SI7713022A8 - Process for obtaining 5'-deoxy-5-fluoro-citidine and 5'-deoxy-5-fluoruridine, respectively - Google Patents

Description

POSTUPAK ZA DOBIVANJE 5 '-DEZOKSI-5-PLUORCITIDINA ODNOSNO 5'-DEZ0KSI-5-PLU0RURIDINAPROCEDURE FOR PREPARATION OF 5 '-DESOXY-5-PLUORCITIDINE OR 5'-DEOXY-5-PLUORURIDINE

1. OBLAST TEHNIKE1. TECHNICAL FIELD

Ovaj pronalazak spada u oblast organske hemije i farmaceutske hemije.The present invention relates to the field of organic chemistry and pharmaceutical chemistry.

2. TEHNIČKI PROBLEM2. TECHNICAL PROBLEM

Pronalazak obuhvata postupak za dobivanje novih pirimidin nukleozida koji se mogu primeniti kao sredstva protiv tumora, posebno postupak za dobivanje 5'-dezoksi-5fluorcitidina i 5'-dezoksi-5-fluoruridina, kao i njihovih fiziološki podnošljivih adicionih soli sa kiselinama,The invention includes a process for the preparation of novel pyrimidine nucleosides that can be used as anti-tumor agents, in particular a process for the preparation of 5'-deoxy-5fluorocytidine and 5'-deoxy-5-fluororidine, as well as their physiologically acceptable acid addition salts.

3. STANJE TEHNIKE3. BACKGROUND OF THE INVENTION

Ranije je opisano uvodjenje 5'-dezoksi supstituenta u pirimidin nukleozide. Tako su Wempen et al., J.Amer,Chem.Soc. 82, 1624 (1960) opisali s/ntezu 5'-dezoksiuridina, 5'-čLezoksi5'-fluoro-citidina, i 5'-dezoksi-5'-fluorouridina. Japanski Patent No. 49-116081 opisuje dobivanje 5'-dezoksicitidina reduk cijom odgovarajuceg 5'-halo (Br iii I) iii 5'-metil iii benzilmerkaptana. Nikakva anti-tumorna aktivnost nije pripisana bilo kod gore pomenutom finalnom proizvodu.The introduction of the 5'-deoxy substituent into pyrimidine nucleosides was described previously. Thus, Wempen et al., J.Amer, Chem.Soc. 82, 1624 (1960) described the synthesis of 5'-deoxyuridine, 5'-lezoxy5'-fluoro-cytidine, and 5'-deoxy-5'-fluorouridine. Japanese Pat. 49-116081 describes the preparation of 5'-deoxycytidine by reduction of the corresponding 5'-halo (Br iii I) or 5'-methyl or benzylmercaptan. No anti-tumor activity was attributed to any of the above-mentioned final products.

15324*0 9.JULH98515324 * 0 9.JULH985

Palco i Pox, J. Med, Chem. 11, 148 (1968) opisuju sintezu l-(5'-dezoksi- β-D-arabinofuranozil)citozina. Nadjeno je da je ovo jedinjenje inaktivno protiv L 1210 leukemije i Burkitt-ovih kultura čelija, verovatno zbog toga što ovakvo jedinjenje ne može da obrazuje 5'-fosforilovani derivat.Palco and Pox, J. Med, Chem. 11, 148 (1968) describe the synthesis of 1- (5'-deoxy-β-D-arabinofuranosyl) cytosine. This compound was found to be inactive against L 1210 leukemia and Burkitt cell cultures, probably because such compound could not form a 5'-phosphorylated derivative.

Hein et al., Nu.deic AcldB Research j, 1125 (1976) su takodje dobili 5'-dezoksiuridin i 2', 5'-didezoksiuridin naizmeničnim redukcionim postupcima. Nikakva biološka aktivnost nije pripisana dobivenim proizvodima.Hein et al., Nu.deic AcldB Research j, 1125 (1976) also obtained 5'-deoxyuridine and 2 ', 5'-dideoxyuridine by alternating reduction methods. No biological activity was attributed to the products obtained.

Japanski Patent No. 51-086481 opisuje dobivanje 2', 5'didezoksi-5-fluoruridina iz odgovaraj uceg 2', 5'-didezoksi-5'j odo jedinjenja. Ukazano je da je proizvod anti-khncerno sredstvo koje inhibira rast Yoshida Sarkoma.Japanese Pat. 51-086481 describes the preparation of 2 ', 5'dideoxy-5-fluorouridine from the corresponding 2', 5'-dideoxy-5'j od compounds. The product has been shown to be an anti-khncerine inhibitor of Yoshida Sarcoma growth.

U.S. Patent No. 3,687,931 opisuje dobivanje 5'-dezoksi5'-hloro iii hromo nukleozida koristeci trifenilfosfin, upotrebljavajuči ugljen tetrahlorid iii ugljen tetrabromid. Otkriveno je da jedinjenja imaju antibiotsku, ant imetabolicnu i enzimski inhibicionu aktivnost.U.S. Patent No. No. 3,687,931 describes the preparation of 5'-deoxy5'-chloro or chromo nucleosides using triphenylphosphine, using carbon tetrachloride or carbon tetrabromide. The compounds have been found to have antibiotic, ant imetabolic and enzymatic inhibitory activity.

Jedinjenja 5'-dezoksiuridin i 2', 5'-didezoksi-5-fluoruridin opisana su u C.A. 76 (1972) 154079p i u Japanskom Patentu No. 76-86481.The compounds 5'-deoxyuridine and 2 ', 5'-dideoxy-5-fluorouridine are described in C.A. 76 (1972) 154079p and in Japanese Pat. 76-86481.

4. OPIS KEŠENJA TEHNIČKOG PROBLEMA SA PRIMBRIMA IZVODJENJA4. DESCRIPTION OF THE TECHNICAL PROBLEM CASE WINDOWS WITH PERFORMANCE

Jedinjenja prema pronalasku dobivaju se lako polazeči iz 5-fluorcitidina, odnosno 5-fluouridina, pri čemu se prvo vrši zaštita obe hidroksilne grupe u 2'- i 3'- položaju obrezovanjem izopropiliden ketala, što se postiže tretiranjemThe compounds of the invention are readily prepared from 5-fluorocytidine and 5-fluouridine, respectively, by protecting both hydroxyl groups in the 2'- and 3'-position by trimming the isopropylidene ketal, which is achieved by treatment

5-fluorcitidina, odnosno 5-fluoruridina sa organskom sulfonskom kiselinom, na pr. p-toluolsulfonskom kiselinom u izopropiliden ketalizirajučem sredstvu, na pr. 2,2-dimetoksipropanu, u pogodnom organskom rastvaraču, prvenstveno ketonskom, kao što je aceton, na temperaturi od oko 0°C do 60°C, prvenstveno sobnoj temperaturi, a zatim halogenovanjem obrazovanog izopropiliden ketala u 5'- položaju, pomoču halogena.5-fluorocytidine, or 5-fluororidine with organic sulfonic acid, e.g. p-toluenesulfonic acid in an isopropylidene ketalizing agent, e.g. 2,2-dimethoxypropane, in a suitable organic solvent, preferably a ketone such as acetone, at a temperature from about 0 ° C to 60 ° C, preferably at room temperature, and then by halogenation of the formed isopropylidene ketal in the 5'-position, by halogen.

Kao halogeni prvenstveni su brom i jod. Uvodjenje joda može da se izvrši na primer tretiranjem sa j odiraj učim sredstvom kao što je metiltrifenoksifosfonijumjodid (MTPI) u polarnom aprotonskom rastvaraču kao *što je dimetilformamid (DMP) na temperaturi izmedju 0 i 100°C, prvenstveno na sobnoj temperaturi. Uvodjenje broma može da se izvrši sa sredstvom za bromovanje u polarnom aprotonskom rastvaraču kao što je DMF, na temperaturi izmedju 10 i 100°C.Halogens are primarily bromine and iodine. The introduction of iodine can be effected, for example, by treatment with a learning agent such as methyltriphenoxyphosphonium iodide (MTPI) in a polar aprotic solvent such as * dimethylformamide (DMP) at a temperature between 0 and 100 ° C, preferably at room temperature. The introduction of bromine can be carried out with a brominating agent in a polar aprotic solvent such as DMF at a temperature between 10 and 100 ° C.

Dobiveno 5'- halogeno jedinjenje se redukuje u odgovarajuče 5'-dezoksi jedinjenje, iii katalitičkim hidrogenovanjem iii sa redukcionim sredstvima kao što su kompleksni metalni hidridi.The 5'-halogen compound obtained is reduced to the corresponding 5'-deoxy compound, either by catalytic hydrogenation or by reducing agents such as complex metal hydrides.

Na ovaj način dobiveni 5'-dezoksi-2',3'-O-izopropiliden5-fluorcitidin iii 5 '-dezoksi-2', 3 '-0-izopropiliden-5-fluoruridin se podvrgavaju hi-drolizi sa 90% trifluorsirčetnom kiselinom u toku 1 sata na sobnoj temperaturi pri čemu se dobiva 5'-dezoksi-5-fluorocitidin, odnosno 5 '-de0oksi-5-fluoruridin.The 5'-deoxy-2 ', 3'-O-isopropylidene 5-fluorocytidine or 5' -deoxy-2 ', 3' -0-isopropylidene-5-fluorouridine thus obtained is subjected to hydrolysis with 90% trifluoroacetic acid in for 1 hour at room temperature to give 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluororidine, respectively.

Prema potrebi dobiveni 5^z-dezoksi-5-fluorcitidin, odnosno 5'-dezoksi-5-fluoruridin se prevode u fiziološki podnošljiVe soli tretiranjem sa nekom fiziološki podnošljivom kiselinom.If necessary, the resulting 5 ^z -deoxy-5-fluorocytidine and 5'-deoxy-5-fluororidine are converted into physiologically tolerable salts by treatment with a physiologically tolerable acid.

Izraz fiziološki podnošljive soli obuhvata ne-toksične soli, koje obrazuju 5'-dezoksi-5-fluorcitidin i 5'-dezoksi5-fluoruridin sa neorganskim mineralnim kiselinama _; i. organskim kiselinama, na pr. hidrohloride, hidrobromide, fosfate, sulfate, nitrate, acetate, formijate, maleate iii benzoate.The term physiologically tolerable salts includes non-toxic salts forming 5'-deoxy-5-fluorocytidine and 5'-deoxy5-fluororidine with inorganic mineral acids _; i. organic acids, e.g. hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, acetates, formates, maleates or benzoates.

5'-Dezoksi-5-fluorcitidin i 5'-dezoksi-5-fluoruridin kao i njihove fiziološki podnošljive adicione soli sa kiselit nama deluj & protiv Ehrlich-ovog karcinoma i sarkoma 180 kod miševa unutar široke oblasti doziranja, oralnog i parenteralnog. Ova jedinjenja su zato dragocena sredstva protiv tumora i mogu se primeniti kao lekovi u obliku farmaceutskih preparata sa direktnim iii usporenim oslobadjanjem aktivne materije.5'-Deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as their physiologically acceptable acid addition salts act against Ehrlich's cancer and sarcoma 180 in mice within a wide dosage range, oral and parenteral. These compounds are therefore valuable anti-tumor agents and can be administered as pharmaceuticals in the form of pharmaceuticals with direct or sustained release of the active substance.

U smesama sa neotrovnim, inertnim, čvrstim iii tečnim nosačima kao što su na primer voda, želatin, gumiarabika, mlečni šečer, škrob, magnezijum stearat, talk, biljna ulja, polialkilenglikoli, vazelin itd., koji su pogodni za enteralnu (na primer oralnu) iii parenteralnu aplikaciju. Farmaceutski preparati mogu biti u čvrstom obliku, na primer kao tablete, dražeje, supozitorije, kapsule, iii u tednom obliku, na primer kao rastvori, suspenzije iii emulzije. U odredjenim slučajevima su oni sterilizirani, odnosno sadrže druge pomočne supstance kao što su sredstva za konzervisanje, stabilizovanje, umrežavanje iii emulgovanje, sredstva za poboljšanje ukusa, soli za promenu osmotskog pritiska iii pufere. Proizvodnja farmaceutskih preparata može se izvesti na način koji je rutinski za svakog stručnjaka.In mixtures with non-toxic, inert, solid or liquid carriers such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc., which are suitable for enteral (eg oral) ) iii parenteral application. The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules, or in weekly form, for example as solutions, suspensions or emulsions. In certain cases, they are sterilized, that is, they contain other excipients such as preservatives, stabilizers, crosslinkers or emulsifiers, flavoring agents, salts to change osmotic pressure or buffers. The manufacture of pharmaceutical preparations can be performed in a manner that is routine for any person skilled in the art.

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Anti-tumor testovi:Anti-tumor tests:

Za davanje životinjama jedinjenja su rastvarana u vodi.For administration to animals, the compounds were dissolved in water.

Sai.com 180-testSai.com 180-Test

18-20 g teškim belim miševima implantirani su pomoču trokara mali delovi tumora (2Ό-30 mg) subkutano u predelu desne prepone.· Delovi tumora uzimani su od Životinja koje su. nosile tumore implantirane 7-10 dana ranije. Tretiranje je započeto na dan implantacije i nastavljeno jednom dnevno u toku 8 dana. Životinje su ubijane 8 dana posle implantacije i tumori su vadjejii i mereni. Izračunavan je onda odnos prosečne težine tumora netretirane kontrolne grupe (C) prema prosečnoj težini tumora tretirane grupe (T). Sprečavanje t18-20 g heavy white mice were implanted with the trocar small portions of the tumor (2Ό-30 mg) subcutaneously in the right groin area · Tumor sections were taken from Animals that were. carried tumors implanted 7-10 days earlier. Treatment was started on the day of implantation and continued once daily for 8 days. Animals were killed 8 days after implantation and tumors were excised and measured. The ratio of the average tumor weight of the untreated control group (C) to the average tumor weight of the treated group (T) was then calculated. Preventing t

rasta tumora dato je u prooentima kao (C-T) . 100/C. Jedno jedinjenje se smatralo aktivnim za neku odredjenu dozu ako je sprečavanje rasta iznosilo 50 iii više procenata.tumor growth was given in prooents as (C-T). 100 / C. A compound was considered active for a given dose if growth inhibition was 50 percent or more.

Ehrlich-ov karcinom-testEhrlich's cancer test

Čvrsti oblik ovog tumora dobiven je pomoču subkutane implantacije 0,5 ml jedne suspenzije čelija ascitiskog tumora razblažene na 1-10 rastvorom kuhinjske soli. Kao davalac služio je jedan 18-20 g težak beli miš, kome je 7-10 dana ranij e implantiran tumor. Trdtiraoje i prikazivanje rezultata vršeno je na več ranij e opisani način.The solid form of this tumor was obtained by subcutaneous implantation of 0.5 ml of one suspension of ascitic tumor cells diluted to 1-10 with sodium chloride solution. As a donor, one 18-20 g heavy white mouse served as a tumor implant 7-10 days earlier. Claiming and presentation of results was done in the manner described earlier.

Rezultati dobiveni sa jedinjenjima opisanim ovim pronalaskom kao i sa dva jedinjenja današnje prakse prikazani su u tabelama 1 i 2.The results obtained with the compounds described in this invention as well as with the two compounds of present practice are shown in Tables 1 and 2.

»e» gabela l» Dejstvo piri&l»~makleegida protiv sarkoma 180 kod njišerm o»E» gabel l »The effect of pyri & l» ~ macleegide against sarcoma 180 in nishermo o

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1,56 la gl Dejstvo pirmidia-nukloosida protlv BAihnvog karoinaaa kod mifleva1.56 la gl Effect of pyrmidia-nuclooside protlv BAihni karoinaaa in miflev

Jedinjenje The compound Dona χ β /mg/kg/ Dona χ β / mg / kg / Ispitivane ftivotinjo Tested ftivotinjo ·— 5S#· · - 5S # · 5 ’-Deoksi-5-fluon- 5 '-Doxy-5-fluon- 400 i.p. 400 i.p. 15 15 14 14 91 91 citidin cytidine 200 200 24 24 23 23 72 72 100 100 16 16 16 16 65 65 50 50 24 24 23 23 57 57 25 25 15 15 15 15 45 45 800 p. o* 800 p. o * 8 8 8 8 99 99 400 400 16 16 16 16 95 95 200 200 24 24 24 24 80 80 100 100 24 24 24 24 71 71 50 50 16 16 16 16 58 58 25 25 16 16 16 16 >7 > 7 5 *-Dec5csi-5-n.uo3>· 5 * -Dec5csi-5-n.uo3> · 400 i«pi 400 and «pi 16 16 14 14 98 98 urldin urldin 200 200 24 24 22 22 86 86 100 100 24 24 20 20 71 71 50 50 24 24 23 23 59 59 25 25 24 24 22 22 45 45 800 p, o. 800 p. 8 8 8 8 99 99 400 400 16 16 16 16 98 98 200 200 16 16 16 16 90 90 100 100 15 15 15 15 70 70 50 50 8 8 8 8 56 56 25 25 8 8 8 8 27 27 5’-De<fcelpIrldin 5'-De <fcelpIrldin 200 i.p. 200 i.p. 8 8 8 8 9 9 100 100 8 8 8 8 41 41 2\5M)ideok3i-5- 2 \ 5M) ideok3i-5- 400 I.p. 400 I.p. 16 16 14 14 81 81 fluoruridin fluororidine 200 200 16 16 14 14 68 68 100 100 16 16 16 16 >7 > 7 200 p.o. 200 p.o. 8 8 8 8 34 34

U Bledečim primerima dato je dobivanje polaznih materijala i dobivanje proizvoda prema pronalasku.The following examples give the starting materials and the product according to the invention.

PRIMER 1 > Suspenzija 2-fluorcitidina (92 g) i mono-hidrata p-toluolsulfonske kiseline (80 g) u acetonu (1500 ml) i 2,2čtimetoksipropana (200 ml) mešana je 2 sata na sobnoj temperaturi. Zatim se dodaje u višku čvrst natrij um bikarbonat i meša se do neutralisanja kiseline. Čvrst ostatak je ocedjen i opran acetonom, a filtrat i rastvor od pranja su upareni do suva. Ostatak se tretira vručim etil acetatom (700 ml) i po hladjenju pocinje lagano njegova kristalizacija. Posle stajanja preko noči vršeno je pranje čvrstog ostatka etil acetatom i sušenje u vakuumu. Prinos: 99,5 g (94 %) 2',3'-0izopropiliden-5-fluorcitidina. Jedan uzorak je prekristalisan iz smeše metanol/etil acetat; t.t. 182-184°C.EXAMPLE 1> A suspension of 2-fluorocytidine (92 g) and p-toluenesulfonic acid mono-hydrate (80 g) in acetone (1500 ml) and 2,2 µmethoxypropane (200 ml) was stirred for 2 hours at room temperature. Then solid sodium bicarbonate is added to the excess and stirred until acid is neutralized. The solid residue was filtered off and washed with acetone, and the filtrate and washing solution were evaporated to dryness. The residue was treated with hot ethyl acetate (700 ml) and, upon cooling, its crystallization began slowly. After standing overnight, the solid residue was washed with ethyl acetate and vacuum dried. Yield: 99.5 g (94%) of 2 ', 3'-0isopropylidene-5-fluorocytidine. One sample was recrystallized from methanol / ethyl acetate; m.p. 182-184 ° C.

Rastvor 2', 3'-0-izopropiliden-5-fluorcitidina (32 g) i metil-trifenoksi-fosfonijum jodida (MTPI,· 60 g) u dimetil formijatu (DMP, 300 ml osušen) ostavljen je da stoji 1 1/2 sata na sobnoj temperaturi. Onda se na to doda metanol (100 ml) i posle 30 minuta upari se smeša do uljane konzistencije.A solution of 2 ', 3'-O-isopropylidene-5-fluorocytidine (32 g) and methyl-triphenoxy-phosphonium iodide (MTPI, · 60 g) in dimethyl formate (DMP, 300 ml dried) was left standing 1 1/2 hours at room temperature. Then methanol (100 ml) was added and the mixture was evaporated to oil consistency after 30 minutes.

Zatim se doda 700 ml etil acetata i 700 ml 5 % vodenog rastvora natrij um tiosulfata i posle mučkanja ostavi se da se slojevi razdvoje. Etil acetatni sloj se pere jednom sa vodenim rastvorom tiosulfata (700 ml) i dva puta sa vodom (700 ml) i upari do uljastog ostatka, koji se rastvori u vručem etil acetatu (400 ml). U vruči rastvor se dodaje do početka kristalizacije heksan. Posle stajanja na 0°C kristalni talog se opere sa heksanom i osuši u vakuumu. Posle obrade matičnog luga dobiveno je ukupno 30,1 g (69 %) 5 '-dezoksi-5'-jod-2', 3'-O-izopropiliden-5fluore itidina, t.t. 192-194°C.Then 700 ml of ethyl acetate and 700 ml of 5% aqueous sodium thiosulphate solution were added and after shaking, the layers were separated. The ethyl acetate layer was washed once with aqueous thiosulphate solution (700 ml) and twice with water (700 ml) and evaporated to an oily residue, which was dissolved in hot ethyl acetate (400 ml). Hexane was added to the hot solution until crystallization began. After standing at 0 ° C, the crystalline precipitate was washed with hexane and dried in vacuo. After treatment with the mother liquor, a total of 30.1 g (69%) of 5 '-deoxy-5'-iodo-2', 3'-O-isopropylidene-5fluore itidine were obtained, m.p. Mp 192-194 ° C.

Rastvor 5 '-dezoksi-5 '-j od-2 ', 3-'-0-izopropiliden-5” fluore it id ina (48 g) u metanolu (500 ml) i trietilaminu (20 ml) hidrogenovan je na sobnoj temperaturi i pod normalnim pritiskom 30 minuta u prisustvu paladij uma na uglju (5 %, 25 g) uz stalno mešanje. Katalizator je uklonjen cedjenjem preko Celite-a® filtrat je uparen do suva i na ostatak je dodat etil acetat (200'ml). Ostavljeno je da stoji preko noči pa su kristali ocedjeni, filtrat je uparen na oko 100 ml i još jednom ostavljen da stoji preko noči. Ponovno obrazovani kristali su ocedjeni, a filtrat je u vakuumu uparen do suva. Dobiveno je 31 g (93 %) 5*-dezoksi-23'-0-izopropiliden-5-fluorcitidina * u obliku pene. Ova supstanca okarakterisana je obrezovanjem kristalnog pikrata, t.t. 168-17O°C.A solution of 5 '-deoxy-5' -j-2 ', 3 -'-O-isopropylidene-5 "fluorothio idine (48 g) in methanol (500 ml) and triethylamine (20 ml) was hydrogenated at room temperature and under normal pressure for 30 minutes in the presence of palladium-based coal (5%, 25 g) with constant stirring. The catalyst was removed by straining through Celite® the filtrate was evaporated to dryness and ethyl acetate (200'ml) was added to the residue. The crystals were allowed to stand overnight and the crystals were drained, the filtrate was evaporated to about 100 ml and left to stand again overnight. The recovered crystals were drained and the filtrate was evaporated to dryness in vacuo. 31 g (93%) of 5 * -deoxy-23'-O-isopropylidene-5-fluorocytidine * are obtained in the form of a foam. This substance is characterized by cropping crystalline picrate, m.p. Mp 168-17 ° C.

5'-dezoksi-2',3-2©-izopropiliden-5-fluorcitidin (31 g) tretiran je 40 minuta 90%-npm trifluorsirčetnom kiselinom (200 ml). Rastvor je uparen do suva, a ostatak je, da bi se uklonili voda i trifluorsirčetna kiselina, više puta uparavan sa etanolom i na kraju je rastvoren u etil acetatu (400 ml). Rastvor je zaalkalisan pomoči trietilamina i posle nekoliko minuta počinjala je kristalizacija. Posle stajanja preko noči kristali su oprani etil acetatom i osušeni u vakuumu. Dobiveno je 14 g (49 %) 5'-dezoksi-5-fluorcitidina. Dodatna količina dobivena je hromatografijom matičnog luga na koloni silikagela (600 g), pri čemu je eluiranje vršeno etil acetatom (4 1) kao i smešom etil acetat/metanol (5:1, ž/z 4 litra). Frakcije koje su bile interesantne uparh ne su do suva i puštene preko kolone od Dowex-a 5C^ (H⁺ - oblik 2.3 x 60 cm). Zatim je izvršeno pranje kolone, prvo vodom i na kraju amonijačnim rastvorom (IN). Amonijačne frakcije su uparene do suva i ostatak je prekristalisan iz metanola. Na taj način je dobiveno još 6,7 g 5'-dezousi5-fluoreitidina. Ukupan prinos: 20,7 g (78 %); t.t. 209-211°C.5'-deoxy-2 ', 3-2 N -isopropylidene-5-fluorocytidine (31 g) was treated with 40% trifluoroacetic acid (200 ml) for 40 minutes. The solution was evaporated to dryness and the residue was repeatedly evaporated with ethanol to remove water and trifluoroacetic acid and finally dissolved in ethyl acetate (400 ml). The solution was calcined using triethylamine and crystallization began after a few minutes. After standing overnight, the crystals were washed with ethyl acetate and dried in vacuo. 14 g (49%) of 5'-deoxy-5-fluorocytidine are obtained. An additional amount was obtained by chromatography on mother liquor on a silica gel column (600 g), eluting with ethyl acetate (4 L) and ethyl acetate / methanol mixture (5: 1, w / z 4 liters). The fractions of interest uparch were not dry and released over a Dowex 5C ^ column (H ⁺ - shape 2.3 x 60 cm). The column was then washed, first with water and finally with ammonia solution (IN). The ammonia fractions were evaporated to dryness and the residue was recrystallized from methanol. In this way another 6.7 g of 5'-desousi5-fluoroitidine is obtained. Total Yield: 20.7 g (78%); mp 209-211 ° C.

10.10.

PRIMER 2EXAMPLE 2

Suspenzija 5-fluoruridina (50 g) i monohidrata p-toluolsulfonske kiseline. (39,3 g) u acetonu (750 ml) i 2,2-dimetoksi propana (94 ml) mepana je na sobnoj temperaturi 50 minuta.Suspension of 5-fluorouridine (50 g) and p-toluenesulfonic acid monohydrate. (39.3 g) in acetone (750 ml) and 2,2-dimethoxy propane (94 ml) was stirred at room temperature for 50 minutes.

U bistar rastvor dodat je višak čvrstog natrij um bikarbonata i smesa je toliko dugo mešana sve dok nije reagovala neutralno. Čvrst ostatak je uklonjen cedjenjem, opran je acetonom, a filtrat je uparen do suva. Čvrst ostatak je prekristalisan iz etil acetata (2 1) i dobiveno je 48 g (83 %) 2',3'-0-izopropiliden-5-fluoruridina, t.t. 196-197°C.An excess of solid sodium bicarbonate of sodium was added to the clear solution and the mixture was stirred until it reacted neutrally. The solid residue was removed by filtration, washed with acetone and the filtrate evaporated to dryness. The solid was recrystallized from ethyl acetate (2 L) to give 48 g (83%) of 2 ', 3'-O-isopropylidene-5-fluororidine, m.p. Mp 196-197 ° C.

Rastvor 2',3'-0-izopropiliden-5-fluoruridina (46,4 g) u DMP-u (250 ml suvog) držan je na sobnoj temperaturi 50 minuta u kontaktu sa MTPI (86,7 g). Dodat je zatim etanol (200 ml) i pošle 30 minuta rastvor je uparen, a uljasti ostatak je raspodeljen izmedju etil acetata ( 1 1) i vodenog rastvora natri« j um tiosulfata (5 %, 11). Etil acetatni sloj je opran dva puta sa po 1 1 vode, osušen natrij um sulfatom i uparen do suva.A solution of 2 ', 3'-O-isopropylidene-5-fluorouridine (46.4 g) in DMP (250 ml dry) was kept at room temperature for 50 minutes in contact with MTPI (86.7 g). Ethanol (200 ml) was then added and after 30 minutes the solution was evaporated and the oily residue was partitioned between ethyl acetate (1 L) and aqueous sodium thiosulphate (5%, 11). The ethyl acetate layer was washed twice with 1 l of water each, dried with sodium sulfate and evaporated to dryness.

Uljasti ostatak iskristalisao je iz etil acetata (350 ml). Dobiveno je 52,9 g (85 %) 5 '-d.ezoksi-5^z-jod-2 ,3^z-0-izopropiliden-5-fluoruridina, t.t. 202-203,5°C.The oily residue was crystallized from ethyl acetate (350 ml). 52.9 g (85%) of 5 '-isoxy-5 ^with- iodo-2,3, ^with -O-isopropylidene-5-fluorouridine, mp 202-203.5 ° C, are obtained.

Rastvor 5 ^z-dezoksi-5 ^z-j od-2 ”, 3'-O-izopropiliden-5-fluoruridina (24 g) u metanolu (800 ml) i trietilaminu (15 ml) hidrogenovan je 90 minuta na sobnoj temperaturi pod normalnim pritiskom, uz stalno mešanje u prisustvu paladij uiqa na uglju (12 g,A solution of 5 ^with -dezoksi-5 ^with the -j-2 ', 3'-O-isopropylidene-5-fluoruridina (24 g) in methanol (800 ml) and triethylamine (15 ml) hidrogenovan 90 minutes at room temperature under normal pressing, with constant stirring in the presence of palladium uiq on coal (12 g,

%). Katalizator je ocedjen preko Celite-a^i opran metanolom, dok je filtrat uparen do suva a na ostatak je dodato 200 ml etil acetata i ostavljeno da stoji 1 sat. Kristalni talog je uklonjen cedjenjem, filtrat je uparen na polovinu i ostavljen da stoji preko noči i još jednom procedjen. Dobiveni filtrat je uparen u vakuumu do suva i dobiven je na ovaj način 5'-dezoksi-2', 3 '-0-izopropiliden-5-fluoruridin /UV (CH^OH):%). The catalyst was filtered off through Celite and washed with methanol, while the filtrate was evaporated to dryness and 200 ml of ethyl acetate were added to the residue and left to stand for 1 hour. The crystalline precipitate was removed by filtration, the filtrate was evaporated in half and allowed to stand overnight and once again treated. The resulting filtrate was evaporated to dryness in vacuo to give 5'-deoxy-2 ', 3' -O-isopropylidene-5-fluororidine / UV (CH 2 OH):

204 nm (£ 10900) i 267 nm (£ 8670). IR (KBr): 3380, 3200, 1710, 1670 cm”¹/, na koji se delovalo još 1 sat vodenim rastvorom trifluor/sirčetne kiseline (90 %, 200 ml). Proizvod je uparen do suva i da bi se uklonila voda i trifluorsirčetna204 nm (£ 10,900) and 267 nm (£ 8670). IR (KBr): 3380, 3200, 1710, 1670 cm ^"1 /, the blade being operated Still 1 hour an aqueous solution of trifluoro / acetic acid (90%, 200 ml). The product was evaporated to dryness to remove water and trifluoroacetic

11.11.

kiselina, više puta je dodavan etanol i rastvor ponovo upara Han a ostatak je iskristalisao iz etil acetata. Dobiveno jeacid, ethanol was added repeatedly and the solution was evaporated again with Han and the residue was crystallized from ethyl acetate. It was obtained

11,35 g 5'-dezoksi-5-fluoruridina, t.t. 189-190°C.11.35 g of 5'-deoxy-5-fluororidine, m.p. Mp 189-190 ° C.

Dos. 9047/168 P-3022/77 9.07.1985Dos. 9047/168 P-3022/77 9/07/1985

12NAJBOUI PODNOSIOCU PRIJAVE POZNAT NAČIN ZA PRIVREDNU UPOTREBU PRIJAVLJENOG PRONALASKA . Suspenzija 2-fluorcitidina (92 g) i mono-hidrata p-toluolsulfonske kiseline (80 g) u acetonu (1500 ml) i 2,2dimetoksipropana (200 ml) mešana je 2 sata na sobnoj temperaturi. Zatim se dodaje u višku čvrst natrijum bikarbonat i meša se do neutralisanja kiseline. Čvrst ostatak je ocedjen i opran acetonom, a filtrat i rastvor od pranja su upareni do suva. Ostatak se tretira vručim etil acetatom (700 ml) i po hladjenju počinje lagano njegova kristalizacija. Posle stajanja preko noči vršeno je pranje čvrstog ostatka etil acetatom i sušenje u vakuumu. Prinos: 99,5 g (94 %) 2',3'-0izopropiliden-5-fluorcitidina. Jedan uzorak je prekristalisan iz smeše metanol/etil acetat’; t.t. 182-184°C.12NOWBOWS AND THE APPLICANT KNOWS A WAY FOR THE ECONOMIC USE OF THE APPLICATION FOUND. A suspension of 2-fluorocytidine (92 g) and p-toluenesulfonic acid mono-hydrate (80 g) in acetone (1500 ml) and 2,2dimethoxypropane (200 ml) was stirred for 2 hours at room temperature. Solid sodium bicarbonate is then added to the excess and stirred to neutralize the acid. The solid residue was filtered off and washed with acetone, and the filtrate and washing solution were evaporated to dryness. The residue was treated with hot ethyl acetate (700 ml) and crystallized slightly after cooling. After standing overnight, the solid residue was washed with ethyl acetate and vacuum dried. Yield: 99.5 g (94%) of 2 ', 3'-0isopropylidene-5-fluorocytidine. One sample was recrystallized from methanol / ethyl acetate '; m.p. 182-184 ° C.

Rastvor 2', 3 '-O-izopropiliden-5-fluorcitidina (32 g) i metil-trifenoksi-fosfonij um jodida (MTPI, 60 g) u dimetil formijatu (DMP, 300 ml osušen) ostavljen je da stoji 1 1/2 sata na sobnoj temperaturi. Onda se na to doda metanol (100 ml) i posle 30 minuta upari se smeša do uljane konzistencije.A solution of 2 ', 3' -O-isopropylidene-5-fluorocytidine (32 g) and methyl-triphenoxy-phosphonium um iodide (MTPI, 60 g) in dimethyl formate (DMP, 300 ml dried) was allowed to stand 1 1/2 hours at room temperature. Then methanol (100 ml) was added and the mixture was evaporated to oil consistency after 30 minutes.

Zatim se doda 700 ml etil acetata i 700 ml 5 % vodenog rastvora natrijum tiosulfata i posle mučkanja ostavi se da se slojevi razdvoje. Etil acetatni sloj se pere jednom sa vodenim rastvorom tiosulfata (700 ml) i dva puta sa vodom (700 ml) i upari do uljastog ostatka, koji se rastvori u vručem etil acetatu (400 ml). U vruči rastvor se dodaje do početka kristalizacije heksan. Posle stajanja na 0°C kristalni talog se opere sa heksanom i osuši u vakuumu. Posle obrade matičnog luga dobiveno je ukupno 3θ,1 g (69 %) 5 '-dezoksi-5'-jod-2', 3'-0-izopropiliden-5fluorcitidina, t.t. 192-194°C.Then 700 ml of ethyl acetate and 700 ml of 5% aqueous sodium thiosulphate were added and, after shaking, the layers were separated. The ethyl acetate layer was washed once with aqueous thiosulphate solution (700 ml) and twice with water (700 ml) and evaporated to an oily residue, which was dissolved in hot ethyl acetate (400 ml). Hexane was added to the hot solution until crystallization began. After standing at 0 ° C, the crystalline precipitate was washed with hexane and dried in vacuo. After treatment with mother liquor, a total of 3θ, 1 g (69%) of 5 '-deoxy-5'-iodo-2', 3'-0-isopropylidene-5fluorocytidine were obtained, m.p. Mp 192-194 ° C.

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BEOGRAD — TAKOVSKi 1 j Telefon 339-442BELGRADE - TAKOVSKI 1 j Phone 339-442

Rastvor 5'-dezoksi-5'-j od-2', 3-'-0-izopropiliden-5fluorcitidina (48 g) u metanolu (500 ml) i trietilaminu (20 ml) hidrogenovan je na sobnoj temperaturi i pod normalnim pritiskom 30 minuta u prisustvu paladij uma na uglju (5 %, 25 g) uz stalno mešanje. Katalizator je uklonjen cedjenjem preko Celiteia®, filtrat je uparen do suva i na ostatak je dodat etil acetat (200 ml). Ostavljeno je da stoji preko noči pa su kristali ocedjeni, filtrat je uparen na oko 100 ml i još jednom ostavljen da stoji preko noči. Ponovno obrazovani kristali su ocedjeni, a filtrat je u vakuumu uparen do suva. Dobiveno je 31 g (93 %) 5'-dezoksi-2',3'-O-izopropiliden-5-fluorcitidina u obliku pene. Ova supstanca okarakterisana je obrazovanjem kristalnog pikrata, t.t. 168-170°C.A solution of 5'-deoxy-5'-of-2 ', 3 -'-0-isopropylidene-5fluorocytidine (48 g) in methanol (500 ml) and triethylamine (20 ml) was hydrogenated at room temperature and under normal pressure 30 minutes in the presence of palladium mind on coal (5%, 25 g) with constant stirring. The catalyst was removed by filtration through Celiteia®, the filtrate was evaporated to dryness and ethyl acetate (200 ml) was added to the residue. The crystals were allowed to stand overnight and the crystals were drained, the filtrate was evaporated to about 100 ml and left to stand again overnight. The recovered crystals were drained and the filtrate was evaporated to dryness in vacuo. 31 g (93%) of 5'-deoxy-2 ', 3'-O-isopropylidene-5-fluorocytidine are obtained as a foam. This substance is characterized by the formation of crystalline picrate, m.p. Mp 168-170 ° C.

5'-dezoksi-23-£©-izopropiliden-5-fluorcitidin (31 g) tretiran je 40 minuta 90%-ηοφ trifluorsirčetnom kiselinom (200 ml). Rastvor je uparen do suva, a ostatak je, da bi se uklonili voda i trifluorsirčetna kiselina, više puta uparavan sa etanolom i na kraju je rastvoren u etil acetatu (400 ml). Rastvor je zaalkalisan pomoči trietilamina i posle nekoliko minuta počinjala je kristalizacija. Posle stajanja preko noči kristali su oprani etil acetatom i osušeni u vakuumu. Dobiveno je 14 g (49 %) 5'-dezoksi-5-fluorcitidina. Dodatna količina dobivena je hromatografijom matičnog luga na koloni silikagela (600 g), pri čemu je eluiranje vršeno etil acetatom (4 1) kao i smešom etil acetat/metanol (5:1, z/z 4 litra). Frakcije koje su bile interesantne uparefae su do suva i puštene preko kolone od Dowex-a 5C^ (H⁺ - oblik 2.3 x 60 cm). Zatim je izvršeno pranje kolone, prvo vodom i na kraju amonijačnim rastvorom (IN). Amonijačne frakcije bu uparene do suva i ostatak je prekristalisan iz metanola. Na taj način je dobiveno još 6,7 g 5'-dezoksi5-fluorcitidina. Ukupan prinos: 20,7 g (78 %); t.t. 209-211°C.5'-deoxy-23-S-isopropylidene-5-fluorocytidine (31 g) was treated with 90% trifluoroacetic acid (200 ml) for 40 minutes. The solution was evaporated to dryness and the residue was repeatedly evaporated with ethanol to remove water and trifluoroacetic acid and finally dissolved in ethyl acetate (400 ml). The solution was calcined using triethylamine and crystallization began after a few minutes. After standing overnight, the crystals were washed with ethyl acetate and dried in vacuo. 14 g (49%) of 5'-deoxy-5-fluorocytidine are obtained. An additional amount was obtained by chromatography on mother liquor on a silica gel column (600 g), eluting with ethyl acetate (4 L) and ethyl acetate / methanol mixture (5: 1, z / z 4 liters). The fractions of interest were evaporated to dryness and released over a column of Dowex 5C ^ (H ⁺ - shape 2.3 x 60 cm). The column was then washed, first with water and finally with ammonia solution (IN). The ammonia fractions were evaporated to dryness and the residue was recrystallized from methanol. An additional 6.7 g of 5'-deoxy5-fluorocytidine is thus obtained. Total Yield: 20.7 g (78%); mp 209-211 ° C.

Na analogan način dobiva se i 5'-dezoksi-5-fluoruridin.5'-deoxy-5-fluorouridine is also obtained in an analogous manner.

Claims (1)

1. Postanek za dobivanje 5'-dežoksi-5-fluorcitidina odnosno 5'-dezoksi-5-fluoruridina kao i njihovih fiziološki podnosljivih ačicionih soli sa kiselinama, naznačen time, što se 5'-dezoksi-2', 3'-0-izopropiliden-5-fluorcitidin iii 5*-dezoksi-2', 3'’-0-izopropiliden-5-fluoruridin hidrolizuju sa 90 %-nom trifluor sirčetnom kiselinom na sobnoj temperaturi., i po potrebi dobiveni 5^r-dezoksi-5-fluorcitidin, odnsaaBO 5'’-dezoksi-5-fluoruridin tretiraju sa fizio loški podnošljjlvom kiselinom.A process for the preparation of 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluororidine as well as their physiologically acceptable acid addition salts, wherein 5'-deoxy-2 ', 3'-0- isopropylidene-5-fluorcitidin iii 5 * -dezoksi-2 ', 3''- 0-isopropylidene-5-fluoruridin hidrolizuju with 90% -nom trifluoro acetic acid at room temperature., and, if necessary, obtained was 5 ^r -dezoksi-5- fluorocytidine, or BO 5 '' - deoxy-5-fluorouridine is treated with physiologically acceptable acid.