S-(2-bromoethyl) ethanethioate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 2.27 g (0.01 mole) of 4-(N,N-dimethylamino)-2-hydroxy-2-phosphonobutanoic acid (prepared as described in Method 1) in 20 ml water and 40 ml ethanol is adjusted to pH 7.0 by addition of 1N aqueous NaOH. To this is added 9.16 g (0.05 mole) of S-acetyl-2-bromoethanethiol, and the reaction is heated at 40°-80° for several hours. The reaction is evaporated to dryness under reduced pressure. The resulting residue is triturated with acetone several times (acetone extracts are discarded). The remaining solid is dissolved in distilled water, and is treated with cation exchange resin in H+ form. The resin is filtered off, the aqueous solution is concentrated to a few ml, and acetone is added dropwise to precipitate the product. This is purified by recrystallization from water/acetone to give N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N,N-dimethylammonium bromide. the reaction is heated at 40°-80° for several hours The reaction is evaporated to dryness under reduced pressure The resulting residue is triturated with acetone several times (acetone extracts are discarded) The remaining solid is dissolved in distilled water is treated with cation exchange resin in H+ form The resin is filtered off the aqueous solution is concentrated to a few ml, and acetone is added dropwise to precipitate the product This is purified by recrystallization from water/acetone

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Octahydro-1-methyl-1-pyrindine-6,6-diphosphonic acid (0.12 mmol) is dissolved in a mixture of water (25 ml) and DMSO (5 ml). To this is added 2-acetylthioethyl bromide (0.60 mmol) and the reaction mixture is heated at 60° for 24 hours. The reaction mixture is cooled, treated with charcoal, filtered and concentrated under reduced pressure. The crude residue is triturated with diethylether and the product can be obtained by recrystallizing the solid residue in water and isopropanol. the reaction mixture is heated at 60° for 24 hours The reaction mixture is cooled filtered concentrated under reduced pressure The crude residue is triturated with diethylether the product can be obtained by recrystallizing the solid residue in water

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

Procedure: In a manner analogous to that described in Example 1(D)(c), from 4 g of tert.butyl 2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 5.43 g of S-(2-bromoethyl) thioacetate there was obtained tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Chromatography gave 1.1 g (20%) of diastereomer A having a melting point of 82°-84° C. (from diethyl ether/hexane) and 0.4 g (7%) of diastereomer B in the form of a colorless oil.

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

Procedure: (c) A solution of 1.27 g of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxyate in 10 ml of dimethylformamide was added to a suspension of 0.4 g of sodium hydride in dimethyformamide. The mixture was stirred at room temperature until the evolution of gas had ceased. 1.86 g of S-bromoethyl thioacetate were added and the mixture was heated at 75° C. for 5 hours. Working-up in the same manner as described in paragraph (D) (a) earlier gave 0.15 g (7%) of tert.butyl 2,2- bis(acetylthiomethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 85°-86° C. (from diethyl ether/hexane). the mixture was heated at 75° C. for 5 hours

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

Procedure: A solution of 2.27 g (0.01 mole) of 4-(N,N-dimethylamino)-2-hydroxy-2-phosphonobutanoic acid (prepared as described in Method 1) in 20 ml water and 40 ml ethanol is adjusted to pH 7.0 by addition of 1N aqueous NaOH. To this is added 9.16 g (0.05 mole) of S-acetyl-2-bromoethanethiol, and the reaction is heated at 40°-80° for several hours. The reaction is evaporated to dryness under reduced pressure. The resulting residue is triturated with acetone several times (acetone extracts are discarded). The remaining solid is dissolved in distilled water, and is treated with cation exchange resin in H+ form. The resin is filtered off, the aqueous solution is concentrated to a few ml, and acetone is added dropwise to precipitate the product. This is purified by recrystallization from water/acetone to give N-(2-(acetylthio)ethyl)-N-(3-carboxy-3-hydroxy-3-phosphonopropyl)-N,N-dimethylammonium bromide. the reaction is heated at 40°-80° for several hours The reaction is evaporated to dryness under reduced pressure The resulting residue is triturated with acetone several times (acetone extracts are discarded) The remaining solid is dissolved in distilled water is treated with cation exchange resin in H+ form The resin is filtered off the aqueous solution is concentrated to a few ml, and acetone is added dropwise to precipitate the product This is purified by recrystallization from water/acetone

Conditions: temp:0.00; pressure:0.00; stir: