Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

yellow fine crystalline powder

General procedure: A mixture of cyclohexanone (1 mmol), an activated nitrile(1 equiv), morpholine (1 equiv) and elemental sulfur (1 equiv) in5 ml of ethanol was stirred at 0 C overnight. After, the solvent was evaporated at reduced pressure and the crude product was extracted with ethyl acetate thrice. The organic layer was treated with anhydrous sodium sulphate and evaporated again. Finally the final compounds were purified by recrystallization from MeOH/water. Yellow crystalline solid. Yield: 98percent, mp 134-135 °C. General procedure: A mixture of the respective aldehyde or ketone (4mmol), ethylcyanoacetate (4mmol), S8 (0.14g, 4.4mmol), and morpholine or diethylamine (5mL) in EtOH (7mL) was put in a vial (G30 size) and submitted to microwave irradiation for 20min at 77°C (Pmax=80W). After cooling, the solution was poured onto 50mL ice water to yield a precipitate which was filtered, washed with water and dried under vacuum. The solid was used without further purification. 2-Amino-4, 5, 6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2b) General procedure: For the synthesis of 4, 5-alkyl-2-aminothiophenes (2a–2j), the general procedures are the same as those of compound 2i. A mixture of N-benzyl-4-piperidone (1i, 380 mg, 2 mmol), malononitrile (132 mg, 2 mmol), sulfur (64 mg, 2 mmol), and basic ionic liquid (bmIm)OH (380 mg, 2.4 equiv.) was heated to 60°C for 2 h. The reaction mixture was cooled to room temperature and washed with diethyl ether or ethyl acetate (340 mL), and the organic layers were concentrated under vacuum to obtain an oily crude product. The crude product was dissolved in ether/hexane (3:1, 50 mL) mixture, insoluble material was decanted, and the organic layer was concentrated to 1/4 of the volume and kept in a refrigerator. The precipitate that formed was filtered and dried.General procedure: To a mixture of ketone (1 eq.), ethyl cyanoacetate (4) (1 eq.), and elemental sulfur (1 eq.) in absolute ethanol (1.7 mL/mmol eq.) was added triethylamine (1.5 eq.), and the mixture was refluxed for 24 h. The reaction mixture was then concentrated and the residue was partitioned between water (10 mL/mmol eq.)and ethyl acetate (10 mL/mmol eq.). The organic layer was separated, dried over MgSO4, and concentrated, and the crude product was purified by crystallization from EtOH/H2O unless otherwise stated. S.1.1 Ethyl 2-amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-3-carboxylate (5a) [S1]. Obtained in 85percent yield as an off-white solid. 1H-NMR (CDCl3), δ: 1.35 (t, J= 7.1 Hz, 3H), 1.77 (m, 4H), 2.51 (m, 2H), 2.72 (m, 2H), 4.27 (q, J= 7.1 Hz, 2H), 5.98 (bs, 2H). 13C-NMR (CDCl3), δ: 14.4, 22.8, 23.2, 24.5, 26.9, 59.3, 105.7, 117.6, 132.46, 161.7, 166.1.Example 13; Preparation of 7-bromo- N-(3-chloro-4-[(3-fluorobenzyl)oxyl phenyl ) [1]benzothieno[2, 3-d]pyrimidin-4-amine; EPO Some Formula (II) compounds can be synthesized, in some embodiments, as summarized in Scheme 2. This Scheme begins with the preparation of the 2-amino-4, 5, 6, 7- tetrahydrobenzo[b]thienophene-3-carboxylic acid ethyl ester by using the Gewald reaction and then preparing the cyclic pyrimidinone compound F, by reacting the 2-aminothiophene carboxylic ester with excess of formamide. Compound F undergoes chlorination using phosphorus oxychloride (POCIGeneral procedure: Diethylamine (0.1mol) was added dropwise for 30min to a suspension of the appropriate ketone (0.1mol), ethyl cyanacetate 0.1mol (11ml) and 3.2g sulfur in 30ml ethanol and the reaction mixture was stirred at room temperature for about 75min. When the synthesis was completed the mixture was cooled. The obtained 2-aminothiophene crystalized in the form of yellow powder. The precipitate was filtrated, washed with water and recrystallized from ethanol to give the 2-aminothiophene derivatives [27].6.1.3 A solution of cyclohexanone (9.8 g, 99.85 mmol, 1.00 equiv) in ethanol (50 mL) was added ethyl 2-cyanoacetate (11.3 g, 99.90 mmol, 1.00 equiv), diethylamine (7.3 g, 99.81 mmol, 1.00 equiv) and S (3.2 g, 0.10 mol, 1.00 equiv) was stirred for 24 h at room temperature. The solids formed were collected by filtration and then washed with EtOAc (20 mL). The solid was dried in an oven at 45 °C for 2 h to give 18 g (80percent) of the desired ethyl 2-amino-4, 5, 6, 7- tetrahydro-l-benzothiophene-3-carboxylate as a yellow solid.General procedure: A mixture of ketone (1.0 eq.), sulfur powder (1.0 eq.) and t-butyl cyanoacetate, ethyl cyanoacetate or malononitrile (1.0 eq.) in EtOH (2mL/mmol) was prepared before morpholine (1.0 eq.) was added dropwise, ensuring that the reaction did not heat up above 60°C during the addition. The mixture was then heated at 40°C and stirred for 4–20h.General procedure: A mixture of ethyl cyanoacetate (5.43 mL, 50.95 mmol), the ketone (5.28 mL, 50.95 mmol), sulfur (1.74g, 50.95 mmol) and morpholine (4.44 mL, 50.95 mmol) in ethanol (100 mL) was allowed to stir for 20 h at 25 General procedure: A mixture of 1 (1 mmol), 2 (1 mmol), elemental sulfur (1 mmol)and BSA (20 mg) was added to 1 mL of DMF. The reaction was incubatedat 50 C and 200 rpm. After the required time, the BSA wasfiltered off to terminate the reaction. For the products with highyields, the solid crude products precipitated in water, and then followedby filtration and drying. For the products with low yields, the crude residues were purified by flash column chromatographyon silica gel using petroleum/ethyl acetate.Preparation of 2-Amino-4, 5, 6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (IV) The production of compounds marked with 1-12.; Ia.; The compound of the formula (III) is produced as follows: 1 mole of cyclohexanone and 1 mole of cyan-acetic acid ethylester are dissolved in 00 milliliter of ethyl alcohol, 1 mole of sulfur powder 35 milliliter of distilled water General procedure: A mixture of 0.070 g 4-propylcyclohexanone (0.5 mmol), 0.030 g malononitrile (0.5 mmol), 0.019 g sulfur powder(0.6 mmol), and 0.1 cmThe mixture of cyclohexanone, ethyl cyanoacetate and sulphur in ethanol was stirred at 50–60 °C, followed by addition of diethylamine dropwise over 15 minutes. The reaction mixture was stirred at same temperature for 2 hours, monitored by TLC. After completion of the reaction, the mixture was cooled to rt, solid precipitate was filtered at vacuum pump and washed with 2x5 ml ethanol. A yellow colored solid was recrystallized from ethanol to yield 74percent product 1.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); brown solid; mp: 116.2-117.2 °C; EXAMPLE 209 - PREPARATION OF INTERMEDIATE Ethyl 2-amino- 4, 5, 6, 7-tetrahydrobenzo[b]thiophene-3-carboxylateTo a solution of ethyl cyanoacetate (42.68 mlMorpholine (20.4 g, 0.234 mol) was added dropwise to a mixture of cyclohexanone (10.0 g, 0.102 mol), ethyl cyanoacetate (11.53 g, 0.102 mol), and sulfur (2.9 g, 0.094 mol) in 30mL of ethanol at ambient temperature in 20 min. The reaction was exothermic, so the temperature increased to 50°C, and a clear solution was obtained. It was filtered from solids and cooled to 0–5°C. After stirring for 1h the product was filtered off, washed with chilled ethanol (15 mL) and sucked dry. The obtained cake was dried in an oven at 50°C for 3h to obtain 14g of the title product. Yield: 66.0percent.1H NMR (ppm): 1.23 (3H, t), 1.61– 1.72 (4H, m), 2.38–2.41 (2H, m), 2.56–2.61 (2H, m), 4.13 (2H, d), 7.21 (2H, br.s).Intermediate A.[00245] Synthesis of compound 3. In to a mixture of cyclohexanone (compound 1) (49 g, 0.5 mol, 1.0 eq), ethyl 2-cyanoacetate (compound 2) (56 g, 0.5 mol, 1.0 eq), and sulphur (16 g, 0.5 mol, 1.0 eq) in 150 mL of ethanol was added morpholine (44 g, 0.5 mol, 1.0 eq). The mixture was stirred for 8 h at room temperature. The reaction mixture was diluted with water and the precipitate was collected by filtration and recrystallized from ethanol to afford compound 3 as yellow solid (62 g, 55percent).To a mixture of cyclohexanone (49 g, 0.5 mol), ethyl2-cyanoacetate (56 g, 0.5 mol), and sulphur (16 g, 0.5 mol)in 150 ml of ethanol was added morpholine (44 g, 0.5 mol).The mixture was stirred for 8 h at room temperature. Thereaction mixture was diluted with water and the precipitatewas collected by filtration and recrystallized from ethanol.Compound 2 as yellow solid (62 g, 55 percent); m.p. = 115 °C;1H NMR (CDCl3, 400 MHz) δ 5.94(s, 2H, Ar–NH2), 4.25 (q, 2H, J = 7 Hz, –O–CH2–), 2.69–2.60 (m, 2H, –CH2–CH2–CH2–), 2.49–2.43(m, 2H, –CH2–CH2–CH2–), 1.76–1.66 (m, 4H, –CH2–CH2–CH2–), 1.33(t, 3H, J = 7 Hz, –OCH2–CH3); ES-MS: m/z 226.3 (M+H)+.A mixture of ethyl cyanoacetate (1.15 g, O.Olmol), sulphur (0.32 g, 0.01 mol), triethyl amine (0.52 g, 0.005 mol) and cyclohexanone (1.0 g, 0.01 mol) in DMF (10 ml) was stirred at 55 A mixture of ethyl cyanoacetate (1.15 g, O.Olmol), sulphur (0.32 g, 0.01 mol), triethyl amine (0.52 g, 0.005 mol) and cyclohexanone (1.0 g, 0.01 mol) in DMF (10 ml) was stirred at 55 General procedure: A one-neck 50-mL flask containing cyclohexanone (2.4 g, 20 mmol), ethyl cyanoacetate (3.4 g, 30 mmol), sulphur (0.96 g, 30 mmol), basic AlGeneral procedure: A mixture of the ketone (1 eq.), cyanoacetate (1 eq.), and elemental sulphur (1eq.) in ethanol were combined and heated at 40-70 °C. Morpholine or diethylamne (1 eq.) was added dropwise. The reaction was stirred at 40-70 °C for 1-4 hours, and then stirred at room temperature overnight. The resulting precipitate was typically collected by filtration and recrystallised from ethanol or toluene.Preparation 1 : Ethyl 2-amino-4.5.6.7-tetrahydro-1-benzothiophene-3-carboxylateTo a solution of ethyl cyanoacetate (427 mL, 4 mol) in ethanol (4 L) was added sulfur (153.88 g, 4.80 mol), morpholine (422 mL, 4.80 mol) and cyclohexanone (497 mL, 4.80 mol) and the resulting solution was stirred at 50°C for 18 hours. The reaction was cooled to room temperature and filtered to remove solids. The filter cake was washed with cold ethanol and then dried to give the title compound as a pale yellow solid, 608.4 g. The mother liquors were cooled in an ice bath and the resulting precipitate was collected by filtration. The solid was purified by dry flash chromatography eluting with ethyl acetate in heptane (20 - 30percent) to yield a further 38.62 g of the title compound. The two solids were combined to give 647.02 g of the title compound in a 72percent yield.

Molecular Weight:225.31
XLogP3:3.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:225.08234989
Monoisotopic Mass:225.08234989
Topological Polar Surface Area:80.6
Heavy Atom Count:15
Complexity:247
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes