苄达明杂质2

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

实验步骤: 6-Fluoro-3-(4-pyridinylamino)benzo[b]thiophene (3.30 g, 13.5 mmol) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 1.35 g, 33.8 mmol, washed with hexanes) in 50 mL dimethylformamide. After the anion formation was completed, 3-dimethylaminopropyl chloride hydrochloride (2.56 g, 16.2 mmol) was added as a powder and the resultant mixture was stirred at 70-75° C. for two hours. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 4.6 g of a brown oil. Elution through silica with 10% methanol in dichloromethane via flash column chromatography yielded 3.3 g of a yellow oil. Kugelrohr distillation (210-220°/0.1 mm Hg) yielded 2.8 g of a clear colorless oil which eventually solidified to a white solid, mp 82-84°. After cooling extracted with ethyl acetate The organic extract was washed with water and saturated sodium chloride solution dried (anhydrous magnesium sulfate) filtered concentrated to 4.6 g of a brown oil Elution through silica with 10% methanol in dichloromethane via flash column chromatography

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

实验步骤: A mixture of 232 g. (2.0 moles) of indene and the free base prepared from 264 g. (1.6 moles) of 3-dimethylaminopropylchloride-hydrochloride is added in portions over 1 hour to a rapidly stirred mixture of 300 g. (7.5 moles) of sodium hydroxide, 300 g. of water and 300 ml. of 40% Triton B in methanol. The initial temperature is 50° and the rate of addition controlled to keep the temperature between 55°-60°. The green mixture is stirred at 60° for 4 hours, cooled, diluted with 1500 ml. of water and extracted with ether. The ether extract is in turn extracted with a solution of 180 ml. of conc. hydrochloric acid in 600 ml. of water and the aqueous phase separated, basified with 100 g. of sodium hydroxide and extracted with ether. Solvent removal gives 182 g. of brown oil which is distilled to give 102 g. of oil, b.p. 88°-93° at 0.05 mm. Redistillation gives 19.6 g.; b.p. 87.5°-89.5° at 0.05 mm. and 71.1 g., b.p. 89.5°-90° at 0.05 mm. A mixture of 232 g is 50° the rate of addition between 55°-60° cooled diluted with 1500 ml of water and extracted with ether The ether extract extracted with a solution of 180 ml of water and the aqueous phase separated of sodium hydroxide and extracted with ether Solvent removal gives 182 g of brown oil which is distilled to give 102 g Redistillation gives 19.6 g

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194-195° C. The aqueous phase was separated acetonitrile was removed at reduced pressure The residue was extracted into DCM The organic solution was washed with H2O and brine dried with MgSO4 The solvent was removed The crystals were collected (2.53 g), m.p.=192-194° C Recrystallization from ethanol

反应条件: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 6° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C. The aqueous phase was separated acetonitrile was removed at reduced pressure The residue was extracted into DCM The organic solution was washed with H2O and brine dried with MgSO4 The solvent was removed The crystals were collected (2.53 g), m.p.=192°-194° C Recrystallization from ethanol

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C. The aqueous phase was separated acetonitrile was removed at reduced pressure The residue was extracted into DCM The organic solution was washed with H2O and brine dried with MgSO4 The solvent was removed The crystals were collected (2.53 g), m.p.=192°-194° C Recrystallization from ethanol

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

实验步骤: A suspension mixture of benzyloxycarbonylpiperazine (14.529, 65.9 mmol), 3-dimethyl-aminopropyl chloride hydrochloride (15.63 g, 98.9 mmol), and triethylamine (20.29, 200 mmol) in ethanol (100 ml) was refluxed for 14 h. Then 3-dimethylaminopropyl chloride hydrochloride (6.32 g, 40 mmol), and triethylamine (11.3 ml, 80 mmol) was added to the reaction mixture and continued to reflux for 24 h. The solvent was evaporated and the residue was extracted with ethyl actate. The extract was washed with water, dried (MgSO4), and concentrated to give 12.65 g of brown viscous oil, which was purified by column chromatography on silica gel (ammonium hydroxide aqueous solution/methanol/dichloromethane: 1/10/100) to give 2.21 g of brown clear oil. was refluxed for 14 h to reflux for 24 h The solvent was evaporated the residue was extracted with ethyl actate The extract was washed with water dried (MgSO4) concentrated

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

实验步骤: Prepared according to the method of Example 60 using 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 9.55 (s, 1H), 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.38 (m, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H), 1.44 (m, 2H); Mass spectrum (esi) m/z=−493.1 (M+H). Prepared

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

实验步骤: Prepared according to the method of Example 16 using methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s, 3H), 1.84 (m, 2H); Mass spectrum (esi) m/z=451.0 (M+H-2HCl). Prepared

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

实验步骤: Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (3-chloro-propyl)-dimethyl-amine hydrochloride and 1-benzofuran-2-sulfonyl chloride.

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C. The aqueous phase was separated acetonitrile was removed at reduced pressure The residue was extracted into DCM The organic solution was washed with H2O and brine dried with MgSO4 The solvent was removed The crystals were collected (2.53 g), m.p.=192°-194° C Recrystallization from ethanol

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8 mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K2CO3 (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phase transfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60° C. overnight. The aqueous phase was separated, and acetonitrile was removed at reduced pressure. The residue was extracted into DCM. The organic solution was washed with H2O and brine, then dried with MgSO4. The solvent was removed and the crude product (4.3 g) was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. The crystals were collected (2.53 g), m.p.=192°-194° C. Recrystallization from ethanol yielded 2.08 g of white crystals, mp=194°-195° C. The aqueous phase was separated acetonitrile was removed at reduced pressure The residue was extracted into DCM The organic solution was washed with H2O and brine dried with MgSO4 The solvent was removed The crystals were collected (2.53 g), m.p.=192°-194° C Recrystallization from ethanol

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

实验步骤: A stirred mixture of 1-chloro-3-(dimethylamino) propane hydrochloride (305.7 g), thiourea (150 g) and ethanol (1530 ml) was heated under reflux for 24 hours then cooled to ambient temperature. Ethyl acetate was added until a faint opalescence was observed, then the mixture was stored at 4° C. for 72 hours. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40° C. to give S-[3-(dimethylamino)propyl]isothiourea dihydrochloride as a white solid (403 g), m.p. 155°-157° C. was heated under reflux for 24 hours The resulting solid was collected by filtration washed with ethyl acetate dried in vacuo at 40° C.