CS269077B1 - Method of 5-azacytosines preparation - Google Patents
Method of 5-azacytosines preparation Download PDFInfo
- Publication number
- CS269077B1 CS269077B1 CS877087A CS708787A CS269077B1 CS 269077 B1 CS269077 B1 CS 269077B1 CS 877087 A CS877087 A CS 877087A CS 708787 A CS708787 A CS 708787A CS 269077 B1 CS269077 B1 CS 269077B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- alkyl
- formula
- carbon atoms
- dimethylformamide
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 11
- MFEFTTYGMZOIKO-UHFFFAOYSA-N 5-azacytosine Chemical class NC1=NC=NC(=O)N1 MFEFTTYGMZOIKO-UHFFFAOYSA-N 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000000354 decomposition reaction Methods 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- -1 amylammonium urea Chemical compound 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- ZBKCUYOBOGCDKC-UHFFFAOYSA-N 2-amino-6-phenyl-1h-1,3,5-triazin-4-one Chemical compound N1C(N)=NC(=O)N=C1C1=CC=CC=C1 ZBKCUYOBOGCDKC-UHFFFAOYSA-N 0.000 claims description 2
- IFVXVYPDZQJILI-UHFFFAOYSA-N diaminomethylideneurea;hydrochloride Chemical compound [Cl-].NC(N)=[NH+]C(N)=O IFVXVYPDZQJILI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- BQFPCTXLBRVFJL-UHFFFAOYSA-N triethoxymethylbenzene Chemical compound CCOC(OCC)(OCC)C1=CC=CC=C1 BQFPCTXLBRVFJL-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- SQSPRWMERUQXNE-UHFFFAOYSA-N Guanylurea Chemical class NC(=N)NC(N)=O SQSPRWMERUQXNE-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 230000001262 anti-secretory effect Effects 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 5
- UUTHDVPZNWJUFV-UHFFFAOYSA-N 2-amino-6-methyl-1h-1,3,5-triazin-4-one Chemical compound CC1=NC(=O)N=C(N)N1 UUTHDVPZNWJUFV-UHFFFAOYSA-N 0.000 description 3
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical class C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical class NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- VBWWCYYBZFKCEX-UHFFFAOYSA-N 6-amino-1h-1,3,5-triazine-2-thione Chemical class NC1=NC=NC(=S)N1 VBWWCYYBZFKCEX-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- XHQYBDSXTDXSHY-UHFFFAOYSA-N Semicarbazide hydrochloride Chemical compound Cl.NNC(N)=O XHQYBDSXTDXSHY-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Resení spadá do oblasti výroby antisekretorických sloučenin. Způsob výroby dle řešení umožňuje výrobu velkých množství látky obecného vzorce I, kde R značí vodík, alkyl C. až Cg nebo fenyl, ve vysokých výtěžcích a ve velmi dobrá kvalitě. Způsob výroby dle řeěení spočívá v zahříváni solí amidinomočovin s estery orthokyselin v prostředí H,H-dialkylamidů.The solution is in the production area antisecretory compounds. Way production according to the solution allows the production of large the amount of the compound of formula I, wherein R is hydrogen, C to C 8 alkyl, or C 1 to C 8 alkyl phenyl, in high yields and very good quality. Method of production according to The solution consists in heating the amidinourea salts with orthoacid esters in the environment H, H-dialkylamides.
Description
CS 269 077 B1 1
Vynález se týká způsoby přípravy 5-azacytosinů, tj. 4-aaino-1,3,5-triazin-2(1H)-onůobecného vzorce I
H kde S značí vodík, alkyl s 1-6 atomy uhlíku nebo fenyl. Některá sloučeniny obecného vzorce 1 vykazují antisekretorické účinky u savců a zá-roveň výrazně snižují výskyt a rozsah žaludečních vředů v dávkách, které jsou pro orga-nismus netoxické. Tak samotný nesubstituovaný 5-azacytosin při dávce 30 mg/kg hmotnostizamezuje téměř na 100 % tvorbu experimentálních žaludečních vředů [čihák, Pískala, KorbováČížková, Kučerová: Experientia 42, 32 (1986)]'. Některé 6-aryl-5azacytosiny inhibují tvor-bu experimentálních žaludečních vředů na 41 až 86 %. [Hurai, Oochata, Aoyagi, Ueda: Jap.pat. vykl. spis č. 7 670 780 (1976); Chem. Abstr. 86, 29889 h (1977)]. 5-Azacytosin je ta-ké významným meziproduktem pro výrobu cytostaticky vysoce účinných 5-azacytosinových nu-klebsidů (5-azacytidin, 2"- deoxy-5-azacytidin a 1-y^-D-arabinoíUranosyl-5-azacytosin). 5-azacytosiny se dají připravit parciální hydrolýzou 2,4-diamino-l,3,5-triazinů, cy-klizací acylamidinomočovin, kondenzací kyanguanidinů s anhydridy kyselin, dále oxidací 2--amino-4-merkapto-1,3,5-triazinů nebo, reakcí acylurethanů s guanidinem (Smolin, Eapoport:s-Triazines and Derivatives, Xnterscience, New York 1959). 5-Azacytosiny se dají dále při-pravit amonolýzou 4-methoxy-1,3,5-triazin-2(1H)-onů [Pískala, Gut: Collect. Czech. Chem.Commun. 28, 1681, 1963)] nebo cyklokondensacemi amidinomočovin s různými deriváty karboxy-lových kyselin [ Pískala: Collect. Czech. Chem. Commun 32, 3966 (1967)]. Nejlepších výsled-ků bylo přitom dosaženo při použití dimethy-lacetalu dimethylformamidu nebo esterů ortho-kyselin. Vzhledem k vysoké ceně dimethylacetalů dimethylflormamidu a obtížné dostupnostidialkylacetalů jiných dialkylamidů je z výrobního hlediska výhodnější použití esterů ort-hokyselin, které jsou podstatně levnějěí a obecně dobře dostupné. Nevýhodou esterů ortho-kyselin je jejich nižěí reaktivita, což vyžaduje použití vySších teplot (okolo 150 °C). Jelikož volné amidinomočoviny jsou při uvedených teplotách nestálé, dochází ke vzniku vedlejSích produktů, což snižuje celkový výtěžek i kvalitu získávaných produktů.
Dalším studiem tohoto přístupu k přípravě 5-azacytosinů bylo zjištěno, že uvedené ne-dostatky se dají odstranit použitím solí amidinomočovin s minerálními nebo karboxylovýmikyselinami. Eeakce těchto solí s estery orthokyselin probíhá překvapivě snadno již při niž·ších teplotách, ve vysokých výtěžcích a získané produkty mají velmi dobrou kvalitu. Nej-lepší průběh měla reakce při použití Ν,Ν-dialkylamidů Jako rozpouštědel. Eeakce byla pro-váděna zahříváním na 100 až 120 °C (teplota lázně), avšak probíhá pomaleji i při nižšíchteplotách. K cyklokondenzacím bylo užíváno alkylesterů orthokyselin, s výhodou ethylesterůorthokyselin. Výhodou předloženého postupu dále je, že zde odpadá příprava volné amidino-močoviny a výchozí 30li amidinomočovin jsou snadno dostupné hydrolýzou velmi levného diky-andiamidu.
Podstata vynálezu způsobu přípravy 5-azacytosinů obecného vzorce I spočívá v tom, žese sůl amidinomočoviny obecného vzorce II nh2 nh2-co-n4-nh2.hk /11/,
kde X Je anion kyseliny halogenvodíkové nebo karboxylové kyseliny s 1 až 4 atomy uhlíku,uvede do reakce s esterem orthokyseliny obecného vzorce III CS 269 077 . zOB·1 B-C-OB1
OR
kde R značí totéž jako ye vzorci I a B1 je alkyl-dialkylamidu obecného vzorce IV A^ kde B je vodík nebo alkyl s 1 až 4 atomy uhlíku /ιη/, s 1 až 4 atomy uhlíku, 7 prostředí 5,5- /XV/, B^ je alkyl β 1 až 4 atomy uhlíku.
Jako výchozí látky se osvědčily dobře dostupné soli amidinomočovlny s kyselinou mra-venčí nebo chlorovodíkovou. Beakce měla rychlý průběh při zahřívání lázně na teplotu 100až 120 °O, pomalu věak probíhala již při teplotě místnosti. K cyklokondenzaci bylo s výho-dou používáno nadbytku ethylesterů orthokyselin. Jako rozpouštědla byl užíván s výhodou5,5-dimethylformamid nebo 5,5-dimethylacetamid. V jiných rozpouštědlech probíhala reakcepomalu. Pále je vynález blíže objasněn v příkladech provedení, aniž se na ně omezuje. Příklad 1 Příprava 5-azacytosinu
Směs 2,94 g mravenčenu amidinomočovlny, 20 ml orthomravenčanu ethylnatého a 30 ml 5,5--di-methylfoímamidu se zahřívá 1 h na 100 až 120 °C (teplota lázně). Po ochlazení se vylou-čený produkt odsaje, promyje methanolem a vysuší při 110 °C ve vakuu vodní vývěvy. Získáse 1,75 g (79 55) 5-azacytosinu; t. t. > 350 °C (rozklad); UV:^max0,15-K31 248 nm (log£3,80). Příklad 2
Směs 2,75 hydrochloridu amidinomočovlny, 20 ml orthomravenčanu ethylnatého a 30 ml 5,5--dimethylformamidu se zahřívá 1,5 h na 100 až 120 °C (teplota lázně). Po ochlazení se vylou-čený produkt odsaje a zpracuje jako v příkladu 1. Získá se 1,62 g (73 55) 5-azacytosinu,t. t. 37-350 °C (rozklad); nV:Amax0,1 5-H01 248 nm (log £ 3,80). Příklad 3 Příprava 6-methyl-5-azacytosinu
Směs 2,94 mravenčenu amidinomočovlny, 20 ml orthooctanu ethylnatého a 30 ml 5,5-dime-thylformamidu se zahřívá 30 min. na 100 až 120 °C (teplota lázně). Po ochlazení se vylou-čený produkt odsaje, promyje methanolem a vysuší při 110 °C ve vakuu vodní vývěvy. Získá se2,10 g (83 55) 6-methyl-5-azacytosinu; t. t. 3>350 °C (rozklad); UV:A_e_0,1 5-HC1 245 nm(loge 3,93). Přiklad 4 S použitím 2,75 g hydrochloridu amidinomočovlny se postupem podle příkladu 3 získá2,02 g (80 55) 6-methyl-5-azacytosinu t. t. 3P-350 °C (rozklad); ϋν:ΑΒαχ0,1 5-HC1 245 nm(log£ 3,93). Přiklad 5
Postupem podle příkladu 3 se za použití 5,5-dimethylacetamidu (30 ml) místo 5,5-dime-thylformamidu získá 2,15 g (85 55) 6-methyl-5-azacytoalnu; t. t. 37-350 °C (rozklad); UV:Amax0»' H-HC1 245 3,93). Příklad 6 Příprava 6-fenyl-5-azacytosinu
EN 269 077 B1 1
The invention relates to processes for the preparation of 5-azacytosines, i.e. 4-aaino-1,3,5-triazin-2 (1H) -one general formula I
H wherein S is hydrogen, alkyl of 1-6 carbon atoms or phenyl. Some compounds of Formula 1 exhibit antisecretory effects in mammals and, at the same time, greatly reduce the incidence and extent of gastric ulcers at non-toxic doses to the organism. Thus, the unsubstituted 5-azacytosine alone at 30 mg / kg weight is almost 100% free of experimental gastric ulcers [čihák, Pískala, Korbová Čížková, Kučerová: Experientia 42, 32 (1986)] '. Some 6-aryl-5azacytosins inhibit the formation of experimental gastric ulcers to 41-86%. [Hurai, Oochata, Aoyagi, Ueda: Jap.pat. vykl. No. 7,670,780 (1976); Chem. Abstr. 86, 29889 (1977)]. 5-Azacytosine is also an important intermediate for the production of cytostatically highly potent 5-azacytosine nuclsides (5-azacytidine, 2 "- deoxy-5-azacytidine and 1-γ-D-arabinourilosyl-5-azacytosine). azacytosines can be prepared by partial hydrolysis of 2,4-diamino-1,3,5-triazines, by cyclization of acylamidoureas, by condensation of cyanoguanidines with acid anhydrides, by oxidation of 2-amino-4-mercapto-1,3,5-triazines, or , by reacting acylurethanes with guanidine (Smolin, Eapoport: s-Triazines and Derivatives, Xnterscience, New York 1959) 5-Azacytosins can be further prepared by amonolysis of 4-methoxy-1,3,5-triazine-2 (1H) - Chem. Commun. 28, 1681, 1963] or by cyclo-condensation of amidinoureas with various carboxylic acid derivatives [Sanda: Collect. Czech. Chem. Commun 32, 3966 (1967)]. The results were obtained using dimethylformamide of dimethylformamide or ortho-acid esters. The use of orthoacid esters, which are considerably cheaper and generally readily available, is more advantageous from the manufacturing point of view for the dimethylformamide and the difficult availability of dialkyl acetals of other dialkylamides. A disadvantage of ortho-acid esters is their lower reactivity, which requires the use of higher temperatures (about 150 ° C). Since the free amidinoureas are unstable at these temperatures, byproducts are formed, which reduces the overall yield and quality of the products obtained.
By further studying this approach to the preparation of 5-azacytosines, it has been found that the abovementioned drawbacks can be avoided by the use of amidinourea salts with mineral or carboxylic acids. The reaction of these salts with orthoacid esters is surprisingly easy even at lower temperatures, in high yields and the products obtained are of very good quality. The best course of action was when using Ν, Ν-dialkylamides as solvents. The reaction was carried out by heating to 100-120 ° C (bath temperature) but slower even at lower temperatures. The orthoacid alkyl esters, preferably ethyl esters, were used for the cyclo-condensations. Furthermore, the advantage of the present process is that there is no need for the preparation of free amidinourea and the starting amine urea is readily available by hydrolysis of a very cheap di-andiamide.
The present invention relates to a process for the preparation of 5-azacytosines of the general formula (I), wherein the amidino urea salt of the formula (II) is nh2 nh2-co- n4-nh2.hk (11),
wherein X is an hydrohalic anion or a carboxylic acid having 1 to 4 carbon atoms, is reacted with an orthoacid ester of formula III CS 269 077. zOB · 1 BC-OB1
STEED
wherein R is the same as in formulas I and B1 is an alkyl dialkylamide of formula IV wherein B is hydrogen or alkyl of 1 to 4 carbon atoms (ηη), of 1 to 4 carbon atoms; B 1 is C 1 -C 4 alkyl.
The available amidineaurea salts with formic acid or hydrochloric acid have proven to be suitable starting materials. The reaction progressed rapidly while the bath was heated to 100-120 ° C, slowly running at room temperature. An excess of orthoacid ethyl esters was preferably used for cyclo-condensation. The solvent used is preferably 5,5-dimethylformamide or 5,5-dimethylacetamide. Other solvents were reacted slowly. The invention is further illustrated by the following non-limiting examples. Example 1 Preparation of 5-azacytosine
A mixture of 2.94 g of amidineaurea formate, 20 ml of ethyl orthoformate and 30 ml of 5,5-dimethylformamide was heated at 100-120 ° C (bath temperature) for 1 h. After cooling, the precipitated product is filtered off with suction, washed with methanol and dried at 110 ° C under a water pump vacuum. 1.75 g (79.55) of 5-azacytosine are obtained; mp> 350 ° C (decomposition); UV: max 0.15-K31 248 nm (log £ 3.80). Example 2
A mixture of 2.75 amidinourea hydrochloride, 20 ml of ethyl orthoformate and 30 ml of 5,5-dimethylformamide was heated at 100-120 ° C (bath temperature) for 1.5 h. After cooling, the precipitated product is filtered off with suction and worked up as in Example 1. 1.62 g (73.55) of 5-azacytosine are obtained, mp 37-350 ° C (decomposition); nV: Amax 0.15-H01 248 nm (log £ 3.80). Example 3 Preparation of 6-methyl-5-azacytosine
A mixture of 2.94 amidine urea formate, 20 ml ethyl orthoacetate and 30 ml 5,5-dimethylformamide was heated for 30 min. at 100-120 ° C (bath temperature). After cooling, the precipitated product is filtered off with suction, washed with methanol and dried at 110 ° C under a water pump vacuum. 2.10 g (83.55) of 6-methyl-5-azacytosine are obtained; mp 3> 350 ° C (decomposition); UV: _0e_0.1 5-HCl 245 nm (loge 3.93). EXAMPLE 4 Using 2.75 g of the amidourea hydrochloride hydrochloride, 2.02 g (80%) of 6-methyl-5-azacytosine (m.p. 3P-350 ° C (decomposition) was obtained by the procedure of Example 3; νν: ΑΒαχ0,1 5-HC1 245 nm (log £ 3.93). Example 5
Following the procedure of Example 3, using 5.5-dimethylacetamide (30 mL) instead of 5,5-dimethylformamide, 2.15 g (85.5%) of 6-methyl-5-azacytoaline is obtained; mp 37-350 ° C (decomposition); UV:? Max =? H-HCl 245 3.93). Example 6 Preparation of 6-phenyl-5-azacytosine
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS877087A CS269077B1 (en) | 1987-10-01 | 1987-10-01 | Method of 5-azacytosines preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS877087A CS269077B1 (en) | 1987-10-01 | 1987-10-01 | Method of 5-azacytosines preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS708787A1 CS708787A1 (en) | 1989-09-12 |
| CS269077B1 true CS269077B1 (en) | 1990-04-11 |
Family
ID=5419339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS877087A CS269077B1 (en) | 1987-10-01 | 1987-10-01 | Method of 5-azacytosines preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS269077B1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7135464B2 (en) | 2002-06-05 | 2006-11-14 | Supergen, Inc. | Method of administering decitabine |
| US7250416B2 (en) | 2005-03-11 | 2007-07-31 | Supergen, Inc. | Azacytosine analogs and derivatives |
| US7276228B2 (en) | 2001-04-24 | 2007-10-02 | Supergen, Inc. | Methods for treating hematological disorders through inhibition of DNA methylation and histone deacetylase |
| US7700567B2 (en) | 2005-09-29 | 2010-04-20 | Supergen, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US9381207B2 (en) | 2011-08-30 | 2016-07-05 | Astex Pharmaceuticals, Inc. | Drug formulations |
| US10485764B2 (en) | 2015-07-02 | 2019-11-26 | Otsuka Pharmaceutical Co., Ltd. | Lyophilized pharmaceutical compositions |
| US10519190B2 (en) | 2017-08-03 | 2019-12-31 | Otsuka Pharmaceutical Co., Ltd. | Drug compound and purification methods thereof |
-
1987
- 1987-10-01 CS CS877087A patent/CS269077B1/en unknown
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7276228B2 (en) | 2001-04-24 | 2007-10-02 | Supergen, Inc. | Methods for treating hematological disorders through inhibition of DNA methylation and histone deacetylase |
| US7135464B2 (en) | 2002-06-05 | 2006-11-14 | Supergen, Inc. | Method of administering decitabine |
| US7144873B2 (en) | 2002-06-05 | 2006-12-05 | Supergen, Inc. | Kit for delivering decitabine in vivo |
| US7250416B2 (en) | 2005-03-11 | 2007-07-31 | Supergen, Inc. | Azacytosine analogs and derivatives |
| US9358248B2 (en) | 2005-09-29 | 2016-06-07 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US8461123B2 (en) | 2005-09-29 | 2013-06-11 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US7700567B2 (en) | 2005-09-29 | 2010-04-20 | Supergen, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US9480698B2 (en) | 2005-09-29 | 2016-11-01 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US10456415B2 (en) | 2005-09-29 | 2019-10-29 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US10933079B2 (en) | 2005-09-29 | 2021-03-02 | Astex Pharmaceuticals, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US9381207B2 (en) | 2011-08-30 | 2016-07-05 | Astex Pharmaceuticals, Inc. | Drug formulations |
| US9913856B2 (en) | 2011-08-30 | 2018-03-13 | Astex Pharmaceuticals, Inc. | Drug formulations |
| US10517886B2 (en) | 2011-08-30 | 2019-12-31 | Astex Pharmaceuticals, Inc. | Drug formulations |
| US10485764B2 (en) | 2015-07-02 | 2019-11-26 | Otsuka Pharmaceutical Co., Ltd. | Lyophilized pharmaceutical compositions |
| US10519190B2 (en) | 2017-08-03 | 2019-12-31 | Otsuka Pharmaceutical Co., Ltd. | Drug compound and purification methods thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CS708787A1 (en) | 1989-09-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4175188A (en) | Process for the production of 1,2,4-triazin-5-one derivatives | |
| CS269077B1 (en) | Method of 5-azacytosines preparation | |
| US4824949A (en) | Process for the preparation of pyrimidines | |
| EP0427335B1 (en) | An aqueous process for the preparation of 5-methyl-N-(aryl)-1,2,4-triazolo (1,5-a)pyrimidine-2-sulfonamides | |
| PL163313B1 (en) | Method of obtaining derivatives of guanine | |
| EP0322401B1 (en) | Tetrahydrophthalimide derivatives, their production and use | |
| US3539569A (en) | Preparation of pyrazinoylguanidines from pyrazinoylureas | |
| Al‐Omran et al. | New routes to 1‐functionally substituted arylbenzotriazoles: 3‐Benzotriazol‐1‐yl‐pyridazine‐4‐ones, 5‐benzotriazol‐1‐yl‐pyridazine‐6‐ones and 5‐benzotriazol‐1‐yl‐pyridazine‐6‐imines | |
| EP0142718B1 (en) | Preparation of substituted and unsubstituted 2-((1-carbamoyl-1,2-dimethylpropyl)-carbamoyl)-3-quinolinecarboxylic, nicotinic and benzoic acids | |
| US4886881A (en) | Preparation of 2-amino triazines | |
| NL8800998A (en) | PROCESS FOR PREPARING AN SUBSTITUTION OR SUBSTITUTED 4 (5) - (OMEGA-AMINOALKYL) IMIDAZOLE. | |
| EP0231159B1 (en) | Indoloquinoxalines with substituents in 6-position containing cyclic groups | |
| US3357976A (en) | Mercury derivatives of certain as-triazine-5 (2h)-ones | |
| Russell et al. | The Reaction of Aromatic Nitriles with Guanidine1 | |
| US5393889A (en) | Water soluble bis-dioxopiperazine derivatives | |
| US3472847A (en) | Conversion of pyrazinoylcyanamides to pyrazinoylguanidines | |
| Khan et al. | Synthesis of isoxazolo [3, 4-b] pyridin-3 (1 H)-one and isoxazolo [5, 4-b]-pyridin-3 (2 H)-one | |
| Beresnev et al. | Interaction of 5-methoxy-1, 2, 4-triazines with ureas as a new route to 6-azapurines | |
| Solovyev et al. | Synthesis and oxidative aromatization of 5-acetyl-2-cyanoimino-6-methyl-4-phenyl-1, 2, 3, 4-tetrahydropyrimidine with manganese dioxide | |
| Chesniuk et al. | Derivatives of sym-triazine. 1. Synthesis and conversions of quaternary methylammonium salts of 2-chloro-4, 6-disubstituted 1, 3, 5-triazines in nucleophilic substitution reactions | |
| Kadry et al. | Studies on 5‐arylidene‐3‐phenyl‐2‐methylmercaptohydantoins | |
| US3198829A (en) | N, n' dicyanoamidines and methods of preparation | |
| AU754043B2 (en) | 3-(hydroxymethyl)chromen-4-ones and process for preparing | |
| CA1084501A (en) | Benzimidazo- 1,2-a -quinolines and process for their preparation | |
| Salih et al. | Pyrimidines, Part XXXI. Synthesis, reactions and properties of 6‐acyl‐1, 3‐dimethylpyrrolo [2, 3‐d] pyrimidine‐2, 4‐diones |