* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: The different ethyl 2-aminothiophene-3-carboxylate (5a-g) (1 eq.) and formamide (3.2mL/mmol eq.) were refluxed for 8 h. The reaction mixture was then cooled in an ice-bath and added of cold water. The precipitate formed was collected by filtration, washed thoroughly with cold water and purified by crystallisation from EtOH/H2O unless otherwise stated.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 31 - 47
2
[ 31891-06-2 ]
[ 56843-79-9 ]
Reference：
[1] Patent: WO2017/31176, 2017, A1,
3
[ 40018-26-6 ]
[ 105-56-6 ]
[ 31891-06-2 ]
Yield
Reaction Conditions
Operation in experiment
79%
With triethylamine In 2,2,2-trifluoroethanol at 60℃; for 6.5 h; Microwave irradiation
General procedure: In a 2–5 mL microwave vial was added the nitrile (0.22 mmol, 1 equiv) and trifluoroethanol (2 mL) which was stirring for 2 min to dissolve. Next, 1,4-dithian-2,5-diol (0.11 mmol, 0.5 equiv) was then added and stirred for 5 min before triethylamine(0.242 mmol; 1.1 equiv) was added and the mixture further stirred for 2 min. The vial was then sealed and heated in the microwave for 390 min at 60 °C. The solvent was evaporated under vacuo and the crude residue was then purified using flash chromatography on silica (EtOAc/hexanes).
64%
With triethylamine In N,N-dimethyl-formamide at 45℃; for 1 h; Inert atmosphere
Triethylamine (1.8 mL, 13.3 mmol) was added dropwise over 10 min. to a mixture of ethyl cyanoacetate(4) (3 g, 26.6 mmol) and 1,4-dithiane-2,5-diol (3) (2 g, 13.3 mmol) in anhydrous DMF (10 mL) at r.t. under N2 atmosphere. After the addition was complete the reaction mixture was heated at 45°C for 1 h. The reaction mixture was diluted with 0.4 M acetic acid (70 mL) and extracted with EtOAc (4 x 50 mL). The combined extracts were washed with water (2 x 100mL), dried over MgSO4, and concentrated in vacuo to give a crude brown oil that was purified by flash column chromatography (n-hexane-EtOAc100:0 v/v increasing to n-hexane-EtOAc 95:5 v/v) giving a colourless oil in 64percent yield. TLC (4:1 nhexane-EtOAc, Rf: 0.55). 1H-NMR (CDCl3), δ: 1.36 (t, J= 7.1 Hz, 3H), 4.29 (q, J= 7.1 Hz, 2H), 5.87 (bs,2H), 6.19 (d, J= 5.9 Hz, 1H), 6.99 (d, J= 5.9 Hz, 1H). 13C-NMR (CDCl3), δ: 14.5, 59.7, 106.8, 107.2,125.9, 162.9, 165.4.
Reference：
[1] Synthesis (Germany), 2013, vol. 45, # 1, p. 45 - 52
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5437 - 5447
[3] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 875 - 883
[4] Chemical Communications, 2013, vol. 49, # 2, p. 190 - 192
[5] Archiv der Pharmazie, 2011, vol. 344, # 7, p. 459 - 465
[6] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5429 - 5433
[7] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 31 - 47
[8] Patent: WO2009/1214, 2008, A2, . Location in patent: Page/Page column 48
4
[ 105-56-6 ]
[ 31891-06-2 ]
Yield
Reaction Conditions
Operation in experiment
71%
With morpholine; sulfur; triethylamine In ethanol; N,N-dimethyl-formamide at 90℃;
General procedure: A mixture of cyclohexanone (1.06 mL, 10 mmol), ethyl cyanoacetate (1.15 mL, 10 mmol), morpholine (0.90 mL, 10 mmol), sulphur (0.32 g, 10 mmol) in ethanol (10 mL) was stirred and refluxed for overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude solid was washed with cold ethanol and filtered though sintered funnel, dried under vacuum. The crude product was dissolved in dichloromethane and washed with brine. The organic layer was collected and concentrated under low vacuum to give the compound 2a; yield: 73percent (1.83 g);
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 270 - 278
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4418 - 4427
5
[ 67-56-1 ]
[ 56387-08-7 ]
[ 31891-06-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
6
[ 31891-06-2 ]
[ 117516-97-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 3, p. 597 - 603
ethyl 3-methoxy-3-(2-trifluoromethyl-phenyl)-propenoate[ No CAS ]
[ 31891-06-2 ]
[ 654667-25-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydride; In tetrahydrofuran; at 0℃; for 15h;Heating / reflux;
EXAMPLE 2 Preparation of Ethyl 4-Chloro-1-methyl-6-[3-(trifluoromethyl)phenyl]-thieno-[2,3-b]pyridine-5-carboxylate A solution of ethyl 3-methoxy-3-[(trifluoromethyl)phenyl]-2-propenoate (1.60 g, 6.14 mmol) and methyl 3-amino-2-thiophenecarboxylate (1.04 g, 6.14 mmol) in THF at 0 C. is treated with NaH (60% dispersion in mineral oil, 501 mg, 12.5 mmol), heated at reflux temperature for 15 h, cooled to 0 C., quenched with aqueous NH4Cl and extracted with EtOAc. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to afford the title product as a tan powder in quantitative yield, identified by H-NMR and mass spectral analyses.
The gummy solid obtained was purified by silica gel column chromatography and the semi-solid product was triturated with water, filtered and washed with light petroleum (b.p. 60-80 C.) and dried to give the title product.
(i) Ethyl 2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate 2,5-Difluoro-nitrobenzene and ethyl 2-amino-thiophene-3-carboxylate, m.p. 125 C. (EtOH).
58
[ 31891-06-2 ]
[ 7693-46-1 ]
[ 106667-62-3 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 23℃; for 1h;
A solution of methyl-3-aminothiophene carboxylate (1-1, prepared according to literature methods, 4.23 g, 24.7 mmol, 1 equiv) in dichloromethane (25 mL) was cooled to 0C then treated with 4-nitrophenyl chloroformate (5.98 g, 29.6 mmol, 1.20 equiv) and N, N- diisopropylethylamine (6.46 mL, 37.1 mmol, 1.50 equiv). The resulting mixture was stirred at 0 C for 15 min, then warmed to 23 C and stirred for 45 min. The resulting yellow solution was diluted with dichloromethane (75 mL) and washed with H20 (85 mL). The organic layer was dried over Na2SO4 and concentrated. The yellow residue was dissolved in dioxane (25 mL) and treated with p-toluidine (3.97 g, 37.1 mmol, 1.50 equiv) and N, N-diisopropylethylamine (6.46 mL, 37.06 mmol, 1.5 equiv). The reaction mixture was stirred at 80 C for 3 h, then cooled to 23 deg C and stirred for 16 h. The reaction mixture was partitioned between ethyl acetate (2x65 mL) and H20 (75 mL), and the combined organic layers were dried over Na2SO4 and concentrated. The residual yellow oil was purified by flash column chromatography (Si02 : 100% Hex grading to 60: 40 Hex: EtOAc) to afford ethyl 2-([(4- methylphenyl) amino] carbonyl} amino) thiophene-3-carboxylate (1-2) as a yellow oil. LRMS m/z : Calc'd for Cl5Hl6N203S (M+H) 305.4, found 305.3.
With formic acid; acetic anhydride; In carbon dioxide;
b Ethyl 2-Formamido-3-thenoate The product from step a) (14.6 g) was added to a mixture of acetic anhydride (24.3 ml) and formic acid (24.3 ml) with stirring and cooling. The mixture was stirred at room temperature for 4 hours and evaporated under reduced pressure. The residue was dissolved in ether and cooled in dry ice. The precipitate was filtered off and dried to give the title product.
With formic acid; acetic anhydride;
a) To acetic anhydride (4.7 ml) under ice cooling, formic acid (4.7 ml) was added dropwise, to which <strong>[31891-06-2]2-aminothiophene-3-carboxylic acid ethyl ester</strong> (2.8 g, 16.4 mmol) was added and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ether was added, and the precipitate that deposited was filtered off. Ether was distilled off under reduced pressure to obtain 2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol).
With formic acid; acetic anhydride;
a) To acetic anhydride (4.7 ml) under ice cooling, formic acid (4.7 ml) was added dropwise, to which <strong>[31891-06-2]2-aminothiophene-3-carboxylic acid ethyl ester</strong> (2.8 g, 16.4 mmol) was added and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ether was added, and the precipitate that deposited was filtered off. Ether was distilled off under reduced pressure to obtain 2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol).
In N-(3-carbomethoxythien-4-yl)-N'-(2-chloroethyl)urea;
EXAMPLE 28 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione The title compound was produced from N-(3-carboethoxythien-2-yl)-N'-(2-chloroethyl)urea which was prepared in the same fashion as described for N-(3-carbomethoxythien-4-yl)-N'-(2-chloroethyl)urea in Example 1(a) except that the thiophene was <strong>[31891-06-2]ethyl 2-amino-3-thiophenecarboxylate</strong> (9.5 g, 55.5 mmol) and the reflux time was 16 hours. This new urea was isolated in 44% yield (6.7 g) by flash silica gel chromatography using 12.5% EtOAc in hexanes, mp 85-87 C. Theor. C10 H13 ClN2 O3 S: C, 43.40; H, 4.73; N, 10.12. Found: C, 43.25; H, 4.83; N, 9.97.
With triethylamine; In tetrahydrofuran; water; toluene;
b. Ethyl 2-(N'-methylureido)-thiophene-3-carboxylate To a stirred soIution of <strong>[31891-06-2]ethyl 2-amino-thiophene-3-carboxylate</strong> (5,0 g, 29 mmol) and triethylamine (4,1 ml, 29 mmol) in dry tetrahydrofuran (100 ml) was added a 20% solution of phosgene in toluene (16 ml, 32 mmol). The mixture was heated to reflux for 3 h, then cooled to room temperature and exposed to a gaseous stream of methylamine for 10 min. After additional stirring for 30 min., the mixture was filtered and the filtrate was evaporated in vacuo, whereafter the crystalline residue was suspended in water, filtered off, and dried to give the title compound as colourless crystals, m.p. 127 C. In the same manner ethyl 2-(N'-ethylureido)-thiophene-3-car boxylate, m.p. 83-87 C., was prepared using ethylamine instead of methylamine in the above procedure.
With triethylamine; In tetrahydrofuran; at 20℃; for 3h;
[0211] To a stirred solution of <strong>[31891-06-2]ethyl 2-aminothiophene-3-carboxylate</strong> (10 g) in THF (150 rnL), was added 4-fluorobenzoyl chloride (10.2 g). Then TEA (12 mL) was added dropwise. After 3 h at RT, the mixture was filtered and the filtrate was concentrated to give ethyl 2-(4-fluorobenzamido)thiophene-3-carboxylate (13.5 g, 74%) as a yellow solid. LCMS: 294 (M+H) +.
3-(2,4-dimethoxy-benzyloxy)-1H-thieno[2,3-d]pyrimidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure Al for the cyclization of ortho-amino esters: The ortho amino ester was refluxed in toluene (0.2 M) along with CDI (1.25 eq.) for 2 hours. The protected hydroxylamine (1.5 eq.) was added (along with 1.5 eq. OfEt3N in cases when the hydroxylamine was supplied as the hydrochloride salt) and refluxing was continued for 1 hour. The solution was concentrated and treated with ethanol to give a 0.2 M suspension. The suspension was treated with NaOH (2M in H2O, 1.5 eq.) and heated to reflux for 1 hour. The solution was cooled and treated with glacial acetic acid (4 eq.). Generally, the resultant O-protected imide precipitated upon cooling to give a 40-70% yield. Cooling and addition of water was occasionally required to affect the precipitation. The precipitate was generally quite clean and was used in further steps without purification. However, in a few cases, chromatography was required in order to obtain pure product.Example 1: 3-Hvdroxy-lH-thienof2,3-dlpyrimidine-2,4-dione2-Amino-thiophene-3-carboxylic acid ethyl ester was transformed to the O-protected intermediate 3-(2,4-Dimethoxy-benzyloxy)-lH-thieno[2,3-d]pyrimidine-2,4-dione using -general procedure -A-I. Deprotection- of this intermediate using-general procedure Dl gave the title compound which was purified by mass triggered preparative HPLC. 1H NMR (DMSO- d6) delta 10.39 (bs, IH), 7.16 (d, IH, J = 5.7 Hz), 7.12 (d, IH, J = 5.7 Hz); Electrospray MS: 183 (M-H); retention time: 1.25 min.
1.1 5-Methyl-thieno[2,3-d1-pyrimidin-4-ol2-Amino-thiophene-3-carboxylic acid ethyl ester (25 g) was dissolved in formamide (200 ml), heated at 180C for 6h and stirred at 150C overnight. Then it was cooled to ambient temperature. The precipitate was filtered and washed with Et2O, then dissolved in hot ethylacetate and methanol. Charcoal was added, stirred for a few min utes, filtered and concentrated in vacuo. The residue was stirred with dichloromethane: methanol 50:1 and then washed with Et2O, filtered and dried.Yield: 10,40 gESI mass spectrum: m/z = 167 (M+H)+
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