2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanol

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

Procedure: A total of 180.0 grams (2.0 moles) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine, and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and di-[1,4-bis(2-hydroxyethyl)piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: 170.8 g of diethanolamine (1.63 mol) is added, and after 6 hours of reaction, 30 g of water that contains 2.3 g of diethanolamine is recovered. The residual acid index is equal to 1.4 mg of KOH/g of product, and the content of N,N′-bis (2-hydroxyethyl) piperazine that is obtained by chromatographic analysis is 2.8%. 448 g of product that can be used directly as is or after dilution that is aimed at appreciably reducing viscosity so that it can be handled easily is recovered in fine. is recovered

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

Procedure: A total of 180.0 grams (2.0 moles) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine, and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and di-[1,4-bis(2-hydroxyethyl)piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: A total of 180.0 grams (2.0 moles) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine, and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and di-[1,4-bis(2-hydroxyethyl)piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(piperazine-1,4-diyl)diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl ester. MS (ES+) m/z calcd. for C39H46Cl2F2N5O5: [(M+H)+]772. found: 772.

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

Procedure: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(piperazine-1,4-diyl)diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl ester, dimer. MS (ES+) m/z calcd. for C70H73Cl4F4N8O8: [(M+H)+]1369. found: 1369.

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N'-tetra-(2-hydroxyethyl)oxamide (2.64 g, 0.01 mol) and diethanolamine (2.10 g, 0.02 mol) are charged in a reaction flask equipped as described in Example 1 and the reaction mixture is heated to 210° C. for 20 hours. Acetone (15 ml) is then added and the precipitate is recovered by filtration and recrystallized from acetone. N,N'-bis-(2-hydroxyethyl)-piperazine (0.7 g) is thus obtained with a yield on N,N'-tetra(2-hydroxyethyl)oxamide of 40.2%, calculated on the starting diethanolamine. equipped the precipitate is recovered by filtration recrystallized from acetone

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

Procedure: A total of 180.0 grams (2.0 mole) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in bis(methyl 2-piperazinoethyl)-carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and bis[1,4-(2-hydroxyethyl)-piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: A total of 180.0 grams (2.0 mole) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle. A reethanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled-and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in bis(methyl 2-piperazinoethyl)-carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and bis[1,4-(2-hydroxyethyl)-piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle A reethanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled- The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: A total of 180.0 grams (2.0 moles) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine, and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and di-[1,4-bis(2-hydroxyethyl)piperazine]carbonate (ca. 9.9 percent). equipped with a straight distillation head and a magnetic stirrer The flask contents were heated to reflux under a nitrogen atmosphere Initial reaction temperatures at reflux were 80° C. at the head and 88° C. in the kettle A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours After this time, the flask contents were cooled The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate and 1,4-bis(2-hydroxyethyl)piperazine dimethyl carbonate The kettle contents were heated for an additional period of 2.5 hours after which the reaction The kettle contents were concentrated in vacuo at 20 mm Hg a temperature of 60° C. a rotary evaporator was obtained

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

Procedure: 170.8 g of diethanolamine (1.63 mol) is added, and after 6 hours of reaction, 30 g of water that contains 2.3 g of diethanolamine is recovered. The residual acid index is equal to 1.4 mg of KOH/g of product, and the content of N,N′-bis (2-hydroxyethyl) piperazine that is obtained by chromatographic analysis is 2.8%. 448 g of product that can be used directly as is or after dilution that is aimed at appreciably reducing viscosity so that it can be handled easily is recovered in fine. is recovered