CS231237B1 - Processing method of 9-+lrs+p-+l2,3-dihydroxypropyl+p-8-hydroxyadenine - Google Patents
Processing method of 9-+lrs+p-+l2,3-dihydroxypropyl+p-8-hydroxyadenine Download PDFInfo
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- 238000003672 processing method Methods 0.000 title 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 101150065749 Churc1 gene Proteins 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 2
- 102100038239 Protein Churchill Human genes 0.000 claims description 2
- 238000011033 desalting Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- RGKBRPAAQSHTED-UHFFFAOYSA-N 8-oxoadenine Chemical class NC1=NC=NC2=C1NC(=O)N2 RGKBRPAAQSHTED-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product 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
- 239000000706 filtrate Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 1
- 101710133389 POU domain, class 3, transcription factor 4 Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Description
Látka vzorce I je klíčovou výchozí surovinou pro přípravu 9-(RS)-(3-aminoalkylamino-2-hydroxypropyl)-8-hydroxyadenihu čs. autorské osvědčení 231 238, která se používají jako ligandy pro afinitní nosiče při čistění S-adenosyl-L-homocystehydrolasy čs. autor, osvědčení 231 239.The compound of formula (I) is a key starting material for the preparation of 9- (RS) - (3-aminoalkylamino-2-hydroxypropyl) -8-hydroxyadenium es. No. 231 238, which are used as ligands for affinity carriers in the purification of S-adenosyl-L-homocystehydrolases. author, certificate 231 239.
Dosavadní popsaná příprava látky vzorce I spočívá v reakci 9-(RS)-3,3-diacetoxypropyl)-N^-acetyl-8-bromadeninu s bezvodým ootanem sodným a následující alkalickou hydrolýzou vzniklého meziproduktu. Tento postup vyžaduje předchozí přípravu výchozí sloučeniny třístupňovou syntézou, reakce probíhá s poměrně malým výtěžkem a isolace čisté látky vzorce I je obtížná (Holý A.: Coll. Czech. Chem. Communs £1, 3 103 /1978/).The preparation of the compound of the formula I described above consists in reacting 9- (RS) -3,3-diacetoxypropyl) -N-acetyl-8-bromoadenine with anhydrous sodium ootane followed by alkaline hydrolysis of the resulting intermediate. This procedure requires the preliminary preparation of the starting compound by a three-step synthesis, the reaction proceeds in relatively low yield, and the isolation of the pure compound of formula I is difficult (Holý A .: Coll. Czech. Chem. Communs £ 1,103 (1978)).
Tyto nevýhody odstraňuje předmětný vynález, jehož podstata je, že se 9-(RS)-(2,3-dihydroxypropyl)adenin vzorce IXThese disadvantages are overcome by the present invention, which is based on the fact that 9- (RS) - (2,3-dihydroxypropyl) adenine of the formula IX
CH2CHCH2OHCH 2 CHCH 2 OH
OH (II), míchá ve vojnám roztoku při teplotě 0 až 30 °C s 1 až 1,5 molárního ekvivalentu bromu, směs se odpaří za sníženého tlaku 0,1 až 2 kPa, odparek se ve vodném roztoku neutralizuje hydroxidem alkalickým na pH 6,9 až 7,1, výsledný 9-(RS)-(2,3-dihydroxypropyl)-8-bromedenin vzorce IIIOH (II), stirred in solution at 0 to 30 ° C with 1 to 1.5 molar equivalents of bromine, evaporated under reduced pressure (0.1 to 2 kPa), neutralized with an alkaline hydroxide to pH 6 in aqueous solution. , 9 to 7.1, the resulting 9- (RS) - (2,3-dihydroxypropyl) -8-bromoedenine of formula III
ch2chch2ohch 2 chch 2 oh
OH (III), se uvede do reakce se směsí acetonu, orthomravenčanu ethylnatého a dimethylformamidu v objemových poměrech 3:1:1 až 1:1:1, nebo acetonu, 2,2-dimethoxypropsnu a dimethylformamidu v objemových poměrech 3:1:1 až 1:1:1 při teplotě 20 až 30 °C a v přítomnosti 1,2 až 2 ekvivalentů bezvodé minerální kyseliny, v výhodou sírové nebo chlorovodíkové, směs se neutralizuje, zbaví rozpouštědel zo sníženého tlaku 0,1 až 2 kPa, získaný prodákt vzorce IVOH (III) is reacted with a mixture of acetone, ethyl orthoformate and dimethylformamide in a 3: 1: 1 to 1: 1: 1 by volume ratio, or acetone, 2,2-dimethoxypropene and dimethylformamide in a 3: 1: 1 by volume ratio to 1: 1: 1 at a temperature of 20 to 30 ° C and in the presence of 1.2 to 2 equivalents of anhydrous mineral acid, preferably sulfuric or hydrochloric, the mixture is neutralized, freed of solvents from the reduced pressure of 0.1 to 2 kPa, the product obtained of formula IV
NH2 \y- e, kir' im n (IV , o — oNH 2 \ y-e, k ir 'im n (IV, o-o
X h3c ch3 se zahřívá s roztokem 20 až ?0 ekvivalentů benzoxidu sodného v dimethylformamidu na teplotu 60 až 100 °C, směs se odpaří za sníženého tlaku 0,1 až 2 kPa, zpracuje roztokem vodné oi-ganieké nebo minerální kyseliny, s výhodou 5 až 10% kyseliny sírové při teplotách 20 až 100 °C a látka vzorce I se po odsolení isoluje krystalisací, s výhodou z vodného ethanolu.X h 3 c ch 3 is heated with a solution of 20 to 0 equivalents of sodium benzoxide in dimethylformamide to 60 to 100 ° C, the mixture is evaporated under reduced pressure (0.1 to 2 kPa), treated with a solution of aqueous oganoic or mineral acid, preferably 5 to 10% sulfuric acid at 20 to 100 ° C and the compound of formula I is isolated after desalting by crystallization, preferably from aqueous ethanol.
Podstatou uvedeného postupu je nová neočekávaná reakce θ-biyjederlvétu vzorce IV β benzoxidem sodným v dimethylformamidu, které poskytuje přímo derivát 8-hydroxyadeninu vzorce VThe essence of this process is a new unexpected reaction of the β-biyederide of formula IV with β sodium benzoxide in dimethylformamide, which directly provides the 8-hydroxyadenine derivative of formula V
XX
HjC CH3 který pak kyselou hydrolýzou uvolňuje aceton a látku vzorce I jako jediné reakční produkty. 9-(RS)-(2,3-Dihydroxypropyl)adenin vzorce II je dostupný několika syntetickými postupy z adeninu a derivátů glycerolu (A. Holý, Collect. Czech. Chem. Commun. 40.H 3 CH 3, which then liberates acetone and the compound of formula I as the only reaction products by acid hydrolysis. 9- (RS) - (2,3-Dihydroxypropyl) adenine of formula II is available by several synthetic procedures from adenine and glycerol derivatives (A. Holy, Collect. Czech. Chem. Commun. 40.
187 /1975/j Collect. Czech. Chem. Commun. 43. 3 103 /1978/; Collect. Czech. Chem. Commun. 43, 2 054 /1978/; čs. autorská osvědčení 191 656/.187 (1975) Collect. Czech. Chem. Commun. 43, 3 103 (1978); Collect. Czech. Chem. Commun. 43, 2054 (1978); čs. author certificates 191 656 /.
Tato látka se převede bromací ve vodě na 8-bromderivát vzorce III, který je málo rozpustný ve vodě a vyloučí se ve vysokém výtěžku a zcela čistý neutralizaci reakční směsi. Reakci s 2,2-dimethoxypropanem přímo nebo vznikajícím in šitu z acetonu a orthomravenčanu vznikne klíčový produkt reakce - látka vzorce IV.This material is converted by bromination in water to an 8-bromo derivative of formula III which is poorly soluble in water and is eliminated in high yield and completely pure neutralization of the reaction mixture. Reaction with 2,2-dimethoxypropane directly or formed in situ from acetone and orthoformate yields a key reaction product - a compound of formula IV.
Po provedení reakce látky vzorce IV s benzoxidem sodným se meziprodukt vzorce V snadno isoluje z odparku reakční směsi roztřepáním mezi vodu a chloroform, přičemž látka vzorce V přechází do vodné fáze a může být z jejího odparku čiětěna krystalizaci. Kyselou hydrolýzou pak dojde k odStěpení acetonu a vzniku produktu vzorce I bez dalších příměsí. Isolace látky vzorce V však není nutná; kyselou hydrolýzu lze provést přímo s odparkem surové létky V (po odstranění nadbytku benzylalkoholu např. extrakcí etherem): v tom případě látku vzorce I je možno zachytit na silně kyselý katex a po jeho promytí vodou eluovat produkt zředěný vodným roztokem amoniaku. Látka vzorce I se čistí nejlépe kystalizací z vodného ethanolu: je chromatograficky čistá a vykazuje ultrafialové spektrum typické pro -9-substituovaný 8-hydroxyadenin.After reaction of the compound of formula IV with sodium benzoxide, the intermediate of formula V is readily isolated from the residue of the reaction mixture by shaking between water and chloroform, whereby the compound of formula V passes into the aqueous phase and can be crystallized from its residue. Acidic hydrolysis then cleaves off the acetone and produces the product of formula I without further admixtures. However, isolation of the compound of formula V is not necessary; acid hydrolysis can be carried out directly with the evaporator of crude V (after removal of excess benzyl alcohol eg by extraction with ether): in this case the compound of formula I can be trapped on a strongly acidic cation exchanger and after washing with water elute the product diluted with aqueous ammonia solution. The compound of formula I is preferably purified by crystallization from aqueous ethanol: it is chromatographically pure and shows an ultraviolet spectrum typical of -9-substituted 8-hydroxyadenine.
Předmět vynálezu je v dalším doložen na příkladech provedení, aniž se tím jakkoliv omezuje.The invention is further illustrated by the following non-limiting examples.
Příklad 1Example 1
K roztoku 3 ml bromu v 500 ml vody se přidé 6,5 g 9-(RS)-(2,3-dihydroxypropyl)adeninu vzorce II, směs se míchá 20 h při teplotě 20 až 25 °C a odpaří při 2 kPa při 40 °C do sucha. Odparek se rozpustí ve 100 ml vody a za míchání se pH nastaví na pH-metru 2 mol.,“’ roztokem hydroxidu sodného (nebo draselného) na 7,0. Vyloučený produkt se odsaje, promyje vodou, ethanolem, etherem a vysuší ve vakuu. Získá se 7,3 g (81 %) světle žluté krystalické létky vzorce III, které netaje do 260 °C. UV-Spektrum (pH 2 a 12): 4max 267 nm ( í 19000). fro CgH10BrN5O2 (288,2) vypočteno: 33,34 % C, 3,50 % H, 24,31 % N, 27,75 % Br; nalezeno: 33,76 % C, 3,59 % H, 24,17 96 N, 27,38 % Br.To a solution of 3 ml of bromine in 500 ml of water is added 6.5 g of 9- (RS) - (2,3-dihydroxypropyl) adenine of formula II, the mixture is stirred for 20 h at 20-25 ° C and evaporated at 2 kPa at 40 ° C to dryness. The residue is dissolved in 100 ml of water and adjusted to pH 7.0 with sodium hydroxide (or potassium hydroxide) solution at pH 7.0 with stirring. The precipitated product is filtered off with suction, washed with water, ethanol, ether and dried in vacuo. 7.3 g (81%) of a pale yellow crystalline fly of formula III are obtained, which do not melt below 260 ° C. UV spectrum (pH 2 and 12): 4 max 267 nm (nm19000). for C 8 H 10 BrN 5 O 2 (288.2) calculated: 33.34% C, 3.50% H, 24.31% N, 27.75% Br; Found: C, 33.76; H, 3.59; N, 24.17; Br, 27.38.
Ke. směsi 20 g látky vzorce III, 150 ml acetonu, 50 ml dimethylformamidu a 50 ml orthomravenčanu ethylnatého se přidá 2 ml 6 mol.I-1 chlorovodíku v dimethylformamidu a směs se míchá 2 h při 20 až 25 °C, přidá se triethylamin do alkalické reakce a směs se odpaří při 40 °C/13 Pa. Odparek poskytne krystalizaci z vroucího 80% vodného ethanolu 19,8 g (86 %) látky vzorce IV. T.t. 195 až 196 °C. Pro C,,H,^BrN^Og (328,2) vypočteno: 40,25 % C,Ke. of a mixture of 20 g of a compound of formula III, 150 ml of acetone, 50 ml of dimethylformamide and 50 ml of ethyl orthoformate, 2 ml of 6 mol.l -1 hydrogen chloride in dimethylformamide are added and the mixture is stirred for 2 h at 20-25 ° C. of the reaction and the mixture was evaporated at 40 ° C / 13 Pa. The residue gives crystallization from boiling 80% aqueous ethanol 19.8 g (86%) of the compound of formula IV. Mp 195-196 ° C. For C 11 H 11 BrN 4 O 6 (328.2) calculated: 40.25% C,
4,30 % H, 24,36 % Br, 21,34 % N; nalezeno: 40,28 % C, 4,27 % H, 24,58 % Br, 21,64 % N.H, 4.30; Br, 24.36; N, 21.34; Found: C 40.28, H 4.27, Br 24.58, N 21.64.
K roztoku 5,2 ml benzylalkoholu v 60 ml dimethylformamidu se přidá 1,2 g hydridu sodné ho a směs se míchá 1 h při 70 °C pod chlorkalciovým uzávěrem. Pak se přidá 5 g látky IV a směs se míchá 4 h při 100 °C. Po odpaření při 40 °C/1 3 Pa se odparek zředí 200 ml chloroformu a extrahuje vodou (3x50 ml).To a solution of 5.2 ml of benzyl alcohol in 60 ml of dimethylformamide was added 1.2 g of sodium hydride, and the mixture was stirred at 70 ° C for 1 h under a chloro-calcium cap. 5 g of IV are then added and the mixture is stirred for 4 h at 100 ° C. After evaporation at 40 ° C / 1 Pa, the residue was diluted with 200 ml of chloroform and extracted with water (3x50 ml).
Vodný roztok se neutralizuje kyselinou chlorovodíkovou, odpaří při 2 kPa dosucha a odparek extrahuje za horka vroucím chloroformem (celkem 500 ml). Tento extrakt se odpaří ve vakuu a látka vzorce V se získá krystalizaci odparku z ethanolu (ether do zákalu).The aqueous solution was neutralized with hydrochloric acid, evaporated to dryness at 20 mbar, and extracted with hot boiling chloroform (total 500 ml). This extract was evaporated in vacuo and the compound of formula V was obtained by crystallizing the residue from ethanol (ether to turbidity).
Získá se 1,8 g (45 %) látky vzorce V o t.t. 251 až 252 °C. UV-Spektrum (pH 7): A 271 nm, (ph 2):Amfly 271, 284 nm; (ph 12):4^ 281 nm.1.8 g (45%) of (V) of m.p. 251-252 ° C are obtained. UV spectrum (pH 7): λ 271 nm, (ph 2): λ mfly 271, 284 nm; (ph 12): 4? 281 nm.
Roztok 5 g látky vzorce V ve 150 ml 0,25 mol.,”’ kyseliny sírové se zahřívá 3 h na 70 °C, neutralizuje rotokem hydroxidu barnatého a zahřeje k varu. Horký roztok se filtruje přes křemelinu a sraženina promyje vroucí vodou (500 ml). Filtrát se odpaří při 40 °C/2 kPa a odparek se krystaluje z 80% vodného ethanolu (ether do zákalu). Získá se 2,6 g (79 %) látky vzorce I, t.t. 229 až 230 °C (monohydrát). Hmotové spektrum: M+ 225. Pro ΟθΗ^Ν^Ο^ (225,2) vypočteno: 42,66 % C, 4,92 % H, 31,10 % N; nalezeno 42,71 % C; 4,81 % H,A solution of 5 g of the compound of formula V in 150 ml of 0.25 mole of sulfuric acid is heated at 70 ° C for 3 hours, neutralized with barium hydroxide solution and heated to boiling. Filter the hot solution through Celite and wash the precipitate with boiling water (500 mL). The filtrate was evaporated at 40 ° C / 2 kPa and the residue was crystallized from 80% aqueous ethanol (ether to turbidity). 2.6 g (79%) of the compound of formula I are obtained, mp 229-230 ° C (monohydrate). Mass spectrum: M + 225. Calculated: C, 42.66; H, 4.92; N, 31.10. found: 42.71% C; 4.81% H,
31,18 % N.31.18% N.
Příklad 2Example 2
Příprava látky vzorce III je stejná jako v příkladě 1. K látce vzorce III v množství 20 g se přidá 150 ml acetonu, 50 ml dimethylformamidu, 50 ml' 2,2-dimethoxypropanu a 2 ml 6 mol.1 chlorovodíku v dimethylformamidu. Směs se míchá 24 h při 20 až 25 °C a zpracuje stejně jako je uvedeno v příkladu 1. Získá se 21 g (81 %} látky vzorce XV, shodná s produktem podle příkladu 1.The preparation of the compound of formula III is the same as in Example 1. To the compound of formula III in an amount of 20 g is added 150 ml of acetone, 50 ml of dimethylformamide, 50 ml of 2,2-dimethoxypropane and 2 ml of 6 mol of hydrogen chloride in dimethylformamide. The mixture was stirred at 20-25 ° C for 24 h and worked up as in Example 1. 21 g (81%) of the compound of formula XV, identical to the product of Example 1, were obtained.
Příklad 3Example 3
Reakce se provede shodně jako je uvedeno v příkladu 1. Po provedení reakce látky vzorce IV s benzylalkoholem a hydridem sodným v dimethylformamidu se extrakce chloroformem za horka neprovádí, ale po odpaření rozpouštědla při 40 °C/13 Pa se odparek zahřívá v 200 ml 0,5 mol.1’ kyseliny sírové 3 h na 70 °C, neutralizuje se za horka roztokem hydroxidu barnatého, filtruje za horka, promyje vodou a filtrát se odpaří pří 2 kPa dosucha. Zbytek v 100 ml vody se nanese na sloupec 150 ml Dowexu 50x8 (v H+-cyklu). Sloupec se pak promyje vodou (1 litr) a nakonec eluuje 2,5% vodným amoniakem. Jímá se UV-absorbujícf eluát, který se odpaří při 2 kPa a odparek krystaluje z 80% vodného ethanolu. Získá se 2,5 (69 %) látky I vlastností shodných s preparátem podle příkladu 1.The reaction is carried out as described in Example 1. After reaction of the compound of formula IV with benzyl alcohol and sodium hydride in dimethylformamide, hot chloroform extraction is not carried out but after evaporation of the solvent at 40 ° C / 13 Pa the residue is heated in 200 ml. 5 mol / l sulfuric acid for 3 h at 70 ° C, neutralized with hot barium hydroxide solution, hot filtered, washed with water and the filtrate evaporated to dryness at 2 kPa. The residue in 100 ml of water was applied to a 150 ml column of Dowex 50x8 (in the H + -cycle). The column was then washed with water (1 L) and finally eluted with 2.5% aqueous ammonia. The UV-absorbing eluate was collected and evaporated at 20 mbar and the residue crystallized from 80% aqueous ethanol. 2.5 (69%) of Compound I with the properties of Example 1 were obtained.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS891882A CS231237B1 (en) | 1982-12-09 | 1982-12-09 | Processing method of 9-+lrs+p-+l2,3-dihydroxypropyl+p-8-hydroxyadenine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS891882A CS231237B1 (en) | 1982-12-09 | 1982-12-09 | Processing method of 9-+lrs+p-+l2,3-dihydroxypropyl+p-8-hydroxyadenine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS231237B1 true CS231237B1 (en) | 1984-10-15 |
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ID=5440411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS891882A CS231237B1 (en) | 1982-12-09 | 1982-12-09 | Processing method of 9-+lrs+p-+l2,3-dihydroxypropyl+p-8-hydroxyadenine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS231237B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0882727A4 (en) * | 1996-07-03 | 2000-01-26 | Japan Energy Corp | NEW PURINE DERIVATIVES |
-
1982
- 1982-12-09 CS CS891882A patent/CS231237B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0882727A4 (en) * | 1996-07-03 | 2000-01-26 | Japan Energy Corp | NEW PURINE DERIVATIVES |
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