PL233191B1 - Method for obtaining 1,2,3-triazole derivatives of uracil - Google Patents
Method for obtaining 1,2,3-triazole derivatives of uracilInfo
- Publication number
- PL233191B1 PL233191B1 PL423449A PL42344917A PL233191B1 PL 233191 B1 PL233191 B1 PL 233191B1 PL 423449 A PL423449 A PL 423449A PL 42344917 A PL42344917 A PL 42344917A PL 233191 B1 PL233191 B1 PL 233191B1
- Authority
- PL
- Poland
- Prior art keywords
- triazole
- ethyl
- uracil
- obtaining
- dihydropyrimidin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 title description 5
- 229940035893 uracil Drugs 0.000 title description 2
- 125000001399 1,2,3-triazolyl group Chemical class N1N=NC(=C1)* 0.000 title 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 10
- -1 2- Ethyl ((methylsulfonyl) oxy) ethyl Chemical group 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- QUHNVZBEWJDBJX-UHFFFAOYSA-N 1H-pyrimidine-2,4-dione 2H-triazole Chemical class C1=CNN=N1.O=C1C=CNC(=O)N1 QUHNVZBEWJDBJX-UHFFFAOYSA-N 0.000 claims description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000006751 Mitsunobu reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229950010765 pivalate Drugs 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RJAJHSYADHZMNA-UHFFFAOYSA-N 3-benzoyl-1h-pyrimidine-2,4-dione Chemical compound O=C1C=CNC(=O)N1C(=O)C1=CC=CC=C1 RJAJHSYADHZMNA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- GTODOEDLCNTSLG-UHFFFAOYSA-N 2h-triazole-4-carboxylic acid Chemical compound OC(=O)C1=CNN=N1 GTODOEDLCNTSLG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- QSBOHTUPGDDWJK-UHFFFAOYSA-N C(C(C)(C)C)(=O)OCN1C(NC=CC1=O)=O Chemical compound C(C(C)(C)C)(=O)OCN1C(NC=CC1=O)=O QSBOHTUPGDDWJK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000010811 mineral waste Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RIWSXLGWFYNTFB-UHFFFAOYSA-N tert-butyl 2,4-dioxopyrimidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC(=O)NC1=O RIWSXLGWFYNTFB-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób otrzymywania 1,2,3-triazolowych pochodnych uracylu o wzorze ogólnym 1, w którym R oznacza grupę hydroksylową lub aminową. Związki te są pochodnymi uracylu i podobnie jak pochodne uracylu mogą znaleźć zastosowanie w produkcji środków farmaceutycznych.The subject of the invention is a process for the preparation of 1,2,3-triazole uracil derivatives of general formula I, in which R represents a hydroxyl or amino group. These compounds are derivatives of uracil and, like uracil derivatives, can be used in the production of pharmaceuticals.
Wzór 1Formula 1
W literaturze chemicznej nie ma opisów otrzymywania koniugatów uracylu z kwasem 1,2,3-triazolokarboksylowym. Opisana jest metoda otrzymywania koniugatów z kwasem 1,2,3-triazolofosfonowym (M. Lukac, D. Hockova, D. T. Keough, L. W. Guddat, Z. Janeba Tetrahedron, 2017, 73, 692-702). Zasadniczy etap opisanej metody polega na alkilowaniu 3-benzoilouracylu estrem kwasu 1-(2-hydroksyetylo)-1/7-1,2,3-triazolo-4-karboksylowego w warunkach Mitsunobu. Metoda ta ma szereg wad. Charakteryzuje się bardzo niekorzystnym bilansem masowym ze względu na stosowanie trifenylofosfiny. Dodatkowym powodem niekorzystnego bilansu masowego reakcji Mitsunobu jest konieczność stosowania reagentów w stosunku molowym znacznie przewyższającym stechiometryczny. Reakcję Mitsunobu należy prowadzić w warunkach bezwodnych i beztlenowych z powodu stosowania azodikarboksylanu dialkilu (dimetylu, dietylu lub diisopropylu). Azod ikarboksylan dietylu jest związkiem wybuchowym. Przez stosowanie azodikarboksylanu diizopropylu niebezpieczeństwo wybuchu jest ograniczone, niestety kosztem bilansu masowego reakcji Mitsunobu. Wydzielenie produktów reakcji Mitsunobu jest zwykle żmudne z powodu tworzenia się tlenku trifenylofosfiny jako odpadu. Tlenek trifenylofosfiny jest związkiem dobrze rozpuszczalnym w typowych rozpuszczalnikach organicznych. Zwykle jego oddzielenie od docelowego produktu wymaga stosowania chromatografii kolumnowej. W takim przypadku znacznie wzrasta zużycie rozpuszczalników organicznych. Dodatkowo jest generowany odpad mineralny w postaci żelu krzemionkowego zanieczyszczonego związkami organicznymi. W reakcji Mitsunobu najczęściej stosuje się tetrahydrofuran lub dioksan w roli rozpuszczalnika. Związki te są mieszalne z wodą i podobnie jak inne etery rozkładają się podczas przechowywania. W wyniku ich rozkładu powstają wybuchowe nadtlenki (Purification of laboratory chemicals, 6 edycja, Edytorzy W. L. F. Armarego, C. L. L. Chai, Elsevier, 2009). Z tego powodu osuszenie tetrahydrofuranu lub dioksanu na drodze destylacji jest operacją wymagającą szczególnej uwagi, także ze względu na konieczność wielogodzinnego ogrzewania tych związków z dodatkiem metalicznego sodu lub potasu.There are no descriptions of the preparation of conjugates of uracil with 1,2,3-triazole carboxylic acid in the chemical literature. A method for the preparation of conjugates with 1,2,3-triazolophosphonic acid is described (M. Lukac, D. Hockova, D. T. Keough, L. W. Guddat, Z. Janeba Tetrahedron, 2017, 73, 692-702). The essential step of the method described is the alkylation of 3-benzoyluracil with a 1- (2-hydroxyethyl) -1 / 7-1,2,3-triazole-4-carboxylic acid ester under Mitsunobu conditions. This method has several disadvantages. It has a very unfavorable mass balance due to the use of triphenylphosphine. An additional reason for the unfavorable mass balance of the Mitsunobu reaction is the necessity to use the reactants in a molar ratio much above the stoichiometric one. The Mitsunobu reaction should be carried out under anhydrous and anaerobic conditions due to the use of a dialkyl azodicarboxylate (dimethyl, diethyl or diisopropyl). Diethyl azodicarboxylate is an explosive compound. By using diisopropyl azodicarboxylate, the danger of explosion is limited, unfortunately at the expense of the mass balance of the Mitsunobu reaction. Isolation of the products of the Mitsunobu reaction is usually tedious due to the formation of triphenylphosphine oxide as waste. Triphenylphosphine oxide is a compound that is well soluble in typical organic solvents. Typically, its separation from the target product requires the use of column chromatography. In this case, the consumption of organic solvents increases significantly. Additionally, mineral waste is generated in the form of silica gel contaminated with organic compounds. Most often, the Mitsunobu reaction uses tetrahydrofuran or dioxane as the solvent. These compounds are miscible with water and, like other ethers, they decompose on storage. As a result of their decomposition, explosive peroxides are formed (Purification of laboratory chemicals, 6th edition, Editors W. L. F. Armary, C. L. L. Chai, Elsevier, 2009). For this reason, drying tetrahydrofuran or dioxane by distillation is an operation that requires special attention, also due to the necessity of heating these compounds for many hours with the addition of metallic sodium or potassium.
PL233 191 Β1PL233 191 Β1
Nieoczekiwanie okazało się, że związki o wzorze ogólnym 1It was surprisingly found that the compounds of general formula 1
Wzór 1 można otrzymać w dwuetapowym procesie. W pierwszym etapie piwalonian (2,6-diokso-2,3-dihydropirymidyn-1(6/-/)-ylo)metylu poddaje się reakcji z 1-(2-((metylosulfonylo)oksy)etylo)-1/7-1,2,3-triazolo-4-karboksylanem etylu w dwumetyloformamidzie w temperaturze pokojowej w obecności zasady, korzystnie węglanu potasu lub sodu. W drugim etapie wyodrębniony produkt pośredni traktuje się wodorotlenkiem metalu alkalicznego korzystnie wodorotlenkiem litu w celu otrzymania związku o wzorze ogólnym 1, w którym R oznacza grupę hydroksylową lub traktuje się metanolowo-wodnym roztworem amoniaku w celu otrzymania związku o wzorze ogólnym 1, w którym R oznacza grupę aminową.Formula 1 can be obtained in a two-step process. In the first step, methyl (2,6-dioxo-2,3-dihydropyrimidin-1 (6H) - yl) methyl pivalate is reacted with 1- (2 - ((methylsulfonyl) oxy) ethyl) -1 / 7- Ethyl 1,2,3-triazole-4-carboxylate in dimethylformamide at room temperature in the presence of a base, preferably potassium or sodium carbonate. In the second step, the isolated intermediate is treated with an alkali metal hydroxide, preferably with lithium hydroxide, to obtain a compound of general formula 1 in which R is hydroxy or treated with a methanol-aqueous ammonia solution to obtain a compound of general formula 1 in which R is amino group.
Sposób według wynalazku został bliżej przedstawiony w przykładach stosowania.The method according to the invention is presented in more detail in the application examples.
Przykład 1. Otrzymywanie piwalonianu (2,6-diokso-2,3-dihydropirymidyn-1 (6/-/)-ylo)-metylu Mieszaninę 1-terf-butoksykarbonylouracylu (0.98 g, 4.64 mmol), węglanu potasu (1.75 g, 12.69 mmol), piwalonianu chlorometylu (0.74 mL, 5.13 mmol) i suchego dwumetyloformamidu (18 mL) miesza się w temperaturze pokojowej przez 24 godziny. Następnie mieszaninę sączy się przez złoże Celitu. Złoże przemywa się dwumetyloformamidem (10 mL). Lotne składniki z przesączu oddestylowuje się pod zmniejszonym ciśnieniem. Pozostałość poddaje się chromatografii kolumnowej (octan etylu/heksan, 2/1 v/v, 3/1/ v/v). Otrzymuje się piwalonian (2,6-diokso-2,3-dihydropirymidyn-1(6/-/)-ylo)metylu (0.43 g, 41%) w postaci białego ciała stałego (tt 138-140°C) i bispiwalonian (2,4-dioksopirymidyno-1,3(2/7,4/-/)-diylo)bis(metylenu) (0.72 g, 44%) w postaci cielistego oleju. Bispiwalonian (2,4-dioksopirymidyno-1,3(2H,4H)-diylo)bis(metylenu): δΗ (500 MHz, CDCb,) 7.48 (1H, d, 3J 8.0), 5.92 (2H, s), 5.75 (1H, d, 3J 8.0), 5.66 (2H, s), 1.18 (9H, s), 1.15 (9H, s). δο (125 MHz, CDCb,) 178.61, 177.59, 161.53, 150.71, 143.58, 102.53, 70.85, 64.56, 38.99 (2xC), 27.69, 27.17. HRMS m/z obliczono dla C16H25N2O6 [M+H]+ 341.1707; oznaczono 341.1708. Piwalonian (2,6-diokso-2,3-dihydropirymidyn-1(6H)-ylo)metylu: δΗ (500 MHz, CDCb, HMBC) 9.81 (1H, brs, NH), 7.23 (1H, dd, 3J8.0, 3J6.0, H-6), 5.94 (2H, s, CH2), 5.81 (1H, dd, 3J 8.0, 4J 1.5, H-5), 1.19 (9H, s, C(CH3)3). δο (125 MHz, CDCb) 177.59 (COC(CH3)3), 162.19 (C-4), 152.40 (C-2), 139.63 (C-6), 102.00 (C-5), 63.99 (CH2), 38.85 (COC(CH3)3), 26.97 (COC(CH3)3). HRMS m/z obliczono dla C10H15N2O4 [M+H]+ 227.1026; oznaczono 227.1027.Example 1. Preparation of (2,6-Dioxo-2,3-dihydropyrimidin-1 (6H) -yl) -methyl pivalate. A mixture of 1-tert-butoxycarbonyluracil (0.98 g, 4.64 mmol), potassium carbonate (1.75 g, 12.69 mmol), chloromethyl pivalate (0.74 mL, 5.13 mmol) and dry dimethylformamide (18 mL) are stirred at room temperature for 24 hours. The mixture is then filtered through a bed of Celite. The bed is washed with dimethylformamide (10 mL). Volatile components in the filtrate are distilled off under reduced pressure. The residue was subjected to column chromatography (ethyl acetate / hexane, 2/1 v / v, 3/1 / v / v). This gave (2, 6-dioxo-2,3-dihydropyrimidin-1 (6H) -yl) methyl pivalate (0.43 g, 41%) as a white solid (mp 138-140 ° C) and bispivalate ( 2,4-dioxopyrimidine-1,3 (2 (7,4)) diyl) bis (methylene) (0.72 g, 44%) as a fleshy oil. (2,4-Dioxopyrimidine-1,3 (2H, 4H) -diyl) bis (methylene) bispivalate: δ Η (500 MHz, CDCb,) 7.48 (1H, d, 3 J 8.0), 5.92 (2H, s) , 5.75 (1H, d, 3 J 8.0), 5.66 (2H, s), 1.18 (9H, s), 1.15 (9H, s). δο (125 MHz, CDCb,) 178.61, 177.59, 161.53, 150.71, 143.58, 102.53, 70.85, 64.56, 38.99 (2xC), 27.69, 27.17. HRMS m / z calcd for C 16 H 25 N 2 O 6 [M + H] + 341.1707; found 341.1708. Methyl (2,6-dioxo-2,3-dihydropyrimidin-1 (6H) -yl) methyl pivalate: δΗ (500 MHz, CDCb, HMBC) 9.81 (1H, brs, NH), 7.23 (1H, dd, 3 J8. 0.3J6.0, H-6), 5.94 (2H, s, CH2), 5.81 (1H, dd, 3 J 8.0, 4 J 1.5, H-5), 1.19 (9H, s, C (CH3) 3 ). δο (125 MHz, CDCb) 177.59 (COC (CH 3 ) 3 ), 162.19 (C-4), 152.40 (C-2), 139.63 (C-6), 102.00 (C-5), 63.99 (CH2), 38.85 (COC (CH 3 ) 3 ), 26.97 (COC (CH 3 ) 3 ). HRMS m / z calcd for C10H15N2O4 [M + H] + 227.1026; found on 227.1027.
Przykład 2. Otrzymanie kwasu 1 -(2-(2,4-diokso-3,4-dihydropirymidyn-1(2/7)-ylo)etylo)-1 H-1,2,3-triazolo-4-karboksylowegoExample 2. Preparation of 1- (2- (2,4-dioxo-3,4-dihydropyrimidin-1 (2/7) -yl) ethyl) -1H-1,2,3-triazole-4-carboxylic acid
1. Etap. Do roztworu piwalonianu (2,6-diokso-2,3-dihydropirymidyn-1(6/7)-ylo)metylu (0.14 g, 0.62 mmol) w suchym dwumetyloformamidzie (5 mL) dodaje się węglan potasu K3CO3 (0.42 g, 3.04 mmol) i 1-(2-((metylosulfonylo)oksy)etylo)-1/7-1,2,3-triazolo-4-karboksylan etylu (0.20 g, 0.75 mmol). Całość miesza się w temperaturze 50°C przez 48 godzin i sączy przez złoże Celitu. Złoże przemywa się dwumetyloformamidem (5 mL). Lotne składniki z przesączu oddestylowuje się pod zmniejszonym ciśnieniem. Pozostałość poddaje się chromatografii kolumnowej (chloroform/metanol, 100/1 v/v). Otrzymuje się produkt (0.23 g, 77%) w postaci białego ciała stałego (tt 153-155 °C). δπ (500 MHz, CDCb) 8.02 (1H, s), 6.80 (1H, d, 3J 8.0), 5.93 (2H, s), 5.60 (1H, d, 3J 8.0), 4.77-4.73 (2H, m), 4.40 (2H, q, 3J 7.5), 4.35-4.33 (2H, m), 1.38 (3H, t, 3J 7.5), 1.19 (9H, s). δο (125 MHz, CDCb)1. Stage. To a solution of (2,6-dioxo-2,3-dihydropyrimidin-1 (6/7) -yl) methyl (0.14 g, 0.62 mmol) in dry dimethylformamide (5 mL) is added potassium carbonate K 3 CO 3 (0.42 g, 3.04 mmol) and ethyl 1- (2 - ((methylsulfonyl) oxy) ethyl) -1 / 7-1,2,3-triazole-4-carboxylate (0.20 g, 0.75 mmol). The mixture is stirred at 50 ° C for 48 hours and filtered through a bed of Celite. The bed is washed with dimethylformamide (5 mL). Volatile components in the filtrate are distilled off under reduced pressure. The residue is subjected to column chromatography (chloroform / methanol, 100/1 v / v). The product (0.23 g, 77%) is obtained as a white solid (mp 153-155 ° C). δπ (500 MHz, CDCb) 8.02 (1H, s), 6.80 (1H, d, 3 J 8.0), 5.93 (2H, s), 5.60 (1H, d, 3 J 8.0), 4.77-4.73 (2H, m ), 4.40 (2H, q, 3 J 7.5), 4.35-4.33 (2H, m), 1.38 (3H, t, 3 J 7.5), 1.19 (9H, s). δο (125 MHz, CDCb)
PL233 191 Β1PL233 191 Β1
177.45, 161.29, 160.16, 150.84, 142.95, 140.69, 128.51, 102.26, 64.55, 61.56, 49.70, 48.28, 38.85, 26.97, 14.25. HRMS m/z obliczono dla C17H24N5O6 [M+H]+ 394.1721; oznaczono 394.1721.177.45, 161.29, 160.16, 150.84, 142.95, 140.69, 128.51, 102.26, 64.55, 61.56, 49.70, 48.28, 38.85, 26.97, 14.25. HRMS m / z calcd for C17H24N5O6 [M + H] + 394.1721; marked 394.1721.
2. Etap. Mieszaninę produktu otrzymanego w 1. etapie (0.12 g), wodorotlenku litu (16 mg, 0.40 mmol), tetrahydrofuranu (3 mL) i wody (3 mL) pozostawia się w temperaturze pokojowej na 24 godziny, dodaje 2% roztwór kwasu solnego (0.7 mL) i oddestylowuje lotne składniki pod zmniejszonym ciśnieniem. Pozostałość krystalizuje się z mieszaniny etanolu i wody (10/1, v/v). Otrzymuje się produkt (52 mg, 69%) w postaci białego ciała stałego (tt 160-175°C, rozkład). 5h (500 MHz, DMSO-cfe) 11.26 (1H, bs), 8.69 (1H, s), 7.31 (1H, d, 3J 7.0), 5.47 (1H, d, 3J 7.0), 4.69-4.66 (2H, m), 4.17-4.14 (2H, m). 5c (125 MHz, DMSO-cfe) 164.05, 162.13, 151.26, 145.60, 140.51, 129.83, 101.54, 48.58, 47.91. HRMS m/z obliczono dla C9H10N5O4 [M+H]+ 252.0727; oznaczono 252.0729.2. Stage. A mixture of the product obtained in step 1 (0.12 g), lithium hydroxide (16 mg, 0.40 mmol), tetrahydrofuran (3 mL) and water (3 mL) is allowed to stand at room temperature for 24 hours, 2% hydrochloric acid (0.7 mL) and distills off volatile components under reduced pressure. The residue is crystallized from a mixture of ethanol and water (10/1, v / v). The product (52 mg, 69%) was obtained as a white solid (mp 160-175 ° C, decomposition). 5h (500 MHz, DMSO-cfe) 11.26 (1H, bs), 8.69 (1H, s), 7.31 (1H, d, 3 J 7.0), 5.47 (1H, d, 3 J 7.0), 4.69-4.66 (2H , m), 4.17-4.14 (2H, m). 5c (125 MHz, DMSO-cfe) 164.05, 162.13, 151.26, 145.60, 140.51, 129.83, 101.54, 48.58, 47.91. HRMS m / z calcd for C9H10N5O4 [M + H] + 252.0727; marked 252.0729.
Przykład 3. Otrzymanie 1 -(2-(2,4-diokso-3,4-dihydropirymidyn-1 (2/-/)-ylo)etylo)-1 /7-1,2,3-triazolo-4-karboksyamiduExample 3. Preparation of 1- (2- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) ethyl) -1 / 7-1,2,3-triazole-4-carboxamide
1. Etap. Piwalonian (2,6-diokso-2,3-dihydropirymidyn-1(6/7)-ylo)metylu (0.14 g, 0.62 mmol) poddaje się reakcji z 1-(2-((metylosulfonylo)oksy)etylo)-1/7-1,2,3-triazolo-4-karboksylanem etylu (0.17 g, 0.74 mmol) w takich samych warunkach jak w przykładzie 1, w 1. etapie.1. Stage. Methyl (2,6-dioxo-2,3-dihydropyrimidin-1 (6/7) -yl) methyl pivalate (0.14 g, 0.62 mmol) is reacted with 1- (2 - ((methylsulfonyl) oxy) ethyl) -1 Ethyl 7-1,2,3-triazole-4-carboxylate (0.17 g, 0.74 mmol) under the same conditions as in Example 1, step 1.
2. Etap. Mieszaninę produktu otrzymanego w 1. etapie (0.22 g, 0.56 mmol), etanolu (3 mL) i 20% roztworu wodorotlenku amonu (2 mL) ogrzewa się w temperaturze 50°C przez trzy dni i oddestylowuje lotne składniki, a pozostałość krystalizuje się z mieszaniny etanolu i wody (5/1, v/v). Otrzymuje się produkt (101 mg, 72%) w postaci białego ciała stałego (tt 219-225°C, rozkład). 5h (500 MHz, DMSO-cfe) 11.25 (1H, bs), 8.53 (1H, s), 7.82 (1H, bs), 7.43 (1H, bs), 7.27 (1H, d, 3J 8.0), 5.45 (1H, d, 3J 8.0), 4.67 (2H, t, 3J 5.5), 4.12 (2H, t, 3J 5.5). 5c (125 MHz, DMSO-cfe) 164.03, 161.88, 151.26, 145.61, 143.45, 127.59, 101.54, 48.52, 47.97. HRMS m/z obliczono dla C9H11N6O3 [M+H]+ 251.0887; oznaczono 252.0885.2. Stage. A mixture of the product obtained in the 1st step (0.22 g, 0.56 mmol), ethanol (3 mL) and 20% ammonium hydroxide solution (2 mL) was heated at 50 ° C for three days and volatile components were distilled off and the residue crystallized from ethanol and water mixtures (5/1, v / v). The product (101 mg, 72%) was obtained as a white solid (mp 219-225 ° C, decomposition). 5h (500 MHz, DMSO-cfe) 11.25 (1H, bs), 8.53 (1H, s), 7.82 (1H, bs), 7.43 (1H, bs), 7.27 (1H, d, 3 J 8.0), 5.45 ( 1H, d, 3 J 8.0), 4.67 (2H, t, 3 J 5.5), 4.12 (2H, t, 3 J 5.5). 5c (125 MHz, DMSO-cfe) 164.03, 161.88, 151.26, 145.61, 143.45, 127.59, 101.54, 48.52, 47.97. HRMS m / z calcd for C9H11N6O3 [M + H] + 251.0887; marked 252.0885.
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