2-氨基-5-氯噻吩

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D20 =+91.9° (c=0.1; DMF).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 400 ml of toluene are dissolved 24.0 g of 2-amino-5-chlorothiophenol and 31.2 g of (4-methoxyphenyl)glycidic acid methyl ester, and the solution is refluxed under nitrogen atmosphere for 2 hours. To the reaction mixture are added 1.43 g of p-toluenesulfonic acid hydrate and 350 ml of xylene and the mixture is refluxed for 2 hours and simultaneously 350 ml of the solvent is distilled. After cooling, precipitated crystals are collected by filtration to give 19.8 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. the solution is refluxed under nitrogen atmosphere for 2 hours the mixture is refluxed for 2 hours simultaneously 350 ml of the solvent is distilled After cooling precipitated crystals are collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 400 ml of toluene are dissolved 24.0 g of 2-amino-5-chlorothiophenol and 31.2 g of (4-methoxyphenyl)glycidic acid methyl ester, and the solution is refluxed under nitrogen atmosphere for 2 hours. To the reaction mixture are added 1.43 g of p-toluenesulfonic acid hydrate and 350 ml of xylene and the mixture is refluxed for 2 hours and simultaneously 350 ml of the solvent is distilled. After cooling, precipitated crystals are collected by filtration to give 19.8 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. the solution is refluxed under nitrogen atmosphere for 2 hours the mixture is refluxed for 2 hours simultaneously 350 ml of the solvent is distilled After cooling precipitated crystals are collected by filtration

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D20 =+91.9° (c=0.1; DMF).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml) is added 96 % potassium hydroxide (1.63 g), and the mixture is distilled to remove ethanol. The resulting solid material is suspended in toluene (70 ml) and thereto is added methyl ° -bromo-4-chlorophenylacetate (7.38 g), and the mixture is refluxed overnight. The reaction mixture is concentrated, and the resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6.58 g) as crystals. M.p. 230°-233.5° C. the mixture is distilled to remove ethanol is added methyl ° -bromo-4-chlorophenylacetate (7.38 g) the mixture is refluxed overnight The reaction mixture is concentrated the resulting precipitate is separated by filtration washed dried recrystallized from tetrahydrofuran-n-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D20 =+91.9° (c=0.1; DMF).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml) is added 96 % potassium hydroxide (1.63 g), and the mixture is distilled to remove ethanol. The resulting solid material is suspended in toluene (70 ml) and thereto is added methyl ° -bromo-4-chlorophenylacetate (7.38 g), and the mixture is refluxed overnight. The reaction mixture is concentrated, and the resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6.58 g) as crystals. M.p. 230°-233.5° C. the mixture is distilled to remove ethanol is added methyl ° -bromo-4-chlorophenylacetate (7.38 g) the mixture is refluxed overnight The reaction mixture is concentrated the resulting precipitate is separated by filtration washed dried recrystallized from tetrahydrofuran-n-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 6-chloro-benzothiazol-2-ylamine (Example 200, 17.8 g, 96.7 mmol) and KOH (EM, 87 g, 1.55 mol) in 150 mL of water was refluxed for 2 d. The mixture was cooled to room temperature and was diluted with ice. The solution was brought to pH 5 with concentrated HCl. The mixture was extracted 3× with EtOAc (300 mL). The organic layers were combined and washed twice with a brine solution (300 mL), dried over Na2SO4. Removal of the solvent under reduced pressure gave 10.5 g product. 1H NMR (400 MHz, DMSO) δ 7.20 (d, J=2.5 Hz, 1H), 6.93 (dd, J=8.6, 2.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H) 5.30 (s, 3H). MS (EI): m/z 160 (M+H). was diluted with ice The mixture was extracted 3× with EtOAc (300 mL) washed twice with a brine solution (300 mL) dried over Na2SO4 Removal of the solvent under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 6-chlorobenzothiazol-2-ylamine (Example 200, 17.8 g, 96.7 mmol) and KOH (EM, 87 g, 1.55 mol) in 150 mL of water was refluxed for 2 d. The mixture was cooled to room temperature and was diluted with ice. The solution was brought to pH 5 with concentrated HCl. The mixture was extracted 3× with EtOAc (300 mL). The organic layers were combined and washed twice with a brine solution (300 mL), dried over Na2SO4. Removal of the solvent under reduced pressure gave 10.5 g product. 1H NMR (400 MHz, DMSO) δ 7.20 (d, J=2.5 Hz, 1H), 6.93 (dd, J=8.6, 2.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H) 5.30 (s, 3H). MS (EI): m/z 160 (M+H). was diluted with ice The mixture was extracted 3× with EtOAc (300 mL) washed twice with a brine solution (300 mL) dried over Na2SO4 Removal of the solvent under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (2.6 g, 13.1 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.0 g, 13.1 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4f, (R=Cl), mp 229-230° C. occurs as light orange crystals; yield: 2.05 g (49.4%). refluxed for 0.5 h Upon cooling The crystals are filtered the remaining mother liquid is poured into cold water, whereupon further precipitation Each precipitate is separately recrystallized twice from EtOH

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (2.53 g, 13.7 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.20 g, 13.7 mmole), in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4e, (R=Cl), mp 226-227° C. occurs as light orange crystals; yield: 1.70 g (36.7%). refluxed for 0.5 h Upon cooling The crystals are filtered the remaining mother liquid is poured into cold water, whereupon further precipitation Each precipitate is separately recrystallized twice from MeOH

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Potassium thiocyanate (38.8 g, 0.40 mole) and 4-chloroaniline (50.9 g, 0.40 mole) are dissolved in 300 mL of glacial acetic acid. The solution is cooled below 10° C. in an ice bath and while stirring, bromine (10 mL, 0.40 mole) in glacial acetic acid (50 mL) is added dropwise over one hour with the temperature maintained below 10° C. with external cooling. Stirring is continued for an additional 30 minutes. The reaction mixture is stirred at room temperature for 16 hours. The hydrobromide salt of 2-amino-6-chlorobenzothiazole 5 (X=Cl) is washed with hexane (2×25 mL). The salt is dissolved in warm water (300 mL) and the product precipitated by addition of dilute (10%) sodium hydroxide. The crude product is filtered and recrystallized from ethanol (mp 198-200° C., yield 16.47 g, 63.3%). A mixture of 2-amino-6-chlorobenzothiazole 5 (15 g, 0.08 mole), potassium hydroxide (75 g, 1.34 mole), and water (150 mL) is heated with stirring under reflux over nitrogen for 8 hours. The vigorous reaction subsides slowly. The mixture is then diluted with water (20 mL) and filtered. To the filtrate is added 5 N acetic acid with vigorous stirring and cooling until it is just acid to pH paper. The yellow crystals are filtered, washed with cold water and recrystallized from absolute ethanol and decolorized with neutral Norit. Yield of 5-chloro-2-aminobenenethiol (6, X=Cl); 40%; mp 108-110° C. (lit 110° C.). The solution is cooled below 10° C. in an ice bath maintained below 10° C. with external cooling Stirring The reaction mixture is stirred at room temperature for 16 hours The hydrobromide salt of 2-amino-6-chlorobenzothiazole 5 (X=Cl) is washed with hexane (2×25 mL) The salt is dissolved in warm water (300 mL) the product precipitated by addition of dilute (10%) sodium hydroxide The crude product is filtered recrystallized from ethanol (mp 198-200° C., yield 16.47 g, 63.3%) is heated with stirring under reflux over nitrogen for 8 hours The vigorous reaction subsides slowly filtered To the filtrate is added 5 N acetic acid with vigorous stirring cooling until it The yellow crystals are filtered washed with cold water recrystallized from absolute ethanol and decolorized with neutral Norit mp 108-110° C. (lit 110° C.)