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[ CAS No. 216167-82-7 ]

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Cat. No.: {[proInfo.prAm]}
2D
Chemical Structure| 216167-82-7
Chemical Structure| 216167-82-7
Structure of 216167-82-7 *Storage: {[proInfo.prStorage]}

Quality Control of [ 216167-82-7 ]

Purity: {[proInfo.showProBatch.pb_purity]}

Related Doc. of [ 216167-82-7 ]

SDS

Product Details of [ 216167-82-7 ]

CAS No. :216167-82-7MDL No. :MFCD08690469
Formula :C35H52O5S2Boiling Point :-
Linear Structure Formula :-InChI Key :N/A
M.W :616.91Pubchem ID :216325
Synonyms :

Computed Properties of [ 216167-82-7 ]

TPSA : - H-Bond Acceptor Count : -
XLogP3 : - H-Bond Donor Count : -
SP3 : - Rotatable Bond Count : -

Safety of [ 216167-82-7 ]

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305 P351 P338UN#:N/A
Hazard Statements:H302-H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 216167-82-7 ]

  • Downstream synthetic route of [ 216167-82-7 ]

[ 216167-82-7 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 216167-82-7 ]
  • butanoic acid, 4-hydroxy-, 4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl ester [ No CAS ]
  • 2
  • [ 108-30-5 ]
  • [ 23288-49-5 ]
  • [ 216167-82-7 ]
  • [ 216168-45-5 ]
YieldReaction ConditionsOperation in experiment
44%; 9% With DBN; In acetonitrile; at 50℃; for 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (150 mg, 1.50 mmol) was added and the resulting solution was heated to 50 C. 1,5-Diazabicyclo[4.3.0]non-5-ene (0.180 mL, 0.15 mmol) was added and the solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 47% probucol by weight.
43 - 45%; 8 - 15% With 1,8-diazabicyclo[5.4.0]undec-7-ene; tetramethylurea; In tetrahydrofuran; at 20 - 50℃; for 2h;Product distribution / selectivity; Example 26 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous tetrahydrofuran. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 45% [216167-82-7]probucol monosuccinate, 15% probucol disuccinate, and 40% probucol by weight.; Example 29 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous tetrahydrofuran. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 49% probucol by weight.
41 - 42%; 10 - 13% With 1,8-diazabicyclo[5.4.0]undec-7-ene; tetramethylurea; In 1,4-dioxane; at 20 - 50℃; for 2h;Product distribution / selectivity; Example 25 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous 1,4-dioxane. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 41% [216167-82-7]probucol monosuccinate, 13% probucol disuccinate, and 46% probucol by weight.; Example 28 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous 1,4-dioxane. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 10% probucol disuccinate, and 48% probucol by weight.
41 - 48%; 9 - 15% With 1,8-diazabicyclo[5.4.0]undec-7-ene; tetramethylurea; In acetonitrile; at 20 - 50℃; for 2h;Product distribution / selectivity; Example 22 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 11% probucol disuccinate, and 46% probucol by weight.; Example 23 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 48% [216167-82-7]probucol monosuccinate, 15% probucol disuccinate, and 37% probucol by weight.; Example 27 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 1.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 45% [216167-82-7]probucol monosuccinate, 13% probucol disuccinate, and 42% probucol by weight.; Example 31 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 5.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 12% probucol disuccinate, and 44% probucol by weight.; Example 32 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.50 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 41% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 50% probucol by weight.
34%; 4% With 1,8-diazabicyclo[5.4.0]undec-7-ene; tetramethylurea; In DMF (N,N-dimethyl-formamide); at 50℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 34% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 62% probucol by weight.
32%; 4% With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In butanone; at 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (150 mg, 1.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous 2-butanone. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 32% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 64% probucol by weight.
32%; 5% With 1,8-diazabicyclo[5.4.0]undec-7-ene; tetramethylurea; In acetone; at 20℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion. To the reaction mixture was added 2.5 mL anhydrous acetone and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 32% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 63% probucol by weight.
32%; 4% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 20℃; for 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous toluene. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 32% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 64% probucol by weight.
25 - 49%; 2 - 20% With 1,8-diazabicyclo[5.4.0]undec-7-ene;dmap; In acetonitrile; at 50℃; for 1h;Product distribution / selectivity; Example 36 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) and 4-(dimethylamino)pyridine (60 mg, 0.49 mmol) were added and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 49% [216167-82-7]probucol monosuccinate, 20% probucol disuccinate, and 31% probucol by weight.; Example 37 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) and 4-(dimethylamino)pyridine (250 mg, 2.05 mmol) were added and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the resulting solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.
24 - 41%; 2 - 16% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 20℃; for 0.75 - 1h;Product distribution / selectivity; Example 5 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous 1,4-dioxane. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 41% [216167-82-7]probucol monosuccinate, 16% probucol disuccinate, and 43% probucol by weight.; Example 12 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous 1,4-dioxane. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and NaCl and the phases were separated. Analysis by HPLC of the organic layer indicated 24% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 73% probucol by weight.
22 - 40%; 2 - 8% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20 - 50℃; for 0.25 - 1h;Product distribution / selectivity; Example 4 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 40% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 51% probucol by weight.; Example 11 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. The reaction was slowly quenched with 1 N HCl, diluted with EtOAc and NaCl and the phases were separated. Analysis by HPLC of the organic layer indicated 22% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 76% probucol by weight.; Example 14 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 29% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 68% probucol by weight.
19 - 25%; 1 - 2% With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 50℃; for 2h;Product distribution / selectivity; Example 45 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 49 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 19% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 80% probucol by weight.
15 - 25% In an appropriately sized vessel, probucol (1 equivalent) and acetone (60 weight percent) are combined. With agitation potassium tert-butoxide (0.67 equivalent) is charged and the resultant solution warmed to 40 C. for about 45 minutes. Succinic anhydride (0.67 equivalent) is charged and the system stirred at 40 C. for at least 30 minutes. A dark reaction mixture forms which is a combination of the salts of di-succinylated probucol (DSP), mono-succinylated probucol (MSP) and unreacted probucol (PRO). The ratio of DSP:MSP:PRO is about 4:29:67. Example 2 The reaction mixture of Example 1 is cooled to 30 C., water is added and the pH of the reaction mixture is adjusted to >13 with 45% aqueous potassium hydroxide. The aqueous system is extracted three times with heptane. The probucol-rich heptane extractions are saved for recycle, while the aqueous acetone phase is saved for trituration. Example 3 To the acetone solution of Example 2, is charged acetone (20 volume percent) and the pH of the system is adjusted to <3 with 85 weight percent (wt %) aqueous phosphoric acid. The acidified solution is mixed for at least 30 minutes and the resulting solids, which are predominately dibasic potassium acid phosphate, are filtered and discarded. The lower, aqueous phase of the resulting two phase filtrate is separated and discarded, reserving the acetone phase. Acetone is removed from the reserved phase by distillation and heptane is added. The resultant slurry is triturated at 75-85 C. for about 30 minutes and filtered. The solid residue is reserved for later extraction. Upon cooling, the product-rich heptane filtrate provides a solid that is approximately 25 mol percent of material having the ratio 2:98, DSP:MSP Example 4 This MSP-enriched material from Example 3 is dissolved in toluene, then washed with 45% KOH. The toluene solution is dried with potassium carbonate and the solids removed by filtration. The toluene solution is then passed through clay absorb 24/48 to remove DSP. Example 5 The toluene solution collected from Example 4 is washed once with 43% aqueous H3PO4 and once with water. The toluene solution is distilled to dryness and slurried with hot heptane. The heptane slurry is cooled and filtered. The solid residue is MSP. It is washed with heptane and dried at 70 C. under vacuum. A yield of approximately 15 to 25 mol percent MSP is obtained. Specific Process Example 6 In an appropriate-sized vessel, probucol (500 g, 0.97 mol) and acetone (300 g) are combined. With agitation potassium tert-butoxide (73 g, 0.65 mol) is charged and the resultant solution warmed to 40 C. for at least 45 minutes. Succinic anhydride (65 g, 0.65 mol) is charged and the system stirred at 40 C. for at least 30 minutes. A dark reaction mixture forms which is a combination of the salt of di-succinylated probucol (DSP), the salt of mono-succinylated probucol (MSP) and unreacted probucol (PRO). The ratio of DSP:MSP:PRO is about 4:29:67. The reaction mixture is cooled to 30 C., water (300 g) is added and the pH of the reaction mixture is adjusted to >13 with 45% aqueous potassium hydroxide (KOH) (about 40 g). The aqueous system is extracted three times with heptane (513 g for each extraction). The probucol-rich heptane extractions are saved for recycle, while the aqueous acetone phase is saved for trituration. To the above-saved acetone solution, acetone is charged (158 g) and the pH of the system is adjusted to <3 with 85 wt % aqueous phosphoric acid (145 g). Additional acetone (200 g) is charged and the acidified solution is mixed for at least 30 minutes. The lower, aqueous phase is separated and discarded, reserving the acetone phase. Acetone is removed from the reserved phase by distillation and heptane (665 g) is added. The resultant slurry is triturated at 80 C. for about 30 minutes and filtered. The solid residue is reserved for later extraction. The product-rich heptane filtrate is cooled to 20 C., and the resulting precipitated MSP-enriched solids are collected by filtration. The 80 C. trituration process is repeated two more times with 410 g and 310 g of heptane, providing 133 g of a solid that is approximately 2:98, DSP:MSP. This MSP-enriched material is dissolved in toluene (500 mL), then washed with 45 g of 45% KOH. The toluene solution is mixed with potassium carbonate (44 g) for not more then 30 minutes and the solids removed by filtration. The toluene solution is then passed through clay absorb 24/48 (135 g, two passes). After each pass, the clay bed is washed twice with toluene (175 g). The toluene solution collected from the passes through the clay absorb is washed once with 43% aqueous H3PO4 (300 g) and once with water (300 g). The toluene solution is distilled to dryness and the resulting residue slurried with heptane (275 g) at 80 C. for no longer than 30 minutes. The heptane slurry is cooled to 10 C. and filtered. The solid residue is MSP. It is washed with heptane (2×70 g) and dried at 70 C. under vacuum for approxi...
15 - 49%; 1 - 18% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 50℃; for 0.25 - 2h;Product distribution / selectivity; Example 3 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 34% [216167-82-7]probucol monosuccinate, 7% probucol disuccinate, and 59% probucol by weight.; Example 7 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 15% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 83% probucol by weight.; Example 8 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 20% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 79% probucol by weight.; Example 9 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 38% [216167-82-7]probucol monosuccinate, 7% probucol disuccinate, and 55% probucol by weight.; Example 13 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was aged for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 18 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion followed by an additional 2.5 mL of acetonitrile and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 37% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 55% probucol by weight.; Example 19 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was heated to 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated overnight. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 10% probucol disuccinate, and 46% probucol by weight.; Example 21 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 5.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 12% probucol disuccinate, and 45% probucol by weight.; Example 33 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.600 mL, 4.01 mmol) was added in 1 portion and the resulting solution was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 27% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 68% probucol by weight.; Example 34 In a dry 10 mL round bottom fitte...
12 - 42%; 1 - 9% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 20 - 50℃; for 0.25 - 1h;Product distribution / selectivity; Example 1 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 6% probucol disuccinate, and 51% probucol by weight.; Example 2 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 33% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 61% probucol by weight.; Example 10 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. Analysis by HPLC of the reaction mixture indicated 12% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 87% probucol by weight.; Example 15 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 28% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 69% probucol by weight.; Example 16 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 17 In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was heated to 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated overnight. Analysis by HPLC of the reaction mixture indicated 26% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 72% probucol by weight.; Example 20 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 40% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 51% probucol by weight.
11%; 1% With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 50℃;Product distribution / selectivity; Example 44 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2CO3 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 11% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 88% probucol by weight.; Example 48 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2CO3 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 14% [216167-82-7]probucol monosuccinate, <1% probucol disuccinate, and 86% probucol by weight.
7 - 28%; < 1 - 3% With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;Product distribution / selectivity; Example 46 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2CO3 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 7% [216167-82-7]probucol monosuccinate, <1% probucol disuccinate, and 93% probucol by weight.; Example 50 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2CO3 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 28% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 69% probucol by weight.
7 - 42%; < 1 - 9% With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃; for 1h;Product distribution / selectivity; Example 47 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 7% [216167-82-7]probucol monosuccinate, <1% probucol disuccinate, and 92% probucol by weight.; Example 51 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 40% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 52% probucol by weight.; Example 53 In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (150 mg, 1.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C. and then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 49% probucol by weight.
32%Chromat.; 4%Chromat. With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In butanone; at 50℃; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (150 mg, 1.50 mmol), and Cs2C03 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous 2-butanone. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 32% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 64% probucol by weight.
44%Chromat.; 9%Chromat. With DBN; In acetonitrile; at 50℃; for 1h; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (150 mg, 1.50 mmol) was added and the resulting solution was heated to 50 C. 1,5-Diazabicyclo [4.3.0]non-5-ene (0.180 mL, 0.15 mmol) was added and the solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 47% probucol by weight.
25 - 49%Chromat.; 2 - 20%Chromat. With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃; for 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) and 4- (dimethylamino)pyridine mg, 0.49 mmol) were added and the resulting solution was heated to 50 C. 1,8- Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 49% [216167-82-7]probucol monosuccinate, 20% probucol disuccinate, and 31% probucol by weight.; Example 37: [0090] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) and 4-(dimethylamino)pyridine (250 mg, 2.05 mmol) were added and the resulting solution was heated to 50 C. 1,8- Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the resulting solution was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.
11 - 14%Chromat.; <= 1%Chromat. With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2C03 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 11% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 88% probucol by weight.; Example 48: [0101] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2C03 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo [5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 14% [216167-82-7]probucol monosuccinate, <1 % probucol disuccinate, and 86% probucol by weight.
7 - 28%Chromat.; < 1 - 3%Chromat. With potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2C03 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undee-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 7% [216167-82-7]probucol monosuccinate, <1% probucol disuccinate, and 93% probucol by weight.; Example 50: [0103] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and K2C03 (140 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 28% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 69% probucol by weight.
19 - 25%Chromat.; 1 - 2%Chromat. With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2C03 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 49: [0102] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2C03 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous dimethylformamide. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 19% [216167-82-7]probucol monosuccinate, 1 % probucol disuccinate, and 80% probucol by weight.
7 - 42%Chromat.; < 1 - 9%Chromat. With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and Cs2CO3 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and aged overnight. Analysis by HPLC of the reaction mixture indicated 7% [216167-82-7]probucol monosuccinate, <1% probucol disuccinate, and 92% probucol by weight.; Example 51: [0104] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (250 mg, 2.50 mmol), and CS2C03 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo [5.4.0]undec-7-ene (0.025 mL, 0.17 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 40% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 52% probucol by weight.; Example 53: [0106] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol), succinic anhydride (150 mg, 1.50 mmol), and Cs2C03 (330 mg, 1.01 mmol) followed by 2.5 mL anhydrous acetonitrile. The resulting reaction mixture was heated to 50 C and then charged with 1,8- diazabicyclo [5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) and heated overnight. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 49% probucol by weight.
32%Chromat.; 4%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 20℃; for 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous toluene. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo [5.4.0]undec-7-ene mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 32% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 64% probucol by weight.
41 - 42%Chromat.; 10 - 13%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; tetramethylurea; at 20 - 50℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous 1,4-dioxane. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 41% [216167-82-7]probucol monosuccinate, 13% probucol disuccinate, and 46% probucol by weight.; Example 28: [0081] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous 1,4-dioxane. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 10% probucol disuccinate, and 48% probucol by weight.
24 - 41%Chromat.; 3 - 16%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 20℃; for 0.75 - 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous 1,4-dioxane. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo [5.4.0]undec-7-ene mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 41% [216167-82-7]probucol monosuccinate, 16% probucol disuccinate, and 43% probucol by weight.; Example 12: [0065] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous 1,4-dioxane. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and NaCI and the phases were separated. Analysis by HPLC of the organic layer indicated 24% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 73% probucol by weight.
34%Chromat.; 4%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); tetramethylurea; at 50℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 34% [216167-82-7]probucol monosuccinate, 4% probucol disuccinate, and 62% probucol by weight.
12 - 42%Chromat.; 1 - 9%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In DMF (N,N-dimethyl-formamide); at 20 - 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo [5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 42% [216167-82-7]probucol monosuccinate, 6% probucol disuccinate, and 51 % probucol by weight.; Example 2: [0055] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8- Diazabicyclo [5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 33% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 61% probucol by weight.; Example 10: [0063] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8- Diazabicyclo [5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. Analysis by HPLC of the reaction mixture indicated 12% probucol mono succinate, 1% probucol disuccinate, and 87% probucol by weight.; Example 15: ' [0068] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 28% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 69% probucol by weight.; Example 16: [0069] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 17: [0070] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was heated to 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated overnight. Analysis by HPLC of the reaction mixture indicated 26% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 72% probucol by weight.; Example 20: [0073] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous dimethylformamide. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 40% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 51 % probucol by weight.
41 - 48%Chromat.; 11 - 15%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; tetramethylurea; at 20 - 50℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 11% probucol disuccinate, and 46% probucol by weight.; Example 23: [0076] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 48% [216167-82-7]probucol monosuccinate, 15% probucol disuccinate, and 37% probucol by weight.; Example 27: [0080] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 1.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 45% [216167-82-7]probucol monosuccinate, 13% probucol disuccinate, and 42% probucol by weight.; Example 31: [0084] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 5.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 12% probucol disuccinate, and 44% probucol by weight.; Example 32: [0085] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.50 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 41% [216167-82-7]probucol monosuccinate, 9% probucol disuccinate, and 50% probucol by weight.
15 - 49%Chromat.; 1 - 18%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 50℃;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 34% [216167-82-7]probucol monosuccinate, 7% probucol disuccinate, and 59% probucol by weight.; Example 7: [0060] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 15% [216167-82-7]probucol monosuccinate, 1% probucol disuccinate, and 83% probucol by weight.; Example 8: [0061] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 20% [216167-82-7]probucol monosuccinate, 1 % probucol disuccinate, and 79% probucol by weight.; Example 9: [0062] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 38% [216167-82-7]probucol monosuccinate, 7% probucol disuccinate, and 55% probucol by weight.; Example 13: [0066] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo [5.4.0]undec-7-ene mL, 1.00 mmol) was added in 1 portion and the reaction was aged for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 25% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 73% probucol by weight.; Example 18: [0071] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion followed by an additional 2.5 mL of acetonitrile and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 37% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 55% probucol by weight.; Example 19: [0072] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was heated to 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated overnight. Analysis by HPLC of the reaction mixture indicated 44% [216167-82-7]probucol monosuccinate, 10% probucol disuccinate, and 46% probucol by weight.; Example 21: [0074] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 5.0 mL anhydrous acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged overnight. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 12% probucol disuccinate, and 45% probucol by weight.; Example 33: [0086] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous acetonitrile. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.600 mL, 4.01 mmol) was added in 1 portion and the resulting solution was aged for an additional 1 h. Analysis by HPLC of the reaction mixture indicated 27% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 68% probucol by weig...
43 - 45%Chromat.; 8 - 15%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; tetramethylurea; at 20 - 50℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous tetrahydrofuran. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 45% [216167-82-7]probucol monosuccinate, 15% probucol disuccinate, and 40% probucol by weight.; Example 29: [0082] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 2.5 mL anhydrous tetrahydrofuran. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the resulting solution was aged at 50 C. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was heated for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 43% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 49% probucol by weight.
22 - 40%Chromat.; 2 - 8%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20 - 50℃; for 0.25 - 1h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo [5.4.0]undec-7-ene (0.300mL, 2.01 mmol) was added in 1 portion and the reaction was aged for an additional 1 h. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and the phases were separated. Analysis by HPLC of the organic layer indicated 40% [216167-82-7]probucol monosuccinate, 8% probucol disuccinate, and 5 1 % probucol by weight.; Example 11: [0064] In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was aged at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.075 mL, 0.50 mmol) was added in 1 portion and the reaction was aged for an additional 45 min. The reaction was slowly quenched with 1 N HCI, diluted with EtOAc and NaCI and the phases were separated. Analysis by HPLC of the organic layer indicated 22% [216167-82-7]probucol monosuccinate, 2% probucol disuccinate, and 76% probucol by weight.; Example 14: [0067] In a dry 10 mL round bottom fitted with a nitrogen inlet, thermocouple and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 2.5 mL anhydrous tetrahydrofuran. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the resulting solution was heated to 50 C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added in 1 portion and the reaction was heated for an additional 15 min. Analysis by HPLC of the reaction mixture indicated 29% [216167-82-7]probucol monosuccinate, 3% probucol disuccinate, and 68% probucol by weight.
32%Chromat.; 5%Chromat. With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetone; tetramethylurea; at 20℃; for 2h;Product distribution / selectivity; In a dry 10 mL round bottom fitted with a nitrogen inlet and stir bar was charged probucol (0.25 g, 0.48 mmol) followed by 0.25 mL 1,1,3,3-tetramethylurea and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.300 mL, 2.01 mmol) was added in 1 portion. To the reaction mixture was added 2.5 mL anhydrous acetone and the resulting solution was aged at room temperature. Succinic anhydride (250 mg, 2.50 mmol) was added in 1 portion and the reaction was aged for an additional 2 h. Analysis by HPLC of the reaction mixture indicated 32% [216167-82-7]probucol monosuccinate, 5% probucol disuccinate, and 63% probucol by weight.
With 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In acetone; at 20℃; for 48h;Product distribution / selectivity; Example 1; To a 20 mL reactor equipped with magnetic stiring was charges probucol (517 mg., 1 mmol) and acetone (2 mL). To the resulting clear solution was charged succinic anhydride (100 mg, 1 mmol). To the new, nearly colorless solution was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (iBuVSB, 330 mg, 1 mmol). Addition of the base provided an exotherm and a deep purple solution. HPLC analysis at the time intervals shown below gave the following area percent ratios (DSP is the disuccinyl ester of probucol, MSP is the monosuccinyl ester of probucol, and PRO is probucol): HPLC after: 10 minutes at ambient temperature, 0.95 DSP, 15.0 MSP, 84.1 PRO; 30 minutes at ambient temperature, unchanged; and 48 hours at ambient temperature, 0.34 DSP, 11.3 MSP, 88.4 PRO.
With 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In toluene; at 20℃; for 14h;Product distribution / selectivity; Example 2; To a 10 mL reactor equipped with magnetic stirring was charged probucol (260 mg, 0.5 mmol) and toluene (1 mL). To the resulting clear solution was charged succinic anhydride (50 mg, 0.5 mmol). The newly formed slurry was sonicated at 25 C. to give a thin slurry. To this slurry was added iBuVSB (165 mg, 0.5 mmol). Addition of the base provided an exotherm and a deep purple solution. HPLC analysis at the time intervals shown below gave the following area percent ratios (DSP is the disuccinyl ester of probucol, MSP is the monosuccinyl ester of probucol, and PRO is probucol): HPLC after: 1.5 hours at ambient temperature, 11.6 DSP, 42.1 MSP, 46.2 PRO; and 14 hours at ambient temperature, 7.64 DSP, 39.3 MSP, 52.9 PRO.
Example 1; Isolation of MSP (acid form); A solution of probucol (4Og) in tetrahydrofuran (THF) (62ml) was formed in a IL reactor, purged with nitrogen. A solution of benzylmagnesium chloride (23.8g) in THF (131ml) was added dropwise over 25 minutes. After a THF line wash (2ml), the temperature of the mixture was raised to 5O0C and a solution of succinic anhydride (8.3g) in THF (100ml) was added slowly. The mixture was stirred for 15 minutes and then sampled by HPLC, which showed that the mixture had a composition of DSP 12.6%, MSP 62.1% and probucol 22.5%.Water (27ml) was added followed by the dropwise addition of concentrated HCl (20ml) and the mixture stirred for 10 minutes. The mixture was cooled to 2O0C and allowed to stand. The lower aqueous phase was then run off. The reaction mixture was then washed twice with water (68ml) and brine (12ml).Heptane (240ml) was then added to the reaction mixture with stirring, followed by water (120ml). With vigorous stirring, a 10% sodium bicarbonate solution (68ml) was added, the mixture stirred for a further 25 minutes before being allowed to settle. The lower phase was run off, and the composition of the upper organic phase checked by HPLC and found to be DSP (2.01%), MSP (67.1%) and probucol (30.8%).The reaction mixture was stirred and heated to 5O0C when acetone (105ml) was added, followed by water (105ml) and 1.0M sodium hydroxide (6.2ml). After vigorous stirring for 10 minutes, the mixture was allowed to stand before the lower phase was run off. In this particular example the NaOH extraction was repeated to minimise the DSP level in the organic phase. The reaction mixture was stirred and cooled to 2O0C and 1.0M HCl (20ml) was added with stirring for 10 minutes. After being allowed to stand until the layers had settled, the lower aqueous phase was run off.The residual organic phase was then washed with water (20ml), and heated so that 290ml of distillate (219.2g) were removed, which included acetone and residual THF. The remaining solution was then cooled to 9O0C and heptane (200ml) added slowly maintaining the temperature at > 8O0C. After further cooling to 6O0C and seeding with MSP, crystallisation began. Once the mixture had been cooled to 2O0C and left, the solid product was filtered off through a sintered glass funnel and the filtrate recycled for recovery of probucol. This was then washed twice with heptane (70ml), dried in a vacuum oven to constant weight to yield a solid product (25.1g, 62.6%) with a composition of 98.3% MSP, 0.04%DSP and 1.7% probucol.Recrystallisation of the solid (2Og) from a mixture of heptane (150ml) and acetone (50ml) by distilling off the acetone yielded MSP with less than 0.25% probucol.; Example 3; Isolation of MSP sodium salt; A IL reactor was purged with nitrogen and charged with probucol (77.39 mmoles;40.00 g;) followed by tetrahydrofuran (62.00 mL]) and the solution was stirred (250rpm) at 25C. Benzylmagnesium chloride (158.00 mmoles; 81.45 g) was transferred to a dropping funnel under nitrogen and added dropwise at a rate that kept the temperature below 55C. A tetrahydrofuran (221.20 mmoles; 18.00 ml) line wash was carried out.Succinic anhydride (82.11 mmoles; 8.30 g) was dissolved in tetrahydrofuran (1.23 moles; 100.00 mL) by stirring in a stopped flask. The reaction mixture was heated to 500C and the succinic anhydride solution was added dropwise over 20 minutes. The reaction mixture was stirred for 15 minutes at 500C. The agitator speed was increased to 350rpm and water (1.50 moles; 27.00 mL) and then 32% hydrogen chloride (208.88 mmoles; 20.00 mL) added dropwise. The mixture was stirred and cooled to 200C and then allowed to stand. The lower phase was run off (53ml).Two water and brine washes were conducted, each by adding water (3.77 moles; 68.00 mL) followed by brine (41.07 mmoles; 12.00 mL), stirring the mixture for 10 minutes before allowing it to stand (5 minutes) and running off the lower aqueous phase.The remaining organic phase was stirred and heptane (1.64 moles; 240.00 mL) added followed by water (6.66 moles; 120.00 mL). The mixture was stirred at 400rpm and sodium bicarbonate (81.60 mmoles; 68.00 mL; 74.80 g) added. The mixture was then stirred for 35 minutes before being allowed to stand. The content of both phases was checked on HPLC at this stage, and this revealed that the upper phase (420ml - clear solution) contained 1.64% DSP : 65.8% MSP : 32.5% probucol, whereas the lower phase (240ml - yellow solution) contained 62.6% DSP : 22.1% MSP : 0.6% probucol.The reaction mixture was stirred and heated to 500C, whereupon acetone (1.43 moles; 105.00 mL; 82.96 g) and water (5.83 moles; 105.00 mL; 105.00 g) were added to the reactor, which was reheated to 500C. Then sodium hydroxide (6.40 mmoles; 6.40 mL; 6.66 g;) was added and the mixture stirred at 400rpm for 10 minutes before being allowed to stand for 10 minutes. The lower phase was then run off.Acetone (652.97 mmoles; 48.00 mL; 37.92 g) and...
EXAMPLE 1Ex-IA: A l L 2-neck round bottom flask equipped with an addition funnel, temperature probe and N2 bubbler was charged with 80.0 g (155 mmol) probucol and 160 mL of anhydrous THF. To this solution was added 157 mL (313 mmol, 2.02 eq) of 2.0 M benzylmagnesium chloride in THF at such a rate that the temperature was kept between 40- 510C. After the addition was complete, the temperature of the mixture was adjusted to 41C and a solution of 17.0 g (170 mmol, 1.1 eq) succinic anhydride in 192.6 g anhydrous THF was added over 30 min. The temperature over the addition was maintained between 40-450C. After the addition was complete the reaction mixture was allowed to stir for 40 min. Analysis by HPLC indicated 58.3% MSP, 12.0% DSP and 27.5% probucol. The reaction was quenched by the slow addition of 98.0 g (370 mmol) of 4 N HCl and148.5 g of water at 40-500C. After the quench, the reaction mixture was cooled to 2O0C and the phases were separated. The organic layer was washed with 160 g of water. The organic layer was washed a second time with 16O g of water. Analysis by HPLC of the organic phase (414.01 g) indicated 58.7% MSP, 12.6% DSP, and 26.1% probucol.; Ex-6A: A l L 2-neck round bottom flask equipped with an addition funnel, temperature probe and N2 bubbler was charged with 80.0 g (155 mmol) probucol and 160 mL of anhydrous THF. To this solution was added 157 mL (313 mmol, 2.02 eq) of 2.0 M benzylmagnesium chloride in THF at such a rate that the temperature was kept between 40- 510C. After the addition was complete, the temperature of the mixture was adjusted to 41C and a solution of 17.0 g (170 mmol, 1.1 eq) succinic anhydride in 194.7 g anhydrous THF was added over 30 min. The temperature over the addition was maintained between 40-45C. EPO After the addition was complete the reaction mixture was allowed to stir for 1 hour. Analysis by HPLC indicated 56.7% MSP, 11.0% DSP and 30.2% probucol.The reaction was quenched by the slow addition of 98.1 g (370 mmol) of 4 N HCl and148.0 g of water at 40-500C. After the quench, the reaction mixture was cooled to 20C and the phases were separated. The organic layer was washed with 160 g of water. The organic layer (401.37 g) was washed a second time with 16O g of water. Analysis by HPLC of the organic phase indicated 58.0% MSP, 12.7% DSP, and 26% probucol.; Ex-17A: A 500 gallon jacketed reactor equipped with baffles, a condenser and a pitched-blade turbine agitator was charged with 150 kg (290 mol) probucol and 220 kg THF. To this solution, at 20C, was added 397 kg (560 mol) of 1.41 M benzylmagnesium chloride in THF at such a rate that the maximum temperature was less than 370C. After the addition was complete, the mixture was heated to about 400C and a solution of 29.5 kg (295 mol) succinic anhydride in 298 kg THF was added over 20 min. The temperature over the addition was maintained at 40-45 C. After the addition was complete the reaction mixture was allowed to stir for 30 min. Analysis by HPLC indicated 60.4% MSP, 12.6% DSP, and 25.4% probucol. An additional charge of 2.9 kg (29.5 mol) succinic anhydride in 29.8 kg THF was loaded to the reactor over 10 min. After the addition was complete the reaction mixture was allowed to stir for 15 min. Analysis by HPLC indicated 62.4% MSP, 16.4% DSP, and 19.7% probucol.The reaction was quenched with the slow addition of 161 kg of 13.7 wt% HCl at a temperature of 40-500C. After the quench, the reaction mixture was cooled to 250C. The mixture was allowed to settle for 30 min and 220 kg of aqueous phase was removed (the aqueous layer was EPO pH 0). The organic layer was washed with 147 kg of 20% brine, and 137 kg of aqueous phase was removed. The organic layer was washed with 147 kg of 20% brine, and 154 kg of aqueous phase was removed. To the organic layer were added 113 kg of 20% brine and 75 kg of 17.0 wt% NaOH. The mixture was allowed to settle for 2 hours and 100 kg of aqueous phase was removed (the aqueous layer was pH 9.8).The volume of the organic phase was reduced by about V% via atmospheric distillation and 532 kg of distillate was removed overhead. The distillation was continued while adding 719 kg of heptanes, and an additional 777 kg of distillate was collected. GC analysis at the end of the distillation indicated that the THF concentration was less than 2 wt% relative to heptanes. An additional 612 kg of heptanes was added over 90 min while maintaining the internal temperature above 70C. The mixture was allowed to cool to 200C over 70 min and then held at this temperature for about 1 hour. The slurry was cooled to 5C and 57 kg of water was added. The slurry was allowed to stir for 90 min. The slurry was filtered in a 30" diameter centrifuge with a 1-3 micron polypropylene filter cloth. Each centrifuge load of wetcake was rinsed with 23 kg of ambient temperature heptanes, and 1045 kg of combined mother liquor and rinse was collected. A total of 293 kg of MSP/DSP sodium salt wetcake (conta...
EXAMPLE 39Ex-39A: A l L 2-neck round bottom flask equipped with an addition funnel, temperature probe and N2 bubbler was charged with 80.0 g (155 mmol) probucol and 210 mL of anhydrous THF. To this solution was added 105 mL (313 mmol, 2.02 eq) of 3.0 M methylmagnesium chloride in THF at such a rate that the temperature was kept between 40- 5O0C. After the addition was complete, the temperature of the mixture was adjusted to 41C and a solution of l7.1 g (171 mmol, 1.1 eq) succinic anhydride in 173 g anhydrous THF was added over 30 min. The temperature over the addition was maintained between 40-45C. After the addition was complete the reaction mixture was allowed to stir for 45 min. Analysis by HPLC indicated 59.5% MSP, 21.6% DSP and 17.6% probucol.The reaction was quenched by the slow addition of 100.3 g (377 mmol) of 4 N HCl and 151.9 g of water at 40-500C. After the quench, the reaction mixture was cooled to 200C and the phases were separated. The organic layer was washed with 148.5 g of 3% brine. The organic layer was washed a second time with 149.5 g of 3% brine and then treated with 48.0 mL (240 mmol) of 5 N NaOH and 200 mL of 10% brine. The reaction mixture was stirred at 2O0C for 1 hour and the layers were separated (aqueous layer pH was 13.1).The organic layer was concentrated to 251.3 g by distillation at 9O0C. After charging 251.2 g of heptanes, the organic layer was concentrated to 234.0 g by distillation at 9O0C. An additional 246.7 g of heptanes was added at 9O0C and the resulting slurry was slowly cooled to 20C and stirred for an additional 1 hour. The slurry was filtered and then washed with 75.3 g of heptanes. The wetcake was washed a second time with 76.9 g of heptanes. A total of 173.4 g of wetcake was collected. Analysis by HPLC indicated 73.2% MSP, 26.4% DSP and 0.4% probucol. Analysis by HPLC of the filtrate indicated 0.2% MSP, 0.1% DSP and 99.5% probucol.; Ex-71 : A 250 mL 2-neck round bottom flask equipped with an addition funnel, temperature probe and N2 bubbler was charged with 20.0 g (38.7 mmol) probucol and 50 mL of anhydrous THF. To this solution was added 25.8 mL (77.4 mmol, 2.0 eq) of 3.0 M methylmagnesiurn chloride in THF at such a rate that the temperature was kept between 40- 50C. After the addition was complete, the temperature of the mixture was adjusted to 41C and a solution of 3.68 g (36.8 mmol, 0.95 eq) succinic anhydride in 37.2 g anhydrous THF was added over 30 min. The temperature during the addition was maintained between 40-45C. After the addition was complete the reaction mixture was allowed to stir for 60 min at 450C. HPLC analysis indicated 57.7% MSP, 15.1% DSP and 26.1% probucol.The reaction was quenched by the slow addition of 24.6 g (98.4 mmol) of 4 N HCl and 43.9 g of water at 40-50C. After the quench, the reaction mixture was cooled to 2O0C and the phases were separated. The organic layer was washed with 40.5 g of 3% brine. The organic layer was washed a second time with 39.7 g of 3% brine. The organic layer was diluted with 82 g of EtOAc and concentrated under reduced pressure at 90C until about 1/2 of the solvent was removed. An additional 106 g of EtOAc was added and the organic solution was concentrated under reduced pressure at 90C until about 1/2 of the solvent was removed. The mixture was diluted with 80 g heptanes and the distillation was repeated Heptanes was added to obtain a 12 wt% MSP solution (22.4 mmol). The heptanes solution was transferred to a 500 mL round bottom flask and heated to5O0C. The solution was treated with 46.1 g of acetone, 41.1 g of 0.5% brine, and 2.50 mL (12.5 mmol) of 5 N NaOH. After stirring for 15 min, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 77.1% MSP, 2.1% DSP, and 20.6% probucol, and the aqueous layer contained 21.4% MSP and 73.5% DSP. The layers were cut. The organic solution was treated with were added 35.1 g of acetone, 41.5 g of 0.5% brine, and 0.22 mL (1.1 mmol, 13.6 mmol total) of 5 N NaOH. After stirring for 15 min at 5O0C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 67.4% MSP, 0.15% DSP, and 32.3% probucol, and the aqueous layer contained 37.7% MSP and 60.6% DSP. The layers were cut. The organic solution was treated with 35.4 g of acetone, 41.1 g of0.5% brine, and 0.22 mL (0.22 mmol, 13.82 mmol total) of 1 N NaOH. After stirring for 15 min at 5O0C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis EPO indicated the organic layer contained 67.1% MSP, 0.0% DSP, and 32.8% probucol, and the aqueous layer contained 83.0% MSP and 9.8% DSP.The layers were cut. The organic solution was transferred to a 500 mL round bottom flask and acidified by adding 3.4 mL of 4 N HCl (13.7 mmol) and 25.4 mL of water. After stirring for 15 min at 50C, the layers were separated and the organic layer was concentrated at 7O0C under 350 mniHg to 1/2 volume...
EXAMPLE 38Ex-38A: A l L 2-neck round bottom flask equipped with an addition funnel, temperature probe and N2 bubbler was charged with 80.0 g (155 mmol) probucol and 160 mL of anhydrous THF. To this solution was added 155 mL (310 mmol, 2.0 eq) of 2.0 M isopropylmagnesium chloride in THF at such a rate that the temperature was kept between 40- 500C. After the addition was complete, the temperature of the mixture was adjusted to 41C and a solution of 16.3 g (163 mmol, 1.05 eq) succinic anhydride in 163 g anhydrous THF was added over 30 min. The temperature over the addition was maintained between 40-450C. After the addition was complete the reaction mixture was allowed to stir for 45 min. Analysis by HPLC indicated 59.8% MSP, 13.5% DSP and 24.2% probucol. The reaction was quenched by the slow addition of 98.4 g (370 mmol) of 4 N HCl and152.0 g of water at 40-500C. After the quench, the reaction mixture was cooled to 200C and the phases were separated. The organic layer was washed with 152.0 g of 3% brine. The organic layer was washed a second time with 152.0 g of 3% brine and then treated with 40.4 mL (202 mmol) of 5 N NaOH and 200 mL of 10% brine. The reaction mixture was stirred at 2O0C for 45 min and the layers were separated (aqueous layer pH was 13.0).The organic layer was concentrated to 251.O g by distillation at 9O0C. After charging 259.0 g of heptanes, the organic layer was concentrated to 253.2 g by distillation at 9O0C. An additional 260.0 g of heptanes was added at 9O0C and the resulting slurry was slowly cooled to EPO 2O0C and stirred for an additional 1 hour. The slurry was filtered and then washed with 81.0 g of heptanes. The wetcake was washed a second time with 74.2 g of heptanes. A total of 145.1 g of wetcake was collected. Analysis by HPLC indicated 80.4% MSP, 18.4% DSP and 0.6% probucol. Analysis by HPLC of the filtrate indicated 99.2% probucol.

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  • 3
  • [ 107-35-7 ]
  • [ 216167-82-7 ]
  • 2-(4-(2,6-di-tert-butyl-4-((2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)propan-2-yl)thio)phenoxy)-4-oxobutanamido)ethane-1-sulfonic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; water; at 20℃; 4-(2,6-di-tert-butyl-4-((2-((3,5-di-tert-butyl-4-hydroxyphenyl))thio)propan-2-yl)) Thio)phenoxy)-4-oxobutanoic acid (1.37 g, 2.21 mmol), sulfuric acid (1.37 g, 11.055 mmol), DCC (0.68 g, 3.31 mmol) and DMAP (0.40 g, 3.31 mmol) To a mixed solution of THF (40 mL) and H 2 O (20 mL). The resulting reaction solution was stirred at room temperature, and the reaction was monitored by TLC. Concentrate under reduced pressure to remove excess organic solvent. (50 mL) and saturated brine (10 mL). Crude product chromatography Column (silica gel, EtOAc: PE = 1:50 to 1:20) to give the product 2-(4-(2,6-di-tert-butyl-4-((2-((3)5-di-tert-butyl) -4-hydroxyphenyl)thio)propan-2-yl)thio)phenoxy)-4-oxobutyramide)ethane-1-sulfonic acid (650 mg, yield 40%), White foamy solid.
  • 4
  • [ 108-30-5 ]
  • [ 23288-49-5 ]
  • [ 216167-82-7 ]
YieldReaction ConditionsOperation in experiment
50% With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃;Inert atmosphere; Under N2 protection, NaH (2.0 g, 58.3 mmol, 70% mineral oil protection) was added in portions to dry THF (30 mL) at 0 C and then added to Probucol (3.0 g, 5.8). Methyl) and succinic anhydride (0.64 g, 6.4 mmol). The resulting mixture was stirred at room temperature and the reaction was monitored by TLC. After the reaction is completed, the organic solvent is concentrated under reduced pressure. The residual liquid was poured into H2O (50 mL).Then EtOAc (100 mL) was added. Crude product chromatography Purification (silica gel, 200-300 mesh,EtOAc: PE = 10:1),A white solid (1.2 g, yield 50%) was obtained.
  • 5
  • mono-succinylprobucol sodium salt [ No CAS ]
  • DSP sodium salt [ No CAS ]
  • [ 216167-82-7 ]
  • [ 216168-45-5 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; water; In n-heptane; acetone; at 50℃; for 0.5h;Purification / work up; Ex-74B: A 100 mL round bottom flask was charged with 10.0 g of MSP/DSP sodium salt wetcake (containing water and heptanes) obtained from Ex-74A, 33.4 g of heptanes. 9.2 g of acetone and 10.4 g of acetone. The resulting mixture was treated with 1.3 mL (5.2 mmol) of 4 N HCl, stirred at 50C for 30 min. The mixture was allowed to settle and the layers were analyzed. HPLC analysis of the organic layer indicated 97.8% MSP, 1.47% DSP and 0.72% probucol and the aqueous layer contained 59.7% MSP and 40.2% DSP
With hydrogenchloride; water; In tetrahydrofuran; at 25℃; for 1h;Purification / work up; EXAMPLE 76Ex-76A: A l L round bottom flask was charged with 70 g of MSP/DSP sodium salt wetcake (containing water and heptanes) obtained from Ex-74A and 110 mL of THF. The solution was treated with 43.3 g of water, 37 mL (148 mmol) of 4N HCl, 60 g of 10% brine, and the mixture was stirred at 250C for 1 hour.The layers were cut and the organic solution was washed twice with 60 g of 10% brine.. HPLC analysis of the organic layer (157 g) indicated the presence of 81.4% MSP, 18.0% DSP and 0.37% probucol.
  • 6
  • mono-succinylprobucol sodium salt [ No CAS ]
  • [ 216167-82-7 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; water; In toluene; at 20 - 50℃; for 0.25 - 4h;pH 0.6 - 8;Purification / work up; Ex-17B: A 300 gallon jacketed reactor equipped with baffles, a condenser, and a pitched-blade turbine agitator was charged with 291 kg of MSP/DSP sodium salt wetcake (containing water and heptanes) obtained from Ex-17A. The wetcake was slurried in 1045 kg of toluene and heated to 75C for about 30 min. The mixture was cooled to 450C and held for 40 min. The slurry was filtered at 45 C in a 30 gallon Nutsche pressure filter with a 1-3 micron polypropylene filter cloth. The filtrate from the Nutsche was transferred to a 500 gallon jacketed reactor equipped with baffles, a condenser, and a pitched-blade turbine agitator. A total of 46 kg of wetcake was collected in 4 loads. The average wetcake composition of the first 3 loads was 22.2% MSP, 77.5% DSP, and 0.3% probucol. The final load of wetcake was rinsed with 65 kg of toluene. The composition of the final load of wetcake was 3.1% MSP and 96.9% DSP. The combined rinse and filtrate contained 87.2% MSP and 12.8% DSP, as measured by HPLC.The filtrate was transferred back to the 300 gallon jacketed reactor and heated to 45C, and then filtered in a 30" diameter centrifuge with a 1-3 micron polypropylene cloth. The EPO filtrate from the centrifuge was transferred to the 500 gallon jacketed reactor. A total of 66 kg of wetcake was collected in 2 loads. The final load of wetcake was rinsed with 9 kg of toluene. The average centrifuge wetcake composition was 24.7% MSP, 75% DSP, 0.3% probucol. The combined rinse and filtrate contained 95.4% MSP, 3.2% DSP, and 1.4% probucol. The filtrate was partially acidified by adding 39.9 kg (150 mol) of 13.7 wt% HCl and234 kg of water. After stirring for 1 hour at 25C, the mixture was allowed to settle for 1.5 hours and 296 kg of aqueous phase was removed (pH of the aqueous layer was 7.4). To the organic phase were added 190 kg of water and 190 kg acetone. After stirring for 1 hour at 50C, the mixture was allowed to settle for 3 hours and 241 kg of aqueous phase was removed. To the organic phase were added 325 kg of water and 168 kg acetone. After stirring for 30 min at 50C, the mixture was allowed to settle for 30 min and 392 kg of aqueous phase was removed. The composition of the remaining organic phase by HPLC was 96.9% MSP, 1.65 % DSP, and 1.3% probucol.To the organic phase was added 340 kg of water. After stirring for 30 min at 50C. the mixture was allowed to settle for 2 hours and 403 kg of aqueous phase was removed. To the organic phase were added 303 kg of water and 45 kg of acetone. After stirring for 40 min at 5O0C, the mixture was allowed to settle for 75 min and 353 kg of aqueous phase was removed. To the organic phase were added 179 kg of water and 1.9 kg (8 mol) of 17 wt% NaOH. After stirring for 35 min at 250C, the mixture was allowed to settle for 1 hour and 192 kg of aqueous phase was removed. To the organic phase was added 340 kg of water. After stirring for 30 min at 250C, the mixture was allowed to settle for 1 hour and 484 kg of aqueous phase was removed. The composition of the remaining organic phase by HPLC was 98.5% MSP, 0.15% DSP, and 1.35% probucol.To the organic phase were added 576 kg of water and 0.8 kg (3.4 mol) of 17 wt% NaOH. After stirring for 30 min at 250C, the mixture was allowed to settle for 2 hours and 597 kg of aqueous phase was removed. The composition of the remaining organic phase by HPLC was 98.5% MSP, 0.12% DSP, and 1.36% probucol.To the organic phase was added 170 kg of water. After stirring for 30 min at 25C, the mixture was allowed to settle for 1 hour and 144 kg of aqueous phase was removed. The composition of the remaining organic phase by HPLC was 98.5% MSP, 0.12% DSP, and 1.35% probucol.The organic phase was acidified by adding 20 kg (75 mol) of 13.7 wt% HCl and 168 kg of water. After stirring for 1 hour at 250C, the mixture was allowed to settle for 1 hour and EPO 211 kg of aqueous phase was removed (pH of the aqueous layer was 0.8). The organic phase was washed with 159 kg of water, and 268 kg of aqueous phase was removed. The organic phase was concentrated by atmospheric distillation until about 636 kg of distillate had been collected. The distillation was continued while adding 272 kg of heptanes, and an additional 135 kg of distillate was collected. GC analysis at the end of the distillation indicated that the toluene concentration was less than 40 wt% relative to heptanes. The temperature was adjusted to 80C and the mixture was diluted with an additional 499 kg of heptanes.The mixture was cooled below 5C and the resulting slurry was held for 12 hours. The slurry was filtered in a 30" diameter centrifuge with a 1-3 micron polypropylene filter cloth. Each centrifuge load of wetcake was rinsed with 45 kg of cold heptanes, and the 500 gallon jacketed reactor was rinsed with 289 kg of heptanes. A total of 1181 kg of combined mother liquor and rinse was collected. A total of 122 kg of wetcake was collected in 4 loads. The average wetcake composition by HPLC ...
With hydrogenchloride; water; In ethyl acetate; at 25℃; for 0.25h;pH 1 - 2;Purification / work up; EXAMPLE 29 Ex-29A: A 500 mL round bottom flask was charged with 385 g of ethyl acetate filtrate containing MSP sodium salt obtained in a similar manner to Ex-23. The composition by HPLC was 97.9% MSP, 1.1% DSP, and 1.0% probucol. The filtrate contained approximately 11 wt% MSP (68.6 mmol) on a free acid basis. The filtrate was acidified by adding 17.6 mL of 4 N HCl (70.4 mmol) and 50 mL of water. The pH of the aqueous layer was 1-2. The aqueous layer was removed and the organic phase was washed with 75 mL of water.The acidified ethyl acetate organic phase was concentrated by distillation at atmospheric pressure until 284 g of distillate was collected. The distillation was continued while adding 250 mL of heptanes, and an additional 250 mL of distillate was collected. The final reactor temperature was 94C. An additional 310 mL of heptanes was added and the mixture was cooled to 5O0C. Some solids precipitated out of solution. All solids were dissolved by adding 120 mL of acetone to the mixture.; Ex-37B: A l L round bottom flask equipped with a stir bar and a N2 bubbler was charged with 136.21 g of MSP/DSP sodium salt wetcake (containing water and heptanes) obtained from Ex-37A. Ethyl acetate (436.8 g) was then added and the resulting slurry was heated to 7O0C for about 1 hour. The mixture was cooled to 25C and held for 1.5 hours. The slurry was filtered and then rinsed with 40 mL of ethyl acetate. The composition of the wetcake by HPLC was 2.0% MSP and 98% DSP. The composition of the combined mother liquor and rinse was 98.0% MSP, 1.0% DSP, and 1.0% probucol.The estimated weight of MSP in the filtrate was 57.73 g (91.95 mmol), assuming a 59.4% yield of MSP from probucol, up to this point in the process. The mixture was then completely acidified by adding 25.5 mL of 4 N HCl and 76.5 mL of water. After stirring for EPO 15 min at 250C, the aqueous phase was removed (pH of the aqueous layer was 1.23). The organic phase was washed twice with 100 mL of water (pH of the aqueous layer following second wash was 3.51). The composition of the final organic phase by HPLC was 98.0% MSP, 1% DSP, and 1% probucol. The organic phase was charged to a 1 L round bottom flask and about 2/3 of the solvent was removed by vacuum distillation at 350 mmHg. The mixture was diluted to the original volume with fresh heptanes and the distillation was repeated. Heptanes was then added to obtain a 12 wt% MSP solution (91.95 mmol). GC analysis indicated that the ethyl acetate concentration was less than 2 wt% relative to heptanes. The MSP free acid/heptanes solution was then transferred to a 2 L round bottom flask and the solution was heated to 5O0C. To the solution were added 132.8 g of acetone, 167 g of 0.5% brine, and 5.52 mL (5.52 mmol) of 1 N NaOH. After 15 min the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 98.1% MSP, 1% DSP, and 0.9% probucol, and the aqueous layer contained 74.0% MSP and 26.0% DSP. The pH of the aqueous layer was 6.52.Without separating the layers, an additional 2.76 mL (2.76 mmol, 8.28 mmol total) of 1 N NaOH was added while the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 98.0% MSP, 0.8% DSP, and 0.8% probucol, and the aqueous layer contained 28% MSP and 71% DSP. The pH of the aqueous layer was 7.11. Without separating the layers, an additional 1.84 mL (1.84 mmol, 10.12 mmol total) of1 N NaOH was added while the mixture was stirred at 50C. HPLC analysis indicated the organic layer contained 98.6% MSP, 0.5% DSP, and 0.8% probucol, and the aqueous layer contained 18% MSP and 81% DSP. The pH of the aqueous layer was 7.43.Without separating the layers, an additional 1.38 mL (1.38 mmol, 11.5 mmol total) of 1 N NaOH was added while the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 98.9% MSP, 0.3% DSP, and 0.7% probucol, and the aqueous layer contained 21% MSP and 78% DSP. The pH of the aqueous layer was 7.65. The layers were cut. To the organic solution at 5O0C were added 132.8 g of acetone and 167 g of 0.5% brine. HPLC analysis indicated the organic layer contained 99% MSP, 0.1% DSP, and 0.8% probucol, and the aqueous layer contained 63% MSP and 37% DSP. The pH of the aqueous layer was 7.68.Without separating the layers, an additional 0.69 mL (0.69 mmol, 12.19 mmol total) of 1 N NaOH was added and the mixture was stirred at 500C. HPLC analysis indicated the EPO organic layer contained 99.0% MSP, 0.07% DSP, and 0.9% probucol, and the aqueous layer contained 68% MSP and 31% DSP. The pH of the aqueous layer was 7.85.The layers were cut. The organic solution was transferred to a 1 L round bottom flask equipped with a N2 bubbler and then completely acidified by adding 3.31 mL of 4 N HCl and 100 mL of water. After stirring for 15 min at 5O0C, the aqueous phase was removed (pH of the aqueous layer was 1.34) and the organic layer at 500C was washed with 100 mL water (...
  • 7
  • [ 216167-82-7 ]
  • [ 216168-45-5 ]
  • mono-succinylprobucol sodium salt [ No CAS ]
  • DSP sodium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.25 - 2h;pH 9.8 - 13.69;Purification / work up; Ex-IB: To 47.31 g of the organic solution obtained from Ex-IA were added 3.45 g(14.4 mmol) of 5 N NaOH and 20 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (50 mL) and toluene (50 mL) were added and the layers were cut. Analysis by HPLC of the organic phase indicated 48% MSP, 0.25% DSP, and 52% probucol, and the aqueous layer contained 68% MSP, 22% DSP5 and 6% probucol.; Ex-2: To 43.92 g of the organic solution obtained from Ex-IA were added 1.94 g (8.1 mmol) of 5 N NaOH and 20 mL water. The solution was concentrated via distillation at 7O0C EPO to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (50 mL) and toluene (50 mL) were added and the layers were cut. Analysis by HPLC of the organic phase indicated 66% MSP, 1.4% DSP, and 32% probucol.; Ex-4: To 41.26 g of the organic solution obtained from Ex-IA were added 1.91 g (7.96 mmol) of 5 N NaOH and 20 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Toluene (50 mL) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 66% MSP, 1.3% DSP, and 32% probucol, and the aqueous phase contained 26% MSP, 66% DSP, and 0.3% probucol. ; Ex-5: To 46.62 g of the organic solution obtained from Ex-IA were added 2.03 g (8.46 mmol) of 5 N NaOH and 20 mL water. Toluene (50 mL) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 66% MSP, 1.8% DSP, and 32% probucol, and the aqueous phase contained 31% MSP, 57% DSP, and 0.6% probucol. Ex-14: To 32.92 g of the organic solution obtained from Ex-6A were added 1.0 g(4.17 mmol) of 5 N NaOH and 15 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 62% EPO MSP, 8.5% DSP, and 29% probucol, and the aqueous layer contained 21% MSP, 55% DSP, and 0.8% probucol.; Ex-18A: A 500 gallon jacketed reactor equipped with baffles, a condenser and a pitched-blade turbine agitator was charged with 150 kg (290 mol) probucol and 180 kg THF. To this solution, at 2O0C, was added 397 kg (560 mol) of 1.41 M benzylmagnesium chloride in THF at such a rate that the maximum temperature was less than 41C. After the addition was complete, the mixture was heated to about 400C and a solution of 29.9 kg (299 mol) succinic anhydride in 303 kg THF was added over 35 min. The temperature over the addition was EPO maintained at 40-45C. After the addition was complete the reaction mixture was allowed to stir for 30 mm. Analysis by HPLC indicated 57.3% MSP, 12.3% DSP, and 28.8% probucol. The reaction was quenched with the slow addition of 181 kg of 13.7 wt% HCl at a temperature of 40-50C. After the quench, the reaction mixture was allowed to cool to 20-250C. The mixture was allowed to settle for 30 min and 246 kg of aqueous phase was removed (the aqueous layer was pH 0). The organic layer was washed with 299 kg of water, and 392 kg of aqueous phase was removed. The orgam'c layer was washed with 331 kg of 2% brine, and 485 kg of aqueous phase was removed. To the organic layer were added 407 kg of 10% brine and 84 kg of 17.0 wt% NaOH. The mixture was allowed to settle for 120 min and 429 kg of aqueous phase was removed (the aqueous layer was pH 12.8).The volume of the organic phase was reduced by about 1A via atmospheric distillation and 355 kg of distillate was collected overhead. The distillation was continued while adding 485 kg of heptanes, and an additional 540 kg of distillate was collected. GC analysis at the end of the distillation indicated that the THF concentration was less than 2.2 wt% relative to heptanes.An additional 612 kg of heptanes was added over 75 min maintaining the internal temperature above 700C. The mixture was allowed to cool to 2O0C over 70 min and then held at this temperature for about 2.5 hours. The slurry was filtered in a 30" diameter centrifuge with a 1-3 micron polypropylene filter cloth. Each centrifuge load of wetcake was rinsed with 45 kg of ambient temperature heptanes, and 867 kg of combined mother liquor and rinse was collected. A total of 243 kg of MSP/DSP sodium salt wetcake (containing water and heptanes) was collected in 3 loads. The average wetcake composition by HPLC was 81.0% MSP, 17.2% DSP, and 1.8% probucol. HPLC analysis of the mother liquor indicated 99.8% probucol.; Ex-19A: A 500 gallon jacketed reactor equipped with baffles, a condenser and a pitched-blade turbine agitator was charged with 150 kg (290 mol) probucol and 179 kg THF. To this solution, at 20C, was added 397 kg (560 mol) of 1.41 M benzylmagnesium chloride in THF at such a rate that the maximum temperature was less than 40C. After the addition was complete, the mixtur...
With sodium hydroxide; In n-heptane; water; ethyl acetate; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 88Ex-88A: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 22.5 g of heptanes, 67.5 g of ethyl acetate and 20 g of acetone. HPLC analysis of the resulting solution indicated 97.4% MSP, 1.14% DSP, and 1.5% probucol.; Ex-88B: To 12.0 g of the MSP solution obtained from Ex-88A were added 4.0 mL water and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.18% DSP, and 1.6% probucol, and the aqueous layer contained 60.2% MSP, 39% DSP and 0.9% probucol. EXAMPLE 89Ex-89: To 12.0 g of the MSP solution obtained from Ex-88A were added 4.0 mL 0.5% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.6% MSP, 0.85% DSP, and 1.5% probucol, and the aqueous layer contained 86% MSP, 12% DSP and 1.5% probucol.; Ex-90: To 12.0 g of the MSP solution obtained from Ex-88A were added 4.0 niL0.13% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.9% MSP, 0. 5% DSP, and 1.6% probucol, and the aqueous layer contained 74.2% MSP, 24.6% DSP and1.3% probucol.; Ex-91 A: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 45 g of heptanes, 45 g of ethyl acetate and 20 g of acetone. HPLC analysis of the resulting solution indicated 97.6%MSP, 1.12% DSP, and 1.3% probucol.; Ex-91B: To 12.0 g of the MSP solution obtained from Ex-91A were added 4.0 mL water and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.18% DSP, and 1.6% probucol, and the aqueous layer contained 85% MSP, 13.5% DSP and 1.34% probucol.; Ex-92: To 12.0 g of the MSP solution obtained from Ex-91A were added 4.0 mL 0.5% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.7% MSP, 0.69%DSP, and 1.5% probucol, and the aqueous layer contained 90.1% MSP, 7.7% DSP and 1.5% probucol.; Ex-93: To 12.0 g of the MSP solution obtained from Ex-91A were added 4.0 mL 0.13% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.1% MSP,0.37% DSP, and 1.6% probucol, and the aqueous layer contained 75.2% MSP, 23.7% DSP and1.1% probucol.; Ex-94A: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 67.5 g of heptanes, 22.5 g of ethyl acetate and 20 g of acetone. HPLC analysis of the resulting solution indicated 97.6%MSP5 0.96% DSP, and 1.5% probucol.; EPO Ex-94B: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 niL water and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.13% DSP, and 1.6% probucol, and the aqueous layer contained 68% MSP5 31% DSP and 1.4% probucol.; Ex-95: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 mL 0.5% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.8% MSP, 0.64% DSP, and 1.6% probucol, and the aqueous layer contained 89.7% MSP, 8.9% DSP and 1.4% probucol.; Ex-96: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 mL 0.13% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.2% MSP, 0.32% DSP, and 1.5% probucol, and the aqueous layer contained 86% MSP, 13% DSP and 1.3% probucol.; Ex-97A: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 mL 0.5% brine, 2 mL acetone and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.55% DSP, and 1.5% probucol, and the aqueous layer contained 68% MSP, 31% DSP and 1.4% probucol.; Ex-97B: Without cutting the layers the biphasic mixture obtained from Ex-97A was heated to 5O0C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.57% DSP, and 1.5% probucol.
With sodium hydroxide; In n-heptane; water; ethyl acetate; at 70℃; for 0.25h;Purification / work up; EXAMPLE 113Ex-113: A 200 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes, 9.5 g of ethyl acetate and 20 mL water. After heating to 7O0C the mixture was treated with 275 uL 1 N NaOH. After stirring for 15 min at 7O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.21% DSP, and 1.5% probucol, and the aqueous layer contained 5.65% MSP and 94.2% DSP. Without cutting the layers 100 mg NaCl was added to the mixture and aged at 700C for 15 min. HPLC analysis indicated the organic layer contained 97.5% MSP, 0.9% DSP, and 1.5% probucol, and the aqueous layer contained 49.6% MSP and 50.4% DSP.
With sodium hydroxide; In ethanol; n-heptane; water; at 20 - 50℃; for 0.0166667 - 0.0833333h;Purification / work up; EXAMPLE 104Ex-104A: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 90 g of heptanes and 20 g of ethyl alcohol. HPLC analysis of the resulting solution indicated 97.3% MSP, 1.1% DSP, and 1.6% probucol.; Ex-104B: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL0.5% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.8% MSP, EPO 0.61% DSP, and 1.6% probucol, and the aqueous layer contained 92.4% MSP, 6% DSP and1.4% probucol.; Ex-105: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL 0.13% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.1% MSP, 0.37% DSP, and 1.6% probucol, and the aqueous layer contained 50% MSP and 50% DSP.; Ex-106: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL water and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.1% MSP, 0.3% DSP, and 1.6% probucol, and the aqueous layer contained 73% MSP and 27% DSP; Ex-107: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL 0.5% brine, 2 mL ethyl alcohol and 50 uL 1 N NaOH. After stirring for 5 min at 5O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.5% MSP, 0.87% DSP, and 1.6% probucol, and the aqueous layer contained 90% MSP and 10% DSP. ; Ex-108: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL0.13% brine, 2 mL ethyl alcohol and 50 uL 1 N NaOH. After stirring for 5 min at 5O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.6% MSP, 0.83% DSP, and 1.6% probucol, and the aqueous layer contained 90.7% MSP and 9.3% DSP.; Ex-109: To 12.0 g of the MSP solution obtained from Ex-104A were added 4.0 mL water, 2 mL ethyl alcohol and 50 uL 1 N NaOH. After stirring for 5 min at 5O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.5% MSP, 0.83% DSP, and 1.6% probucol, and the aqueous layer contained 92.9% MSP and 7.1% DSP.; Ex-110: A 200 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes and 10 g of ethyl alcohol. The mixture was then heated to 500C. HPLC analysis of the resulting solution EPO indicated 97.3% MSP, 1.2% DSP, and 1.5% probucol. Water (20 niL) and 275 uL 1 N NaOH were then added. After stirring for 5 min at 5O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.13% DSP, and 1.5% probucol, and the aqueous layer contained 46.6% MSP and 53.4% DSP; Ex-Ill : A 200 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes and 10 g of ethyl alcohol. The mixture was then heated to 5O0C. HPLC analysis of the resulting solution indicated 97.4% MSP, 1.2% DSP3 and 1.4% probucol. 0.13% Brine (20 mL) and 275 uL 1 N NaOH were then added. After stirring for 5 min at 5O0C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.25% DSP, and 1.5% probucol, and the aqueous layer contained 39.2% MSP and 60.8% DSP. After 1 hour at 5O0C the biphasic mixture was heated to 7O0C and held. HPLC analysis indicated the organic layer contained 98.4% MSP, 0.19% DSP, and 1.4% probucol, and the aqueous layer contained 41.7% MSP and 58.3% DSP.
With sodium hydroxide; In tetrahydrofuran; n-heptane; water; at 65℃; for 0.25h;Purification / work up; Ex-112: A 200 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes, 7.65 g of THF and 20 mL water. After heating to 650C the mixture was treated with 275 uL 1 N NaOH and 100 mg NaCl. After stirring for 15 min at 650C the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.1% MSP, 0.43% DSP, and 1.5% probucol, and the aqueous layer contained 59.8% MSP and 40.2% DSP.
With sodium hydroxide; In n-heptane; water; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 100Ex-IOOA: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 90 g of heptanes and 36 g of acetone. HPLC analysis of the resulting solution indicated 97.5% MSP, 0.9% DSP, and 1.7% probucol.; Ex-IOOB: To 12.0 g of the MSP solution obtained from Ex-IOOA were added 4.0 mL0.5% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.4% MSP, 0.3%DSP, and 1.3% probucol, and the aqueous layer contained 92.1% MSP, 6.5% DSP and 1.5% probucol.; Ex-IOOC: Without cutting the layers the biphasic mixture obtained from Ex-IOOB was heated to 5O0C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.17% DSP, and 1.5% probucol, and the aqueous layer contained 31% MSP and 69% DSP.; Ex-103A: To 12.0 g of the MSP solution obtained from Ex-IOOA were added 4.0 mL 0.13% brine and 50 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.5% MSP, 0.12% DSP, and 1.4% probucol, and the aqueous layer contained 77.9% MSP, 21% DSP and 1.0% probucol.; Ex-103B: Without cutting the layers the biphasic mixture obtained from Ex-103 A was heated to 500C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 98.4% MSP, 0.07% DSP, and 1.5% probucol, and the aqueous layer contained 53.5% MSP and 46.5% DSP.; Ex-76B: 31.5 g of the organic solution obtained from Ex-76A was concentrated under reduced pressure at 80C. The clear yellow oil was taken up in 50 g of acetone, concentrated under reduced pressure at 80C and repeated. GC analysis indicated no residual THF present. The residue was diluted with heptanes to yield a 12 wt% MSP solution (11.7 mmol). The heptanes solution was treated with 16.8 g of acetone, 22.4 g of 0.5% brine and heated to 5O0C. The reaction mixture was treated with 0.59 mL (2.90 mmol) of 5 N NaOH. After stirring 15 min at 5O0C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 93.3% MSP, 6.12% DSP, and 0.40% probucol, and the aqueous layer contained 9.4% MSP and 90.5% DSP.An additional 0.23 mL (1.17 mmol, 4.07 mmol total) of 5 N NaOH was added to the reaction mixture. After stirring 15 min at 5O0C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 95.6% MSP, 3.83% DSP, and 0.44% probucol, and the aqueous layer contained 13.5% MSP and 86.3% DSP.An additional 0.23 mL (1.17 mmol, 5.24 mmol total) of 5 N NaOH was added to the reaction mixture. After stirring 15 min at 5O0C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 98.1% MSP, 1.24% DSP, and 0.51% probucol, and the aqueous layer contained 36.5% MSP and 63.2% DSP.An additional 0.23 mL (1.17 mmol, 6.41 mmol total) of 5 NNaOH was added to the reaction mixture. After stirring 15 min at 500C, the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 98.6% MSP, 0.66% DSP, and 0.60% probucol, and the aqueous layer contained 55.9% MSP and 43.7% DSP.
In hexanes; water; ethyl acetate; acetone; at 20℃; for 0.0166667h;Purification / work up; EXAMPLE 82Ex-82A: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 10 g of MSP, 100 mg of DSP, 100 mg of probucol, 45 g of hexanes, 45 g of ethyl acetate and 18 g of acetone. HPLC analysis of the resulting solution indicated 97.5% MSP,1.1% DSP, and 1.4% probucol.Ex-82B: To 9.15 g of the MSP solution obtained from Ex-82A were added 3.5 mL water, 1.5 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.4% MSP, 0.18% DSP, and 1.4% probucol, and the aqueous layer contained 54% MSP and 46%DSP.; Ex-83: To 9.15 g of the MSP solution obtained from Ex-82A were added 3.5 mL water, 3 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3%MSP, 0.15% DSP, and 1.5% probucol, and the aqueous layer contained 70% MSP, 29% DSP and 1.0% probucol.; Ex-84: To 9.15 g of the MSP solution obtained from Ex-82A were added 3.5 mL water, 4.5 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.4%MSP, 0.14% DSP, and 1.4% probucol, and the aqueous layer contained 64% MSP5 35% DSP and 0.8% probucol.; Ex-85: To 9.15 g of the MSP solution obtained from Ex-82A were added 3.5 mL water, 6 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.4% EPO MSP, 0.19% DSP, and 1.5% probucol, and the aqueous layer contained 70% MSP and 30%DSP.; Ex-86: To 9.15 g of the MSP solution obtained from Ex-82A were added 3.5 mL 1% brine, 3 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.4% MSP, 0.9% DSP, and 1.7% probucol, and the aqueous layer contained 85% MSP, 14% DSP and 1.3% probucol.; Ex-87: To 9.15 g of the MSP solution obtained from Ex-82 A were added 3.5 mL0.5% brine, 3 mL acetone and 45 uL 1 N NaOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.8% MSP, 0.73% DSP, and 1.4% probucol, and the aqueous layer contained 66.9% MSP, 31.7% DSP and 1.3% probucol.
In n-heptane; water; acetone; at 50℃; for 0.5h;Purification / work up; EXAMPLE 40Ex-40: A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes and 18 g of acetone. HPLC analysis of the resulting solution indicated 97.7% MSP, 0.8% DSP, and 1.5% probucol. The solution was then charged with 20 mL of 0.5% brine and heated to 5O0C. To the mixture were added 0.275 mL (0.275 mmol) of 1 N NaOH. After 30 min the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 98.2% MSP, 0.2% DSP, and 1.6% probucol, and the aqueous layer contained 27% MSP and 73% DSP.The layers were cut. To the organic solution at 500C were added 9 g of acetone and 20 mL of water. HPLC analysis indicated the organic layer contained 98.4% MSP and 1.6% probucol, and the aqueous layer contained 75% MSP and 25% DSP.; Ex-41 : A 250 mL round bottom flask equipped with a stir bar and a N2 bubbler was charged with 5 g of MSP, 50 mg of DSP, 50 mg of probucol, 45 g of heptanes and 18 g of acetone. HPLC analysis of the resulting solution indicated 97.8% MSP, 0.8% DSP, and 1.4% probucol. The solution was then charged with 20 mL of 0.13% brine and heated to 50C. To EPO the mixture were added 0.275 mL (0.275 mmol) of 1 N NaOH. After 30 min the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 98.5% MSP and 1.5% probucol, and the aqueous layer contained 38% MSP and 62% DSP. The layers were cut. To the organic solution at 5O0C were added 9 g of acetone and 20 mL of water. HPLC analysis indicated the organic layer contained 98.6% MSP, and 1.4% probucol, and the aqueous layer contained 88% MSP and 12% DSP.

  • 8
  • [ 216167-82-7 ]
  • [ 216168-45-5 ]
  • C35H51O5S2(1-)*Li(1+) [ No CAS ]
  • C39H54O8S2(2-)*2Li(1+) [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium hydroxide; In tetrahydrofuran; water;Purification / work up; EXAMPLE 3 Ex-3: To 32.11 g of the organic solution obtained from Ex-IA were added 7.42 mL(7.42 mmol) of 1 N LiOH and 20 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (50 mL) and toluene (50 mL) were added and the layers were cut. Analysis by HPLC of the organic phase indicated 66% MSP, 1.9% DSP, and 32% probucol. The aqueous layer was extracted with additional ethyl acetate (25 mL) and toluene (25 mL). Analysis by HPLC of the organic phase indicated 67% MSP, 1% DSP, and 32% probucol, and the aqueous phase contained 22% MSP, 65% DSP, and 0.3% probucol.; Ex-6B: To 42.61 g of the organic solution obtained from Ex-6A were added 13.5 mL(13.5 mmol) of 1 N LiOH and 4 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (37 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 48%MSP, 1.7% DSP, and 50% probucol, and the aqueous layer contained 64% MSP, 18% DSP, and 15% probucol.; Ex-7: To 39.47 g of the organic solution obtained from Ex-6A were added 10 mL(10.0 mmol) of 1 N LiOH and 6 mL water. The solution was concentrated via distillation at7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (37 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 58%MSP, 2% DSP, and 39% probucol, and the aqueous layer contained 58% MSP3 30% DSP, and 5% probucol.; Ex-8: To 40.18 g of the organic solution obtained from Ex-6A were added 6.3 mL (6.3 mmol) of 1 N LiOH and 12 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (37 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 63%MSP, 6% DSP, and 30% probucol, and the aqueous layer contained 27% MSP, 56% DSP, and1% probucol.; Ex-9: To 52.74 g of the organic solution obtained from Ex-6A were added 16.7 mL (16.7 mmol) of 1 N LiOH and 4 mL water. Ethyl acetate (37 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 54% MSP, 4% DSP, and 40% probucol, and the aqueous layer contained 62% MSP, 21% DSP, and 12% probucol.; Ex-15: To 30.30 g of the organic solution obtained from Ex-6A were added 3.89 mL (3.89 mmol) of 1 N LiOH and 11 mL water. The solution was concentrated via distillation at 700C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 62% MSP, 8.8% DSP, and 29% probucol, and the aqueous layer contained 18% MSP, 57% DSP, and 0.7% probucol.
With lithium hydroxide; In n-heptane; water; ethyl acetate; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 98Ex-98A: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 mL 0.5% brine and 50 uL 1 N LiOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.52% DSP, and 1.6% probucol, and the aqueous layer contained 92% MSP, 6.5% DSP and 1.4% probucol.; EPO Ex-98B: Without cutting the layers the biphasic mixture obtained from Ex-98A was heated to 500C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.57% DSP, and 1.6% probucol.
With lithium hydroxide; In n-heptane; water; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 101Ex-IOlA: To 12.0 g of the MSP solution obtained from Ex-IOOA were added 4.0 mL0.5% brine and 50 uL 1 N LiOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.3%DSP, and 1.4% probucol, and the aqueous layer contained 86.9% MSP, 11.7% DSP and 1.4% probucol.; EPO Ex-IOlB: Without cutting the layers the biphasic mixture obtained from Ex-IOlA was heated to 500C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.19% DSP, and 1.5% probucol, and the aqueous layer contained 66.7% MSP3 32.3% DSP, and 0.96% probucol.
  • 9
  • [ 216167-82-7 ]
  • [ 216168-45-5 ]
  • C35H51O5S2(1-)*K(1+) [ No CAS ]
  • C39H54O8S2(2-)*2K(1+) [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; In tetrahydrofuran; water;Purification / work up; Ex-IO: To 36.87 g of the organic solution obtained from Ex-6A were added 2.94 g (12.25 mmol) of 5 N KOH and 15 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 45% MSP, 0.7% DSP. and 54% probucol, and the aqueous layer contained 66% MSP, 20% DSP3 and 10% probucol.; Ex-Il: To 34.34 g of the organic solution obtained from Ex-6A were added 2.19 g (9.13 mmol) of 5 N KOH and 15 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 57% MSP, 1.6% DSP, and 41% probucol, and the aqueous layer contained 60% MSP5 29% DSP, and 5% probucol.; Ex-12: To 29.93 g of the organic solution obtained from Ex-6A were added 1.48 g (6.17 mmol) of 5 N KOH and 15 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 63% MSP, 3% DSP, and 33% probucol, and the aqueous layer contained 39% MSP, 49% DSP, and 1.5% probucol.; Ex-13: To 37.05 g of the organic solution obtained from Ex-6A were added 1.18 g (4.92 mmol) of 5 N KOH and 15 mL water. The solution was concentrated via distillation at 7O0C to remove the tetrahydrofuran and then cooled to ambient temperature. Ethyl acetate (26 g) was added and the layers were cut. Analysis by HPLC of the organic phase indicated 62% MSP, 8.8% DSP, and 29% probucol, and the aqueous layer contained 22% MSP, 55% DSP, and 1% probucol.
With potassium hydroxide; In n-heptane; water; ethyl acetate; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 99 Ex-99A: To 12.0 g of the MSP solution obtained from Ex-94A were added 4.0 niL0.5% brine and 50 uL 1 N KOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.5%DSP, and 1.5% probucol, and the aqueous layer contained 85.6% MSP, 13% DSP and 1.3% probucol.; Ex-99B: Without cutting the layers the biphasic mixture obtained from Ex-99A was heated to 5O0C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.51% DSP, and 1.6% probucol.
With potassium hydroxide; In n-heptane; water; acetone; at 20 - 50℃; for 0.0166667 - 0.1h;Purification / work up; EXAMPLE 102Ex-102A: To 12.0 g of the MSP solution obtained from Ex-IOOA were added 4.0 mL 0.5% brine and 50 uL 1 N KOH. After stirring for 1 min at ambient temperature the layers were allowed to settle. HPLC analysis indicated the organic layer contained 98.2% MSP, 0.3% DSP, and 1.5% probucol, and the aqueous layer contained 86% MSP, 13% DSP and 1.3% probucol.; Ex-102B: Without cutting the layers the biphasic mixture obtained from Ex-102 A was heated to 5O0C for 5 min and then held at 50c for the layers to separate. HPLC analysis indicated the organic layer contained 98.3% MSP, 0.15% DSP, and 1.5% probucol, and the aqueous layer contained 57.7% MSP and 42.3% DSP.
  • 10
  • [ 216167-82-7 ]
  • mono-succinylprobucol sodium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 3; Isolation of MSP sodium salt; A IL reactor was purged with nitrogen and charged with probucol (77.39 mmoles;40.00 g;) followed by tetrahydrofuran (62.00 mL]) and the solution was stirred (250rpm) at 25C. Benzylmagnesium chloride (158.00 mmoles; 81.45 g) was transferred to a dropping funnel under nitrogen and added dropwise at a rate that kept the temperature below 55C. A tetrahydrofuran (221.20 mmoles; 18.00 ml) line wash was carried out.Succinic anhydride (82.11 mmoles; 8.30 g) was dissolved in tetrahydrofuran (1.23 moles; 100.00 mL) by stirring in a stopped flask. The reaction mixture was heated to 500C and the succinic anhydride solution was added dropwise over 20 minutes. The reaction mixture was stirred for 15 minutes at 500C. The agitator speed was increased to 350rpm and water (1.50 moles; 27.00 mL) and then 32% hydrogen chloride (208.88 mmoles; 20.00 mL) added dropwise. The mixture was stirred and cooled to 200C and then allowed to stand. The lower phase was run off (53ml).Two water and brine washes were conducted, each by adding water (3.77 moles; 68.00 mL) followed by brine (41.07 mmoles; 12.00 mL), stirring the mixture for 10 minutes before allowing it to stand (5 minutes) and running off the lower aqueous phase.The remaining organic phase was stirred and heptane (1.64 moles; 240.00 mL) added followed by water (6.66 moles; 120.00 mL). The mixture was stirred at 400rpm and sodium bicarbonate (81.60 mmoles; 68.00 mL; 74.80 g) added. The mixture was then stirred for 35 minutes before being allowed to stand. The content of both phases was checked on HPLC at this stage, and this revealed that the upper phase (420ml - clear solution) contained 1.64% DSP : 65.8% MSP : 32.5% probucol, whereas the lower phase (240ml - yellow solution) contained 62.6% DSP : 22.1% MSP : 0.6% probucol.The reaction mixture was stirred and heated to 500C, whereupon acetone (1.43 moles; 105.00 mL; 82.96 g) and water (5.83 moles; 105.00 mL; 105.00 g) were added to the reactor, which was reheated to 500C. Then sodium hydroxide (6.40 mmoles; 6.40 mL; 6.66 g;) was added and the mixture stirred at 400rpm for 10 minutes before being allowed to stand for 10 minutes. The lower phase was then run off.Acetone (652.97 mmoles; 48.00 mL; 37.92 g) and water (4.44 moles; 80.00 mL; 80.00g;) were charged to the reactor and allowed to heat to 500C. Sodium hydroxide (1.20 mmoles; 1.20 mL; 1.25 g) was then added and the mixture stirred at 400rpm for 10 minutes before allowing to stand for 10 minutes. Again, the lower phase was run off. The residual upper phase was found to contain 0.07% DSP : 66.4% MSP (in the form of the sodium salt): 33.5% probucol. The organic phase was stirred and water (13.2 moles; 240ml) added followed by sodium bicarbonate solution (57.60 moles; 48.00ml; 52.8Og). The mixture was stirred for 60minutes, whereupon the lower aqueous phase was run off (355ml) and discarded.Water (1.11 moles; 20.00ml) and brine (68.44 mmoles;20.00ml) were added and the mixture stirred for 5 minutes before allowing to stand. The lower phase was checked on HPLC and found to contain almost no product. The organic phase was then washed with brine (68.44 mmoles; 20.00 mL; 20.00 g), and then heated to distill off the acetone. The heptane solution containing MSP sodium salt and probucol was then distilled at atmospheric pressure collecting 160ml of distillate.The solution was cooled to 900C and heptane (1.09 moles; 160.00 mL; 109.38g;) added slowly maintaining the temperature above 800C. The solution was cooled to 600C, and seeded with (lOmg) MSP sodium salt. The solution was then allowed to self cool and stir over the weekend at room temp.The resultant solid was filtered off using a glass sintered funnel. The product was de- liquored and the liquors returned to the reactor and stirred vigorously to facilitate removal of product residues in the reactor.The liquors were filtered through the sinter and the product de-liquored. Heptane (409.32 mmoles; 60.00 mL; 41.02 g;) was charged to the reactor and stirred for 5 minutes in the reactor before using to wash the product. This was repeated with a further charge of heptane (409.32 mmoles; 60.00 mL; 41.02 g). The product was thoroughly de-liquored and then after pulling dry on the sinter for 20 minutes, was dried in a vacuum oven at 400C to constant weight. Wt of product = 25.8g. which was determined by HPLC to comprise: 0.00% DSP : 98.7% MSP (sodium salt): 1.28% probucol.
With sodium hydroxide; In water; acetone; toluene; at 50℃;pH 7.2 - 7.8;Purification / work up; EXAMPLE 36 Ex-36: 117.7 g of a toluene/MSP free acid solution was charged to a 250 mL round bottom flask. The composition of the filtrate by HPLC was 98.1% MSP, 1.0% DSP and 1.0% probucol. Based on HPLC assay, the filtrate contained 8.2 wt% MSP (14.85 mmol MSP). To this solution were added 30 mL of water and 30 mL of acetone. The mixture was heated to EPO 5O0C and 0.322 g (0.309 mmol) of 1 N NaOH was added. The mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 99.0% MSP and 1.0% DSP, and the aqueous layer contained 95% MSP and 5% DSP. The pH of the aqueous layer was 7.2. Without separating the layers, an additional 0.153 g (0.147 mmol, 0.456 mmol total) of1 N NaOH was added and the mixture was stirred at 50C. HPLC analysis indicated the organic layer contained 99.2% MSP and 0.8% DSP, and the aqueous layer contained 33% MSP and 67% DSP. The layers separated cleanly, and the pH of the aqueous layer was 7.8.Without separating the layers, an additional 0.158 g (0.152 mmol, 0.608 mmol total) of I N NaOH was added and the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 99.5% MSP and 0.5% DSP, and the aqueous layer contained 18% MSP and 82% DSP. The layers separated cleanly.Without separating the layers, an additional 0.150 g (0.144 mmol, 0.752 mmol total) of 1 N NaOH was added and the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 99.6% MSP and 0.4% DSP, and the aqueous layer contained 23% MSP and 77% DSP. The layers separated cleanly.Without separating the layers, an additional 0.144 g (0.138 mmol, 0.890 mmol total) of 1 N NaOH was added and the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 99.8% MSP and 0.2% DSP, and the aqueous layer contained 44% MSP and 56%DSP. The layers separated cleanly.Without separating the layers, an additional 0.135 g (0.130 mmol, 1.020 mmol total) of 1 N NaOH was added and the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 99.85% MSP and 0.15% DSP, and the aqueous layer contained 19% MSP and 81% DSP. The layers separated more slowly, with a slight white rag layer. Without separating the layers, an additional 0.142 g (0.136 mmol, 1.156 mmol total) of1 N NaOH was added and the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 99.88% MSP and 0.12% DSP. The layers separated slowly, with a large white rag layer.Without separating the layers, an additional 0.16O g (0.154 mmol, 1.310 mmol total) of I N NaOH was added and the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 99.90% MSP and 0.10% DSP. The layers separated very slowly, with a large white rag layer.
With sodium hydroxide; In n-heptane; water; acetone; at 50℃; for 0.25h;pH 6.14 - 7.93;Purification / work up; Ex-47C: 81.88 g of the organic solution (containing 9.24 g MSP) obtained from Ex- 47B was charged to a 250 mL round bottom flask and about 2/3 of the solvent was removed by vacuum distillation at 6O0C (350 mmHg). The mixture was diluted to the original volume with fresh heptanes and the distillation was repeated Heptanes was then added to obtain a 12 wt% MSP solution (15.0 mmol). GC analysis indicated that the ethyl acetate concentration was about 6 wt% relative to heptanes.The MSP free acid/heptanes solution was then heated to 50C. To the solution were added 26.4 g of acetone, 33 g of 0.5% brine, and 0.62 mL (0.62 mmol) of 1 N NaOH. After 15 min the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 97.0% MSP, 0.99% DSP, and 1.8% probucol, and the aqueous layer contained 73% MSP and 27% DSP. The pH of the aqueous layer was 6.14.Without separating the layers, an additional 0.413 mL (0.413 mmol, 1.03 mmol total) of 1 N NaOH was added while the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 97.1% MSP, 0.90% DSP, and 1.8% probucol, and the aqueous layer contained 51% MSP and 42% DSP. The pH of the aqueous layer was 6.82.Without separating the layers, an additional 0.62 mL (0.62 mmol, 1.65 mmol total) of 1 N NaOH was added while the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 97.9% MSP, 0.31% DSP, and 1.8% probucol, and the aqueous layer contained 24.5% MSP and 67.6% DSP. The pH of the aqueous layer was 7.58. The layers were cut. To the organic solution at 5O0C were added 13.2 g of acetone and33 g of 0.5% brine. HPLC analysis indicated the organic layer contained 98.0% MSP, 0.2% DSP, and 1.8% probucol, and the aqueous layer contained 44% MSP, 51% DSP, and 0% probucol. The pH of the aqueous layer was 7.32. EPO Without separating the layers, an additional 0.10 mL (0.10 mmol, 1.75 mmol total) of 1 N NaOH was added and the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 98.1% MSP5 0.14% DSP, and 1.81% probucol, and the aqueous layer contained 39% MSP, 56% DSP, and 0% probucol. The pH of the aqueous layer was 7.61. Without separating the layers, an additional 0.413 mL (0.413 mmol, 2.16 mmol total) of 1 N NaOH was added and the mixture was stirred at 500C. HPLC analysis indicated the organic layer contained 98.6% MSP, 0.05% DSP, and 1.36% probucol, and the aqueous layer contained 39% MSP and 56% DSP.; Ex-48: 86.91 g of the organic solution (containing 9.8 g MSP) obtained from Ex-47B was washed with 19 g of water. The layers were cut. The organic phase was then charged to a 250 mL round bottom flask and about 2/3 of the solvent was removed by vacuum distillation at 600C (350 mmHg). The mixture was diluted to the original volume with fresh heptanes and the distillation was repeated Heptanes was then added to obtain a 12 wt% MSP solution (15.91 mmol). GC analysis indicated that the ethyl acetate concentration was about 5 wt% relative to heptanes.The MSP free acid/heptanes solution was then heated to 500C. To the solution were added 28 g of acetone, 35 g of 0.5% brine, and 0.62 mL (0.62 mmol) of 1 N NaOH. After 15 min the mixture was allowed to settle and the layers were analyzed. HPLC analysis indicated the organic layer contained 97.2% MSP, 0.99% DSP, and 1.6% probucol, and the aqueous layer contained 65% MSP and 35% DSP. The pH of the aqueous layer was 6.14. Without separating the layers, an additional 0.62 mL (0.62 mmol, 1.24 mmol total) of 1 N NaOH was added while the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 97.7% MSP, 0.79% DSP, and 1.40% probucol. The pH of the aqueous layer was 7.04.Without separating the layers, an additional 0.207 mL (0.207 mmol, 1.45 mmol total) of 1 N NaOH was added while the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 97.5% MSP, 0.52% DSP, and 1.85% probucol, and the aqueous layer contained 17.2% MSP and 72.9% DSP. The pH of the aqueous layer was 7.34. Without separating the layers, an additional 0.413 mL (0.413 mmol, 1.86 mmol total) of 1 N NaOH was added while the mixture was stirred at 5O0C. HPLC analysis indicated the organic layer contained 98.1% MSP, 0.18% DSP, and 1.66% probucol, and the aqueous layer contained 29.70% MSP and 63.18% DSP. The pH of the aqueous layer was 7.73. EPO The layers were cut. To the organic solution at 5O0C were added 14 g of acetone and 35 g of 0.5% brine. HPLC analysis indicated the organic layer contained 98.0% MSP, 0.07% DSP, and 1.87% probucol, and the aqueous layer contained 55% MSP and 41% DSP. The pH of the aqueous layer was 7.69; Ex-49: 77.75 g of the organic solution (containing 8.78 g MSP) obtained from Ex-47B was washed with 17 g of 3% brine. The layers were cut. The organic solution was then charged to a 250 niL round bottom flask and about 2/3 of the solvent was removed by vacuum distil...
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