NO133234B

NO133234B -

Info

Publication number: NO133234B
Application number: NO462371A
Authority: NO
Inventors: M Murakami; N Inukai; M Uda; Y Ishii
Original assignee: Yamanouchi Pharma Co Ltd
Priority date: 1970-12-17
Filing date: 1971-12-15
Publication date: 1975-12-22
Also published as: DK134067B; NO133234C; DK134067C; DE2146440A1; CA931567A; SE384681B

Description

Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av 2-methylthio-6-mercapto-4,8-dihydroxypyrimido-[5,4-d]pyrimidin av formel (I) The present invention relates to a new process for the production of 2-methylthio-6-mercapto-4,8-dihydroxypyrimido-[5,4-d]pyrimidine of formula (I)

Den nye fremgangsmåte er karakterisert ved at en oxaleddiksyreester av den generelle formel (II) The new method is characterized in that an oxaloacetic acid ester of the general formula (II)

hvor R^ og R^ hver er en lavere alkylgruppe og M er et alkalime- where R^ and R^ are each a lower alkyl group and M is an alkalime-

>tall, omsettes i nærvær av ammoniakk med et S-methylisothiourea av den generelle, formel (III) >number, is reacted in the presence of ammonia with an S-methylisothiourea of the general formula (III)

hvorved der tilveiebringes et 4-carbamoyl-6-hydroxy-2-methylthio-pyrimidin av formel (IV) som derefter halogeneres på kjent måte, hvorefter reaksjonsproduktet omsettes med ammoniakk hvorved der tilveiebringes 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin av formelen (V) og at amidet derefter overfores til en behandling med en dithio-forbindelse av den generelle formel (VI) hvor X er hydrogen, en lavere alkoxygruppe eller en di-lavere- • alkylaminogruppe. Reaksjonsproduktet fra denne fremgangsmåte er et viktig mellomprodukt ved fremstilling av 2,6-bis(diethanol-amino)-4,8-dipiperidinopyrimido[5,4-dJpyrimidin (vanligvis kaldt "dipyridamol") som er verdifull som vasodilator til kransarteri-ene. Det er kjent en fremgangsmåte for fremstilling av den onskede forbindelse (I) hvor pyrimidopyrimidinringen dannes ved at et pyrimidincarboxylsyrederivat av den generelle formel whereby a 4-carbamoyl-6-hydroxy-2-methylthio-pyrimidine of formula (IV) is provided which is then halogenated in a known manner, after which the reaction product is reacted with ammonia whereby 5-amino-4-carbamoyl-6-hydroxy-2 -methylthiopyrimidine of the formula (V) and that the amide is then transferred to a treatment with a dithio compound of the general formula (VI) where X is hydrogen, a lower alkoxy group or a di-lower alkylamino group. The reaction product from this process is an important intermediate in the production of 2,6-bis(diethanol-amino)-4,8-dipiperidinopyrimido[5,4-dJpyrimidine (usually called "dipyridamole") which is valuable as a vasodilator for the coronary arteries. A method is known for the preparation of the desired compound (I) in which the pyrimidopyrimidine ring is formed by a pyrimidinecarboxylic acid derivative of the general formula

hvor R^ er mercapto, lavere alkylthio, lavere alkyl eller aralkyl, R2 er amino eller halogen, og R3 er hydrogen eller hydroxyl, eller et funksjonelt derivat derav, omsettes med thiourea, urea eller et rhodanat under oppvarmning, som angitt i tysk patent nr. 1.093.801. where R^ is mercapto, lower alkylthio, lower alkyl or aralkyl, R2 is amino or halogen, and R3 is hydrogen or hydroxyl, or a functional derivative thereof, is reacted with thiourea, urea or a rhodanate under heating, as indicated in German patent no. .1,093,801.

Imidlertid er denne fremgangsmåte lite praktisk, da en omsetning av 5-amino-2-lavere alkylthioorotsyre eller et amid derav, og thiourea eller ammoniumrhodanat ifolge det tyske patentskrift forloper svært langsomt ved temperaturer under 100°C, og ved temperaturer over 100°C ville dannes biprodukter i stor grad sammen med hydrogensulfid, og utbytte såvel som renhet ville bli meget lav. However, this method is not very practical, as a reaction of 5-amino-2-lower alkylthioorotic acid or an amide thereof, and thiourea or ammonium rhodanate according to the German patent document proceeds very slowly at temperatures below 100°C, and at temperatures above 100°C would by-products are formed to a large extent together with hydrogen sulphide, and yield as well as purity would be very low.

Folgelig er fremgangsmåten ifolge det tyske patent ueg-net for industrielle formål (se tabeller I - III). Consequently, the method according to the German patent is unsuitable for industrial purposes (see tables I - III).

Videre er ikke utgangsmaterialet kommersielt tilgjengelig og må fremstilles fra en annen kommersielt tilgjengelig forbindelse. Eksempelvis kan utgangsmateria let fremstilles ved at en oxaleddiksyreester, som også anvendes som utgangsmateteriale ved foreliggende fremgangsmåte, omsettes med en S-lavere alkyl-isothiourea under dannelse av en 2-lavere alkylthioorotsyre, som derefter halogeneres efter kjente metoder, at reaksjonsproduktet omsettes med ammoniakk under dannelse av en 5-amino-2-lavere alkylthioorotsyre. Furthermore, the starting material is not commercially available and must be prepared from another commercially available compound. For example, starting material can be easily prepared by reacting an oxaloacetic acid ester, which is also used as starting material in the present process, with an S-lower alkyl isothiourea to form a 2-lower alkylthioorotic acid, which is then halogenated according to known methods, that the reaction product is reacted with ammonia under formation of a 5-amino-2-lower alkylthioorotic acid.

Ved fremstilling av det onskede produkt av formel (I) efter den i det tyske patentskrift angitte fremgangsmåte er det antatt mest egnet å fremstille utgangsmaterialet efter den ovenfor angitte fremgangsmåte. Imidlertid er det totale utbytte av det onskede produkt ifolge denne oppfinnelse fra oxaleddiksyreester relativt lavt. When producing the desired product of formula (I) according to the method specified in the German patent document, it is believed to be most suitable to produce the starting material according to the method specified above. However, the total yield of the desired product according to this invention from oxaloacetic acid ester is relatively low.

Resultater erholdt ved anvendelse av den i tysk patent nr. 1.093.801 er diskutert nedenfor. Results obtained using that in German Patent No. 1,093,801 are discussed below.

Fremstilling av 2-methylthio-6-mercapto-4,8-dihydroxy-pyrimido[5,4-d]pyrimidin *monohydrat: ;1. Omsetning av 5-amino-2-methylthioorotsyre (1 g) og ammoniumrhodanat (3,8 g) i et molforhold på 1:10. ;Bemerk: S-innholdet i produktet var den verdi som ble erholdt ved analyse av produktet (fast) fra hvilket uomsatt ammoniumrhodanat var fjernet ved behandling av reaksjonsproduktet med vann. Når reaksjonstemperaturen var hoyere enn 175°C, forlop spaltningen voldsomt og S-innholdet i produktet var mindre enn 15 % eller produktet var ganske urent. 2. Tilsvarende reaksjon i et opplosningsmiddel mettet med hydrogensulfid og i en lukket glasskolbe. (Molforhold mel-lom utgangsmateriale og reagens 1:5). 3. Omsetning av 5-amino-2-methylthioorotsyreamid (1,00 mg) og ammoniumrhodanat (380 mg) i et molforhold på 1:10. ;Som resultater av de ovenfor angitte undersokelser er funnet at 2-methylthio-6-mercapto-4,8-dihydroxypyrimido[5,4-d ] - pyrimidin av hoy renhetsgrad kan fremstilles fra en oxaleddiksyreester med totalt utbytte på 43 % ved den ovenfor angitte fremgangsmåte. ;Også 2,6-dimercapto-4,8-dihydroxypyrimido[5,4-d]pyrimi-din (VII) kan erholdes med hdyt utbytte ved anvendelse av en kjent fremgangsmåte (se J. Chem. Soc. 1955, 1853 - 1858) på forbindelse I. ;Oppfinneren har lykkes ved utvikling av en prosess for fremstilling av Dipyridamol med hoyt utbytte fra forbindelse VII ;(O.L.S. 2.003.043). Den tidligere utviklede fremgangsmåte er til tross for sin overlegenhet, beheftet med den ulempe at utgangsmaterialet, dvs. forbindelse VII, ikke oppnåes lonnsomt industrielt. ;En fremgangsmåte ved fremstilling av 4,8-dihydroxy-2,6-dimercaptopyrimido[5,4-d]pyrimidin av formel VII, ved hvilken fremgangsmåte 2,6-diklor-4,8-dihydroxypyrimido[5,4-d]pyrimidin omsettes med et alkalihydrosulfid, er kjent fra fransk patent nr. 1.184.519. Ved denne fremgangsmåte erholdes forbindelse VII fra utgangsmaterialene i hoyt utbytte (86 %), men utgangsmateria let er ikke kommersielt tilgjengelig og må fremstilles fra andre forbindelser. F.eks. må utgangsmate rialet 2,6-diklor-4,8-dihydroxy-pyrimido[5,4-d]pyrimidin fremstilles ved en kjent fremgangsmåte, idet man starter fra 4-hydroxy-2-mercapto-6-methylpyridin, som er fremstillet ved omsetning av aceteddiksyreester og thiourea, og over trinnene 5-nitroorotsyre, 5-aminoorotsyre, 2,4,6,8-tetra-hydroxypyrimido[5,4-d]pyrimidin, og 2,4,6,8-tetraklorpyrimido-[5,4-]pyrimidin. I det tilfelle hvor denne kjente fremgangsmåte benyttes for fremstilling av utgangsmaterialet 2,6-diklor-4,8-dihydroxypyrimido[5,4-d]pyrimidin er så mange som syv reaksjons-trinn nodvendig for å fremstille forbindelse VII fra den kommersielt tilgjengelige aceteddiksyre, og forbindelse VII erholdes med et totalt utbytte på mindre enn 15 %. Folgelig er den i det franske patent angitte fremgangsmåte av liten industriell verdi, om ikke utgangsmaterialet er lett tilgjengelig. ;Imidlertid er de ovenfor angitte ulemper nu overvunnet, idet forbindelsen VII nu kan oppnåes med hoyt utbytte (totale utbytte på ca. 35 %) ved fremgangsmåten ifolge foreliggende oppfinnelse, slik at det nu har lykkes å fremstille Dipyridamol med la-ve kostnader. ;Fremgangsmåten ifolge foreliggende oppfinnelse og de ovenfor angitte,kjente fremgangsmåter er vist i de efterfolgende reaksjonsskjemaer: ;hvor R-p B.^ og R^ hver er lavere alkyl og X er halogen. ;Fremgangsmåte Ifolge foreliggende oppfinnelse hvor R, og R2 hver er lavere alkyl og X er halogen. ;Det er kjent at 2-carboxy-6-hydroxy-2-methylthiopyrimi-din erholdes ved omsetning av oxaleddiksyreesteren av formel (II) og S-methylisothiourea av formel (III, men det er ganske uventet og overraskende at 4-carbamoyl-6-hydroxy-2-methylthiopyrimidin av formel (IV) erholdes direkte i nærvær av ammoniakk slik som i ;forste trinn i foreliggende fremgangsmåte. ;I tysk patentskrift nr. 1.093.801 foreslåes der å danne pyrimido[5,4-d]pyrimidinringen ved å omsette 5-amino-2-mercapto, 4-carboxy-6-hydroxy-lavere alkylthiopyrimidin eller et funksjonelt derivat derav med en monothioforbindelse slik som ammoniumrhodanat, men ved en slik kjent fremgangsmåte dannes der store mengder biprodukter, og det er umulig å erholde det onskede produkt med hoyt utbytte og hoy renhetsgrad under milde reaksjonsbe-tingelser (tabeller I - III). ;Ganske uventet er det derfor at pyrimido[5,4-d]pyrimidin-ringen kan dannes uten dannelse av biprodukter ved å omsette et 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin og en dithio-forbindelse av formel (VI) under tilsvarende milde reaksjonsbe-tingelser, eksempelvis i et organisk opplosningsmiddel som i fjerde trinn ifolge fremgangsmåten. ;Således kan 2-methylthio-6-mercapto-4,8-dihydroxypyrimi-do[5,4-d]pyrimidin av formel (I) erholdes fra oxaleddiksyreester av formel (II) ved en kombinasjon av uventede trinn, med godt utbytte, dvs. et totdt utbytte på 43 %, noe som gjor denne fremgangsmåte meget lonnsom i industriell målestokk. ;Forste trinn ;Forste trinn må utfores ved å sette forbindelsen av formel (II) og en ekvimolar mengde - overskuddsmengde av S-methylisothiourea av formel (III) ved romtemperatur eller under avkjoling, fortrinnsvis ved temperaturer lavere enn 5°C i nærvær av ammoniakk, f.eks. i 5 - 28 %, fortrinnsvis IO - 15 % vandig ammoniakk. ;Den derved dannede forbindelse av formel (IV) lar seg lett krystallisere ved bare å justere reaksjonsopplosning en til en sur tilstand. Ved oppsamling av de derved dannede krystaller kan disse benyttes i det annet trinn som de foreligger, men hvis nødvendig kan krystallene ytterligere renses ved omkrystallisasjon eller lignende. ;Annet trinn ;Halogenering av forbindelsen av formel (IV) utfores efter kjente fremgangsmåter. Eksempelvis kan halogeneringen utfores ved å suspendere forbindelsen av formel (IV) i iseddik, inn-fore i suspensjonen en ekvimolar mengde brom eller klor, og opp-varme blandingen til fortrinnsvis 50 - 100°C. ;Ved å kjole det flytende reaksjonsprodukt krystalliserer forbindelsen av formel (IV). De dannede krystaller kan utvinnes ved filtrering for bruk i det påfolgende tredje trinn, men, hvis nodvendig kan de isoleres eller renses ved omkrystallisasjon, etc. ;Tredje trinn ;Aminering av forbindelsen av formel (IV) med ammoniakk utfores efter en kjent fremgangsmåte. Eksempelvis kan aminering av forbindelsen av formel (IV) utfores ved å omsette forbindelsen i et overskudd ammoniakk, vanligvis i vandig ammoniakk under nærvær av kobberpulver, og ved oppvarmning til 90 - 100°C. ;Forbindelsen av formel (V) krystalliseres ved kjoling ;av reaksjonsblandingen, og de derved dannede krystaller utvinnes ved filtrering, krystallene opploses i vandig ammoniakk, og opp-løsningens pH justeres til sur tilstand, fortrinnsvis til ca. 6. Ved utvinning av bunnfallet ved filtrering, kan dette benyttes i det påfolgende fjerde trinn, men hvis nodvendig kan produktet isoleres ellar renses ved omkrystallisasjon og lignende. ;Fjerde trinn ;Ved å omsette forbindelsen av formel (V) og forbindelsen av formel (VI) i et mengdeforhold stor re enn det ekvimolare eller storre enn 1:10 (mol) i et organisk opplosningsmiddel slik som pVridin, dimethylformamid eller en alkohol under tilbakelops-betingelser i IO - 20 timer, dannes pyrimidopyrimidinringen. ;Separering av den derved dannede forbindelse av formel (I) utfores ved kjente metoder slik som konsentrering, ekstrak-sjon, omkrystallisasjon og lignende. ;Eksempler på dithioforbindelsen av formel (VI) som benyttes i oppfinnelsen innbefatter dithiocarbonsyrederivater, f.eks. xantogensyre og dithiocarbonsyre-o-methylester, frie eller substituerte dithiocarbamylsyrer, f.eks. N,N-diethylthiocar-baminsyre og dithiomaursyre. Videre kan funksjonelle derivater av dithioforbindelsene med den samme aktivitet benyttes i foreliggende oppfinnelse. Ved omsetningen er det en fordel å benytte dithioforbindelsen som ovenfor angitt i form av et organisk salt eller et uorganisk salt, slik som et alkalimetalisalt, et jord-alkalimetilsalt, eller et organisk aminsalt,og som salter kan nevnes natriumsalter, kaliumsalter, aminsalter etc. I stedet for di-forbindelsene som ovenfor angitt, kan der benyttes et materia-le som er istand til å danne forbindelsen under reaksjonens gang. Eksempler på slike materialer innbefatter blandinger av carbonbisulfid og kaliumhydroxyd som er istand til å danne et xanthogenat når en lavere alkohol benyttes som reaksjonsmiddel eller en blanding av carbonbisulfid og et amin som er istand til å danne en ;substituert dithiocarbaminsyre i reaksjonsblandingen. ;Oppfinnelsen skal nu forklares ytterligere under henvis-ning til de folgende eksempler. ;Eksempel 1 ;Trinn 1 a ;Til 50 ml 14 %'s isavkjolt vandig ammoniakk ble tilsatt 5,0 g av natriumsaltet av oxaleddiksyreethylmethylester, og blandingen ble orarort 1 time under isavkjoling. Til den derved frem-stillede opplosning ble tilsatt 3,8 g S-methylisothioureasulfat, og blandingen ble ytterligere omrort 3 timer under isavkjoling. Efter at reaksjonen var fullfort, ble systemet pH-justert til 4 - 5 ved tilsetning av iseddik, og systemet ble tillatt å stå en stund, hvorved et hvitt krystallinsk pulver av 4-carbamoyl-6-hyd-roxy-2-methylthiopyrimidin utfeldtes, som ble gjenvunnet ved filtrering og vasket med en liten mengde vann. Produktmengden var 2,9 g (utbytte 61 %), og smeltepunktet var 270 - 272°C. Produktet ble omkrystallisert fra ethanol og hadde et smeltepunkt på 276&C. ;Trinn 1 b ;Til 50 ml 7 %'s vandig ammoniakk kjolt til en temperatur lavere enn 5°C ble tilsatt 5,0 g av natriumsaltet av bxaleddiksy-reethylmethylester, og blandingen ble omrort 2 timer ved samme temperatur. Til den derved dannede opplosning ble tilsatt 3,8 g S-methylisothioureasulfat, og blandingen ble ytterligere omrort 3 timer ved samme temperatur. ;Efter at reaksjonen var over, ble reaksjonsproduktopp-losningens pH justert til 4-5 ved tilsetning av iseddik og ble tillatt å stå en stund hvorved et hvitt krystallinsk pulver av 2-methylthioorotsyreamid utfeldtes, som ble gjenvunnet ved filtrering og vasket med en liten mengde vann. Produktmengden var 3,2 g (68 %), og smeltepunkt var 275 - 276°C. ;Trinn 1 c ;Til 50 ml 28 %'s vandig ammoniakk kjolt til under 5°C ble tilsatt 5,0 g av natriumsaltet av oxaleddiksyreethylmethylester, og blandingen omrort 30 minutter ved samme temperatur. Derefter ble der til opplosningen tilsatt 3,8 g S-methylisothioureasulfat og blandingen omrort ytterligere 3 timer ved samme temperatur. Efter at reaksjonen var over, ble reaksjonsproduktet behandlet som angitt i trinn 1 a, hvorved der ble erholdt 2,6 g (55 %) av et hvitt krystallinsk pulver av 4-carbamoyl-6-hydroxy-2-methylthiopyrimidin med smeltepunkt 272 - 273°C. ;, Trinn 1 d ;Til 50 ml 14 %'s vandig ammoniakk kjolt til under 5°C ble tilsatt 5,0 g av natriumsaltet av oxaleddiksyreethylmethy1-ester.. og blandingen omrort 1 time ved samme temperatur. Derefter ble til opplosningen tilsatt 5,3 g S-methylisothioureasulfat og blandingen omrort 3 timer ved samme temperatur. Efter at reaksjonen var over, ble reaksjonsproduktet behandlet som angitt i eksempel 1, hvorved der ble erholdt 3,7 g (79 %) av et hvitt, krystallinsk pulver av 4-carbamoy1-6-hydroxy-2-methylthiopyrimi-din med smeltepunkt 270 - 271°C. ;Trinn 1 e ;Til 100 ml toluen ble tilsatt 5,9 g dimethyloxalat, 2,7 g natriummethylat og 4,4 g ethylacetat og blandingen omrort 3 timer ved 60°C. Derefter ble opplosningen kjolt til under 5°C, og 90 ml 7 %'s vandig ammoniakk kjolt til under 5°C tilsatt opplosningen. Den resulterende blanding ble omrort 2 timer ved temperatur lavere enn 5°C. ;Derefter ble 7,0 g S-methylisothioureasulfat tilsatt opplosningen og blandingen omrort 3 timer ved temperatur lavere enn 5°C. Det derved dannede vandige lag ble gjenvunnet fra reaksjonsblandingen. Når det vandige lags pH ble justert til 4-5 ved tilsetning av iseddik og systemet ble tillatt å stå en stund, utfeldtes 4-carbamoyl-6-hydroxy-2-methylthiopyrimidin som et hvitt krystallinsk pulver som ble gjenvunnet ved filtrering og vasket med en liten mengde vann. Produktmengden var 5,4 g (totalt utbytte 58 %) og smeltepunkt var 276<0>C. ;Trinn 2 ;I 400 ml iseddik ble suspendert 50 g 4-carbamoy1-6-hydroxy-2-methylthiopyrimidin, og under omrdring av suspensjonen ble 49,3 g brom tilsatt dråpevis. Derefter ble suspensjonen oppvarmet til 50°C, og efter omroring i 1 time ble den ytterligere oppvarmet til 100°C og omrort i 1 time. Suspensjonen ble tillatt å avkjdles ved romtemperatur, og de derved dannede krystaller ble gjenvunnet ved filtrering og vasket med en liten mengde iseddik. Krystallene ble derefter suspendert i 125 ml benzen og suspensjonen kokt i 30 minutter. Efter avkjoling ble krystallene gjenvunnet ved filtrering og vasket med en liten mengde methanol, hvorved der ble erholdt 53,7 g (utbytte 74,9 %) 5"brom-4-carbamoy1-6-hydroxy-2-methylthiopyrimidin. ;Produktet ble omkrystallisert fra dimethylformamid-methanol og hadde et smeltepunkt på 244 - 245°C. ;Trinn 3 ;Til 180 ml 28 %'s vandig ammoniakk ble tilsatt 50 g 5-brom-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin, og efter tilsetning av 0,5 g kobberpulver ble blandingen oppvarmet 3 timer til 90 - 100°C i en lukket kolbe. Efter at reaksjonen var over ble det flytende reaksjonsprodukt avkjolt, de utfeldte gule krystaller ble gjenvunnet ved filtrering og derefter opplost i 800 ml 2 %'s vandig ammoniakk under oppvarmnin g". Efter tilsetning av aktivert kull til opplosningen og filtrering ble filtratet kjolt og oppløsningens pH justert til 6 ved tilsetning av eddiksyre, hvorved gule krystaller utfeldtes. De derved dannede krystaller ble gjenvunnet ved filtrering, vasket med vann og derefter methanol og tdrket, hvorved der ble erholdt 29,2 g (utbytte 77 %) 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin med smeltepunkt 280°C. ;Til det ovenfor angitte filtra.t ble tilsatt aktivert kull, og blandingen ble filtrert. Filtratets pH ble justert til 6 ved tilsetning av eddiksyre, hvorved gule krystaller utfeldtes. Krystallene ble gjenvunnet ved filtrering, vasket med vann og opplost i 400 ml 2 %'s vandig ammoniakk under oppvarmning. Derefter ble aktivert kull tilsatt opplosningen fulgt av filtrering. Filtratet ble avkjolt, og opplosningens pH justert ti 1 6 ved tilsetning av eddiksyre, hvorved gule krystaller utfeldtes. Krystallene ble gjenvunnet ved filtrering, vasket med en liten mengde vann og derefter methanol og tdrket, hvorved der ble erholdt 4,05 g (utbytte IO,7 %) 5-amino-4-carbamoyl-6-hydroxy-2-methyl-thiopyrimidin med smeltepunkt 280°C. Total mengde av produktet var 33,25 g (totalt utbytte 87,7 %). ;Trinn 4 a ;Til IO ml pyridin og 6 ml ethanol ble tilsatt lOO mg 5-amino-4-carbamoy1-6-hydroxy-2-methylthiopyrimidin og 1,6 g kalium-ethylxanthogenat, og blandingen ble kokt under tilbakelop over natten. Oppldsningsmidlet ble destillert fra, 3 ml vann ble tilsatt de gule krystaller, og blandingens pH ble justert til 4-5 med eddiksyre. Krystallene ble gjenvunnet ved filtrering og vasket to ganger, hver gang med 0,5 ml vann- De derved erholdte krystaller ble opplost i 10 ml 3N vandig ammoniakk. Aktivert kull ble tilsatt opplosningen, og blandingen ble filtrert. Filtratets pli ble justert til 4-5 ved tilsetning åv eddiksyre, og ;de derved dannede kremfarvede krystaller ble gjenvunnet ved filtrering, vasket to ganger, hver gang med 1 ml vann, og torket, hvorved der ble erholdt 96 ml (utbytte 74 %) 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido [5,4-dJpyrimidin med smeltepunkt hoyere enn 280°C. ;Elementæranalyse som C7H6N4S2°2"<H>2°<:>;;Trinn 4 b ;I 10 ml pyridin ble opplost lOO mg 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin og 2,2 g N,N-diethyldithiocarb-aminsyre-diethylaminsalt, og opplosningen ble derefter kokt ved tilbakelop over natten. Reaksjonsproduktet ble konsentrert, og 3 ml vann ble tilsatt det svartbrune residuum. Efter at blandingens pH var justert til 4-5 ved tilsetning av eddiksyre, ble ;10 ml ether tilsatt blandingen som ble rystet godt. Blandingen ;fikk stå 1 time ved romtemperatur, de derved dannede krystaller ble gjenvunnet ved filtrering og vasket to ganger, hver gang med 0,5 ml vann. De erholdte krystaller ble opplost i IO ml 3 N ;vandig ammoniakk, aktivert kull ble tilsatt blandingen, og carbon og uoppldste forbindelser ble filtrert fra. Filtratet ble gjort svakt surt med eddiksyre, og de derved dannede lysegule krystaller ble gjenvunnet ved filtrering og vasket to ganger, hver gang med 1 ml vann, og torket, hvorved der ble erholdt 80 mg (utbytte 61,5 %). Det infrardde absorpsjonsspektrum av forbindelsen var fullstendig lik forbindelsen erholdt i trinn 4 a. ;Elementæranalose som C_H,N.S_0„•H_0: ;7 0 4 2 2 <£ ;Trinn 4 c ;Til en opplosning av 0,28 g kaliumhydroxyd i 3 ml ethanol ble tilsatt 0,38 g carbonbisulfid, hvorefter 50 mg 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin og 5 ml pyridin ble tilsatt blandingen. Efter kokning ved tilbakeldp 23 timer ble reaksjonsproduktopplosningen behandlet som i trinn 4 a, hvorved der ble erholdt 30,5 mg kremfarvede krystaller av det onskede produkt med et utbytte på 47 %. Det infrardde absorpsjonsspektrum til forbindelsen var fullstendig lik spektret til produktet fremstillet i trinn 4 a.» ;Elementæranalyse som C7H^N4S202*H 0: Preparation of 2-methylthio-6-mercapto-4,8-dihydroxy-pyrimido[5,4-d]pyrimidine *monohydrate: ;1. Reaction of 5-amino-2-methylthioorotic acid (1 g) and ammonium rhodanate (3.8 g) in a molar ratio of 1:10. Note: The S content in the product was the value obtained by analysis of the product (solid) from which unreacted ammonium rhodanate had been removed by treating the reaction product with water. When the reaction temperature was higher than 175°C, the decomposition proceeded violently and the S content in the product was less than 15% or the product was quite impure. 2. Corresponding reaction in a solvent saturated with hydrogen sulphide and in a closed glass flask. (Molar ratio between starting material and reagent 1:5). 3. Reaction of 5-amino-2-methylthioorotic acid amide (1.00 mg) and ammonium rhodanate (380 mg) in a molar ratio of 1:10. As a result of the above investigations, it has been found that 2-methylthio-6-mercapto-4,8-dihydroxypyrimido[5,4-d]-pyrimidine of high purity can be prepared from an oxaloacetic acid ester with a total yield of 43% at the above stated procedure. ;Also 2,6-dimercapto-4,8-dihydroxypyrimido[5,4-d]pyrimidine (VII) can be obtained in high yield using a known method (see J. Chem. Soc. 1955, 1853 - 1858 ) on compound I. ;The inventor has succeeded in developing a process for the production of Dipyridamole with a high yield from compound VII ;(O.L.S. 2.003.043). The previously developed method, despite its superiority, suffers from the disadvantage that the starting material, i.e. compound VII, cannot be obtained profitably industrially. ;A process for the preparation of 4,8-dihydroxy-2,6-dimercaptopyrimido[5,4-d]pyrimidine of formula VII, in which process 2,6-dichloro-4,8-dihydroxypyrimido[5,4-d] pyrimidine is reacted with an alkali hydrosulphide, is known from French patent no. 1,184,519. By this method, compound VII is obtained from the starting materials in high yield (86%), but the starting material is not commercially available and must be prepared from other compounds. E.g. the starting material 2,6-dichloro-4,8-dihydroxy-pyrimido[5,4-d]pyrimidine must be prepared by a known method, starting from 4-hydroxy-2-mercapto-6-methylpyridine, which is prepared by reaction of acetoacetic ester and thiourea, and over the steps 5-nitroorotic acid, 5-aminoorotic acid, 2,4,6,8-tetra-hydroxypyrimido[5,4-d]pyrimidine, and 2,4,6,8-tetrachloropyrimido-[5 ,4-]pyrimidine. In the case where this known method is used for the preparation of the starting material 2,6-dichloro-4,8-dihydroxypyrimido[5,4-d]pyrimidine, as many as seven reaction steps are necessary to prepare compound VII from the commercially available acetoacetic acid , and compound VII is obtained with a total yield of less than 15%. Consequently, the method indicated in the French patent is of little industrial value, if the starting material is not readily available. However, the above-mentioned disadvantages have now been overcome, since the compound VII can now be obtained with a high yield (total yield of approx. 35%) by the method according to the present invention, so that it has now succeeded in producing Dipyridamole with low costs. The method according to the present invention and the above-mentioned known methods are shown in the following reaction schemes: where R-p B.^ and R^ are each lower alkyl and X is halogen. Method According to the present invention where R, and R2 are each lower alkyl and X is halogen. ;It is known that 2-carboxy-6-hydroxy-2-methylthiopyrimidine is obtained by reacting the oxaloacetic acid ester of formula (II) and S-methylisothiourea of formula (III), but it is rather unexpected and surprising that 4-carbamoyl-6 -hydroxy-2-methylthiopyrimidine of formula (IV) is obtained directly in the presence of ammonia as in the first step of the present method. In German patent document No. 1,093,801 it is proposed to form the pyrimido[5,4-d]pyrimidine ring by to react 5-amino-2-mercapto, 4-carboxy-6-hydroxy-lower alkylthiopyrimidine or a functional derivative thereof with a monothio compound such as ammonium rhodanate, but with such a known method large amounts of by-products are formed, and it is impossible to obtain the desired product in high yield and high degree of purity under mild reaction conditions (Tables I - III). ;Quite unexpectedly it is therefore that the pyrimido[5,4-d]pyrimidine ring can be formed without the formation of by-products by reacting a 5 -amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and a dithio compound of formula (VI) under correspondingly mild reaction conditions, for example in an organic solvent as in the fourth step according to the method. Thus, 2-methylthio-6-mercapto-4,8-dihydroxypyrimido[5,4-d]pyrimidine of formula (I) can be obtained from oxaloacetic acid ester of formula (II) by a combination of unexpected steps, with good yield, i.e. a total yield of 43%, which makes this method very profitable on an industrial scale. ;First step ;The first step must be carried out by putting the compound of formula (II) and an equimolar amount - excess amount of S-methylisothiourea of formula (III) at room temperature or under cooling, preferably at temperatures lower than 5°C in the presence of ammonia , e.g. in 5 - 28%, preferably 10 - 15% aqueous ammonia. The thus formed compound of formula (IV) can be easily crystallized by simply adjusting the reaction solution to an acidic condition. When collecting the crystals thus formed, these can be used in the second step as they are, but if necessary the crystals can be further purified by recrystallization or the like. ;Second step ;Halogenation of the compound of formula (IV) is carried out according to known methods. For example, the halogenation can be carried out by suspending the compound of formula (IV) in glacial acetic acid, introducing into the suspension an equimolar amount of bromine or chlorine, and heating the mixture to preferably 50 - 100°C. By cooling the liquid reaction product, the compound of formula (IV) crystallizes. The crystals formed can be recovered by filtration for use in the subsequent third step, but, if necessary, they can be isolated or purified by recrystallization, etc.; Third step; Amination of the compound of formula (IV) with ammonia is carried out according to a known method. For example, amination of the compound of formula (IV) can be carried out by reacting the compound in an excess of ammonia, usually in aqueous ammonia in the presence of copper powder, and by heating to 90 - 100°C. The compound of formula (V) is crystallized by cooling the reaction mixture, and the crystals thus formed are recovered by filtration, the crystals are dissolved in aqueous ammonia, and the pH of the solution is adjusted to an acidic state, preferably to approx. 6. When recovering the precipitate by filtration, this can be used in the following fourth step, but if necessary the product can be isolated or purified by recrystallization and the like. ;Fourth step ;By reacting the compound of formula (V) and the compound of formula (VI) in a quantity ratio greater than the equimolar or greater than 1:10 (mol) in an organic solvent such as pVridine, dimethylformamide or an alcohol under reflux conditions for 10 - 20 hours, the pyrimidopyrimidine ring is formed. Separation of the thereby formed compound of formula (I) is carried out by known methods such as concentration, extraction, recrystallization and the like. Examples of the dithio compound of formula (VI) used in the invention include dithiocarboxylic acid derivatives, e.g. xanthogenic acid and dithiocarboxylic acid o-methyl ester, free or substituted dithiocarbamyl acids, e.g. N,N-diethylthiocarbamic acid and dithiomauric acid. Furthermore, functional derivatives of the dithio compounds with the same activity can be used in the present invention. In the reaction, it is an advantage to use the dithio compound as stated above in the form of an organic salt or an inorganic salt, such as an alkali metal salt, an alkaline earth metal salt, or an organic amine salt, and as salts sodium salts, potassium salts, amine salts etc. can be mentioned. Instead of the di-compounds as stated above, a material which is able to form the compound during the course of the reaction can be used. Examples of such materials include mixtures of carbon bisulfide and potassium hydroxide which are capable of forming a xanthogenate when a lower alcohol is used as the reactant or a mixture of carbon bisulfide and an amine which is capable of forming a substituted dithiocarbamic acid in the reaction mixture. The invention will now be explained further with reference to the following examples. ;Example 1 ;Step 1 a ;To 50 ml of 14% ice-cooled aqueous ammonia was added 5.0 g of the sodium salt of oxaloacetic acid ethyl methyl ester, and the mixture was stirred for 1 hour under ice-cooling. 3.8 g of S-methylisothioureasulfate was added to the resulting solution, and the mixture was further stirred for 3 hours under ice cooling. After the reaction was complete, the system was pH-adjusted to 4-5 by adding glacial acetic acid, and the system was allowed to stand for a while, whereby a white crystalline powder of 4-carbamoyl-6-hydroxy-2-methylthiopyrimidine precipitated, which was recovered by filtration and washed with a small amount of water. The amount of product was 2.9 g (yield 61%), and the melting point was 270 - 272°C. The product was recrystallized from ethanol and had a melting point of 276°C. ;Step 1 b ;To 50 ml of 7% aqueous ammonia cooled to a temperature lower than 5°C was added 5.0 g of the sodium salt of bxaleddioxy-reethyl methyl ester, and the mixture was stirred for 2 hours at the same temperature. 3.8 g of S-methylisothioureasulfate was added to the resulting solution, and the mixture was further stirred for 3 hours at the same temperature. After the reaction was over, the pH of the reaction product solution was adjusted to 4-5 by adding glacial acetic acid and allowed to stand for a while, whereby a white crystalline powder of 2-methylthioorotic acid amide was precipitated, which was recovered by filtration and washed with a small water. The amount of product was 3.2 g (68%), and the melting point was 275 - 276°C. ;Step 1 c ;To 50 ml of 28% aqueous ammonia cooled to below 5°C was added 5.0 g of the sodium salt of oxaloacetic acid ethyl methyl ester, and the mixture stirred for 30 minutes at the same temperature. Then 3.8 g of S-methylisothioureasulfate was added to the solution and the mixture was stirred for a further 3 hours at the same temperature. After the reaction was over, the reaction product was treated as indicated in step 1 a, whereby 2.6 g (55%) of a white crystalline powder of 4-carbamoyl-6-hydroxy-2-methylthiopyrimidine with melting point 272 - 273 were obtained °C. ;, Step 1 d ;To 50 ml of 14% aqueous ammonia cooled to below 5°C was added 5.0 g of the sodium salt of oxaloacetic acid ethyl methyl ester.. and the mixture stirred for 1 hour at the same temperature. Then 5.3 g of S-methylisothioureasulfate was added to the solution and the mixture was stirred for 3 hours at the same temperature. After the reaction was over, the reaction product was treated as indicated in Example 1, whereby 3.7 g (79%) of a white, crystalline powder of 4-carbamoyl-6-hydroxy-2-methylthiopyrimidine with a melting point of 270 - 271°C. ;Step 1 e ;To 100 ml of toluene, 5.9 g of dimethyl oxalate, 2.7 g of sodium methylate and 4.4 g of ethyl acetate were added and the mixture was stirred for 3 hours at 60°C. Then the solution was cooled to below 5°C, and 90 ml of 7% aqueous ammonia cooled to below 5°C was added to the solution. The resulting mixture was stirred for 2 hours at a temperature lower than 5°C. Then 7.0 g of S-methylisothioureasulfate was added to the solution and the mixture stirred for 3 hours at a temperature lower than 5°C. The aqueous layer thus formed was recovered from the reaction mixture. When the pH of the aqueous layer was adjusted to 4-5 by addition of glacial acetic acid and the system was allowed to stand for some time, 4-carbamoyl-6-hydroxy-2-methylthiopyrimidine precipitated as a white crystalline powder which was recovered by filtration and washed with a small amount of water. The amount of product was 5.4 g (total yield 58%) and the melting point was 276<0>C. ;Step 2 ;In 400 ml of glacial acetic acid, 50 g of 4-carbamoyl-6-hydroxy-2-methylthiopyrimidine was suspended, and while stirring the suspension, 49.3 g of bromine was added dropwise. The suspension was then heated to 50°C, and after stirring for 1 hour, it was further heated to 100°C and stirred for 1 hour. The suspension was allowed to cool at room temperature, and the crystals thus formed were recovered by filtration and washed with a small amount of glacial acetic acid. The crystals were then suspended in 125 ml of benzene and the suspension boiled for 30 minutes. After cooling, the crystals were recovered by filtration and washed with a small amount of methanol, whereby 53.7 g (yield 74.9%) of 5"bromo-4-carbamoy1-6-hydroxy-2-methylthiopyrimidine were obtained. The product was recrystallized from dimethylformamide-methanol and had a melting point of 244 - 245° C. ;Step 3 ;To 180 ml of 28% aqueous ammonia was added 50 g of 5-bromo-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine, and after addition of 0.5 g of copper powder, the mixture was heated for 3 hours to 90 - 100 ° C in a closed flask. After the reaction was over, the liquid reaction product was cooled, the precipitated yellow crystals were recovered by filtration and then dissolved in 800 ml of 2% 's aqueous ammonia during heating". After adding activated charcoal to the solution and filtering, the filtrate was cooled and the pH of the solution was adjusted to 6 by adding acetic acid, whereby yellow crystals were precipitated. The crystals thus formed were recovered by filtration, washed with water and then methanol and dried, thereby obtaining 29.2 g (yield 77%) of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine with melting point 280° C. Activated charcoal was added to the above filtrate and the mixture was filtered. The pH of the filtrate was adjusted to 6 by adding acetic acid, whereby yellow crystals precipitated. The crystals were recovered by filtration, washed with water and dissolved in 400 ml of 2% aqueous ammonia under heating. Then activated charcoal was added to the solution followed by filtration. The filtrate was cooled, and the pH of the solution was adjusted to 1 6 by adding acetic acid, whereby yellow crystals were precipitated. The crystals were recovered by filtration, washed with a small amount of water and then methanol and dried to give 4.05 g (yield 10.7%) of 5-amino-4-carbamoyl-6-hydroxy-2-methyl-thiopyrimidine with melting point 280°C. Total amount of product was 33.25 g (total yield 87.7%). ;Step 4 a ;To 10 ml of pyridine and 6 ml of ethanol were added 100 mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and 1.6 g of potassium ethyl xanthogenate, and the mixture was refluxed overnight. The solvent was distilled off, 3 ml of water was added to the yellow crystals, and the pH of the mixture was adjusted to 4-5 with acetic acid. The crystals were recovered by filtration and washed twice, each time with 0.5 ml of water. The crystals thus obtained were dissolved in 10 ml of 3N aqueous ammonia. Activated charcoal was added to the solution and the mixture was filtered. The pH of the filtrate was adjusted to 4-5 by adding acetic acid, and the resulting cream-colored crystals were recovered by filtration, washed twice, each time with 1 ml of water, and dried, whereby 96 ml were obtained (yield 74%) 4,8-dihydroxy-6-mercapto-2-methylthiopyrimido [5,4-dJpyrimidine with a melting point higher than 280°C. ;Elementary analysis as C7H6N4S2°2"<H>2°<:>;;Step 4 b ;In 10 ml of pyridine were dissolved lOO mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and 2.2 g of N ,N-diethyldithiocarbamic acid-diethylamine salt, and the solution was then refluxed overnight. The reaction product was concentrated, and 3 ml of water was added to the black-brown residue. After the pH of the mixture was adjusted to 4-5 by adding acetic acid, ; 10 ml of ether was added to the mixture which was shaken well. The mixture was allowed to stand for 1 hour at room temperature, the crystals thus formed were recovered by filtration and washed twice, each time with 0.5 ml of water. The crystals obtained were dissolved in 10 ml of 3 N aqueous ammonia, activated charcoal was added to the mixture, and carbon and undissolved compounds were filtered off. The filtrate was made weakly acidic with acetic acid, and the light yellow crystals thus formed were recovered by filtration and washed twice, each time with 1 ml of water, and dried to give 80 mg (yield 61.5%). The infrared absorption spectrum of the compound was completely similar to the compound obtained in step 4 a. ;Elementary analose as C_H,N.S_0„ H_0: ;7 0 4 2 2 <£ ;Step 4 c ;To a solution of 0.28 g of potassium hydroxide in 3 ml of ethanol was added to 0.38 g of carbon bisulfide, after which 50 mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and 5 ml of pyridine were added to the mixture. After boiling at reflux for 23 hours, the reaction product solution was treated as in step 4 a, whereby 30.5 mg of cream-colored crystals of the desired product were obtained with a yield of 47%. The infrared absorption spectrum of the compound was completely similar to the spectrum of the product prepared in step 4 a."; Elemental analysis as C7H^N4S202*H 0:

Trinn 4 d Step 4 d

Til en natriumalkoholatoppldsning fremstillet ved tilsetning av 0,115 g metallisk natrium til 3 ml ethanol ble tilsatt 0,38 g carbondisulfid. Til den gule oppldsning ble tilsatt 50 mg 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin og 5 ml pyridin, og blandingen ble kokt under tilbakelop i 18 timer. Opplosningen ble derefter kjolt til romtemperatur, og de utfeldte krystaller ble gjenvunnet ved filtrering. Til krystallene ble tilsatt 1 ml vann, og blandingens pH ble justert til 4 ved tilsetning av eddiksyre. De lysegule krystaller ble gjenvunnet ved filtrering, vasket to ganger, hver gang med 0,5 ml vann, og torket, hvorved der ble erholdt 53,4 mg av det onskede produkt med utbytte 82,2 %. Det infrardde absorpsjonsspektrum til produktet To a sodium alcoholate solution prepared by adding 0.115 g of metallic sodium to 3 ml of ethanol was added 0.38 g of carbon disulfide. To the yellow solution was added 50 mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and 5 ml of pyridine, and the mixture was refluxed for 18 hours. The solution was then cooled to room temperature and the precipitated crystals were recovered by filtration. 1 ml of water was added to the crystals, and the pH of the mixture was adjusted to 4 by adding acetic acid. The pale yellow crystals were recovered by filtration, washed twice, each time with 0.5 ml of water, and dried, whereby 53.4 mg of the desired product was obtained with a yield of 82.2%. The infrared absorption spectrum of the product

var fullstendig lik det til produktet fremstillet i trinn 4 a. was completely similar to that of the product prepared in step 4 a.

Trinn 4 e Step 4 e

Til 5 ml dimethylformamid ble tilsatt 50 mg 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidin og 0,8 g kaliumethyl-xanthogenat og opplosningen oppvarmet 19 timer til 110 - 115°C. Efter at reaksjonen var over, ble de derved utfeldte gule krystaller gjenvunnet ved filtrering. Det mdrkegronne filtrat ble konsentrert under redusert trykk, og det dannede residuum ble blandet med de ovenfor angitte krystaller. Til blandingen ble tilsatt 3 ml vann, og blandingens pH ble justert ti 1 4 ved tilsetning av eddiksyre. De dannede krystaller ble gjenvunnet ved filtrering og vasket to ganger, hver gang med 0,5 ml vann. 50 mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine and 0.8 g of potassium ethyl xanthogenate were added to 5 ml of dimethylformamide and the solution was heated for 19 hours to 110 - 115°C. After the reaction was over, the yellow crystals thus precipitated were recovered by filtration. The dark green filtrate was concentrated under reduced pressure, and the resulting residue was mixed with the above-mentioned crystals. 3 ml of water was added to the mixture, and the pH of the mixture was adjusted to 1 4 by adding acetic acid. The crystals formed were recovered by filtration and washed twice, each time with 0.5 ml of water.

De således erholdte krystaller ble opplost i 7 ml 3N vandig ammoniakk, og efter behandling av opplosningen med aktivert carbon som ble filtrert fra, ble filtratets pH justert til 4 med eddiksyre. De utfeldte krystaller ble gjenvunnet ved filtrering, vasket to ganger, hver gang med 0,5 ml vann, tdrket, hvorved der ble erholdt 49 mg (utbytte 75,4 %) gule krystaller. Det infrardde absorpsjonsspektrum til produktet var fullstendig lik det til produktet erholdt i trinn 4 a. The crystals thus obtained were dissolved in 7 ml of 3N aqueous ammonia, and after treating the solution with activated carbon which was filtered off, the pH of the filtrate was adjusted to 4 with acetic acid. The precipitated crystals were recovered by filtration, washed twice, each time with 0.5 ml of water, dried, whereby 49 mg (yield 75.4%) of yellow crystals were obtained. The infrared absorption spectrum of the product was completely similar to that of the product obtained in step 4 a.

Trinn 4 f Step 4 f

Til en blanding av 5 ml pyridin og 3 ml ethanol ble tilsatt 50 mg 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidinTo a mixture of 5 ml of pyridine and 3 ml of ethanol was added 50 mg of 5-amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine

og 1 g kaliumdithioformiat, og blandingen ble kokt under tilbakelop 22 timer. Reaksjonsblandingen ble konsentrert, og det svartbrune residuum behandlet som i trinn 4 a, hvorved der ble erholdt 38 mg gule krystaller av 4,8-dihydroxy-6-mercapto-2-methylthio-ppyrimido[5,4-d]pyrimidin med et utbytte på 58,5 %. Det infrardde absorpsjonsspektrum til produktet var fullstendig lik det til produktet erholdt i trinn 4 a. and 1 g of potassium dithioformate, and the mixture was refluxed for 22 hours. The reaction mixture was concentrated, and the black-brown residue treated as in step 4 a, whereby 38 mg of yellow crystals of 4,8-dihydroxy-6-mercapto-2-methylthio-pyrimido[5,4-d]pyrimidine were obtained in a yield of 58.5%. The infrared absorption spectrum of the product was completely similar to that of the product obtained in step 4 a.

Referanseeksempel Reference example

En opplosning av 16 g metallisk natrium i 200 ml vannfri methanol ble tilsatt 28 g tdrket hydrogensulfid, hvoretter methan-olen ble avdestillert ved undertrykk. Residuet ble tilsatt 1000 ml vannfri ethylenglycol, og blandingen ble oppvarmet ved et undertrykk på 70 - 80 mm Hg og konsentrert inntil oppløsningens temperatur var 135°C, hvorefter opplosningen ble avkjolt. I den således tilberedte ethylenglycoloppldsning av vannfritt natriumhyd-rogensulfid ble 80 g 2-methylthio-6-mercapto-4,8-dihydroxypyri-mido-[5,4-d]pyrimidin suspendert, og blandingen ble under langsom tilledning av hydrogensulfid omrort 30 minutter ved romtemperatur hvorefter temperaturen forsiktig og langsomt ble hevet til 120 - 135°C for å unngå skumutvikling, hvorefter omrdring ble fortsatt ved denne temperatur under tilledning av hydrogensulfid i ytterligere 9 timer. Reaksjonsblandingen ble avkjolt og tilsatt 800 ml methanol og omrort IO minutter, hvorefter de erholdte gule krystaller ble filtrert fra og vasket med 200 ml methanol. A solution of 16 g of metallic sodium in 200 ml of anhydrous methanol was added to 28 g of dried hydrogen sulphide, after which the methanol was distilled off under reduced pressure. The residue was added to 1000 ml of anhydrous ethylene glycol, and the mixture was heated at a vacuum of 70 - 80 mm Hg and concentrated until the temperature of the solution was 135°C, after which the solution was cooled. In the thus prepared ethylene glycol solution of anhydrous sodium hydrogen sulphide, 80 g of 2-methylthio-6-mercapto-4,8-dihydroxypyrimido-[5,4-d]pyrimidine were suspended, and the mixture was stirred for 30 minutes under the slow addition of hydrogen sulphide at room temperature, after which the temperature was carefully and slowly raised to 120 - 135°C to avoid foaming, after which stirring was continued at this temperature under the addition of hydrogen sulphide for a further 9 hours. The reaction mixture was cooled and 800 ml of methanol was added and stirred for 10 minutes, after which the yellow crystals obtained were filtered off and washed with 200 ml of methanol.

De således erholdte krystaller av natriumsaltet av 2,6-dimercapto-4,8-dihydroxypyrimido-[5,4-d]pyrimidin ble derefter oppvarmet under tilsetning av 2000 ml 1 %'s natriumlut til 30 - 40°C for å bringe blandingen i oppldsning, hvorefter uoppldselige bestanddeler ble filtrert fra. Filtratet ble innstillet med eddiksyre på en pH-verdi på 4 ved en temperatur på hdyst 40°C. Opplosningen ble gjennomluftet ca. 30 minutter, hvorefter avfiltrer-te krystaller av produktet forst ble vasket med 320 ml vann, og derefter med 160 ml methanol. Efter 1 times tdrking med varm luft av 70 - 80°C ble erholdt 65 g 2,6-dimercapto-4,8-dihydroxy-pyrimido- [5,4-d]pyrimidin (utbytte: 86,2 %). The thus obtained crystals of the sodium salt of 2,6-dimercapto-4,8-dihydroxypyrimido-[5,4-d]pyrimidine were then heated with the addition of 2000 ml of 1% sodium hydroxide solution to 30-40°C to bring the mixture in solution, after which insoluble components were filtered out. The filtrate was adjusted with acetic acid to a pH value of 4 at a temperature of at least 40°C. The solution was aerated approx. 30 minutes, after which filtered off crystals of the product were first washed with 320 ml of water, and then with 160 ml of methanol. After 1 hour of drying with hot air of 70 - 80°C, 65 g of 2,6-dimercapto-4,8-dihydroxy-pyrimido-[5,4-d]pyrimidine were obtained (yield: 86.2%).

Claims

Procedure for the preparation of 2-methylthio-6-mercap-tp-4,8-dihydroxypyrimido[5,4-d]pyrimidine of formula:

characterized in that oxaloacetic acid esters of the general formula: where R 1 and R 2 are each lower alkyl and M is alkali metal, is reacted with S-methylisothiourea of the general formula: in the presence of ammonia, forming 2-methy1-4-carbamoy1-6-hydroxy-2-methylthiopyrimidine of the formula: that the amide formed is halogenated in a manner known per se, that the reaction product is reacted with ammonia to form 5- amino-4-carbamoyl-6-hydroxy-2-methylthiopyrimidine of the formula: and that the product is then subjected to a treatment with a dithiophene compound of the general formula: where X is hydrogen, a lower alkoxy group or a di-lower alkylamino group.