge oppfinnelsen. Bare gjennom forbindelse (IV) med klorsulf<p->nylgrupper, som fåes ved hjelp av denne hye reaksjon, kan dipyridamol fremstilles i godt utbytte, samtidig som reaksjonen utfores under milde betingelser, slik det vil bli forklart nedenfor. Furthermore, a reaction such as that which constitutes the third step of the method according to the invention, where the piperidinosulfeno groups in compound (III), which is a type of acid amide, are transferred to -chlorosulfonyl groups by simultaneous oxidation and chlorination under the influence of chlorine, has hitherto been unknown. The third step thus constitutes one of the most characteristic features of the method according to the invention. Only through compound (IV) with chlorosulf<p->nyl groups, which is obtained by means of this high reaction, can dipyridamole be produced in good yield, while the reaction is carried out under mild conditions, as will be explained below.
Videre var det ugjennomførlig ved de kjente fremgangsmåter å innfore diethanolaminogrupper bare i 2- og 6-stillingene i pyrimido-[5A-d]-pyrimidinringen, uten å påvirke piperidinogruppene i de mer reaktive h- og 8-stillinger. En hoy reaksjonstemperatur var nodvendig for å skifte ut eventuelle, kjente substituenter i 2- og 6-stillingene, når halogenatomer unntas, med aminogrupper såsom diethanolaminogrupper. I lys av denne lære er det overraskende at man ved hjelp av det fjerde trinn av fremgangsmåten ifolge oppfinnelsen kan oppnå utskifting av klorsulfonylgrupper med diethanolaminogrupper i bare 2- og 6-stillingene ved en såpass relativt lav temperatur som 100 - 120°C. Ved å gjore bruk av denne kombinasjon av spesielle trinn muliggjor fremgangsmåten ifolge oppfinnelsen anvendelse som utgangsmateriale for fremstilling av dipyridamol av det kjente Li-,8-dihydroxy-2,6-dimercapto-pyrimido-[5,^-d]-pyrimidin, som hittil ikke har vært viet noen særlig oppmerksomhet. Dessuten fåes sluttprodukter ved denne fremgangsmåte i et såpass hoyt utbytte som <>>+0 % eller mer. Fremgangsmåten er derfor en meget lonn-som fremgangsmåte for fremstilling av dipyridamol i industriell målestokkeFurthermore, it was impracticable with the known methods to introduce diethanolamino groups only in the 2- and 6-positions of the pyrimido-[5A-d]-pyrimidine ring, without affecting the piperidino groups in the more reactive h- and 8-positions. A high reaction temperature was necessary to replace any known substituents in the 2- and 6-positions, when halogen atoms are excluded, with amino groups such as diethanolamino groups. In light of this teaching, it is surprising that by means of the fourth step of the method according to the invention, replacement of chlorosulfonyl groups with diethanolamino groups in only the 2- and 6-positions can be achieved at such a relatively low temperature as 100 - 120°C. By making use of this combination of special steps, the method according to the invention enables the use as starting material for the production of dipyridamole of the known Li-,8-dihydroxy-2,6-dimercapto-pyrimido-[5,^-d]-pyrimidine, which so far no particular attention has been paid. Moreover, end products are obtained by this method in such a high yield as <>>+0% or more. The method is therefore a very profitable method for the production of dipyridamole on an industrial scale
I det folgende beskrives de enkelte trinn av fremgangsmåten ifolge oppfinnelsen. In the following, the individual steps of the method according to the invention are described.
1. Fremgangsmåtens 1, trinn: 1. Step 1 of the procedure:
Dette trinn utfores ved å oppvarme forbindelse (I) sammen This step is carried out by heating compound (I) together
med fosforpentaklorid. Vanligvis benyttes et overskudd av fosforpentaklorid. Det er fordelaktig å benytte fosforoxyklorid som reaksjonsopplosningsmiddel. Når det benyttes en flytende blanding av fosforpentaklorid og foBforoxyklorid, kan reaksjonen gjerne utfores under koking med tilbakelopskjoling. Den dannede forbindelse (II) kan fraskilles ved å fjerne fosforoxykloridet og overskuddet av fosforpentaklorid ved destillasjon, ved sublimering eller på annen måte. Den således erholdte urene forbindelse (II) kan anvendes i det annet trinn uten ytterligere rensing. Om nodvendig kan imidlertid eventuelt kloreringsmiddel som måtte forurense produktet, fjernes fra dette ved å dispergere det urene produkt i et opplosningsmiddel såsom kloroform, diklorethan eller lignende, i hvilket kloreringsmidlet er opploselig men ikke forbindelse (II), og deretter oppsamle sistnevnte ved filtrering. with phosphorus pentachloride. An excess of phosphorus pentachloride is usually used. It is advantageous to use phosphorus oxychloride as reaction solvent. When a liquid mixture of phosphorus pentachloride and phosphorus oxychloride is used, the reaction can preferably be carried out under reflux. The compound (II) formed can be separated by removing the phosphorus oxychloride and the excess of phosphorus pentachloride by distillation, by sublimation or in some other way. The thus obtained impure compound (II) can be used in the second step without further purification. If necessary, however, any chlorinating agent that might contaminate the product can be removed from it by dispersing the impure product in a solvent such as chloroform, dichloroethane or the like, in which the chlorinating agent is soluble but not compound (II), and then collecting the latter by filtration.
2. Fremgangsmåtens 2. trinn: 2. The 2nd step of the procedure:
Dette trinn utfores ved å omsette hvert mol av forbindelse This step is carried out by reacting each mole of compound
(II) med mer enn h mol, fortrinnsvis 8 mol, piperidin ved romtemperatur eller under avkjoling. Ennskjont reaksjonen kan utfores uten bruk av opplosningsmiddel, kan den også utfores i et inert organisk opplosningsmiddel såsom dioxan eller lignende. Det er likeledes mulig å anvende en mindre mengde piperidin ved å til-sette reaksjonsblandingen et tertiært amin såsom pyridin, kinolin eller lignende. Etter fullfort reaksjon avdestilleres opplosningsmidlet og/eller overskuddet av piperidin, og residuet dispergeres i vann, hvorved forbindelse (III) krystalliserer. Produktet fraskilles ved filtrering og kan anvendes som sådant i det tredje trinn. Om nodvendig kan det imidlertid renses ved ekstraksjon, ved omkrystallisering eller på annen måte. (II) with more than h mol, preferably 8 mol, of piperidine at room temperature or during cooling. Although the reaction can be carried out without the use of a solvent, it can also be carried out in an inert organic solvent such as dioxane or the like. It is also possible to use a smaller amount of piperidine by adding a tertiary amine such as pyridine, quinoline or the like to the reaction mixture. After the reaction is complete, the solvent and/or excess piperidine is distilled off, and the residue is dispersed in water, whereby compound (III) crystallizes. The product is separated by filtration and can be used as such in the third step. If necessary, however, it can be purified by extraction, by recrystallization or in some other way.
3. Fremgangsmåtens 3. trinn:- 3. The 3rd step of the procedure:-
Dette trinn utfores ved å omsette forbindelse (III) med et overskudd av klor i et reaksjonsopplosningsmiddel såsom vann, en lavere alkohol eller lignende, eller i en blanding av slike opp-losningsmidler, ved romtemperatur eller under avkjoling. Vanligvis forloper reaksjonen greit etterhvert som klorgass innfores i en suspensjon av forbindelse (III). Produktet (IV), som er uoppløse-lig i opplosningsmidlet, kan lett fraskilles bare ved filtrering og påfolgende vasking med vann, og det kan anvendes i det fjerde trinn uten å renses ytterligere. This step is carried out by reacting compound (III) with an excess of chlorine in a reaction solvent such as water, a lower alcohol or the like, or in a mixture of such solvents, at room temperature or during cooling. Usually, the reaction proceeds smoothly as chlorine gas is introduced into a suspension of compound (III). The product (IV), which is insoluble in the solvent, can be easily separated only by filtration and subsequent washing with water, and it can be used in the fourth step without further purification.
h. Fremgangsmåtens h, trinn: h. Step h of the procedure:
Dette trinn utfores ved å oppvarme forbindelse (IV) sammen med mer enn den doble molare mengde, fortrinnsvis mer enn h mol, diethanolamin ved en temperatur hoyere enn 100°C, vanligvis ved en temperatur mellom 110 og 120°C. This step is carried out by heating compound (IV) together with more than twice the molar amount, preferably more than h mol, of diethanolamine at a temperature higher than 100°C, usually at a temperature between 110 and 120°C.
Denne reaksjon kan også utfores ved romtemperatur eller under avkjoling, hvorved bare kloratomene i forbindelse (IV) skiftes ut med diethanolaminogrupper og 2,6-bis-(diethanolamino-sulfonyl) -^,8-dipiperidino-pyrimido-[ 5A-d ]-pyrimidin f åes. Deretter kan denne forbindelse overfores til sluttforbindelsen (V) ved å oppvarme den i nærvær eller i fravær av diethanolamin. Denne modifikasjon av fremgangsmåten kan illustreres ved de folgende reaksjonsligninger: This reaction can also be carried out at room temperature or during cooling, whereby only the chlorine atoms in compound (IV) are replaced by diethanolamino groups and 2,6-bis-(diethanolamino-sulfonyl)-^,8-dipiperidino-pyrimido-[ 5A-d ]- pyrimidine is obtained. Then this compound can be transferred to the final compound (V) by heating it in the presence or in the absence of diethanolamine. This modification of the procedure can be illustrated by the following reaction equations:
Reaksjonen kan utfores enten i fravær av noen reaksjonsopplosningsmiddel eller i nærvær av et inert organisk opplosningsmiddel. Det er likeledes mulig å anvende et stort overskudd av diethanolamin, som også tjener som reaksjonsopplosningsmiddel. For separasjon og rensing av sluttproduktet benyttes de vanlige metoder, såsom konsentrering, ekstraksjon, soylekromatografering, omkrystallisering og lignende. The reaction can be carried out either in the absence of any reaction solvent or in the presence of an inert organic solvent. It is also possible to use a large excess of diethanolamine, which also serves as a reaction solvent. For separation and purification of the end product, the usual methods are used, such as concentration, extraction, soil chromatography, recrystallization and the like.
De nedenstående eksempler illustrer fremgangsmåten ifolge oppfinnelsen. The following examples illustrate the method according to the invention.
Eksempel 1 - Trinn a) Example 1 - Step a)
k- ,8-Diklor-2,6-bis-(klorsulfeno)-pyrimido-[5,V-d]-pyrimidin k-,8-Dichloro-2,6-bis-(chlorosulfeno)-pyrimido-[5,V-d]-pyrimidine
En blanding av h g <1>+,8-dihydroxy-2,6-dimercapto-pyrimido-[5,<*>+-d]-pyrimidin, 22 g fosforpentaklorid og 120 ml fosforoxyklorid ble kokt med tilbakelopskjoling på et oljebad i 30 minutter. Reaksjonsblandingen ble inndampet til et residuum under redusert trykk, fra hvilket residuum overskudd av fosforpentaklorid ble fjernet så grundig som mulig ved sublimering ved ca. 70°C under redusert trykk. Ved tilsetning av 5 ml kloroform til residuet ble 1+,8-diklor-2,6-bis-(klorsulfeno)-pyrimido-[ 5,1+-d]-pyrimidin utfelt. Utfelningen ble fraskilt ved filtrering. Utbyttet var 5,1 g (87 %). Smeltepunkt 198 - 199°C. A mixture of h g <1>+,8-dihydroxy-2,6-dimercapto-pyrimido-[5,<*>+-d]-pyrimidine, 22 g of phosphorus pentachloride and 120 ml of phosphorus oxychloride was refluxed in an oil bath for 30 minutes. The reaction mixture was evaporated to a residue under reduced pressure, from which residue excess phosphorus pentachloride was removed as thoroughly as possible by sublimation at approx. 70°C under reduced pressure. By adding 5 ml of chloroform to the residue, 1+,8-dichloro-2,6-bis-(chlorosulfeno)-pyrimido-[5,1+-d]-pyrimidine was precipitated. The precipitate was separated by filtration. The yield was 5.1 g (87%). Melting point 198 - 199°C.
Trinn b) Step b)
h ,8-Dipiperidino-2,6-bis-(piperidinosulf eno) -pyrimido-[ 5A-d ]-pyrimidin h ,8-Dipiperidino-2,6-bis-(piperidinosulf eno)-pyrimido-[5A-d]-pyrimidine
Til en opplosning av 350 mg av det ovenfor erholdte ^,8-diklor-2,6-bis-(klorsulfeno)-pyrimido-[5,1+-d]-pyrimidin i 10 ml tort dioxan ble 0,8 ml piperidin tilsatt dråpevis under omrbring og avkjoling. Reaksjonsblandingen ble deretter omrort ved romtemperatur i ytterligere 1 time og deretter ved 50°C i 30 minutter, hvoretter den ble inndampet. Residuet ble opplost i 50 ml kloroform, og oppløsningen ble vasket tre ganger med vann, hver gang med 10 ml. Etter torring av oppløsningen over vannfritt natriumsulfat ble kloroformen fjernet ved destillasjon under redusert trykk. Fra det således erholdte residuum ble produktet utfelt som krystaller ved tilsetning av 1 - 2 ml ethylacetat. Krystallene ble fraskilt ved filtrering og vasket med en liten mengde ethylacetat, hvorved det ble erholdt 370 mg (67 %) <1>+,8-dipiperidino-2,6-bis-(piperidinosulfeno)-pyrimido-[ 5,1+-d]~Pyrimidin med smeltepunkt 165 - 167°C. To a solution of 350 mg of the above-obtained ^,8-dichloro-2,6-bis-(chlorosulfeno)-pyrimido-[5,1+-d]-pyrimidine in 10 ml of dry dioxane, 0.8 ml of piperidine was added drop by drop during dressing and cooling. The reaction mixture was then stirred at room temperature for a further 1 hour and then at 50°C for 30 minutes, after which it was evaporated. The residue was dissolved in 50 ml of chloroform, and the solution was washed three times with water, each time with 10 ml. After drying the solution over anhydrous sodium sulfate, the chloroform was removed by distillation under reduced pressure. From the residue thus obtained, the product was precipitated as crystals by the addition of 1 - 2 ml of ethyl acetate. The crystals were separated by filtration and washed with a small amount of ethyl acetate, whereby 370 mg (67%) of <1>+,8-dipiperidino-2,6-bis-(piperidinosulfeno)-pyrimido-[ 5,1+- d]~Pyrimidine with melting point 165 - 167°C.
Trinn c) Step c)
2,6-Bis-(klorsulfonyl)-^,8-diperidino-pyrimido-f 5, h- d]-pyrimidin 2,6-Bis-(chlorosulfonyl)-^,8-diperidino-pyrimido-f 5,h-d]-pyrimidine
I en suspensjon av 100 mg <l>+,8-dipiperidino-2,6-bis-(piperi-dinosulfeno)-pyrimido-[5,^-d]-pyrimidin i 7 ml av en blanding av vann og methanol i forholdet 5 : 2 ble klorgass innfort i 2 timer under omroring og avkjoling på is. De erholdte gule krystaller ble frafiltrert, vasket med vann og opplost i 50 ml kloroform. Den erholdte opplosning ble vasket tre ganger med 10 ml<1>s porsjoner 3 %' lg vandig natriumbicarbonatopplosning og deretter tre ganger med vann, hver gang med 10 ml. Oppløsningen ble deretter torret over vannfritt natriumsulfat. Fra den torrede opplosning ble råproduktet utfelt som krystaller ved avdestillering av kloroformen under redusert trykk og triturering med 2 ml ethylacetat. Krystallene ble frafiltrert og vasket med en liten mengde ethylacetat, hvorved det ble erholdt 90 mg (96 %) 2,6-bis-(klorsulfonyl)-^,8-dipiperidino-pyrimido-[5,^-d]-pyrimidin med smeltepunkt 208-209°C (under spaltning). In a suspension of 100 mg <l>+,8-dipiperidino-2,6-bis-(piperi-dinosulfeno)-pyrimido-[5,^-d]-pyrimidine in 7 ml of a mixture of water and methanol in the ratio 5:2, chlorine gas was introduced for 2 hours while stirring and cooling on ice. The yellow crystals obtained were filtered off, washed with water and dissolved in 50 ml of chloroform. The resulting solution was washed three times with 10 ml portions of 3% lg aqueous sodium bicarbonate solution and then three times with water, each time with 10 ml. The solution was then dried over anhydrous sodium sulfate. From the dried solution, the crude product was precipitated as crystals by distilling off the chloroform under reduced pressure and trituration with 2 ml of ethyl acetate. The crystals were filtered off and washed with a small amount of ethyl acetate, whereby 90 mg (96%) of 2,6-bis-(chlorosulfonyl)-^,8-dipiperidino-pyrimido-[5,^-d]-pyrimidine of m.p. 208-209°C (under decomposition).
Trinn d) Step d)
2,6-Bis-(diethanolamino) -^-,8-dipiperidino-pyrimido-[ 5 A-d) -pyrimidin 2,6-Bis-(diethanolamino)-^-,8-dipiperidino-pyrimido-[5 A-d)-pyrimidine
En blanding av 300 mg 2,6-bis-(klorsulfonyl)-^,8-dipiperidino-pyrimido-[5,1+-d]-pyrimidin og 1,3 g diethanolamin ble omrort i 5 timer under oppvarmning på et oljebad av 160°C eller i >+5 minutter ved 200°C. Etter å ha stått til avkjoling ble reaksjonsopplosnin-gen opplost i kloroform, vasket med vann og torret over vannfritt natriumsulfat. Kloroformen ble deretter fjernet ved destillasjon under redusert trykk. Det viskose rodbrune residuum ble triturert med en liten mengde aceton, hvorved det ble erholdt 230 mg (75,2$) produkt, ..som ble fraskilt ved filtrering. Ved omkrystallisering fra ethylacetat ble det erholdt fine, skinnende gule nåler med smeltepunkt 160 - 162°C. Det ble ikke observert noen smeltepunktned-settelse ved blanding av produktet med en autentisk prove frem-stilt ved en annen fremgangsmåte.. A mixture of 300 mg of 2,6-bis-(chlorosulfonyl)-^,8-dipiperidino-pyrimido-[5,1+-d]-pyrimidine and 1.3 g of diethanolamine was stirred for 5 hours while heating on an oil bath of 160°C or for >+5 minutes at 200°C. After allowing to cool, the reaction solution was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was then removed by distillation under reduced pressure. The viscous red-brown residue was triturated with a small amount of acetone to give 230 mg (75.2$) of product, which was separated by filtration. On recrystallization from ethyl acetate, fine, shiny yellow needles with a melting point of 160 - 162°C were obtained. No lowering of the melting point was observed when the product was mixed with an authentic sample prepared by another method.
Eksempel 3 Example 3
2,6-Bis-(diethanolamino) -i+jS-dipiperidino-pyrimido-f 5 A-d]-pyrimidin 2,6-Bis-(diethanolamino)-i+jS-dipiperidino-pyrimido-f 5 A-d]-pyrimidine
En blanding av 1 g 2,6-bis-(klorsulfonyl)-^,8-diperidino-pyrimido-[5,1+-d]-pyrimidin og 10 g diethanolamin ble omrort i 72 timer ved 120°C. Etter å ha stått til avkjoling ble reaksjonsblandingen hellet over i 50 ml kloroform. Kloroformskiktet ble deretter vasket med vann og torret over vannfritt natriumsulfat. Kloroformen ble fjernet ved destillasjon under redusert trykk, hvorved det ble erholdt 800 mg (78,5 %) råprodukt. Råproduktet ble renset ved soylekromatografering på kiselsyregel med 2 % methanol-ethylacetat som elueringsmiddel. Ved inndampning av eluatet ble det erholdt 615 mg (60,3 %) av produktet i form av gule krystaller med smeltepunkt 161 - 163°C. A mixture of 1 g of 2,6-bis-(chlorosulfonyl)-^,8-diperidino-pyrimido-[5,1+-d]-pyrimidine and 10 g of diethanolamine was stirred for 72 hours at 120°C. After allowing to cool, the reaction mixture was poured into 50 ml of chloroform. The chloroform layer was then washed with water and dried over anhydrous sodium sulfate. The chloroform was removed by distillation under reduced pressure, whereby 800 mg (78.5%) of crude product was obtained. The crude product was purified by column chromatography on silica gel with 2% methanol-ethyl acetate as eluent. By evaporation of the eluate, 615 mg (60.3%) of the product was obtained in the form of yellow crystals with a melting point of 161 - 163°C.
Eksempel 3Example 3
2,6-Bis-(diethanolaminosulfonyl)-1+,8-dipiperidino-pyrimido-[ 5,1+]d]-pyrimidin 2,6-Bis-(diethanolaminosulfonyl)-1+,8-dipiperidino-pyrimido-[5,1+]d]-pyrimidine
Til en opplosning av 100 mg 2,6-bis-(klorsulfonyl)-M-,8-di-piperidino-pyrimido-[5A-d]-pyrimidin i tort dioxan ble det tilsatt 85 mg diethanolamin under omroring og avkjoling. Blandingen ble omrort i ytterligere 1 time ved romtemperatur. Reaksjonsblandingen ble så inndampet under redusert trykk. Residuet ble opplost i kloroform, og den erholdte opplosning ble suksessivt vasket 1 gang med vann, 2 ganger med IN vandig saltsyre, 2 ganger med To a solution of 100 mg of 2,6-bis-(chlorosulfonyl)-M-,8-di-piperidino-pyrimido-[5A-d]-pyrimidine in dry dioxane, 85 mg of diethanolamine was added while stirring and cooling. The mixture was stirred for an additional 1 hour at room temperature. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in chloroform, and the resulting solution was successively washed 1 time with water, 2 times with IN aqueous hydrochloric acid, 2 times with
5 $-ig vandig natriumbicarbonatopplosning og 3 ganger med vann, hvoretter den ble torret over vannfritt natriumsulfat. Fra denne opplosning ble kloroformen fjernet ved destillasjon under redusert 5 µg aqueous sodium bicarbonate solution and 3 times with water, after which it was dried over anhydrous sodium sulfate. From this solution the chloroform was removed by distillation under reduction
trykk. Den erholdte lysegule oljeaktige substans ble opplost i en liten mengde kloroform og renset ved soylekromatografering på kiselsyregel under anvendelse av en blanding av kloroform og methanol i forholdet 13:1 som elueringsmiddel. Den farvelbse eller lysegule oljeaktige substans som ble erholdt ved inndampning av eluatet, ble tillatt å stå ved romtemperatur. De derved erholdte hvilte nåler av 2,6-bis-(diethanolamino)-<1>+,8-diperidino-pyrimido-[5A-d]-pyrimidin ble fraskilt ved filtrering og vasket med en liten mengde ethylacetat. Produktet ble erholdt i en mengde av 65 mg (63 %) og smeltet ved 107 - 112°C (under spaltning). Print. The light yellow oily substance obtained was dissolved in a small amount of chloroform and purified by column chromatography on silica gel using a mixture of chloroform and methanol in the ratio 13:1 as eluent. The pale yellow or pale yellow oily substance obtained by evaporation of the eluate was allowed to stand at room temperature. The thus obtained resting needles of 2,6-bis-(diethanolamino)-<1>+,8-diperidino-pyrimido-[5A-d]-pyrimidine were separated by filtration and washed with a small amount of ethyl acetate. The product was obtained in an amount of 65 mg (63%) and melted at 107 - 112°C (under decomposition).
Eksempel 4 Example 4
2,6-Bis-(diethanolamino) -1+,8-dipiperidino-pyrimido-[ 5,1+-d]-pyrimidin 2,6-Bis-(diethanolamino)-1+,8-dipiperidino-pyrimido-[5,1+-d]-pyrimidine
En blanding av 1 g 2,6-bis-diethanolaminosulfonyl)-<1>+,8-di-piperidino-pyrimido-^A-dJ-pyrimidin og 10 g diethanolamin ble omrort i 72 timer ved 120°C Reaksjonsblandingen ble viderebehand-let på samme måte som beskrevet i eksempel 5, hvorved det ble erholdt 680 mg (85,2 %) råprodukt. Ved rensning ble det erholdt 560 mg (70,3 %) produkt med smeltepunkt 161 - 163°C A mixture of 1 g of 2,6-bis-diethanolaminosulfonyl)-<1>+,8-di-piperidino-pyrimido-^A-dJ-pyrimidine and 10 g of diethanolamine was stirred for 72 hours at 120°C. The reaction mixture was further treated was carried out in the same way as described in example 5, whereby 680 mg (85.2%) of crude product was obtained. Upon purification, 560 mg (70.3%) of product with melting point 161 - 163°C was obtained
Claims (2)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP546069 | 1969-01-25 | ||
| JP546169 | 1969-01-25 | ||
| JP545969 | 1969-01-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO125820B true NO125820B (en) | 1972-11-06 |
| NO125820C NO125820C (en) | 1980-02-26 |
Family
ID=27276756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO70255A NO125820C (en) | 1969-01-25 | 1970-01-23 | PROCEDURE FOR PREPARING 2,6-BIS- (DIETHANOL-AMINO) -4,8-DIPIPERIDINO-PYRIMIDO- (5,4-D) -PYRIMIDINE |
Country Status (3)
| Country | Link |
|---|---|
| DK (1) | DK130979B (en) |
| NO (1) | NO125820C (en) |
| SE (1) | SE349302B (en) |
-
1970
- 1970-01-23 NO NO70255A patent/NO125820C/en unknown
- 1970-01-23 DK DK31070AA patent/DK130979B/en unknown
- 1970-01-23 SE SE00818/70A patent/SE349302B/xx unknown
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| Publication number | Publication date |
|---|---|
| DK130979B (en) | 1975-05-12 |
| SE349302B (en) | 1972-09-25 |
| DK130979C (en) | 1975-10-06 |
| NO125820C (en) | 1980-02-26 |
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