* 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.
Stage #1: With toluene-4-sulfonic acid In ethanol at 20℃; for 48 h; Stage #2: With sodium hydrogencarbonate In ethyl acetate
The alkyne of formula II (R=Me) (200 mg, 0.40 mmol) is dissolved in absolute ethanol (0.8 ml) and then treated with monohydrate p-toluenesulfonic acid (383 mg, 2.02 mmol). After 10 minutes, Ph3AuCl (4 mg, 0.0081 mmol, 2percent molar) and AgCF3SO3 (2 mg, 0.0081 mmol, 2percent molar) are added. After 48 h, at room temperature, the ethanol is evaporated under reduced pressure and the residue is taken up with ethyl acetate and basified till pH 10-11 with a NaHCO3 solution. The phases are separated, and the aqueous one is extracted with ethyl acetate. The organic phases are collected, dried with Na2SO4, filtered off and evaporated under reduced pressure. The crude reaction is purified by flash chromatography (acetate/methanol 9:1 as eluent) and 198 mg of title keto compound are obtained as a white solid, with a yield of 95percent.1H NMR (400 MHz, CDCl3) δ ppm: 7.94 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 4H), 7.43 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.22-7.17 (m, 2H), 3.65 (s, 3H), 3.04-2.95 (m, 4H), 2.49-2.42 (m, 3H), 2.05-1.92 (m, 4H, 1H exchanges with D2O), 1.62 (s, 6H), 1.52-1.41 (m, 4H).
28.3%
at 55℃; for 3.5 h;
Methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate To a vial was added the methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)but-1-yn-1-yl)phenyl)-2-methylpropanoate (KSC-335-054) (0.074 g, 0.149 mmol). The mercuric oxide (1.493 ml, 0.045 mmol) was made into a 0.03 M solution in 4percent w/v sulfuric acid and added to the starting material then heated to 55° C. and stirred for 3.5 h. The reaction turned a milky white color upon addition of the mercuric oxide solution. The reaction was removed from heat and diluted with saturated NaHCO3 (10 mL) and extracted with DCM (3*10 mL). The DCM layers were combined and dried with MgSO4, filtered and concentrated then purified by reverse-phase MPLC (10-100percent MeCN:water) to produce methyl 2-(4-(4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate (0.0217 g, 0.042 mmol, 28.3percent yield). 1H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m, 2H), 7.48-7.45 (m, 4H), 7.42-7.39 (m, 2H), 7.30-7.26 (m, 4H), 7.19-7.14 (m, 2H), 3.63 (s, 3H), 2.96-2.88 (m, 4H), 2.44-2.34 (m, 3H), 2.08 (br s, 1H), 1.60 (s, 6H), 1.62-1.56 (m, 4H), 1.46-1.30 (m, 4H).
Reference：
[1] Patent: US2010/228034, 2010, A1, . Location in patent: Page/Page column 3
[2] Patent: EP1260505, 2002, A1, . Location in patent: Example 6
[3] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562
[5] Patent: US2015/238473, 2015, A1, . Location in patent: Paragraph 0237
2
[ 115-46-8 ]
[ 154477-54-0 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium hydrogencarbonate; potassium iodide In toluene at 80℃; for 30 h; Reflux
1000 mL reaction flask, 55.4 g of diphenylpiperidine methanol was added successively, 42.1 g of potassium bicarbonate, 3.1g potassium iodide, 310 mL of toluene, Heated to 80 ° C, A solution of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI) (53.3 g) in toluene (150 ml) was slowly added dropwise, Plus, Reflux reaction about 30h, HPLC monitoring reaction is complete, The reaction solution was cooled to 10 to 15 ° C, filter, The filtrate was concentrated to give 107 g of crude product; With 250mL anhydrous ethanol heated reflux solution, Dropping 80 mL of water, After refluxing for 30 min, Natural cooling to 10 ~ 15 deg C, Insulation stirring 4h, Filtration gave an off-white solid, Drying 90g; And then recrystallized with EA, To obtain 77.4 g of methyl 2- [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -butanoyl] phenyl] -2-methylpropionate (VII) as a white solid, Purity 99.5percent Yield 80percent. among them, The molar ratio of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI), potassium iodide and base is 1: 0.1: 2.23.
With zinc(II) fluoride; tri-tert-butyl phosphine In N,N-dimethyl-formamide at 80℃; for 2 h;
EXAMPLE 8 Two grams of 3, 90 mg of P(tBu)3, 300 mg of Pd(dba)2, 250 mg of ZnF2 and 1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture was heated to 80° for two hours, cooled to room temperature, diluted with ether and worked up as described in example 1. The resulting product was filtered through silica to provide 1.3 g (62percent) of 6.
Scheme A, optional step f: Preparation of 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid methyl ester 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL of acetone and chilled in an ice-bath. To the solution was added Jones reagent (Prepared via the method of Feiser and Feiser) dropwise until a red color persisted. The reaction was allowed to warm to room temperature and then stirred for 18 hours at ambient temperature. The mixture was concentrated under vacuum to give a green solid. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated, washed with water (3*100 mL), brine (1*100 mL) and treated with MgSO4, filtered and concentrated in vacuo to give a light green solid. Purification via column chromatography yielded 1.25 g (61percent yield) of the title compound as a white solid. MH+514.6.
Reference：
[1] Patent: US2003/105329, 2003, A1,
5
[ 1451149-72-6 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
5.8 g
With sulfuric acid; water In methanol at 40℃; for 12 h;
EXAMPLE 12 Synthesis of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate (Compound VIII) In a reaction flask 7.0 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methylpropanoate (0.01 mol), 35 ml methanol, 5 ml water, 1.5 g sulfuric acid 96percent (0.015 mol) were charged, the temperature was brought to 40° C. and the reaction mixture was kept under these conditions for twelve hours. At the end of the reaction, the temperature was brought to 15° C., 20 ml water and ammonia 30percent solution up to pH 8 were added, the resultant solid was filtered and dried in oven at 40° C. under vacuum to give 5.8 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate.
With sodium hydrogencarbonate; potassium iodide In water; toluene for 20 h; Reflux
EXAMPLE 8 Preparation of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate In a reaction flask 5 g methyl 4-(4-bromo-1-oxybutyl)-α,α-dimethylphenylacetate (0.15 mol), 25 ml toluene, 4.08 g azacyclonol (0.015 mol), 10 ml water, 1.53 g sodium bicarbonate (0018 mol) and 0.25 g potassium iodide (0.0015 mol) were charged, the reaction mixture was brought to the reflux temperature and kept under these conditions for 20 hours. At the end of the reaction, the temperature was brought to 25° C., the separated organic phase was concentrated to residue by distillation under vacuum to give 7 g methyl 2-(4-(4-(4-(hydroxy-diphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate.
The alkyne of formula II (R=Me) (200 mg, 0.40 mmol) is dissolved in absolute ethanol (0.8 ml) and then treated with monohydrate p-toluenesulfonic acid (383 mg, 2.02 mmol). After 10 minutes, Ph3AuCl (4 mg, 0.0081 mmol, 2% molar) and AgCF3SO3 (2 mg, 0.0081 mmol, 2% molar) are added. After 48 h, at room temperature, the ethanol is evaporated under reduced pressure and the residue is taken up with ethyl acetate and basified till pH 10-11 with a NaHCO3 solution. The phases are separated, and the aqueous one is extracted with ethyl acetate. The organic phases are collected, dried with Na2SO4, filtered off and evaporated under reduced pressure. The crude reaction is purified by flash chromatography (acetate/methanol 9:1 as eluent) and 198 mg of title keto compound are obtained as a white solid, with a yield of 95%.1H NMR (400 MHz, CDCl3) delta ppm: 7.94 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 4H), 7.43 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.22-7.17 (m, 2H), 3.65 (s, 3H), 3.04-2.95 (m, 4H), 2.49-2.42 (m, 3H), 2.05-1.92 (m, 4H, 1H exchanges with D2O), 1.62 (s, 6H), 1.52-1.41 (m, 4H).
28.3%
With sulfuric acid; mercury(II) oxide; at 55℃; for 3.5h;
Methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate To a vial was added the methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)but-1-yn-1-yl)phenyl)-2-methylpropanoate (KSC-335-054) (0.074 g, 0.149 mmol). The mercuric oxide (1.493 ml, 0.045 mmol) was made into a 0.03 M solution in 4% w/v sulfuric acid and added to the starting material then heated to 55 C. and stirred for 3.5 h. The reaction turned a milky white color upon addition of the mercuric oxide solution. The reaction was removed from heat and diluted with saturated NaHCO3 (10 mL) and extracted with DCM (3*10 mL). The DCM layers were combined and dried with MgSO4, filtered and concentrated then purified by reverse-phase MPLC (10-100% MeCN:water) to produce methyl 2-(4-(4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate (0.0217 g, 0.042 mmol, 28.3% yield). 1H NMR (400 MHz, CDCl3): delta 7.93-7.91 (m, 2H), 7.48-7.45 (m, 4H), 7.42-7.39 (m, 2H), 7.30-7.26 (m, 4H), 7.19-7.14 (m, 2H), 3.63 (s, 3H), 2.96-2.88 (m, 4H), 2.44-2.34 (m, 3H), 2.08 (br s, 1H), 1.60 (s, 6H), 1.62-1.56 (m, 4H), 1.46-1.30 (m, 4H).
Preparation of substantially pure fexofenadine Step A: Preparation of Methyl 4- [4- [4- (HYDROXYBIPHENYLMETHYL)-L-PIPERIDINYL]-L- hydroxybutyl]-a, a-dimethyl phenyl acetate Methyl 4- [4- [4- (HYDROXYDIPHENYLMETHYL)-1-PIPERIDINYL]-1-OXOBUTYL]-2, 2- dimethylphenylacetate (20 g) was added to methanol (60 ml), at 25-35C followed by the addition of solid sodium borohydride (0.81 g) in small portions. The reaction mixture was further stirred at 25-35C for 2-3 hours and monitored by HPLC. The reaction was quenched with acetic acid and cooled to 0-5C. The solid was filtered and washed with cold methanol, dried to get methyl 4- [4- [4- (HYDROXYBIPHENYLMETHYL)-L-PIPERIDINYL]-L- hydroxybutyl]-a, a-dimethyl phenyl acetate (18-18.5 g). Step B: Preparation of substantially pure fexofenadine Methyl 4- [4- [4- (hydroxybiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-a, a- dimethylphenyl acetate (200 g) obtained in Step A was added to a mixture of ethanol (95%, 600 ml) and sodium hydroxide (23.2 g), and heated to reflux for about 3-4 hours. The reaction mixture was cooled to 50C and a solution of sodium borohydride (0.8 g) and sodium hydroxide (0.8 g) in water (10 ml) was added. The reaction mixture was again heated to reflux for about 1 hour and cooled to 8-10C ; the product was filtered and washed with water and ethanol (95%). The material was dried to give 162 g of substantially pure product having keto analog less than 0.05%.
With sodium tetrahydroborate; In methanol;
Example 7 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]alpha,alpha-dimethylphenylacetate A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate in 250 mL of CH3 OH is cooled in an ice CH3 OH bath, and 1.8 g of NaBH4 was added in portions. After 1 hr, the mixture was concentrated to a solid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion was extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylphenylacetate as a foam.
In methanol; sodium tetrahydroborate;
Example 6 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylphenylacetate A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate, prepared in accordance with Example 5, in 250 mL of CH3 OH was cooled in an ice-CH3 OH bath and 1.8 g of NaBH4 was added in portions. After 1 hr, the mixture was concentrated to a solid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion was extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 9.5.g (70%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylphenylacetate as a foam.
With sodium tetrahydroborate; In methanol;
Example 7 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha, alpha-dimethylphenylacetate A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha, alpha-dimethylphenylacetate, prepared in accordance with Example 6, in 250 mL of CH3OH is cooled in an ice CH3OH bath, and 1.8 g of NaBH4 is added in portions. After 1 hr, the mixture is concentrated to a solid. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion is extracted with EtOAc. The combined organics are washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha, alpha-dimethylphenylacetate as a foam.
d) Reduction of Carbinol viz, (Methyl-4{4-r4-(hvdroxydiphenyhnetyl)-l-piperidinyl}-l- hydroxybutyll -alpha , alpha-dimethylbenzene acetate)Methyl-4{4-[4-(hydroxydiphenylmetyl)-l-piperidinyl}-l-hydroxybutyl]-alpha,alpha- dimethylbenzene acetate (carbinol) obtained as oily mass in example 3 was dissolved in methanol and cooled to about 0 to 20C followed by addition of sodium borohydride. At the same temperature reaction mass stirred for 2 to 5 hours. After the reduction was completed the reaction mass was stirred at room temperature in presence of water and chloroform. Organic layer was separated followed by rewashing with aqueous layer. Combined organic layer was pooled and washed with potable water and submitted for chloroform distillation under reduced pressure to get thick oily mass of dicarbinol, i.e., Methyl-4{4-[4-(hydroxydiphenylmetyl)-l- piperidinyl}-l-hydroxybutyl]-alpha,alpha-dimethyl benzene acetate; B) Dicarbinol (Methyl-4{4-[4-(hydroxydiphenylmetyl)-l-pipedinyl}-l-hydroxybutylJ-a, a- dimethylbenzene acetate)Above oily mass of Carbinol was dissolved in 600 Ltr methanol and it was cooled to 0 to 200C. To it was added Sodium borohydride, 10 Kg (0.2645 Kmole) in lots. After complete addition, reaction mass was stirred at 0 to 2O0C for 2 to 5 hours. After completion, the reaction mass was stirred at room temperature with 400 Ltr potable water and 200 Ltr Chloroform for 1 hour. Separated chloroform layer. The aqueous layer was again washed with 100 Ltr Chloroform. Combined chloroform extract was washed with potable water and then submitted for chloroform distillation under vacuum to get thick oily mass of dicarbinol.
With sodium tetrahydroborate; In methanol; at 25 - 65℃; for 2 - 2.5h;Product distribution / selectivity;
Example-IPREPARATION OF HIGHLY PURE FEXOFENADINEStep-1: Preparation of fexofenadineMethyl 4- [4- [4-(hydroxydiphenylmethyl)- 1 -piperidinyl] - 1 -oxobutyl] -alpha,alpha-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35C followed by the addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-400C for one and half hours and further at 60-65C for one hour and monitored by HPLC. After completion of reaction (i.e. staring material was 0.04%), methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-650C and the resulting reaction mixture was refluxed for 6 hours. The reaction mixture was cooled to 50-550C; pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and stirred at 70-750C for further one hour. Thereafter reaction mixture was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-50C. The reaction mixture was filtered, washed with water and dried at 60- 650C to obtain 44.3 g of title compound having purity 97.88 % by HPLC.; Example-IIPREPARATION OF HIGHLY PURE FEXOFENADINEMethyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-alpha5alpha-dimethyl benzene acetate (50 g) was added to methanol (500 ml), at 25-35C followed by the <n="9"/>addition of solid sodium borohydride (2.5 g) in small portions. The reaction mixture was stirred at 35-40C for 1 hour and further at 60-65C for lhour. After completion of reaction, methanol (300 ml) was distilled off. To the reaction mass sodium hydroxide solution (7g in 75 ml of water) was added at 60-65C and refiuxed for 6 hours. The reaction mixture was cooled to 50-55C, pH was adjusted to 6.5-7.0 using dilute hydrochloric acid and further stirred at 70-75C for one hour. Thereafter reaction mass was cooled to room temperature maintaining pH at 6.5-7.0 and further cooled to 0-5C. The reaction mixture was filtered, washed with water and dried at 60-65C to obtain 46.7g of title compound which was slurred in ethanol (95%, 233ml) and was refiuxed for 3 hours. Thereafter reaction mixture was cooled to 0-5C, filtered, washed with ethanol and dried to obtain 44.8 g of title compound having purity 99.79 % by HPLC, meta impurity 0.03% and keto impurity is not detected.
To a stirred solution of 2-(4-{4-[4-(hydroxy-diphenyl-methyl)-piperidin-l-yl]-butyryl}-phenyl)- 2-methyl-propionic acid methyl ester (10 g, 19.47 mmol) of the formula IX in methanol (30 ml) at O0C was added sodium borohydride (0.38 g, 10 mmol) in portions and stirred at 30-35cC for 1 hour. The completion of reaction was checked by HPLC (starting should be NMT 1%). Acetic acid (0.31 g) was added at 30-350C and the reaction mixture was heated to 50-550C for 30 minutes. Demineralized water (20 ml) was added slowly at 50-550C and stirred for 30 minutes. The reaction mixture was cooled and stirred. The product obtained was filtered, washed with demineralized water and dried at 50-550C for 6-8 hours to obtain 9.0 g of 2-(4-{l-hydroxy-4-[4- (hydroxyl -diplienyl-methyl)-piperidin- 1 -yl] -butyl} -phenyl )-2-methyl-propionic acid methyl ester.
With hydrogen;5%-palladium/activated carbon; In methanol; at 50℃; under 4500.45 Torr;
EXAMPLE 4In a four-necked flask equipped with a mechanical stirrer, lOOg of 4-[4-[4- (hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-a,a-dimethylbenzeneacetic acid- methyl ester and 600 ml of methanol are loaded. When the ester is completely solubilised, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 5O0C and 6 bar pressure until the complete <n="7"/>conversion of the benzylketone into the corresponding alcohol. Once the reaction is completed, the catalyst is filtered, 60 n of 30% sodium hydroxide are added and the mixture is heated at reflux and kept under stirring until the complete hydrolysis of the ester, about 5 hours. The fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65C.55 g of fexofenadine are obtained with HPLC purity of about 60% and an impurity with A% equal to 32, which, from the calculation of the molecular weight, has one less oxygen.
With water; potassium carbonate; In methanol; at 20 - 40℃; for 16 - 26h;Product distribution / selectivity;
To a stirred solution of 4-[4-(hydiOxy-diphenyl-Jiiethyl)-piperidin-l-yl]-2-[4-(l- methoxycarbonyl-1 -methyl-ethyl) -benzoyl] -butyric acid ethyl ester (30 g, 51.22 mmol) in methanol (120 ml ) was added a solution of potassium carbonate (17.7 g, 128 mmol) in water (30 ml) at 28-320C. The reaction mixture was stirred at 28-320C for 10 hours and then at 35-4O0C for 6 hours. The reaction mixture was cooled to ambient temperature and water (60 ml) was added. The precipitated product was filtered, washed with aqueous methanol (35 ml) and dried to <n="16"/>obtain 21.6g of 2-(4-{4-[4-(hydroxy-diphenyl-methyl)-piperidin.-l-yl]-butyryl}-pherLyl)-2- methyl-propionic acid methyl ester. The product is purified using isobutanol.; To a stirred solution of 4-[4-(hydroxy-diphenyl-methyl)-pipeiidin-l-yl]-2-[4-(l- methoxycarbonyl-l-methyl-ethyl)-benzoyl] -butyric acid ethyl ester (34Og) in methanol (1.36 lit) was added a solution of potassium carbonate (200.5g) in dimineralized water (340 ml). The reaction mixture was stirred at ambient temperature for 20 hours and then at 35-4O0C for 6 hours. The reaction mixture was cooled to ambient temperature and dimineralized water (680 ml) was added. The precipitated product was filtered, washed with aqueous methanol (350 ml x 1) and dried to obtain 265g of title compound. The crude product was purified aqueous methanol.
To a stirred solution of 2-(4-{4-[4-(hydroxy-diphenyl-methyl)-piperidin-l-yl]-butyryl] -phenyl)- 2-methyl-propionic acid methyl ester (165 g) of the formula IX in methanol (1650 ml), sodium borohydride (12.15 g) was added at room temperature and reaction mixture was stirred at 30- <n="20"/>350C for 1 hour. The temperature was further raised to 65-7O0C and reaction mass was stirred for one^ hour, The solvent was distilled off and to the residue methanol (660 ml) and sodium hydroxide (25.7g) were added at 50-550C and further heated at 70-750C till less then 0.5% of fexofenadine methyl ester in HPLC. The reaction mixture was cooled to 50-550C and pH was adjusted to 6.5-7.0 using hydrochloric acid. The reaction mixture was cooled to 0-50C, stirred for 1.5 hours, filtered, washed with water and dried at 50-550C for 6-8 hours to afford 155 g of fexofenadine. The product is purified using ethanol to obtain 152 g of pure fexofenadine.
In a four-necked flask equipped with a mechanical stirrer, 100 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid-methyl ester obtained according to example 2, 600 ml of methanol and 60 ml of 30% sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 50 C. and 6 bar pressure until the complete conversion of the benzylketone into alcohol. Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65 C.85 g of crude fexofenadine are obtained on average with HPLC purity >99%; meta isomer <0.2%
6.7 g
EXAMPLE 9 Synthesis of fexofenadine In a reaction flask, 7.0 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate (0.01 mol), 20 ml methanol, 2.0 g sodium hydroxide 30% solution in water (0.015 mol) were charged, the temperature were brought to the reflux temperature of the solvent and the reaction mixture was kept under these conditions for seven hours. At the end of the reaction, the temperature was brought to 10 C., 0.2 g sodioborohydride (0.005 mol) were charged and the temperature was brought to 40 C. and kept under these conditions for fifteen hours. At the end of the reaction, the temperature was brought to 15 C. and 1.2 g acetic acid (0.02 mol) and 10 ml water were charged. The suspension was filtered and the solid was washed with a 1:1 water/methanol mixture (2*4 ml). The solid was dried under vacuum at 40 C. obtaining 6.7 g fexofenadine.
methyl 4'-(4-chloro-1-oxobutyl)-α,α-dimethylbenzene acetate[ No CAS ]
[ 115-46-8 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydrogencarbonate;potassium iodide; In water; toluene; for 72h;
Step a 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic Acid Methyl Ester Mix methyl 4'-(4-chloro-1-oxobutyl)-alpha,alpha-dimethylbenzene acetate (0.335 mol), alpha,alpha-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 ML) and water (220 ML).. Stir at reflux for 72 hours, add toluene (200 ML) and deionized water (100 ML).. Filter through filter aid while at 80 C. and separate the organic phase.. Dry (MgSO4), filter and purify by chromatography to give the title compound.
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; chloroform;
Step g: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic Acid Hydrochloride Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester (0.131 mol) in methanol (2.5 L) and add 10% sodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68 C. and evaporate the solvent in vacuo to a residue. Add chloroform (1 L) and stir until the solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3*300 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give a residue. Treat the residue with ethereal HCl, filter and dry to give the title compound.
With sodium hydroxide; In methanol; chloroform;
Step g 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester (0.131 mol) in methanol (2.5 L) and add 10% sodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68 C. and evaporate the solvent in vacuo to a residue. Add chloroform (1 L) and stir until the solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3*300 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give a residue. Treat the residue with ethereal HCl, filter and dry to give the title compound.
With sodium hydroxide; In methanol; chloroform; for 1.5h;Heating / reflux;
Step g 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic Acid Hydrochloride Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester (0.131 mol) in methanol (2.5 L) and add 10% sodium hydroxide (769 ML, 1.92 mol).. Stir at reflux for 1.5 hours, cool to 68 C. and evaporate the solvent in vacuo to a residue.. Add chloroform (1 L) and stir until the solids are dissolved.. Separate the organic phase and extract the aqueous phase with chloroform (3*300 ML).. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give a residue.. Treat the residue with ethereal HCl, filter and dry to give the title compound.
With potassium hydrogencarbonate; potassium iodide; In toluene; at 80℃; for 30h;Reflux;
1000 mL reaction flask, 55.4 g of diphenylpiperidine methanol was added successively, 42.1 g of potassium bicarbonate, 3.1g potassium iodide, 310 mL of toluene, Heated to 80 C, A solution of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI) (53.3 g) in toluene (150 ml) was slowly added dropwise, Plus, Reflux reaction about 30h, HPLC monitoring reaction is complete, The reaction solution was cooled to 10 to 15 C, filter, The filtrate was concentrated to give 107 g of crude product; With 250mL anhydrous ethanol heated reflux solution, Dropping 80 mL of water, After refluxing for 30 min, Natural cooling to 10 ~ 15 deg C, Insulation stirring 4h, Filtration gave an off-white solid, Drying 90g; And then recrystallized with EA, To obtain 77.4 g of methyl 2- [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -butanoyl] phenyl] -2-methylpropionate (VII) as a white solid, Purity 99.5% Yield 80%. among them, The molar ratio of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI), potassium iodide and base is 1: 0.1: 2.23.
With potassium carbonate; potassium iodide; In DMF (N,N-dimethyl-formamide); 4-methyl-2-pentanone; at 120℃; for 18h;
METHYL-2- [4- (4-CHLORO-L-OXO-BUTYL] phenyl] -2-methyl propionate (Intermediate 8) (0.5 kg), anhydrous potassium carbonate (349 gms), potassium iodide (9.7 gms), azacyclonol (328 gms), MIBK (2.0 LTR) and DMF (0.5 LTR) were charged to a reactor. A Dean and Stark arrangement for water removal was set up (about 10 ml of water separated out). The reaction mass was heated for 18 hours at 120C. THE reaction mass was then cooled to room temperature and the inorganics filtered. The MIBK layer was then washed with water. The MIBK was concentrated to obtain 800 gms of oil. 2 volumes of alcohol were charged and stirred at 40C for 2 hours, followed by cooling to 5C. The solids were filtered and dried to obtain the title compound.
With sodium hydrogencarbonate; In water; 4-methyl-2-pentanone; for 24h;Heating / reflux;
EXAMPLE 4In a 1-litre, 4-necked flask, 50 g of purified 4-[4-chloro-l-oxobutyl]~2,2- dimethylphenyl acetic acid methyl ester obtained in example 1, 38 g of <n="6"/>azacyclanol, 18 g of sodium bicarbonate, 250 ml of MIBK and 50 ml of water are loaded. The mixture is heated at reflux and kept under stirring for about 24 hours.Once the reaction is terminated, the mixture is cooled down, 200 ml of water are added and the phases are separated.The organic phase is concentrated under vacuum to 50 ml. A white precipitate is obtained, which is filtered and dried under vacuum. 63 g of 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidyl] - 1 -oxobutyl] -alpha,alpha-dimethylbenzeneacetic acid-methyl ester are obtained.
With potassium hydrogencarbonate;potassium iodide; In acetonitrile; at 78 - 80℃;
A mixture of alpha,alpha-diphenyl-4-piperidinemethanol (7.5 g) and methyl-4-(4-chloro- l-oxobutyl]-alpha,alpha-dimethylphenyl acetate (10.0 g) in presence of 0.10 g potassium bicarbonate (1 1.0 g, 0.1 1 moles) and catalytic amount of potassium iodide (0.10 g) in 50 ml of acetonitrile was stirred at 78-80 0C for 10-15 hours. Subsequently the mixture was cooled to 25-30 0C and filtered. The acetonitrile was removed under vacuum at 40-45C to obtain a residue. To the residue methanol (30 ml) was added and the mixture stirred at 5-1O0C followed by addition of sodium borohydride solution (0.4 g in methanol). The mixture was further stirred at 20-25C for 3 h, cooled to 5-10 0C and again stirred for 1 h. The suspension was filtered and washed with chilled methanol (10 ml). The solid obtained was dried under vacuum to obtain 4-[4-(4-(hydroxydiphenylmethyl)-l -piperidinyl]- 1- oxobutyl]-alpha,alpha,-dimethylbenzene acetic acid methyl ester. The 4-[4-(4- (hydroxydiphenylmethyl)-l -piperidinyl]- l-oxobutyl]-alpha,alpha,-dimethylbenzene acetic acid methyl ester is subsequently converted to fexofenadine by employing conventional methods.
With sodium hydrogencarbonate; In water; 4-methyl-2-pentanone; for 24h;Reflux;
In a 1-litre, 4-necked flask, 50 g of purified 4-[4-chloro-1-oxobutyl]-2,2-dimethylphenyl acetic acid methyl ester obtained in example 1, 38 g of azacyclanol, 18 g of sodium bicarbonate, 250 ml of MIBK and 50 ml of water are loaded. The mixture is heated at reflux and kept under stirring for about 24 hours. Once the reaction is terminated, the mixture is cooled down, 200 ml of water are added and the phases are separated.The organic phase is concentrated under vacuum to 50 ml. A white precipitate is obtained, which is filtered and dried under vacuum. 63 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid-methyl ester are obtained.
4- [4- (4-HYDROXYDIPHENYL METHYL)-L-PIPERIDINYL]-L-OXO-BUTYL]-A, a-dimethyl benzene acetic, methyl ester (20 gms) (Intermediate 9) was suspended in isopropanol (75 ml) and 25% sodium hydroxide solution (4 ml) was added. The mixture was refluxed for 5 hours. The pH of the reaction mixture was adjusted to 5.5-6 with dilute acetic acid. The precipitated product was filtered and dried to give 4- [4- (4-HYDROXYDIPHENYL METHYL)-L-PIPERIDINYL]-L-OXO- BUTYL]-A, a-dimethyl benzene acetic acid. The above product was suspended in methanol and sodium borohydride (0.75 gms) was added slowly over 2 hours. The mixture was stirred at 30C for 10 hours. The pH of the mixture was adjusted to 5. 5 to 6 with dilute acetic acid. The precipitated product was filtered and dried to give fexofenadine base monohydrate. The above product was suspended in methanol and sodium borohydride (0.75 gms) was added slowly over 2 hours. The mixture was stirred at 30C for 10 hours. The pH of the mixture was adjusted to 5. 5 to 6 with dilute acetic acid. The precipitated product was filtered and dried to give fexofenadine base monohydrate.
With methanol; sodium hydroxide; water; for 5h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 1In a four-necked flask equipped with a mechanical stirrer, lOOg of 4-[4-[4- (hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid- methyl ester, 600 ml of methanol and 60 ml of 30% sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 50C and 6 bar pressure until the complete conversion of the benzylketone into the corresponding alcohol. Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65C.85 g of crude fexofenadine are obtained on average with HPLC purity > 99%. EXAMPLE 3In a four-necked flask equipped with a mechanical stirrer, lOOg of 4- [4- [4- (hydroxydiphenylmethyl)- 1 -piperidyl] - 1 -oxobutyl] -alphajalpha-dimethylbenzeneacetic acid- methyl ester, 600 ml of methanol and 60 ml of 30 % sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 50C and 10 bar pressure until the complete conversion of the benzylketone into the corresponding alcohol. Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 650C.85 g of crude fexofenadine are obtained on average with HPLC purity > 99%.
With sodium hydroxide; water; isopropyl alcohol; for 5h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 2In a four-necked flask equipped with a mechanical stirrer, lOOg of 4-[4-[4- (hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-a,a-dimethylbenzeneacetic acid- methyl ester, 600 ml of water, 150 ml of Isopropanol and 73 ml of 30 % sodium hydroxide are loaded. The mixture is heated at reflux and kept under <n="6"/>stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 50C and 6 bar pressure until the complete conversion of the benzylketone into the corresponding alcohol. Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65C.85 g of crude fexofenadine are obtained on average with HPLC purity > 99%.
With methanol; sodium hydroxide; water; for 2 - 5h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 5In a four-necked flask equipped with a mechanical stirrer, lOOg of 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidyl] - 1 -oxobutyl] -alpha^-dimethylbenzeneacetic acid- methyl ester obtained according to example 2, 600 ml of methanol and 60 ml of 30 % sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of5% palladium on carbon are loaded into the reactor and are hydrogenated at 50C and 6 bar pressure until the complete conversion of the benzylketone into alcohol.Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65C.85 g of crude fexofenadine are obtained on average with HPLC purity > 99%; meta isomer < 0.2%. EXAMPLE 6In a four-necked flask equipped with a mechanical stirrer, lOOg of 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidyl]-l-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid- methyl ester obtained according to example 2, 600 ml of methanol and 130 ml of 30% sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 2 hours. When the ester is completely hydrolysed, the <n="7"/>solution is cooled down and 7 g of sodium borohydride are added. The reaction solution is heated again at 500C and kept at this temperature until the complete conversion of benzylketone into alcohol. Once the reaction is completed, 10 ml of acetone are added, it is left under stirring for 30 minutes, it is cooled down and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65C.85 g of crude fexofenadine are obtained on average with HPLC purity: 90%; meta isomer < 0.2%.
With zinc(II) fluoride; tri-tert-butyl phosphine;bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 80℃; for 2h;
EXAMPLE 8 Two grams of 3, 90 mg of P(tBu)3, 300 mg of Pd(dba)2, 250 mg of ZnF2 and 1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture was heated to 80 for two hours, cooled to room temperature, diluted with ether and worked up as described in example 1. The resulting product was filtered through silica to provide 1.3 g (62%) of 6.
Scheme A, optional step f: Preparation of 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL of acetone and chilled in an ice-bath. To the solution was added Jones reagent (Prepared via the method of Feiser and Feiser) dropwise until a red color persisted. The reaction was allowed to warm to room temperature and then stirred for 18 hours at ambient temperature. The mixture was concentrated under vacuum to give a green solid. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated, washed with water (3*100 mL), brine (1*100 mL) and treated with MgSO4, filtered and concentrated in vacuo to give a light green solid. Purification via column chromatography yielded 1.25 g (61% yield) of the title compound as a white solid. MH+514.6.
Step a: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic Acid Methyl Ester Mix methyl 4'-(4-chloro-1-oxobutyl)-alpha,alpha-dimethylbenzene acetate (0.335 mol), alpha,alpha-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and deionized water (100 mL). Filter through filter aid while at 80 C. and separate the organic phase. Dry (MgSO4), filter and purify by chromatography to give the title compound.
Example 6 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]1-oxobutyl]-alpha,alpha-dimethylphenylacetate A solution of 12.6 g of methyl 4-(4-chloro-1-oxobutyl)-alpha,alpha-dimethylphenylacetate in 500 mL of toluene in a one liter three neck flask with mechanical stirring was added 8.8 g of 4-(alpha,alpha-diphenyl)piperidinemethanol and 23 g of K2 CO3 and the mixture was refluxed for 7 hr. The cooled reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in Et2 O and treated with excess ethereal HCl. The mixture was then concentrated to a solid. The solid was treated with EtOAc and collected by filtration. The product was then partitioned between EtOAc and 2N Na2 CO3. The organics were dried over MgSO4, filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate.
13.5 g (79%)
Example 5 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate A solution of 12.6 g of methyl 4-(4-iodo-1-oxobutyl)-alpha,alpha-dimethylphenylacetate, prepared in accordance with Example 4, in 500 mL of toluene in a one liter three neck flask with mechanical stirring was added 8.8 g of 4-(alpha,alpha-diphenyl)piperidinemethanol and 23 g of K2 CO3 and the mixture was refluxed for 7 hr. The cooled reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in Et2 O and treated with excess ethereal HCl. The mixture was then concentrated to a solid. The solid was treated with EtOAc and collected by filtration. The product was then partitioned between EtOAc and 2N Na2 CO3. The organics were dried over MgSO4, filtered, and concentrated in vacuo to afford 13.5 g (79%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate.
Illustrative examples of compounds of this invention are the following: ... 2-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxoethyl]-alpha,alpha-dimethylbenzeneacetic acid, ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetate, n-pentyl 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetate, ethyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetate, methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetate, ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetate, n-propyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethyl-2-hydroxybenzeneacetate, n-hexyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetate, ...
Example 6 Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha, alpha-dimethylphenylacetate A solution of 12.6 g of methyl 4-(4-chloro-1-oxobutyl)-alpha,alpha-dimethylphenylacetate, prepared in accordance with Example 5, in 500 mL of toluene in a one liter three neck flask with mechanical stirring is added 8.8 g of 4-(alpha,alpha-diphenyl)piperidinemethanol and 23 g of K2CO3 and the mixture is refluxed for 7 hr. The cooled reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in Et2O and treated with excess ethereal HCl. The mixture is then concentrated to a solid. The solid is treated with EtOAc and collected by filtration. The product is then partitioned between EtOAc and 2N Na2CO3. The organics are dried over MgSO4, filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylphenylacetate.
Step a 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid methyl ester Mix methyl 4'-(4-chloro-1-oxobutyl)-alpha,alpha-dimethylbenzene acetate (0.335 mol), alpha,alpha-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and deionized water (100 mL). Filter through filter aid while at 80 C. and separate the organic phase. Dry (MgSO4), filter and purify by chromatography to give the title compound.
15
2-[3-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, methyl ester[ No CAS ]
[ 115-46-8 ]
[ 154477-54-0 ]
[ 937009-94-4 ]
[ 154477-55-1 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydrogencarbonate; potassium iodide; In water; toluene; for 30 - 40h;Heating / reflux;Product distribution / selectivity;
MethodMethyl-4-(4-chloro-l-oxobutyryl)-alpha,alpha-dimethylrhohenyl acetate (Ketone) (meta and para isomers) was dissolved in toluene followed by addition of Azacyclanol and water in presence of potassium carbonate and potassium iodide. Reaction mixture was refluxed for about 30 to 40 hours. After the reaction was completed, reaction mixture was cooled to room temperature and aqueous layer was discarded. Organic layer was filtered through Nutsche and distilled under reduced pressure and degassed for 2 hours to get the oily mass of carbinol, i.e., Methyl-4{4- [4-(hydroxydiphenylmethyl)-l-piperidinyl}-l-oxobutyl]-alpha, alpha-diphenylmethyl benzene acetate.A) Carbinol:(Methyl-4{4-[4- (hydroxydiphenylmetyl)-l-piperidinyl}-l-oxobutyl]- a, a- dimethylbenzene acetate) Method (I)Methyl-4-(4-chloro-l-oxobutyryl)-alpha,alpha-dimethyl phenyl acetate (Ketone), 70 Kg (0.2482 Kmole) was dissolved in 500 to 700 Ltr toluene and to it was added Azacyclanol, 50 to 60 Kg followed by potassium bicarbonate, 74 Kg (0.7391 Kmole) and potassium iodide, 0.50 to 1.20 Kg. Finally, to it was added 53 Ltr water. Reaction mixture was refluxed for 30 to 40 Hours. Completion of the reaction was monitored by HPLC. On completion the reaction mixture was cooled to room temperature and aqueous layer was discarded. Toluene layer was filtered through Nutsche. Finally toluene was distilled under reduced pressure and degassed for 2 hours to get the oily mass of carbinol.
With potassium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 90℃; for 2 - 12h;Product distribution / selectivity;
Method 2Methyl-4-(4-Chloro-l-oxobutyryl)-alpha, alpha-dimethylphenyl acetate, (Ketone) (meta and para isomers) was dissolved in dimethyl formamide followed by addition of Azacyclnol, potassium carbonate and potassium iodide. The reaction mixture was heated at 9018C for about 7 to 12 hours. Reaction was monitored by HPLC. After the reaction was completed it was cooled to room temperature and the product was extracted with chloroform and was well washed with water. Removal of the organic solvent at reduced pressure yielded thick oily carbinol.Carbinol:(Methyl-4{4-[4-(hydroxydiphenyhnetyl)-l-piperidinyl}-l-oxobutyl]-a, a- dimethylbenzene acetate) Method (H) EPO <DP n="13"/>Methyl-4-(4-chloro-l-oxobutyryl)-alpha,alpha-dimethyl phenyl acetate (Ketone), 0.50 Kg (0.001769 mole) was dissolved in 400 nil dimethylformamide and to it was added Azacyclanol, 0.428 Kg (0.00160 mole) followed by potassium bicarbonate, 0.528 Kg (0.00528 mole) and potassium iodide, 0.00357 Kg. Reaction mixture was heated at 9O0C for 7 to 2 Hours. Completion of the reaction was monitored by HPLC. On completion the reaction mixture was cooled to room temperature and the product was extracted twice with chloroform and finally washed with water. Removal of the solvent at reduced pressure provides thick oily carbinol.
2-[4-[4-[4-[hydroxyl(diphenyl)methyl]-1-piperidinyl]butanoyl]phenyl]-2-methylpropanoic acid sodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; for 5h;Reflux;Product distribution / selectivity;
Example 1 In a four-necked flask equipped with a mechanical stirrer, 100 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid-methyl ester, 600 ml of methanol and 60 ml of 30% sodium hydroxide are loaded. The mixture is heated at reflux and kept under stirring for about 5 hours. When the ester is completely hydrolysed, 10 g of 5% palladium on carbon are loaded into the reactor and are hydrogenated at 50 C. and 6 bar pressure until the complete conversion of the benzylketone into the corresponding alcohol. Once the reaction is completed, the catalyst is filtered and the fexofenadine is precipitated by adjusting the pH to 5-8 with acetic acid. The solid obtained is filtered and dried under vacuum at 65 C. 85 g of crude fexofenadine are obtained on average with HPLC purity >99%. Optimum temperature for hydrogenation: 35-45 C.; pH of precipitation 5-6.
With sulfuric acid; water; In methanol; at 40℃; for 12h;
EXAMPLE 12 Synthesis of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate (Compound VIII) In a reaction flask 7.0 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methylpropanoate (0.01 mol), 35 ml methanol, 5 ml water, 1.5 g sulfuric acid 96% (0.015 mol) were charged, the temperature was brought to 40 C. and the reaction mixture was kept under these conditions for twelve hours. At the end of the reaction, the temperature was brought to 15 C., 20 ml water and ammonia 30% solution up to pH 8 were added, the resultant solid was filtered and dried in oven at 40 C. under vacuum to give 5.8 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate.
With sodium hydrogencarbonate; potassium iodide; In water; toluene; for 20h;Reflux;
EXAMPLE 8 Preparation of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate In a reaction flask 5 g methyl 4-(4-bromo-1-oxybutyl)-alpha,alpha-dimethylphenylacetate (0.15 mol), 25 ml toluene, 4.08 g azacyclonol (0.015 mol), 10 ml water, 1.53 g sodium bicarbonate (0018 mol) and 0.25 g potassium iodide (0.0015 mol) were charged, the reaction mixture was brought to the reflux temperature and kept under these conditions for 20 hours. At the end of the reaction, the temperature was brought to 25 C., the separated organic phase was concentrated to residue by distillation under vacuum to give 7 g methyl 2-(4-(4-(4-(hydroxy-diphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate.
Stage #1: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, methyl ester With methanol; sodium tetrahydridoborate at 5 - 30℃; for 1h; Large scale;
Stage #2: With lithium hydroxide monohydrate; sodium hydroxide for 4h; Reflux; Large scale;
Stage #3: With hydrogenchloride In lithium hydroxide monohydrate at 10℃; for 2h; Large scale;
1.4-1.5; 5-9
Add 110kg of methanol to the 200L reaction kettle, add 14kg of intermediate III under stirring, control the temperature to 5°C, add 1.06kg of sodium borohydride in batches, after the addition, heat up to 20-30°C and continue the reaction for 1h, add 21kg of hydrogen Sodium oxide solution (4.2kg sodium hydroxide+16.8kg purified water), heat up to reflux reaction, until dissolved and clear (about 4h), add 0.2kg activated carbon and continue to reflux for 0.5h, filter, cool the filtrate to 10 , add 6mol dropwise /L hydrochloric acid solution, adjust pH=2.5, add 94kg of purified water, continue to stir for 2h, a large amount of solids are precipitated, centrifuge to obtain wet product, the wet product is placed in a vacuum drying box, and dried at 50 ~ 60 to obtain 13.1kg of fexofil hydrochloride That would be crude.The molar yield was 89.5%.Add 67kg of acetone to the 200L reactor, add 13kg of fexofenadine hydrochloride crude product under stirring, heat up to reflux for 3h, drop to room temperature, centrifuge, and dry the filter cake at 50-60°C in a vacuum drying oven to obtain fexofenadine hydrochloride The final product is about 11.5kg.The molar yield was 88.5%.
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