2-chloro-1,1,1-trimethoxyethane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Method J) A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) and KOH (7.4 g, 112.2 mmol, 20 equiv.) in 2-methoxy-ethanol (9 ml) and H2O (9 ml), was stirred under N2 and under reflux, for 20 h. After cooling at r.t., the mixture was poured into water (150 ml) and extracted with CH2Cl2 (2×40 ml). The aqueous phase was neutralised with conc. HCl and extracted again with CH2Cl2 (3×70 ml). The combined neutral extracts were washed with water (2×60 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g, 10.4 mmol) and the mixture was stirred, under N2, at 60° C., for 4 h. Volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH2Cl2/hexane (10% and 50%), to give a yellow liquid (406 mg, 34% yield over two steps). HPLC-MS (method 1): m/z 212 [M+H]+, Rt=5.00 min under reflux, for 20 h extracted with CH2Cl2 (2×40 ml) extracted again with CH2Cl2 (3×70 ml) The combined neutral extracts were washed with water (2×60 ml) dried (Na2SO4) evaporated to dryness under reduced pressure Volatiles were removed by evaporation under reduced pressure the brown liquid residue was purified by column chromatography on silica eluted with CH2Cl2/hexane (10% and 50%) to give a yellow liquid (406 mg, 34% yield over two steps)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with a mixture of 648 g (4 mol) of 1,1,1-triethoxyethane and 70 g (approx. 11% by weight) of ethanol. Within 4 hours, 260 g (3.70 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 520 g of 2-chloro-1,1,1 trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%. A 1000 ml flask equipped with a stirrer and gas inlet tube did not rise above 15° C the mixture was worked-up by distillation to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with 480 g (4 mol) of 1,1,1-trimethoxyethane. Within 4 hours, 220 g (3.14 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 413 g of 2-chloro-1,1,1-trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%. A 1000 ml flask equipped with a stirrer and gas inlet tube did not rise above 15° C the mixture was worked-up by distillation to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with a mixture of 240 g (2 mol) of 1,1,1-trimethoxyethane and 1% of NaOCH3 (30%). Within 4 hours, 110 g of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. Using a distillation apparatus having approx. 5 theoretical plates, low boilers such as methanol and methyl acetate were removed in the first stages of distillation at a reflux ratio of 5:1. In the main fraction, 234 g of 2-chloro-1,1,1-trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 76%. A 500 ml flask equipped with a stirrer and gas inlet tube did not rise above 15° C the mixture was worked-up by distillation were removed in the first stages of distillation at a reflux ratio of 5:1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved in DMF (50 mL) and treated with a solution of 2-chloro-1,1,1-trimethoxyethane (0.463 g, 3.00 mmol, 2 equivalents). The reaction is stirred at room temperature until mass spectrometry shows conversion to the chloromethylbenzoxazole derivative. The solution is then treated with n-propylamine (10 mL, excess) and stirred until mass spectrometry shows conversion to the n-propylaminomethyl benzoxazole. The mixture is concentrated under reduced pressure to remove excess n-propylamine, and then poured slowly into ether (1 L) and HCl/ether is added to precipate the salt. The solid is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units with aqueous ammonia, and extracted with dichloromethane. The fractions extracted at pH 4–4.5 are combined, dried (Na2SO4), filtered and concentrated nearly to dryness. A small volume of methanol is added and the solution is treated with 1M HCl in ether. The precipitated solid is collected by filtration, washed with fresh ether and dried under vacuum to yield 0.067 g of the product as its HCl salt. stirred until mass spectrometry The mixture is concentrated under reduced pressure to remove excess n-propylamine poured slowly into ether (1 L) and HCl/ether is added The solid is rinsed with fresh ether dried under vacuum The crude solid is dissolved in water (100 mL) giving a solution at pH 2 extracted with dichloromethane The fractions extracted at pH 4–4.5 dried (Na2SO4) filtered concentrated nearly to dryness A small volume of methanol is added the solution is treated with 1M HCl in ether The precipitated solid is collected by filtration washed with fresh ether dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and trimethyl chloro-orthoacetate. Yield: 65%. mp 108.5-109° C. MS (M+H, 309.05).

Conditions: temp:118.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%). Solvent was removed under reduced pressure the residue was purified by crystallization from cold diethyl ether

Conditions: temp:118.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1C (0.3M) was added 2-chloro-1,1,1-trimethoxyethane (4.0 equivalents) and acetic acid (2.0 equivalents). The mixture was stirred for 12 hr at 118° C. Solvent was removed under reduced pressure and the residue was purified by crystallization from cold diethyl ether to afford tert-butyl 2-(chloromethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1D, 67%). Solvent was removed under reduced pressure the residue was purified by crystallization from cold diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-1,1,1-trimethoxyethane (bp 138° C.) at 130° C. for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing. Concentrate the mixture under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Reflux a solution of 2-amino-4-bromobenzamide (27 g, 0.13 mol; see Joshi and Chaudhari, (1987) Indian J. Chem., Sect. B, 26B(6):602–4) in 2-chloro-1,1,1-trimethoxyethane (50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 28 g of 7-bromo-2-chloromethyl-3H-quinazolin-4-one as a white solid. Evaporate the mixture fully triturate with ether to collect 28 g of 7-bromo-2-chloromethyl-3H-quinazolin-4-one as a white solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-1,1,1-trimethoxyethane (bp 138° C.) at 130° C. for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing. Concentrate the mixture under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-1,1,1-trimethoxyethane (bp 138° C.) at 130° C. for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing. Concentrate the mixture under reduced pressure