Home Cart Sign in  
Chemical Structure| 84449-80-9 Chemical Structure| 84449-80-9
Chemical Structure| 84449-80-9

Raloxifene Benzoic Acid Impurity

CAS No.: 84449-80-9

4.5 *For Research Use Only !

Cat. No.: A426746 Purity: 95%

Change View

Size Price

US Stock

Global Stock

In Stock
1g łÇǶÊÊ Inquiry Inquiry
5g łÇÿ¶ÊÊ Inquiry Inquiry
10g łË§¶ÊÊ Inquiry Inquiry
25g łÍ§¶ÊÊ Inquiry Inquiry
100g łÇòÿ¶ÊÊ Inquiry Inquiry

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

  • 1g

    łÇǶÊÊ

  • 5g

    łÇÿ¶ÊÊ

  • 10g

    łË§¶ÊÊ

  • 25g

    łÍ§¶ÊÊ

  • 100g

    łÇòÿ¶ÊÊ

In Stock

- +

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

  • 1-2 Day Shipping
  • High Quality
  • Technical Support
Product Citations

Alternative Products

Product Details of Raloxifene Benzoic Acid Impurity

CAS No. :84449-80-9
Formula : C14H20ClNO3
M.W : 285.77
SMILES Code : O=C(O)C1=CC=C(OCCN2CCCCC2)C=C1.[H]Cl
MDL No. :MFCD06657755
Boiling Point : No data available
InChI Key :CMVTYSMYHSVDIU-UHFFFAOYSA-N
Pubchem ID :5743835

Safety of Raloxifene Benzoic Acid Impurity

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Raloxifene Benzoic Acid Impurity

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 84449-80-9 ]

[ 84449-80-9 ] Synthesis Path-Downstream   1~30

  • 1
  • [ 84449-80-9 ]
  • [ 166975-76-4 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; In N-methyl-acetamide; 1,2-dichloro-ethane; EXAMPLE 5 6-acetoxy-2-(4-acetoxyphenyl)-3-[4(2-piperidinoethoxy)benzoyl]benzo[B]thiophene, hydrochloride An acylating agent, in acid chloride form, was prepared by combining 26.3 g of 4-(2-piperidino-ethoxy)benzoic acid, hydrochloride, 36.5 g of thionylchloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane.
With thionyl chloride; In N-methyl-acetamide; 1,2-dichloro-ethane; EXAMPLE 9 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride An acylating agent, in acid chloride form, was prepared by combining 26.3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 36.5 g. of thionyl chloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane.
With thionyl chloride; In N-methyl-acetamide; 1,2-dichloro-ethane; EXAMPLE 1 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride An acylating agent, in acid chloride form, was prepared by combining 26.3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 36.5 g. of thionyl chloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane.
  • 2
  • [ 89407-97-6 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In acyl acetate; water; for 5 - 13h;Heating / reflux;Product distribution / selectivity; Example 1; Preparation of 4-(2-piperidinoethoxy)Benzoic Acid Hydrochloride; To a 2000 gallon reaction tank were added: 1320L of amyl acetate, 167.42 kg of methyl 4-hydroxybenzoate, 408.6 kg of anhydrous potassium carbonate, and 283.5 kg of beta-chloroethylpiperidine hydrochloride. The mixture was heated to 120° C.-125° C. for 5 hours, at which time HPLC analysis indicated complete consumption of the methyl 4-hydroxybenzoate. The tank was cooled to less than 50° C. 880 L of deionized water were added to the tank. The layers were separated and the aqueous layer was discarded. In a glass-lined tank was mixed 367 liters of food grade hydrochloric acid and 184 L of deionized water. The acid mixture was combined with the organic layer. The layers were separated and the organic layer was discarded. The mixture of the intermediate ester in aqueous acid heated to reflux until HPLC suggested no further consumption of the ester (13 hours). The mixture was cooled to less than 40° C., 550 liters of acetone was added to the mixture and the mixture was cooled to 0° C.-5° C. and stirred for 1 hour. The product was collected by filtration on a centrifuge. The wet cake was rinsed on the centrifuge with 400 L of acetone. The product was dried in a rotary vacuum (double cone) dryer at less than 50° C. and 25-27 inches in mercury. Yield was 91percent of theoretical. Example 2; Preparation of 4-(2-piperidinoethoxy)Benzoic Acid Hydrochloride; A 17.57 g portion of methyl 4-hydroxybenzoate and 132 mL of amyl acetate were combined. To this slurry at ambient temperature, was added 29.19 g of potassium carbonate sesquihydrate (particle size 96percent greater than 100 mesh, 100percent greater than 200 mesh) and 20.26 g of beta-chloroethylpiperidine hydrochloride. The mixture was heated to 110° C.-115° C. for 4.5 hours. The solution was cooled to less than 50° C. and 88 ml of deionized water were added. The layers were separated and the aqueous layer was discarded. To the organic phase was added 88 mL of deionized water the biphasic mixture stirred for 15 minutes and the phases separated. The aqueous phase was discarded. A dilute solution of aqueous hydrochloride acid was prepared by adding 42.6 g of reagent grade hydrochloric acid to 15 mL of deionized water. This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. After approximately 1.5 hours at reflux the desired product began to precipitate. The product slurry was cooled to less than 40° C. and 55 mL of acetone was added. The mixture was cooled to 0° C.-5° C. and stirred for 1 hour. The product was collected by filtration and washed with a minimum of acetone pre-chilled to 0° C. The product was dried in a vacuum oven at ambient temperature. Yield was 90.6percent of theory. The potency of the product by HPLC compared to a reference standard was 99.2percent. Example 3; Preparation of 4-(2-piperidinoethoxy)Benzoic Acid Hydrochloride; A 17.57 g portion of methyl 4-hydroxybenzoate and 132 mL of amyl acetate were combined. To this slurry at ambient temperature, was added 29.19 g of powdered potassium carbonate (11percent water by Karl Fischer particle size not less than 95percent passing a 100 mesh sieve and not less than 90percent passing a 200 mesh sieve) and 20.26 g of beta-chloroethylpiperidine hydrochloride. The mixture was heated to 110° C.-115° C. for 4.5 hours. The solution was cooled to less than 50° C. and 88 mL of deionized water were added. The layers were separated and the aqueous layer was discarded. To the organic phase was added 88 mL of deionized water the biphasic mixture stirred for 15 minutes and the phases separated. The aqueous phase was discarded. A dilute solution of aqueous hydrochloride acid was prepared by adding 42.6 g of reagent grade hydrochloric acid to 15 mL of deionized water. This solution was added to the organic phase, stirred for 15 minutes and the phases separated. The organic phase was discarded. The aqueous phase was heated to reflux for 5 hours. After approximately 1.5 hours at reflux the desired product began to precipitate. The product slurry was cooled to less than 40° C. and 55 mL of acetone was added. The mixture was cooled to 0° C.-5° C. and stirred for 1 hour. The product was collected by filtration and washed with a minimum of acetone pre-chilled to 0° C. The product was dried in a vacuum oven at ambient temperature. Yield was 93.4percent of theory. The potency of the product by HPLC calibrated against a reference standard was 101.0percent. Example 4; Preparation of 4-(2-piperidinoethoxy)Benzoic Acid Hydrochloride; A 17.57 g portion of methyl 4-hydroxybenzoate and 132 mL of amyl acetate were combined. To this slurry at ambient temperature, was added 29.19 g of powdered potassium carbonate (11percent water by Karl Fischer particle size not less than 95percent passing a 100 mesh sieve and not less than 90percent passing ...
  • 3
  • [ 84449-80-9 ]
  • 4-[2-(piperidin-1-yl)ethoxy]benzoyl chloride hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; In toluene; at 110℃; for 1.5h; To a solution of <strong>[84449-80-9]4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride</strong> (7.0 g) in thionyl chloride (70 ml) was added toluene (70 ml), the solution was stirred for 1.5 hours at 110°C, then the solvent was evaporated in vacuo. To a suspension of the resulting 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (4.5 g) in dichloromethane (100 ml) were sequentially added 3-bromoanisole (1.7 ml) and aluminum chloride (4.1 g) on an ice bath under a nitrogen atmosphere, and the solution was stirred overnight at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto on the ice bath, the solution was filtered through celite pad, anhydrous magnesium sulfate was added thereto followed by stirring. The residue obtained by filtration, and then evaporation of the solvent in vacuo, was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.8 g).1H-NMR (400MHz, CDCl3); delta (ppm): 1.41-1.50 (m, 2H), 1.57-1.64 (m, 4H), 2.46-2.54 (m, 4H), 2.79 (t, 2H), 3.86 (s, 3H), 4.17 (t, 2H), 6.92 (dd, 1H), 6.93 (d, 2H), 7.17 (d, 1H), 7.29 (d, 1H), 7.77 (d, 2H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; To a solution of <strong>[84449-80-9]4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride</strong> (1.0 g) in dichloromethane solution (20 ml) were sequentially added oxalyl chloride (0.4 ml) and N,N-dimethylformamide (0.05 ml), the solution was stirred for 2 hours at room temperature, and then the solvent was evaporated in vacuo. To the residue were sequentially added tetrahydrofuran (20 ml), N,N-diisopropylethylamine (5 ml) and 6-(2-amino-4-methoxyphenyl)-2-methoxy-5,6,7,8-tetrahydronaphthalene (800 mg), and the solution was stirred for 30 minutes at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), to a solution of the resultingN-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (1.1 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (0.4 g), and the solution was refluxed for 20 minutes. The solution was cooled on an ice, then ammonia solution (1 ml) and anhydrous magnesium sulfate was added, the solution was filtered, then the solvent was evaporated in vacuo. To a solution of the total amount of the resulting [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl] [4-(2-piperidin-1-ylethoxy)benzyl]amine (crude product) in dichloromethane (15 ml) were added pyridine (0.5 ml) and acetic anhydride (0.4 ml), and the solution was stirred for 1 hour at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the resultingN-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-N-[4-(2-piperidin-1-ylethoxy)benzyl]acetamide (1.3 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (0.4 g), and the solution was refluxed for 20 minutes. The solution was cooled on an ice, then ammonia solution (1 ml) and anhydrous magnesium sulfate were added thereto, the solution was filtered, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl] [4-(2-piperidin-1-ylethoxy)benzyl]amine (570 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (480 mg).1H-NMR (400MHz, CDCl3); delta (ppm): 0.93 (t, 3H), 1.44-1.47 (m, 2H), 1.62-1.75 (m, 6H), 2.21-2.63 (m, 6H), 2.77-2.80 (m, 4H), 2.86-2.92 (m, 2H), 3.56-3.59 (m, 1H), 3.89 (s, 2H), 4.07 (t, 2H), 6.57-6.61 (m, 3H), 6.66 (d, 1H), 6.69 (d, 2H), 6.86 (d, 2H), 7.05 (d, 2H), 7.08 (d, 2H).
With thionyl chloride; In dichloromethane; at 40℃; 4-[2-(Piperidinyl)ethoxy]benzoic acid hydrochloride (55 g) is charged into a round bottom flask containing dichloromethane (200 mL) and the mixture is stirred for about 1 0 minutes. Thionyl chloride (56 mL) is added slowly and the mixture is heated to 40°C and maintained for 2-3 hours until completion of the reaction. Solvent is distilled completely under vacuum, then petroleum ether (2x 1 1 9 mL) is added to the residue and distilled completely under vacuum, to afford 4-[2- (piperidinyl)ethoxy]benzoyl chloride hydrochloride.
  • 6
  • [ 84449-80-9 ]
  • 1-[4-{2-(1-piperidinyl)ethoxy}phenylcarbonyl]-3,5-bis((E)-phenylmethylene)-4-piperidone hydrochloride [ No CAS ]
  • 7
  • [ 84449-80-9 ]
  • 3,5-bis((E)-4-methylphenylmethylene)-1-[4-{2-(1-piperidinyl)ethoxy}phenylcarbonyl]-4-piperidone hydrochloride [ No CAS ]
  • 8
  • [ 84449-80-9 ]
  • 3,5-bis((E)-4-chlorophenylmethylene)-1-[4-{2-(1-piperidinyl)ethoxy}phenylcarbonyl]-4-piperidone hydrochloride [ No CAS ]
  • 9
  • [ 84449-80-9 ]
  • 3,5-bis((E)-4-nitrophenylmethylene)-1-[4-{2-(1-piperidinyl)ethoxy}phenylcarbonyl]-4-piperidone hydrochloride [ No CAS ]
  • 10
  • [ 84449-80-9 ]
  • 2-(4-methoxy-2-(3-fluoropropyl)phenyl)-3-[4-(2-(piperidin-1-yl)ethoxy)benzoyl]-6-methoxybenzo[b]thiophene [ No CAS ]
  • 11
  • [ 84449-80-9 ]
  • 6-(tert-butyldiphenylsilyloxy)-2-dimethylamino-3-[4-(2-(piperidin-1-yl)ethoxy)benzoyl]benzo[b]thiophene [ No CAS ]
  • 12
  • [ 84449-80-9 ]
  • [ 84449-90-1 ]
  • 14
  • [ 84449-80-9 ]
  • [ 84541-36-6 ]
  • 16
  • [ 93148-78-8 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
To a solution of 4-hydroxybenzoic acid ethyl ester (5.0 g) inN,N-dimethylformamide (50 ml) were sequentially added potassium carbonate (6.2 g) and 1-(2-chloroethyl)piperidine (8.3 g), and the solution was stirred for 1.5 hours at 60°C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (8.3 g). To a solution of 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (34 g) dissolved in ethanol (200 ml) was added an aqueous solution of 2N sodium hydroxide (100 ml), and the solution was refluxed for 1 hour. Ethanol was evaporated in vacuo, water was added and stirred, the solid that was precipitated by adding 2N hydrochloric acid (180 ml) was filtered to provide the title compound (28.2 g).1H-NMR (400MHz, DMSO-d6); delta (ppm): 1.31-1.48 (m, 1H), 1.60-1.83 (m, 5H), 2.85-3.60 (m, 6H), 4.46 (t, 2H), 7.07 (d, 2H), 7.91 (d, 2H), 10.29 (brs, 1H), 12.68 (brs, 1H).
1.36 g With methanol; sodium hydroxide;Inert atmosphere; In a round bottomed flask equipped with nitrogen inlet and magnetic stir bar, a solution of ethyl 4-(2-(piperidin-l-yl)ethoxy)benzoate (1.58 g, 5.7 mmol) in methanol (25 mL) was added. To the above solution, 8 mL of 5percent NaOH solution was added and the reaction was stirred overnight. Methanol was evaporated and 15 mL cold water was added to the residue. The precipitated solid was filtered, washed with 5 mL water and the, dried in vacuo to give 1.36 g of 1 -(2-(4-carboxyphenoxy)ethyl)piperidin-l -ium chloride (0271) lH NMR (400 MHz, Chloroform-d) delta 7.93 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.30 (bs, 1H), 4.84 (bs, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.86 (bs, 1H), 2.07 - 1.53 (m, 4H), 1.36 (t, J = 7.1 Hz, 2H). HPLC-MS: Expected: 250; Found: 250.
YieldReaction ConditionsOperation in experiment
83% B. Preparation of 4-(2-piperidinoethoxy)benzoic Acid Hydrochloride A solution of the compound prepared as described in Example 12A (about 13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15 mL), and heated to 40° C. After 4 1/2 hours, water (40 mL) was added. The resulting mixture was cooled to 5°-10° C., and concentrated hydrochloric acid (18 mL) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40°-50° C. to give 83percent yield of the title compound. Melting point 270°-271° C.
83% B. Preparation of 4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride A solution of the compound prepared as described in Example 6A (about 13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15 mL), and heated to 40° C. After 41/2 hours, water (40 mL) was added. The resulting mixture was cooled to 5°-10° C., and concentrated hydrochloric acid (18 mL) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40°-50° C. to give 83percent yield of the title compound. Melting point 270°-271° C.
83% B. Preparation of 4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride A solution of the compound prepared as described in Example 12A (about 13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15 mL), and heated to 40° C. After 41/2 hours, water (40 mL) was added. The resulting mixture was cooled to 5°-10° C., and concentrated hydrochloric acid (18 mL) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40°-50° C. to give 83percent yield of the title compound. Melting point 270°-271° C.
83% B. Preparation of 4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride A solution of the compound prepared as described in Example 7A (about 13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15 mL), and heated to 40° C. After 41/2 hours, water (40 mL) was added. The resulting mixture was cooled to 5°-10° C., and concentrated hydrochloric acid (18 mL) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40°-50° C. to give 83percent yield of the title compound. Melting point 270°-271° C.
83% B. 4-[2-(Piperidin-1-yl)ethoxy]benzoic acid hydrochloride A solution of the compound prepared as described supra (about 13.87 g) in methanol (30 ml) was treated with 5 N sodium hydroxide (15 ml), and heated to 40°C. After 4 1/2 hours, water (40 ml) was added. The resulting mixture was cooled to 5-10°C, and concentrated hydrochloric acid (18 ml) was added slowly. The title compound crystallized during acidification. This crystalline product was collected by filtration, and dried in vacuo at 40-50°C to give 83percent yield of the title compound. Melting point 270-271°C.
EXAMPLE 6 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 125 mL 3 neck flask with mechanical stirring, condensers, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g -chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was slowly heated under nitrogen in an oil bath to 97° C. The reaction was allowed to proceed overnight. The mixture was cooled to ambient temperature and 40 mL deionized water was added to dissolve the solids. The aqueous layer was separated and discarded and the water wash repeated. 25 mL of 8N hydrochloric acid were added in a single aliquot to extract the intermediate. The layers were separated and the acidic aqueous layer returned to the reaction flask. The aqueous layer was heated to 95° C. and the reaction was allowed to proceed for 24 hours as a stress test. After 6 hours, 0.3percent of ester remained. The mixture was cooled to 40° C. and 25 mL acetone was added. The mixture was cooled to 0° C.-5° C. for 1 hour. The filter cakes were rinsed with approx. 25 mL acetone and dried. HPLC revealed 0.2 g of product in filtrate. Yield (crystalline) 13.38 g (95.1percent of theoretical).
EXAMPLE 8 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 100 mL round bottom flask equipped with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 4.155 g ethyl 4-hydroxybenzoate, 5.985 g beta-chloroethylpiperidene hydrochloride, 9.295 g potassium carbonate and 30 mL amyl acetate. The reaction mixture was heated to 120° C. under nitrogen and monitored by HPLC. The mixture was allowed to react at this temperature for approximately 5 hours. The reaction mixture was cooled to approximately 50° C. and 20 mL of distilled water was added to dissolve the solids. The mixture was cooled to ambient temperature. The aqueous layer was separated and discarded. The water wash was then repeated. 12.5 mL of 8N hydrochloric acid were added with stirring to extract the analysis indicated complete reaction. The acid extract was heated to 95° C. until HPLC. The mixture was then cooled to less than 40° C., at which time 12.5 mL acetone was added. The mixture was then further cooled to 0° C.-5° C. and the precipitate filtered. The filter cake was rinsed with acetone and dried. Yield=5.19 g solid.

  • 18
  • aqueous sodium chloride [ No CAS ]
  • [ 63675-74-1 ]
  • [ 84449-80-9 ]
  • [ 82640-04-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; EXAMPLE 3 6-hydroxy-2-(4-hydroxyphenyl)-3[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride Under a nitrogen blanket, a mixture of 3 g. of 4-(2-piperidinoethoxy) benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of chlorobenzene was heated at 70°-75° C. for about one hour. The excess thionyl chloride and 15-20 ml. of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml. of dichloromethane, 2.7 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of aluminum chloride. The solution was stirred for about one hour, 7.5 ml. of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml. of tetrahydrofuran was added, followed by 15 ml. of 20percent hydrochloric acid, with an exotherm to reflux. Fifty ml. of water and 25 ml. of saturated aqueous sodium chloride were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml of water, 40 ml of 25percent aqueous tetrahydrofuran, and 35 ml. of water. The solids were then dried at 40° C. under vacuum to obtain 5.05 g. of product, which was identified by nmr. delta1.7(6H, m, N(CH2 CH2)2 CH2); 2.6-3.1 (2H, m, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4 (2H, m, OCH2); 6.6-7.4 (9H, m, aromatic); 7.7 (2H, d, aromatic o to CO); 9.8(2H, m, OH).
With hydrogenchloride; thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; PREPARATION 3 6-hydroxy-2-(4-hydroxyphenyl)-3[-4-(2piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride Under a nitrogen blanket, a mixture of 3 g. of 4-(2piperidinoethoxy)benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of chlorobenzene was heated at 70°-75° C. for about one hour. The excess thionyl chloride and 15-20 ml. of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml. of dichloromethane, 2.7 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of aluminum chloride. The solution was stirred for about one hour, 7.5 ml. of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml. of tetrahydrofuran was added, followed by 15 ml. of 20percent hydrochloric acid, with an exotherm to reflux. Fifty ml. of water and 25 ml. of saturated aqueous sodium chloride were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml. of water, 40 ml of 25percent aqueous tetrahydrofuran, and 35 ml. of water. The solids were then dried at 40° C. under vacuum to obtain 5.05 g. of product, which was identified by nmr. delta1.7(6H, m, N(CH2 CH2)2 CH2); 2.6-3.1(2H, m, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4(2H, m, OCH2); 6.6-7.4(9H, m, aromatic); 7.7(2H, d, aromatic o to CO); 9.8(2H, m, OH).
With hydrogenchloride; thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; EXAMPLE 1 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride Under a nitrogen blanket, a mixture of 3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of chlorobenzene was heated at 70°-75° C. for about one hour. The excess thionyl chloride and 15-20 ml. of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml. of dichloromethane, 2.7 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of aluminum chloride. The solution was stirred for about one hour, 7.5 ml. of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml. of tetrahydrofuran was added, followed by 15 ml. of 20percent hydrochloric acid, with an exotherm to reflux. Fifty ml. of water and 25 ml. of saturated aqueous sodium chloride were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml. of water, 40 ml. of 25percent aqueous tetrahydrofuran, and 35 ml. of water. The solids were then dried at 40° C. under vacuum to obtain 5.05 g. of product, which was identified by its nmr spectrum, using a 90 mHz instrument and deuterochloroform. delta1.7 (6H, m, N(CH2 CH2)2 CH2); 2.6-3.1 (2H, m, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4 (2H, m, OCH2); 6.6-7.4 (9H, m, aromatic); 7.7(2H, d, aromatic o to CO); 9.8 (2H, m, OH).
With hydrogenchloride; thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; EXAMPLE 1 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride Under a nitrogen blanket, a mixture of 2 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of chlorobenzene was heated at 70°-75° C. for about one hour. The excess thionyl chloride and 15-20 ml. of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml. of dichloromethane, 2.7 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of aluminum chloride. The solution was stirred for about one hour, 7.5 ml. of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml. of tetrahydrofuran was added, followed by 15 ml. of 20percent hydrochloric acid, with an exotherm to reflux. Fifty ml. of water and 25 ml. of saturated aqueous sodium chloride were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml. of water, 40 ml. of 25percent aqueous tetrahydrofuran, and 35 ml. of water. The solids were then dried at 40° under vacuum to obtain 5.05 g. of crude product, which was identified by its nmr spectrum, using a 90 mHz instrument and deuterochloroform. delta1.7 (6H, m, N(CH2 CH2)2 CH2); 2.6-3.1 (2H, m, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4 (2H, m, OCH2); 6.6-7.4 (9H, m, aromatic); 7.7(2H, d, aromatic o to CO); 9.8 (2H, m, OH).
With hydrogenchloride; CO; thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; EXAMPLE 8 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride Under a nitrogen blanket, a mixture of 3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 ml. of thionyl chloride and 40 ml. of chlorobenzene was heated at 70°-75° C. for about one hour. The excess thionyl chloride and 15-20 ml. of solvent were then distilled off. The remaining suspension was cooled to ambient temperature, and to it were added 100 ml. of dichloromethane, 2.7 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 10 g. of aluminum chloride. The solution was stirred for about one hour, 7.5 ml. of ethanethiol was added, and the mixture was stirred for 45 minutes more. Then 40 ml. of tetrahydrofuran was added, followed by 15 ml. of 20percent hydrochloric acid, with an exotherm to reflux. Fifty ml. of water and 25 ml. of saturated aqueous sodium chloride was added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 ml. of water, 40 ml. of 25percent aqueous tetrahydrofuran, and 35 ml. of water. The solids were then dried at 40° C. under vacuum to obtain 5.05 g. of product, which was identified by nmr. delta1.7 (6H, m, N(CH2 CH2)2 CH2); 2.6-3.1 (2H, m, NCH2); 3.5-4.1 (4H, m, NCH2); 4.4 (2H, m, OCH2); 6.6-7.4 (9H, m, aromatic); 7.7 (2H, d, aromatic o to CO); 9.8 (2H, m, OH). The following group of examples illustrates the preparation of ester derivatives of this invention from the dihydroxy compound.

  • 19
  • [ 93148-78-8 ]
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
87.7% With potassium carbonate; In Isopropyl acetate; water; EXAMPLE 4 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g beta-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL isopropyl acetate. The mixture was heated slowly to 80° C. After 5 hours, high performance liquid chromatography showed reaction to be 90percent complete. After being left overnight at 80° C., reaction was complete. The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added. The mixture was stirred until all solids dissolved. The aqueous layer was separated and discarded. The organic layer was extracted 3 times with 20 mL 4N hydrochloride. The combined aliquots, containing 4-(2-piperidinoethoxy)benzoic acid, ethyl ester, were heated at reflux (92° C., 30 minutes required to reach reflux). After 7.5 hours at reflux, the mixture was then distilled to remove approximately 10 mL water and cooled in an ice bath for 15 minutes. The resulting crystalline 4-(2-piperidinoethoxy)benzoic acid, hydrochloride was removed by filtration and rinsed with acetone and dried. Yield=12.53 g of product (87.7percent of theoretical).
  • 20
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; ethyl acetate; EXAMPLE 9 Preparatlon of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 250 mL 3 neck flask with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following was added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of beta-chloroethylpiperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of ethyl acetate. The mixture was heated slowly to reflux. After overnight reflux, the mixture was cooled to ambient temperature, after which 60 mL of deionized water was added. The aqueous layer was separated and discarded. The organic layer was extracted with 4N hydrochloride (3 aliquots of 20 mL). The combined acid extracts were heated to reflux. After 1 hour at reflux, HPLC indicated the saponification to be 60percent complete. After 4 hours, the reaction was near 100percent complete. The mixture was cooled to 0° C.-5° C. and stirred. The resulting crystals were filtered, rinsed with acetone and dried.
  • 21
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 89407-97-6 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
95.3% With potassium carbonate; In Isopropyl acetate; water; a. To a 250 mL 3 neck flask, with mechanical stirring, condenser, and RTD probe were added the following under nitrogen atmosphere: 0.05 mol methyl 4-hydroxybenzoate, 0.06 mol beta-chloroethylpiperidine hydrochloride, 16.59 grams of potassium carbonate, and 60 mL of isopropyl acetate. The mixture was heated at 75° C.-80° C. for 20 hours, at which time all the methyl 4-hydroxybenzoate was consumed. 60 mL of water was then added to dissolve the potassium carbonate. The organic and aqueous phases were then Separated and the aqueous layer discarded. The organic layer was washed with a second 60 mL aliquot of water; the layers were separated and the aqueous layer discarded. The reaction product, 4-(2-piperidinoethoxy)benzoic acid, methyl ester, was then extracted into 25 mL 8N hydrochloric acid. The aqueous phase was separated and the organic phase discarded. The aqueous phase was refluxed in a 50 mL round bottomed flask with magnetic stirring and condenser for 48 hours. The mixture was then cooled to 0° C.-5° C. and the crystals removed by filtration. The crystals were rinsed with acetone and dried overnight in 50° C. vacuum oven. 13.63 g of 4-(2-piperidinoethoxy)benzoic acid hydrochloride were recovered, which is 95.3percent of the theoretical yield.
  • 22
  • [ 628-63-7 ]
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
12.61 g (83.6% theoretical) With hydrogenchloride; potassium carbonate; In water; EXAMPLE 5 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g beta-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was heated in an oil bath under nitrogen to 115° C.-120° C. for 4 hour. HPLC indicated that the reaction was complete. The mixture was then cooled to ambient temperature and 40 mL of deionized water were added to dissolve solids. The aqueous layer was separated and discarded and the water wash was repeated. 5 mL of the organic phase was removed as an analytical standard. 25 mL 8N hydrochloric acid was added to remaining organic phase to extract the intermediate. The layers were separated and the acidified aqueous layers returned to the reaction flasks. The organic phase was discarded. The aqueous phase was heated to 95° C. until HPLC indicated complete hydrolysis of the ester (about 4 hours). The mixtures were cooled to 0° C.-5° C. for 1 hour and filtered. The filter cakes were rinsed with acetone (approx. 25 mL) and dried. Yield 12.61 g (83.6percent theoretical).
With hydrogenchloride; potassium carbonate; In water; acetone; EXAMPLE 7 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g beta-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was heated overnight under nitrogen in an oil bath to 125° C., and was allowed to proceed until HPLC indicated complete consumption of the methyl 4-hydroxybenzoate. The mixture was cooled to ambient temperature and 40 mL deionized water was added to dissolve the solids. The aqueous layer was separated and discarded. The water wash was repeated. 25 mL of 8N hydrochloric acid were added to extract intermediate. The layers were separated and the acid layer returned to the reaction flask. The acid solution was heated to 95° C. for about 24 hours as a "stress" test; (after 6 hours 1percent of the uncleaved ester remained.) The mixture was cooled to 40° C. and 25 mL acetone added. The mixture was cooled to 0° C.-5° C. for 1 hour. The mixture was filtered and the cakes rinsed with approx. 25 mL acetone and dried. Yield=12.0 g (84.1percent of theoretical).
  • 23
  • [ 408538-22-7 ]
  • [ 628-63-7 ]
  • [ 99-76-3 ]
  • [ 98-59-9 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dichloromethane; acetone; Preparation 2 4-(2-piperidinoethoxy) benzoic acid hydrochloride Into a 50 ml round bottom flask is placed 6.40 g (33.6 mmol) of p-toluenesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 4.00 g (31.0 mmol) of 1-piperidinoethanol in 6 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. The solid residue is transferred to a 100 ml round bottom flask with 45 ml of amyl acetate. Potassium carbonate (6.87 g, 49.7 mmol) and methyl 4-hydroxybenzoate (2.82 g, 18.5 mmol) are added to the slurry. The resulting mixture is heated to 145° C. for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water. The organic layer is extracted with 11 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 3 hours. The resulting slurry is cooled to 50° C. and 11 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 920 mg of product, (17percent).
With potassium carbonate; In dichloromethane; acetone; Example 2 Preparation of 4-(2-piperidinoethoxy) benzoic acid hydrochloride Into a 50 ml round bottom flask is placed 6.40 g (33.6 mmol) of p-toluenesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 4.00 g (31.0 mmol) of 1-piperidinoethanol in 6 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. The solid residue is transferred to a 100 ml round bottom flask with 45 ml of amyl acetate. Potassium carbonate (6.87 g, 49.7 mmol) and methyl 4-hydroxybenzoate (2.82 g, 18.5 mmol) are added to the slurry. The resulting mixture is heated to 145°C for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water. The organic layer is extracted with 11 ml of 8 N hydrochloric acid. The aqueous layer is heated at gentle reflux for 3 hours. The resulting slurry is cooled to 50°C and 11 ml of acetone is added. The slurry is cooled to 0-5°C and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50°C in vacuoto yield 920 mg of product, (17percent).
  • 24
  • [ 408538-22-7 ]
  • [ 1648-99-3 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dichloromethane; 1-pentyl acetate; acetone; Preparation 3 4-(2-piperidinoethoxy) benzoic acid hydrochloride Into a 50 ml round bottom flask is placed 4.93 g (27.0 mmol) of 2,2,2-trifluoroethanesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 3.22 g (24.9 mmol) of 1-piperidinoethanol in 7 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a waxy residue. The solid residue is slurried in 45 ml of amyl acetate and then potassium carbonate (5.50 g, 39.9 mmol) and methyl 4-hydroxybenzoate (2.26 g, 14.8 mmol) are added. The resulting mixture is heated to 140° C. for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water and the organic layer is extracted with 10.5 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50° C. and 11 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 3.94 g of product, (90percent).
With potassium carbonate; In dichloromethane; 1-pentyl acetate; acetone; Example 3 Preparation of 4-(2-piperidinoethoxy) benzoic acid hydrochloride Into a 50 ml round bottom flask is placed 4.93 g (27.0 mmol) of 2,2,2-trifluoroethanesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 3.22 g (24.9 mmol) of 1-piperidinoethanol in 7 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a waxy residue. The solid residue is slurried in 45 ml of amyl acetate and then potassium carbonate (5.50 g, 39.9 mmol) and methyl 4-hydroxybenzoate (2.26 g, 14.8 mmol) are added. The resulting mixture is heated to 140°C for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water and the organic layer is extracted with 10.5 ml of 8 N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50°C and 11 ml of acetone is added. The slurry is cooled to 0-5°C and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50°C in vacuoto yield 3.94 g of product, (90percent).
  • 25
  • [ 408538-22-7 ]
  • [ 628-63-7 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; potassium carbonate; In dichloromethane; water; acetone; Preparation 1 4-(2-piperidinoethoxy) benzoic acid hydrochloride Into a 500 ml round bottom flask is placed 23.38 g (197 mmol) of thionyl chloride and 140 ml of methylene chloride. The resulting solution is cooled with an ice bath as 21.91 g (170 mmol) of 1-piperidinoethanol in 30 ml of methylene chloride is added over 30 minutes. After the addition is complete, the ice bath is removed and the mixture is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. Amyl acetate (225 ml), potassium carbonate (34.4 g, 249 mmol), and methyl 4-hydroxybenzoate (14.1 g, 92 mmol) are added to the residue. The resulting slurry is heated to 135° C. for 5 hours. The reaction mixture is cooled to room temperature and washed twice with 100 ml of water. The organic layer is extracted with 53 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50° C. and 50 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 17.9 g of product, (67percent).
With thionyl chloride; potassium carbonate; In dichloromethane; water; acetone; Example 1 Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride Into a 500 ml round bottom flask is placed 23.38 g (197 mmol) of thionyl chloride and 140 ml of methylene chloride. The resulting solution is cooled with an ice bath as 21.91 g (170 mmol) of 1-piperidinoethanol in 30 ml of methylene chloride is added over 30 minutes. After the addition is complete, the ice bath is removed and the mixture is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue. Amyl acetate (225 ml), potassium carbonate (34.4 g, 249 mmol), and methyl 4-hydroxybenzoate (14.1 g, 92 mmol) are added to the residue. The resulting slurry is heated to 135°C for 5 hours. The reaction mixture is cooled to room temperature and washed twice with 100 ml of water. The organic layer is extracted with 53 ml of 8 N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50°C and 50 ml of acetone is added. The slurry is cooled to 0-5°C and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50°C in vacuoto yield 17.9 g of product, (67percent).
  • 26
  • [ 84449-64-9 ]
  • [ 84449-80-9 ]
  • [ 84449-83-2 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 10 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The process of this example was run as was the process of Example 9, starting with the acid chloride formed from 18.9 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, and 20 g. of 6-benzoyloxy-2-(4-benzoyloxyphenyl)benzo[b]thiophene. The reaction mixture was stirred for 1.5 hours, and was then worked up as described in Example 9 to obtain the desired product as an oil. A small portion of the crude product was crystallized from denatured ethanol to provide an analytical sample, m.p. 230°-233°, the identity of which was confirmed by nmr analysis. delta1.30-2.50 (6H, m, NH(CH2 CH2)2 CH2); 2.50-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 4.56 (2H, m, OCH2 CH2 N); 6.77 (2H, d, J=9 Hz, aromatic o to OCH2); 7.10 (2H, d, J=9 Hz, aromatic o to OCO); 7.10-7.90 (17H, m, aromatic); 8.00-8.27 (6H, m, aromatic o to CO); 12.30-12.80 (1H, broad s, NH).
EXAMPLE 2 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The process of this example was run as was the process of Example 1, starting with the acid chloride formed from 18.9 g. of 4-(2-piperidinoethoxy)-benzoic acid, hydrochloride, and 20 g. of 6-benzoyloxy-2-(4-benzoyloxyphenyl)-benzo[b]thiophene. The reaction mixture was stirred for 1.5 hours, and was then worked up as described in Example 1 to obtain the desired product as an oil. A small portion of the crude product was crystallized from denatured ethanol to provide an analytical sample, m.p. 230°-233° C., the identity of which was confirmed by nmr analysis. delta1.30-2.50 (6H, m, NH(CH2 CH2)CH2); 2.50-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 4.56 (2H, m, OCH2 CH2 N); 6.77 (2H, d, J=9 Hz, aromatic o to OCH2); 7.10 (2H, d, J=9 Hz, aromatic o to OCO); 7.10-7.90 (17H, m, aromatic); 8.00-8.27 (6H, m, aromatic o to CO); 12.30-12.80 (1H, broad s, NH).
  • 27
  • [ 63675-74-1 ]
  • [ 84449-80-9 ]
  • [ 82640-04-8 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; chlorobenzene; EXAMPLE 11 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride A mixture of 1.5 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 20 ml. of chlorobenzene, 3 ml. of thionyl chloride and 2 drops of dimethylformamide was stirred at 75°-79° for 2 hours, to prepare the corresponding acid chloride. Vacuum was then applied, and the temperature dropped to 65°. Distillation was continued until the pot temperature was 90°. Twenty ml. of additional chlorobenzene was added, and the mixture was redistilled to a pot temperature of 90°, and was then cooled. To the mixture was added 15 ml. of dichloromethane, 1.35 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, 5 g. of aluminum chloride and 15 ml. of additional dichloromethane. The mixture was stirred at 27°-29° for 90 minutes, and then 1.6 ml. of ethanethiol was added. The mixture was stirred with cooling to maintain it at or below 35°. After 30 minutes, the mixture was worked up as described in Example 8 above, except that only 18 ml. of tetrahydrofuran and of water were used, to obtain 2.6 g. of the crude desired product, m.p. 217°, which was found to be substantially identical to the product of Example 1 by nmr and thin layer chromatography.
With thionyl chloride; ethanethiol;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; chlorobenzene; EXAMPLE 16 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride A mixture of 1.5 g. of 4-(2-piperidinoethoxy)-benzoic acid, hydrochloride, 20 ml. of chlorobenzene, 3 ml. of thionyl chloride and 2 drops of dimethylformamide was stirred at 75°-79° for 2 hours, to prepare the corresponding acid chloride. Vacuum was then applied, and the temperature dropped to 65°. Distillation was continued until the pot temperature was 90°. Twenty ml. of additional chlorobenzene was added, and the mixture was redistilled to a pot temperature of 90°, and was then cooled. To the mixture was added 15 ml. of dichloromethane, 1.35 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, 5 g. of aluminum chloride and 15 ml. of additional dichloromethane. The mixture was stirred at 27°-29° for 90 minutes, and then 1.6 ml. of ethanethiol was added. The mixture was stirred with cooling to maintain it at or below 35°. After 30 minutes, the mixture was worked up as described in Example 8 above, except that only 18 ml. of tetrahydrofuran and of water were used, to obtain 2.6 g. of the crude desired product, m.p. 217°, which was found to be substantially identical to the product of Example 8 by nmr and thin layer chromatography.
Example 13 Preparation of Raloxifene Hydrochloride [6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzyl]benzo[b]Thiophene Hydrochloride] Under a nitrogen blanket, a mixture of 3 g of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 2 drops of dimethylformamide, 2.5 mL of thionyl chloride and 40 mL of chlorobenzene was heated at 70° C.-75° C. for about 1 hour. The excess thionyl chloride and 15-20 mL solvent were then distilled off. The remaining suspension was cooled to ambient temperature and to it were added 100 mL of dichloromethane, 2.7 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (preparation of which is described in Example 14) and 10 g of aluminum chloride. After the solution was stirred for about 1 hour, 7.5 mL of ethanethiol was added, and the mixture was stirred for an additional 45 minutes. Then 40 mL of tetrahydrofuran was added, followed by 15 mL of 20percent hydrochloric acid, with an exotherm to reflux. 50 mL of water and 25 mL of saturated aqueous sodium chloride were added. The mixture was stirred and allowed to cool to ambient temperature. The precipitate was collected by filtration and washed successively with 30 mL of water, 40 mL of 25percent aqueous tetrahydrofuran and 35 mL of water. The solids were then dried at 40° C. under vacuum to obtain 5.05 g of product, which was identified by nuclear magnetic resonance as (6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-peridinoethoxy)benzyl]benzo[b]thiophene hydrochloride).
4-(2-Piperidinoethoxy)-benzoic acid hydrochloride (120 gm) was added to toluene (600 ml) and then added dimethylformamide (2 ml) and thionyl chloride (160 gm) under stirring. The temperature of the reaction mass was raised to 80°C and maintained for 2 hours. The reaction mass was distilled off solvent completely under vacuum at 65° to obtain residue. To the residue was added methylene chloride (1500 ml) and then added 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene (100 gm). To the reaction mass was added aluminum chloride (360 gm) for 1 hour and maintained for 2 hours at room temperature. The reaction mass was cooled to 10°C and then added propanethiol (100 ml) for 1 hour 30 minutes under stirring. The temperature of the reaction mass was gradually raised to room temperature and maintained for 1 hour 30 minutes. The reaction mass was cooled to 5°C and then added methanol (600 ml). The reaction mass was stirred for 30 minutes at 5 C and then added dilute hydrochloric acid (2N, 800 ml). To the reaction mass was added saturated sodium chloride solution (800 ml) and water (800 ml). The reaction mass was stirred for 2 hours and filtered. To the wet solid was added diluted hydrochloric acid (IN, 800 ml) and stirred for 1 hour, filtered. To the wet solid was added acetone (500 ml) and heated to reflux, and maintained for 30 minutes. The suspension was cooled to room temperature and stirred for 1 hour 30 minutes. The separated solid was filtered and dried at 55 to 60°C for 2 hours to obtain 220 gm of raloxifene hydrochloride.

  • 28
  • [ 63675-74-1 ]
  • [ 84449-80-9 ]
  • [2-(4-hydroxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)-ethoxy]phenyl]methanone hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; thionyl chloride;aluminium trichloride; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; chlorobenzene; EXAMPLE 19 6-Methoxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride A mixture of 9 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 100 ml. of chlorobenzene, 15 ml. of thionyl chloride and 5 drops of dimethylformamide was stirred at 75°-79° C. for 2 hours, to prepare the corresponding acid chloride. Excess thionyl chloride and part of the chlorobenzene was removed by distillation under vacuum to a maximum pot temperature of 85° C. Fifty ml. of additional chlorobenzene was added, and the distillation of 85° C. was repeated. The residue was then dissolved in 100 ml. of dichloromethane, and to it was added 8.1 g. of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, 50 ml. of additional dichloromethane and 30 g. of aluminum chloride. The mixture ws stirred at 27°-29° C. for 90 minutes, and was then cooled. To the mixture was added 108 ml. of tetrahydrofuran, followed by 30 ml. of 20percent aqueous hydrochloric acid and 108 ml. of water. The water phase was then removed, and was extracted with 50 ml. of dichloromethane. The organic layers were combined, and extracted with 90 ml. of water. The organic portion was then dried over sodium sulfate, and evaporated to a solid under vacuum. About 31 g. of wet crude product was obtained. The crude product was slurried in 200 ml. of hot chlorobenzene, and the slurry was cooled in an ice bath and filtered at 5° C. The solids were washed with 30 ml. of chlorobenzene, and dried under vacuum to obtain 10.6 g. of the desired product. About 1.8 g. of additional product was obtained by chromatography of the filtrate on silica gel, eluding with methanol. The melting point of the main product was 216° C. dec. Its identity was confirmed by 90 mHz nmr in CDCl3, which showed the following characteristic features. delta1.6 (m, 2H, N(CH2 CH2)2 CH2); 2.0 (m, 4H, N(CH2 CH2)2); 3.1 (m, 4H, N(CH2 CH2)2); 3.3 (m, 2H, CH2 N(CH2)5); 3.7 and 3.9 (s, 3H, OCH3); 4.5 (n, 2H, OCH2) 6.7-7.8 (m, 11H, aromatic).
  • 29
  • [ 84449-65-0 ]
  • [ 84449-80-9 ]
  • [ 84449-85-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; trifluorormethanesulfonic acid; In methanol; dichloromethane; EXAMPLE 12 6-methanesulfonyloxy- 2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The acid chloride was formed from 2.0 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 9, and was combined with 2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in 50 ml. of dichloromethane. A 2.4 g. portion of trifluoromethanesulfonic acid was added, and the mixture was stirred overnight under reflux. The reaction mixture was then poured over ice and sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to a yellow foam, which was treated with excess 3% hydrogen chloride in anhydrous methanol. The mixture was evaporated to dryness under vacuum to obtain a white foam which was dissolved in 18 ml. of boiling methanol. The solution was cooled to obtain 3.1 g. of the desired product, m.p. 128-130 C., which was identified by nmr analysis. delta1.50-2.00 (6H, m, N-(CH2 CH2)2 CH2); 2.57-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 3.36 (3H, s, CH3 SO2); 3.46 (3H, s, CH3 SO2); 4.45 (2H, broad t, J=6 Hz, OCH2 CH2 N); 6.97 (2H, d, J=9 Hz, aromatic o to OCH2); 7.25-7.80 (8H, m, aromatic); 8.25 (1H, d, J=2 Hz, aromatic, o to O and S); 10.70-11.00 (1H, broad s, NH).
With hydrogenchloride; trifluorormethanesulfonic acid; In methanol; dichloromethane; Preparation 8 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]-thiophene, hydrochloride The acid chloride was formed from 2.0 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 1, and was combined with 2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-benzo[b]thiophene in 50 ml. of dichloromethane. A 2.4 g. portion of trifluoromethanesulfonic acid was added, and the mixture was stirred overnight under reflux. The reaction mixture was then poured over ice and sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to a yellow foam, which was treated with excess 3% hydrogen chloride in anhydrous methanol. The mixture was evaporated to dryness under vacuum to obtain a white foam which was dissolved in 18 ml. of boiling methanol. The solution was cooled to obtain 3.1 g. of the desired product, m.p. 128-130 C., which was identified by nmr analysis. delta1.50-2.00 (6H, m, N--(CH2 CH2)2 CH2); 2.57-3.75 (6H, m, NH(CH2 CH2)2 CH2 and OCH2 CH2 N); 3.36 (3H, s, CH3 SO2); 3.46 (3H, s, CH3 SO2); 4.45 (2H, broad t, J=6 Hz, OCH2 CH2 N); 6.97 (2H, d, J=9 Hz, aromatic o to OCH2); 7.25-7.80 (8H, m, aromatic); 8.25 (1H, d, J=2 Hz, aromatic, o to O and S); 10.70-11.00 (1H, broad s, NH).
With thionyl chloride; In methanol; aluminium trichloride; ice-water; chloroform; toluene; EXAMPLE 13 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride The acid chloride was prepared from 19.7 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride in 200 ml. of toluene with 44.9 g. of thionyl chloride, and the acid chloride was used to acylate 20 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene in the presence of 59.6 g. of aluminum chloride. The aluminum chloride was added portionwise over a period of 30 minutes, and the reaction mixture was then stirred for 16 hours. It was poured over 2 liters of ice-water, and the product was extracted from the aqueous layer with two 200 ml. portions of warm chloroform. The organics were combined, dried and evaporated to obtain an oil, which was crystallized from 350 ml. of methanol to obtain 28 g. of crude product, m.p. 133-135.
  • 30
  • 6-benzenesulfonyloxy-2-(4-benzenesulfonyloxyphenyl)benzo[b]thiophene [ No CAS ]
  • [ 84449-80-9 ]
  • [ 84449-84-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride;aluminium trichloride; In methanol; chloroform; 1,2-dichloro-ethane; EXAMPLE 11 6-benzenesulfonyloxy-2-(4-benzenesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride An acid chloride was formed from 8.21 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 9, and was combined with 10 g. of 6-benzenesulfonyloxy-2-(4-benzenesulfonyloxyphenyl)benzo[b]thiophene in 500 ml. of 1,2-dichloroethane and treated with 22.9 g. of aluminum chloride. The mixture was stirred at ambient temperature overnight, and worked up as described in Example 9 above. The product was 15 g. of tan foam which would not crystallize. A 1 g. sample of the crude product was purified by column chromatography over a 4*20 cm. silica gel column, eluding first with chloroform, and then with 25percent methanol in chloroform. The product-containing fractions were combined, treated with hydrochloric acid to form the hydrochloride salt, and evaporated to dryness under vacuum to provide the product as an oil, the identity of which was confirmed by an absorption maximum at 1645 cm-1 in its infrared spectrum, indicative of the --CO-- function of the desired product. Its identity was further confirmed by its conversion to 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene in Example 28 below.
With hydrogenchloride;aluminium trichloride; In methanol; chloroform; 1,2-dichloro-ethane; Preparation 7 6-benzenesulfonyloxy-2-(4-benzenesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo-[b]thiophene, hydrochloride An acid chloride was formed from 8.21 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 1, and was combined with 10 g. of 6-benzenesulfonyloxy-2-(4-benzenesulfonyloxyphenyl)-benzo[b]thiophene in 500 ml. of 1,2-dichloroethane and treated with 22.9 g. of aluminum chloride. The mixture was stirred at ambient temperature overnight, and worked up as described in Example 1 above. The product was 15 g. of tan foam which would not crystallize. A 1 g. sample of the crude product was purified by column chromatography over a 4*20 cm. silica gel column, eluding first with chloroform, and then with 25percent methanol in chloroform. The product-containing fractions were combined, treated with hydrochloric acid to form the hydrochloride salt, and evaporated to dryness under vacuum to provide the product as an oil, the identity of which was confirmed by an absorption maximum at 1645 cm-1 in its infrared spectrum, indicative of the --CO-- function of the desired product. Its identity was further confirmed by its conversion to 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene in Example 6 below.
 

Historical Records

Technical Information

Categories