Name: 83799-24-0|2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid|95%
Brand: Ambeed
SKU: A191730
Price: 28.0 USD
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[ 154825-96-4 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With water; lithium hydroxide; In tetrahydrofuran; at 80℃; for 18h;	2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid To a vial was added the methyl 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoate (KSC-335-080) (0.094 g, 0.182 mmol) and THF (Volume: 3 mL,). The LiOH (0.022 g, 0.911 mmol) was dissolved in water (3.00 mL) and then added to the reaction stirred at 80 C. for 18 h. The reaction was removed from heat and cooled to rt and 1.0 M HCl in water was added to adjust to pH to 4 and a gummy off-white solid formed. DCM (5 mL) was added to the mixture and it was sonicated to break up the solid. The DCM layer was removed and the aqueous was extracted with DCM (2*5 mL). The DCM layer was concentrated and the residue was purified by reverse-phase MPLC (20 min, 10-100% MeCN:water) to produce the product with impurities. This was submitted to the purification core. The pure sample was recovered to produce 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid (0.0378 g, 0.075 mmol, 41% yield). 1H NMR (400 MHz, DMSO-d6): delta 8.22 (s, 1H), 7.52-7.49 (m, 4H), 7.29-7.26 (m, 8H), 7.15-7.10 (m, 2H), 4.47 (t, J=5.9 Hz, 1H), 2.94-2.86 (m, 3H), 2.35-2.30 (m, 2H), 2.05-1.95 (m, 2H), 1.60-1.35 (m, 12H), 1.28-1.22 (m, 2H). 13C NMR (125 MHz, CDCl3): delta 177.7, 163.7, 147.2, 144.4, 143.4, 127.8, 125.8, 125.7, 125.6, 125.1, 78.4, 71.8, 57.7, 53.4, 53.2, 45.5, 43.1, 37.3, 26.5, 25.6, 22.6. LCMS Retention time: 2.612 min. LCMS purity 100%. HRMS (ESI): m/z calcd for C32H39NO4 [M+H]+ 502.2879. found 502.2952.
	With sodium hydroxide; In methanol; water; for 1h;Heating / reflux;	EXAMPLE 6 One hundred fifty milligrams of 7 was slurried in 5 mL of water and 10 mL of methanol. To the slurry was added 175 mg of sodium hydroxide. The slurry was refluxed for one hour, cooled to room temperature and the methanol removed in vacuo. The resulting aqueous solution was distributed between water and chloroform, the chloroform layer was discarded, the aqueous layer was adjusted to pH 2.3 and extracted with chloroform. The organic layer was dried, filtered and reduced in vacuo to provide fexofenadine.
		e) Deprotection of carboxyl function of Methyl-4{4-r4-(hydroxydiphenylmetyl)-l-piperidinyl}- l-hvdroxybutyll-alpha,alpha-dimethyl benzene acetate to yield crude isomer of Fexofenadine baseThe dicarbinol prepared in example 3 was dissolved in methanol followed by addition of sodium hydroxide in potable water followed by refluxed for about 3 to 6 hours. Methanol was distilled off, once the reaction deprotection was completed. The reaction mixture was cooled to room temperature and to it chloroform was added. Reaction mixture was cooled to about 0 to 2O0C. pH of the reaction mass was adjusted to about 6.4 to 6.8 with 50 % aqueous hydrochloric acid solution. Reaction mixture was stirred for 1 hour at the same pH. EPO <DP n="10"/>Chloroform was separated and aqueous layer was washed twice with chloroform. Organic layer was pooled and submitted for distillation under reduced pressure. To the above mass methanol was added and heated 45 to 50C for about half an hour. The mass was cooled to room temperature and methylethyl ketone was added to it. The crystallized mass was stirred for about 30 to 35 hours at room temperature and centrifuged to get crude fexafenadine baseC) Fexofenadine ?VIethyl-4{4-r4-(hydroxydiphenylmetyl)-l-piperidmyl}-l-hydroxybutyll-alpha,alpha- dimethylbenzene acetate)The above oily mass of Dicarbinol was dissolved in 300 Ltr methanol and to it was added 120 to 130 Kg Sodium hydroxide dissolved in 400 Ltr potable water. Reaction mixture was refluxed for 3 to 6 hours. On completion of the reaction the methanol was distilled out under vacuum. Cooled the reaction mixture to room temperature and added 200 to 400 Ltr Chloroform. Finally the reaction mass was cooled to 0 to 200C. Adjusted the pH of the reaction mass 6.4 to 6.8 with 50% aqueous hydrochloric acid solution. At pH 6.4 to 6.8 the reaction mass was stirred for 1 hour and chloroform layer was separated. The aqueous layer was again washed twice with chloroform. Finally chloroform layer was submitted for distillation under vacuum. To the above mass added 30 Ltr methanol and heated at 45 to 5O0C temperature for half an hour. Then cooled the mass to room temperature and added 60 Ltr EPO <DP n="14"/>methylethyl ketone. The crystallization mass was stirred for 30 to 35 hours at room temperature. Then centrifuged the material. The sample was submitted for loss on drying and impurity profile. Yield = 40 to 45 Kg

		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 sodium hydroxide (1.24 g, 31 mmols) in denatured spirit (30 ml) was added 2-(4-{l-hydroxy-4-[4-(hydroxy-diphenyl-methyl)-piperidin-l-yl]-butyl}-phenyl)-2- methyl-propionic acid methyl ester (10 g, 19.4 mmols) at 3O0C. The reaction mixture was heated to reflux for 3 hrs. HPLC was checked (starting material should be absent). After completion of reactions, ethanol was distilled off completely under vacuum and water 50 ml was added to make a clear solution. The resulting solution was washed with methyl tertiary butyl ether (20 ml x 4) and methylene, dichloride. The aqueous solution was cooled to 0-50C and the pH was adjusted to 6.0 - 6.5 with hydrochloric acid. The precipitated solid was filtered and dried at 50- 550C to afford 8.5 g of fexofenadine having purity 99.4% by HPLC.
		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.
		Step-4 Preparation of fexofenadine from methyl 2-(4-bromophenyl)-2-methylpropionate:A mixture of 3-butyn-1-ol (30.7 grams), tetrakis (triphenyl phosphine) palladium (0) (1.5 grams) and copper iodide (6 grams) was charged to 1 L flask containing methyl 2-(4-bromophenyl)-2-methylpropionate (step-3 material, 75 grams, purity of about 98.2%) and potassium carbonate (120 grams) in toluene (500 ml). Reaction mass temperature gradually raised to reflux temperature and stirred for 24 hours. The resultant dark solution was filtered. The clear filtrate (toluene layer) was washed with saturated ammonium chloride solution (400 ml), 20% sodium chloride solution (400 ml), dried using anhydrous sodium sulphate and concentrated under reduced pressure to obtain constant weight oily material. This oily material (70 grams) dissolved in methanol (250 ml) and added to a mixture of mercuric oxide (5 grams) and 5% sulphuric acid solution in water. Reaction solution was stirred for 2 hours at 25-35 C. The reaction solution diluted with water (500 ml) and basified to pH: 7-8 using ammonium hydroxide solution and extracted with ethylacetate (2×250 ml). Ethylacetate layer was washed with water (3×350 ml), dried with sodium sulphate, filtered and concentrated. Resultant brown colored thick oily material (68 grams) treated with phosphorus oxychloride (23 ml) in dichloromethane (300 ml) at 25-35 C. under stirring for 24 hours. Reaction was quenched in to chilled water (500 ml). Dichloromethane layer was separated, dried with anhydrous sodium sulphate and concentrated to constant weight. The resultant oily material (48 grams) was refluxed with the mixture of azacyclonol (35 gram), potassium carbonate (94 grams) and potassium iodide (1.5 gram) in toluene (250 ml) for 36 hours. Reaction was quenched with chilled water (500 ml) and toluene layer separated. Aqueous layer was extracted with toluene (2×500 ml). Combined toluene layer was dried and concentrated. Resultant crude material (78.4 grams) was dissolved in methanol (200 ml) at 25-35 C. To this solution, sodium borohydrate (9 grams) added lot wise during 30 minutes (Note: addition of sodium borohydride causes exothermic reaction). Reaction mixture stirred for 16 hours, quenched by adding 2% acetic acid in water (20 ml) and stirred for 30 minutes. The resulted solid material filtered and dried at 60 C. The resultant solid material (31.36 grams of fexofenadine methyl ester) was dissolved in methanol (150 ml). To this solution 2N sodium hydroxide solution (150 ml) was added and heated to 70-75 C. for 16 hours. Reaction solution was clarified by filtration through hyflow bed and the clear filtrate was neutralized with 1N hydrochloric acid. Resulting gummy solid was stirred with methanol for 16 hours. Resulting white crystals of fexofenadine was filtered to obtain 23.5 grams of fexofenadine invariably having a purity of 99.9% and ?impurity-B? (isomeric impurity [3-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-alpha,alpha-dimethyl benzeneacetic acid below detection levels.
		Step-4 Preparation of fexofenadine from methyl 2-(4-bromophenyl)-2-methylpropionate: A mixture of 3-butyn-1-ol (30.7grams), (triphenyl phosphines) palladium (0) (1.5grams) and copper iodide (6 grams) was charged into a 1L flask containing 2-(4-bromophenyl)-2-methylpropionate (step-3 material, 75 grams, purity of about 98.2%) and potassium carbonate (120 grams) in toluene (500ml). The reaction mass temperature was gradually raised to reflux temperature and stirred for 24 hours. The resultant dark solution was filtered. The clear filtrate (toluene layer) was washed with saturated ammonium chloride solution (400ml), 20% sodium chloride solution (400ml), dried using anhydrous sodium sulphate and concentrated under reduced pressure to obtain constant weight oily material. This oily material (70 grams) was dissolved in methanol (250ml) and added to a mixture of mercuric oxide (5 grams) and 5% sulphuric acid solution in water. The reaction solution was stirred for 2 hours at 25-35C. The reaction solution was diluted with water (500ml) and basified to pH 7-8 using ammonium hydroxide solution and extracted with ethyl acetate (2x250ml). The ethyl acetate layer was washed with water (3x350ml), dried with sodium sulphate, filtered and concentrated. The resultant brown colored thick oily material (68 grams) was treated with phosphorus oxychloride (23ml) in dichloromethane (300ml) at 25-35C under stirring for 24 hours. The reaction was quenched by adding to chilled water (500ml). The dichloromethane layer was separated, dried with anhydrous sodium sulphate and concentrated to constant weight. The resultant oily material (48 grams) was refluxed with a mixture of azacyclonol (35 gram), potassium carbonate (94 grams) and potassium iodide (1.5gram) in toluene (250ml) for 36 hours. The reaction was quenched with chilled water (500ml) and the toluene layer separated. The aqueous layer was extracted with toluene (2x500ml). The combined toluene layers were dried and concentrated. The resulting crude material (78.4 grams) was dissolved in methanol (200 ml) at 25-35C. To this solution, sodium borohydrate (9 grams) was added lotwise during 30 minutes (Note: addition of sodium borohydride causes an exothermic reaction). The reaction mixture was stirred for 16 hours, quenched by adding 2% acetic acid in water (20ml) and stirred for 30 minutes. The resulting solid material way filtered and dried at 60C. The resulting solid material (31.36 grams of fexofenadine methyl ester) was dissolved in methanol (150ml). To this solution 2N sodium hydroxide solution (150ml) was added and heated to 70-75 C for 16 hours. The reaction solution was clarified by filtration through hyflow bed and the clear filtrate was neutralized with 1N hydrochloric acid. The resulting gummy solid was stirred with methanol for 16 hours. The resulting white crystals of flexoflenadine were filtered to obtain 23.5 grams of fexofenadine invariably having a purity of 99.9% and 'impurity-B' (isomeric impurity [3-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-alpha,alpha-dimethyl benzeneacetic acid) below detection levels.

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Il Farmaco,1999,vol. 54,p. 600 - 610
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562
[4]Patent: US2015/238473,2015,A1 .Location in patent: Paragraph 0242
[5]Patent: US2006/63808,2006,A1 .Location in patent: Page/Page column 8-14
[6]Patent: WO2007/7347,2007,A1 .Location in patent: Page/Page column 8-9; 12-13
[7]Patent: WO2007/49303,2007,A2 .Location in patent: Page/Page column 7-8
[8]Patent: WO2007/135693,2007,A2 .Location in patent: Page/Page column 15
[9]Patent: WO2008/12858,2008,A1 .Location in patent: Page/Page column 5-6
[10]Patent: US2012/309973,2012,A1 .Location in patent: Page/Page column 4
[11]Patent: EP2532644,2012,A1 .Location in patent: Page/Page column 6-7

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[ 174483-06-8 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; acetic acid; In methanol;	Ethyl 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-alpha,alpha-dimethylbenzeneacetate (0.5 g) was dissolved in MeOH (10 mL), and sodium hydroxide solution (0.35 g, water 3 mL) was added. The reaction mixture was heated at reflux for 5 h, and cooled to 22 C., followed by the addition of acetic acid to reach a pH 4-5. MeOH (5 mL) was added to the solution and stirred for 1 h. The precipitate was collected by filtration to give 0.42 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid. 1 H NMR (DMSO-d6) d 1.45-1.49 (m, 2H), 1.67 (s, 6H), 1.67-1.78 (m, 6H), 2.12-2.20 (m, 2H), 2.45-2.50 (m, 2H), 2.68-2.78 (m 3H), 3.10 (broad s, 2H), 4.71 (m, 1H), 5.50 (broad s, 1H), 7.35-7.40 (m, 2H), 7.45-7.55 (m, 8H), 7.76-7.78 (m, 4H). MH+ 502.3
0.26 g	With sodium hydroxide; In methanol; water; for 3h;pH 5;Reflux;	(5) A solution of 0.71 mmol a, a-dimethyl-4- [1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] Butyl] phenylacetate was dissolved in a mixture of 15 ml of methanol and 4 ml of a 10% aqueous solution of sodium hydroxide, and the mixture was heated under reflux 3 h, remove the methanol under reduced pressure, the residue dissolved in 10ml of water, add 10ml 10% acetic acid solution to rhoEta = 5, precipitation of white precipitate. After filtration, the filter cake was dried and recrystallized from methanol to give 0.26 g of white

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[2]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155
[3]Patent: US5925761,1999,A
[4]Patent: CN103333100,2016,B .Location in patent: Paragraph 0022

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[ 32454-35-6 ]
[ 105955-84-8 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

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[ 50679-08-8 ]
[ 83799-24-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5423 - 5426
[2]Tetrahedron,2008,vol. 64,p. 11738 - 11744

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[ 76811-98-8 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
87%		(6) 40 g (0.08 mol) of 4-{4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-butyryl group was placed in a 500 ml three-necked flask equipped with a magnetic stirrer. }-alpha,alpha-dimethyl-phenylacetic acid (VI) and 150 ml of methanol,After cooling to 0 C, 80 ml of 1 N potassium hydroxide solution was added dropwise, and after the dropwise addition was completed,After adding 4.32 g (0.08 mol) of potassium borohydride and returning to room temperature for 1 hour, an additional 2.16 g of potassium borohydride was added, and the mixture was heated to 50 C for 3 hours.The pH was then adjusted to 5 with 50% phosphoric acid to precipitate a solid which was filtered and washed with water.The wet product is recrystallized and purified by using methanol and water mixed solvent to obtain 35 g of high-purity fexofenadine (I), the yield is 87%, and the HPLC content is >99.7%;
		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 hydrogen;5%-palladium/activated carbon; In methanol; water; at 50℃; under 4500.45 Torr;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%.

	With sodium tetrahydroborate; In methanol; water; at 50℃;Product distribution / selectivity;	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%.
		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 tetrahydroborate; sodium hydroxide; In water; at 38 - 40℃; for 4h;	In a 2L four-neck flask equipped with mechanical stirrer, a thermometer and a condenser, sodium hydroxide (22.6 g, 567 mmol) was added to 2-(4-(4-(4- (hydroxydiphenylmethyl)piperidin- l -yl)butanoil)phenyl)-2-methylpropanoic acid (V) (278 g), in methanol (765 mL) and water (350 mL). The mixture was heated to 38-40C until complete dissolution of the solid, and a solution of sodium borohydride (9.8 g, 259 mmol), water (47 mL) and sodium hydroxide ( 100 mg) was dropped. The reaction mixture was stirred at 38-40C for about 4 hours and monitored by HPLC. The suspension was filtered and the solid was washed with a mixture of 1 : 1 water/methanol (2 x 80 mL), cooled to - 10C and finally washed with water (2 x 100 mL). The solid was dried under vacuum at 40C to give 265 g of Fexofenadine free base (VI), as a white solid.

Reference： [1]Patent: CN104557671,2018,B .Location in patent: Paragraph 0047; 0053; 0064; 0065
[2]Patent: WO2008/12858,2008,A1 .Location in patent: Page/Page column 4; 5
[3]Patent: WO2008/12859,2008,A2 .Location in patent: Page/Page column 5
[4]Patent: WO2008/12859,2008,A2 .Location in patent: Page/Page column 5-6
[5]Patent: WO2008/12858,2008,A1 .Location in patent: Page/Page column 4-5
[6]Patent: WO2011/158262,2011,A1 .Location in patent: Page/Page column 13

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Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610
[2]Patent: US2012/309973,2012,A1
[3]Patent: EP2532644,2012,A1
[4]Patent: CN103333100,2016,B

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[ 2173-69-5 ]
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Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 18755-52-7 ]
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Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610
[2]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155

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[ 57625-74-8 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 252022-32-5 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 154477-54-0 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610
[2]Patent: US2013/237709,2013,A1
[3]Patent: US2013/237709,2013,A1

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[ 169032-11-5 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610
[2]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155

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[ 169032-13-7 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 169032-14-8 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 252022-31-4 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 169032-12-6 ]
[ 83799-24-0 ]

Reference： [1]Il Farmaco,1999,vol. 54,p. 600 - 610

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[ 1126-09-6 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

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[ 96067-93-5 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

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[ 115-46-8 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; sodium borohydrid; In methanol; hexane; water; ethyl acetate;	The foregoing reaction was repeated on a larger scale as follows: To a solution of the mixture cis/trans (77 g crude 0.200 mol) in methanol (650 mL) was added alpha,alpha-diphenyl-4-piperidinemethanol (55 g, 0.206 mol). The reaction mixture was heated at 50 C. for 1 h (A clear solution was obtained). The reaction solution was then cooled with an ice-water bath to 10 to 15 C., and sodium borohydride (15 g,) was added over 15 min. The reaction was exothermic and the inner temperature rose to 40 C. The reaction mixture was stirred for 30 min after the addition of NaBH4. The reaction was quenched by addition of water (10 mL), and concentrated to remove the solvent to give a solid residue. It was suspended in water (500 mL) and extracted with ethyl acetate (400 mL, 200 mL). The combined organic phases were washed with water (100 mL), brine (50 mL), dried over Na2 SO4 for 1 h, filtered, the filtrate was concentrated to give a thick oil which contained about 50 mL of EtOAc. To it was added hexane (400 mL) with stirring, and a white precipitate was collected by filtration. The solid was washed with hexane (60 mL and dried to give 105 g crude product (91% pure by HPLC, 66.4% overall yield from the aldehyde). The crude product was used for next step, or could be purified by passing through a short column of silica gel (EtOAc) to give the desired product (85%). 4-[1-Hydroxy-4-[4-(Hydroxydiphenylmethyl)-1-Piperidinyl]butyl]-alpha,alpha-Dimethylbenzeneacetic Acid:

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710
[2]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[3]Patent: US5925761,1999,A
[4]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

20
[ 101184-73-0 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

21
[ 160809-38-1 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

22
[ 185454-47-1 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,1996,vol. 26,p. 4699 - 4710

23
[ 52787-37-8 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[2]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

24
[ 32454-24-3 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[2]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[3]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

25
[ 211105-00-9 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704
[2]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

26
[ 207301-59-5 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

27
[ 211105-11-2 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

28
[ 207301-40-4 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

29
[ 207301-64-2 ]
[ 83799-24-0 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 2701 - 2704

30
[ 154825-97-5 ]
[ 83799-24-0 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Patent: US2012/309973,2012,A1
[3]Patent: EP2532644,2012,A1
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562

31
[ 154825-93-1 ]
[ 83799-24-0 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Patent: US2013/237709,2013,A1
[3]Patent: US2013/237709,2013,A1
[4]Patent: US2013/237709,2013,A1
[5]Patent: US2013/237709,2013,A1
[6]Patent: US2013/237709,2013,A1
[7]Patent: US2013/237709,2013,A1
[8]Patent: US2013/237709,2013,A1
[9]Patent: US2013/237709,2013,A1
[10]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562

32
[ 154825-94-2 ]
[ 83799-24-0 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562

33
[ 154825-95-3 ]
[ 83799-24-0 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Patent: WO2011/158262,2011,A1
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562

34
[ 154477-55-1 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
		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.

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2620 - 2622
[2]Patent: WO2007/135693,2007,A2 .Location in patent: Page/Page column 18-19
[3]Patent: US2010/16599,2010,A1 .Location in patent: Page/Page column 2
[4]Patent: US2013/237709,2013,A1 .Location in patent: Paragraph 0107; 0108
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 8540 - 8562

35
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid hydrochloride [ No CAS ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium borohydrid; In ethanol; dichloromethane; water;	Step c: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add, by dropwise addition, to a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at room temperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo and stir the residue with methylene chloride (15 mL) and deionized water (15 mL). Dry (MgSO4), acidify to pH 3 with gaseous hydrogen chloride and evaporate the solvent. Add ether with stirring, filter the white solid and wash with additional ether. Dry to give the title compound.
	With sodium hydroxide; sodium borohydrid; In ethanol; dichloromethane; water;	Step c 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 mL) and add, by dropwise addition, to a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 mL). Stir at room temperature for 3.5 hours at pH 7-8. Evaporate the solvent in vacuo and stir the residue with methylene chloride (15 mL) and deionized water (15 mL). Dry (MgSO4), acidify to pH 3 with gaseous hydrogen chloride and evaporate the solvent. Add ether with stirring, filter the white solid and wash with additional ether. Dry to give the title compound.
	With sodium hydroxide; sodium tetrahydroborate; In diethyl ether; ethanol; dichloromethane; water; at 20℃; for 3.5h;pH 7 - 8;	Step c 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid Add sodium borohydride (0.105 g, 2.77 mmol) to a solution of sodium hydroxide (0.053 g, 1.33 mmol) in deionized water (2 ML) and add, by dropwise addition, to a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-alpha,alpha-dimethylbenzeneacetic acid hydrochloride (0.70 g, 1.31 mmol) in ethanol (30 ML).. Stir at room temperature for 3.5 hours at PH 7-8.. Evaporate the solvent in vacuo and stir the residue with methylene chloride (15 ML) and deionized water (15 ML).. Dry (MgSO4), acidify to PH 3 with gaseous hydrogen chloride and evaporate the solvent.. Add ether with stirring, filter the white solid and wash with additional ether.. Dry to give the title compound.

Reference： [1]Patent: US6147216,2000,A
[2]Patent: US6242606,2001,B1
[3]Patent: US6348597,2002,B2 .Location in patent: Page column 101

36
[ 169280-30-2 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium hydroxide; In isopropyl alcohol; for 2h;Heating / reflux;	Step i 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid Dissolve N-methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide (8.35 g, 15.33 mmol) in isopropanol (50 ML) and add potassium hydroxide (8.63 g, 153.7 mmol).. Heat to reflux for 2 hours, add additional potassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional 16 hours.. Cool to room temperature, treat with concentrated HCl by dropwise addition until PH=3.. Dilute with water (100 ML), stir vigorously for 2 hours, add ethyl acetate (30 ML) and stir for 1 hour.. Filter to give the title compound (7.15 g, 87%) as an off-white solid. MS (CI, CH4) m/e 502 (M++1), 107. Anal. Calcd for C32H39NO4.HCl.2.6H2O: C, 65.70; H, 7.61; N, 2.39; Found: C, 65.25; H, 7.70; N, 2.36.
41%	With potassium hydroxide; In isopropyl alcohol; for 18h;Heating / reflux;	Dissolve N,N-dimethyl-2-(4-{1-hydroxy-4-[4-hydroxy-diphenylmethyl)-piperidin-1-yl]-butyry}-phenyl)-isobutyramide (15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide (8.63 g, 153.7 mmol). Heat to reflux for 2 hours, add additional potassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional 16 hours. Cool to room temperature, treat with concentrated HCl by dropwise addition until pH=3. Dilute with water (100 mL), stir vigorously for 2 hours, add ethyl acetate (30 mL) and stir for 1 hour. Filter to give the title compound (41%).

Reference： [1]Patent: US6348597,2002,B2 .Location in patent: Page column 108
[2]Patent: US6348597,2002,B2 .Location in patent: Page column 108

37
[ 1319714-86-7 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; water;pH 7;	after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanolbutanone to give 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, M.P. 195-197 C.

Reference： [1]Patent: US6407119,2002,B1 .Location in patent: Page column 25

38
[ 83799-24-0 ]
[ 138452-21-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; In water; ethyl acetate; at 20 - 40℃;	In a 500 mL four-neck flask equipped with mechanical agitator, a thermometer and a condenser, a suspension of 2-(4-( l -hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin- l -yl)butyl)phenyl)-2- methylpropanoic acid (VI) (9 g, 1 7.9 mmol) in ethyl acetate (90 mL) was heated to 40C. Then 36% aqueous hydrochloric acid (2 g, 20 mmol) was dropped to the mixture and the final solution was stirred at 40C for 1 hour and at room temperature overnight. The crystallized solid was filtered, washed with ethyl acetate and dried under vacuum at 50C, to give 8.5 g of polymorph phi of <strong>[83799-24-0]Fexofenadine</strong> hydrochloride, as a white solid. Yield: 88%.
84.7%	With hydrogenchloride; pyrographite; In ethanol; at 75℃; for 0.5h;pH 3;	(6) Take 0.12mol of non-Sophafenidine dissolved in 1000ml 60% ethanol, heated to a temperature of 75 C, and gradually drop Add concentrated hydrochloric acid, adjust the pH to 3. 0; add 10g activated carbon, decolor 30 minutes, filtration, the filtrate cooled to 0 C, Anhydrous ethanol washing filter cake, dry, get crude 57g, the crude dissolved in 400ml acetone, heated to reflux 3-4h, filtered, vacuum dry Dry, the product of <strong>[83799-24-0]fexofenadine</strong> hydrochloride 48g, yield 84. 7%.
	With hydrogenchloride; In methanol; isopropyl alcohol; at 0℃; for 0.25h;	[HCVIPA] (1.6 [ML)] (6.05-6. 24 N) was added to methanol (20 ml) and was cooled in an ice water bath. This solution was added to <strong>[83799-24-0]fexofenadine</strong> free base (5 grams) in a round bottom flask with a magnetic stirrer in an ice bath. The <strong>[83799-24-0]fexofenadine</strong> base dissolved immediately. The solution was filtered thru a glass fiber filter [(GF/F),] and the solvent evaporated off in a water bath at a temperature of [25 C] using a water aspirator, followed by a diaphragm pump, which was followed by an oil pump. Heptane (15 [ML)] was added. The stirrer was turned on, 5 [ML] of methanol was added and the slurry was stirred overnight. The next day it was filtered and dried in the vacuum oven for 2 hours at 65C. PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride. KF= 6.685% Elemental analysis: C: 66.28% H: 7-89% Cl : 5.65%; Example 1 was repeated, except 4 [ML] of methanol was used in the crystallization step instead of 5 ml. PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride. KF= 6.507% Elemental analysis: C: 66.80% H: 7.91 % Cl : 6.23%; Example 1 was repeated, except 3 ml of methanol was used in the crystallization step instead of 5 ml. PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride. KF= 6. [221%] Elemental analysis : C: 67.18% H: 7.74% Cl : 6.35%; Example 1 was repeated, except 2 [ML] of methanol was used in the crystallization step instead of 5 [ML.] PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride. KF= 7. 314% Elemental analysis: C: 65.95% H: 7.77% Cl : 6.34%; Example 1 was repeated, except 2.5 [ML] of methanol was used in the crystallization step instead of 5 ml. PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride. [KIL--6.] 250% Elemental analysis: C: 66.70% H: 7.64% Cl : 6.40%; <strong>[83799-24-0]Fexofenadine</strong> free base (20 grams) was crushed and put into a 250 [ML] round bottom flask in an ice bath with a magnetic stirrer. [HC1/IPA] (6.5 [ML)] was added to [80] [ML] methanol and cooled in an ice bath, and then added to the flask with mixing. After 15 minutes, the flask was filtered, and the filtrate evaporated off at room temperature first with a water aspirator then with a diaphragm pump and finally with an oil pump. The remaining material (5 grams) was stirred as a slurry overnight with a mixture of heptane (15 [ML)] and methanol (1.5 ml), filtered and dried for 1 hour at [65 C] under vacuum. PXRD analysis confirmed presence of Form XVI of <strong>[83799-24-0]fexofenadine</strong> hydrochloride.

	With hydrogenchloride; In methanol; water; at 10℃;	The diluted [HCL/METHANOL] solution was cooled [(T&LT;10C).] Fexofendine base (50 grams) (1.88% [H20)] was reacted with the diluted [HCL/METHANOL] solution, to form a [FEXOFENADINE-HCL] solution. The molar ratio between <strong>[83799-24-0]fexofenadine</strong>-base and [HC1] was 1: 1.
	With hydrogenchloride; In methanol; water; at -15 - 5℃; for 2 - 16h;Product distribution / selectivity;	Methanol (120 ml), water (6 ml), and 32% HCl solution (10 g) were added to a reactor. The solution was cooled to negative 5C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation was continued until full dissolution was obtained. The solution was cooled under agitation to-12C. The suspension was stirred for 2 to 16 hours at -12C . The product was filtered. Pure <strong>[83799-24-0]fexofenadine</strong> HCl Form XVI was obtained. The resulting wet cake of <strong>[83799-24-0]fexofenadine</strong> HCl Form XVI was dried under vacuum (10 mmHg) at a temperature of 65C to 80C. After 16 hours of drying, pure <strong>[83799-24-0]fexofenadine</strong> Form XVI was obtained; Example 6 - Preparation of <strong>[83799-24-0]Fexofenadine</strong> Hydrochloride Form XIX, mixed with Form XVI Methanol (120ml), water (6ml) and 32% HCl solution (lOg) were added to a reactor. The solution was cooled down to 5C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation was continued until full dissolution was obtained. The solution was cooled down (under agitation). Samples were taken out at 0C, -5C and -10C. The mixture was cooled down to-12C. After stirring the suspension for additional 2-16 hours, the product was filtered, and dried under vacuum at a temperature of 65-80C for 6h. The following table describes the crystal Form obtained during the cooling stage progress: Filtration temperature Crystal Form T (C) XVI+XIX 0 XVI -5 XVI-10 XVI-12, Example 15 - Preparation of <strong>[83799-24-0]Fexofenadine</strong> Form XVI A reactor was charged with 73.8 kg methanolic solution (5% HCl in methanol), 8 liter of methanol, and 5 kg of process water. The reactor was cooled to a temp below 5C, and <strong>[83799-24-0]Fexofenadine</strong> Base Pure (50 kg) was gradually added,while the temp in the reactor is kept below 5C. The solution was filtered from foreign particles, and then seeding was performed. After the material start to precipitate, the reactor content is cooled to below (-15C). The reactor content was filtered and the filter cake was washed with 300 liter of Heptane. The material was dried in a vacuum dryer at 60- 70C and then it was dried at Fluidized Bed Dryer at 60-70C. The material was milled and then it was fluidized in Fluidized Bed Dryer at 25C and relative humidity of 70-85% for 30minutes. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XVI was obtained. Water content by KF is 8%.
	With hydrogenchloride; In water; isopropyl alcohol; at -10 - 5℃; for 1h;	Isopropanol (80ml), water (2ml), and 32% HCl solution (10g) were added to a reactor. The solution was cooled to 5C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation continued until full dissolution was obtained. The solution was cooled down under agitation to -10C. After stirring the suspension for an additional 1 hour, the product was filtered and dried under vacuum in a temperature of 65C for 16h. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XIX (27g) was obtained
	With hydrogenchloride; In n-heptane; water; isopropyl alcohol; at -12 - 10℃; for 2 - 16h;Product distribution / selectivity;	Isopropyl-alcohol (150ml) and 32% HCl solution (11.5g) were added to a reactor. The solution was cooled down to10C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (50g) was added to a reactor. Agitation continued until full dissolution was obtained. The solution was cooled down (under agitation) to-12C. Heptane (5ml) was added to the reactor and cloudiness appeared. After stirring the suspension for additional 2-16 hours, the product was filtered. Pure <strong>[83799-24-0]Fexofenadine</strong> HCl Form XVI was obtained. The wet cake was dried under vacuum at a temperature of 65-80C. After 16 hrs of drying <strong>[83799-24-0]fexofenadine</strong>, Form XVI was obtained.
	With hydrogenchloride; In methanol; n-heptane; water; at 25℃;Product distribution / selectivity;	6g of HCl 32% (1 eq) and 2vol. of methanol were introduced into a 1 liter reactor. 25gr of <strong>[83799-24-0]Fexofenadine</strong> Base pure were dissolved at 25C under stirring 20vol. of Heptane and 2vol. of soft water were added. The crystals obtained were filtered at 20C. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XIX was obtained.
	With hydrogenchloride; In methanol; water; at -12 - 40℃; for 0.5 - 16h;Product distribution / selectivity;	2vol. of methanol and lvol. of soft water were Introduce into a 1 liter reactor. 25g of <strong>[83799-24-0]Fexofenadine</strong> Base pure were dissolved at 25C under stirring. HCl 32% (leq.) was added. The mixture was heated to 40C into complete dissolution, and than cooled to 20C. The mixture was stirred for 30 min. 2vol.of Heptane were then added at 25C. The mixture was cooled to 15C within 1hr, and then filtered. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XIX was obtained; Example 4 - Preparation of <strong>[83799-24-0]Fexofenadine</strong> Hydrochloride Form XIX Methanol (120ml), water (12ml) and 32% HCl solution (lOg) were added to a reactor. The solution was cooled down to 5C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation was continued until full dissolution was obtained. The solution was cooled down (under agitation) to (-12) C. After stirring the suspension for additional 2-16 hours, the product was filtered and dried under vacuum in a temperature of 65-80C. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XIX was obtained immediately after filtration as a wet product and also after drying. <strong>[83799-24-0]Fexofenadine</strong> HCl Fonn XIX was obtained. Water content by KF=7.1 %; Example 5 - Preparation of <strong>[83799-24-0]Fexofenadine</strong> Hydrochloride Form XIX Methanol (80ml) and water (8ml) and 32% HCl solution (lOg) were added to a reactor . The solution was cooled down to 5C under agitation . <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation continued until full dissolution was obtained. The solution was cooled down under agitation to-12C. After stirring the suspension for an additional 2-16 hours, the product was filtered and dried under vacuum in a temperature of 65-80C for 16h. <strong>[83799-24-0]Fexofenadine</strong> HCl Form XIX was obtained immediately after filtration as a wet product and also after drying. Water content by KF=4.4%.
	With hydrogenchloride; In methanol; water; at -12 - -5℃; for 2 - 16h;	Methanol (120 ml), water (6 ml), and 32% HCl solution (10 g) were added to a reactor. The solution was cooled to negative 50C under agitation. <strong>[83799-24-0]Fexofenadine</strong> base (40g) was added to the reactor. Agitation was continued until full dissolution was obtained. The solution was cooled under agitation to -120C. The suspension was stirred for 2 to 16 hours at -120C. The product was filtered. Pure <strong>[83799-24-0]fexofenadine</strong> HCl Form XVI was obtained. The resulting wet cake of <strong>[83799-24-0]fexofenadine</strong> HCl Form XVI was dried under vacuum (10 mmHg) at a temperature of 650C to 8O0C. After 16 hours of drying, pure <strong>[83799-24-0]fexofenadine</strong> Form XVI was obtained.
	With hydrogenchloride; In methanol; water; at 0 - 20℃; for 2h;pH 2.4 - 2.6;Product distribution / selectivity;	g) <strong>[83799-24-0]Fexofenadine</strong> hydrochloride<strong>[83799-24-0]Fexofenadine</strong> base having moisture content about 2.5 to 6% was taken in methanol and treated with 50 % aqueous HCl to make the pH of the solution between 2.4 to 2.6. The clear solution was filtered to remove any solid contaminant. Chilled potable water was added to the solution at 0 to 20C. The hydrochloride salt of <strong>[83799-24-0]fexofenadine</strong> was obtained as white crystals. Additional volume of water was added to the reaction mixture at the same temperature and stirred for 2 hours. Material was centrifuged and dried.EXAMPLE 5<strong>[83799-24-0]Fexofenadine</strong> Hydrochloride<strong>[83799-24-0]Fexofenadine</strong> Base pure, 25 Kg was suspended in 65 Ltr methanol on reaction mixture was cooled 0 to 2O0C. Then it was added 50% aqueous hydrochloric acid solution to adjust EPO <DP n="15"/>pH 2.4 to 2.6. At pH 2.4 to 2.6 the solution was clear and was filtered through module. To this solution 65 Ltr chilled potable water was added at 0 to 200C. pH was found 2.5. Material was thrown out as white crystals. Again to it 100 Ltr chilled water was added at temperature 0 to 200C. The reaction mixture was stirred for 2 hours. Centrifuged the material. It was dried in FBD at 60 to 800C for 7 to 8 hours till moisture content 2.0 to 6.0% . HPLC purity = 99% . Yield = 24 Kg.The above material, 24 Kg was treated with acetone, 140 Ltr at reflux for an hour. Then it was cooled 0 to 50C. The material was stirred for 1 hour at 0 to 50C. Centrifuged the material and dried in FBD for 6 to 8 hours at 60 to 8O0C. HPLC purity = 99% . Moisture content = 0.3% . Yield = 23 Kg.
	With hydrogenchloride; In isopropyl alcohol; at 5 - 10℃; for 0.5h;pH 3.0 - 3.5;	To a cooled mixture of <strong>[83799-24-0]fexofenadine</strong> (150g) and isopropanol (450 ml) was added isopropanol hydrogen chloride at 5-1O0C till pH was adjusted to 3.0 - 3.5 and was stirred for further 30 minutes. The reaction mass was charcolised and after filtering the carbon, isopropanol was distilled off and fresh isopropanol (75 ml) was added and reaction mass was heated to 40-45upsilonC. To this ethyl acetate (750ml) was added and stirred at 40-450C. The reaction mass was cooled to ambient temperature, filtered, washed with ethyl acetate and dried to afford 149 g of <strong>[83799-24-0]fexofenadine</strong> hydrochloride having purity 99.59% by HPLC.
		Example 10: Preparation of amorphous <strong>[83799-24-0]fexofenadine</strong> hydrochloride: To a solution of <strong>[83799-24-0]fexofenadine</strong> (10 g) in acetonitrile (50 ml) was added formic acid (99 %, 0.96 g) and stirred for 2 hour at 25-30 0C. The reaction mixture was cooled to 0 0C and dry hydrochloric acid gas was passed through it till pH of 2-3. The solvent was distilled off and n- heptane (50 ml) was added and stirred for 1 hour, filtered and dried to obtain 8.5 g of title compound.
	With hydrogenchloride; In methanol; water;	<strong>[83799-24-0]Fexofenadine</strong> dimethyl formamide solvate obtained from the ExampIe-2 (100 g) was slowly added to methanol (300 ml). The reaction mixture was cooled and Cone. Hydrochloric acid (20 g) was added. Reaction was stirred for 15-30 min. Solid was filtered, washed with water and dried to yield <strong>[83799-24-0]Fexofenadine</strong> hydrochloride.
	With hydrogenchloride; In isopropyl alcohol; at 20 - 30℃; for 0.25h;pH 2.5 - 3;Product distribution / selectivity;	Example-l; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Isopropyl alcohol (150ml) was added to <strong>[83799-24-0]fexofenadine</strong> base (50g) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 2.9-3.0 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred for 15 minutes and was filtered to remove any foreign particle. The <n="8"/>filtrate was distilled off under vacuum at 35-4O0C. To the residue, iso propyl alcohol(25ml) was added followed by addition of ethyl acetate (250ml) at 5O0C. The reaction mixture was heated at 45-5O0C for 3 hours (till complete crystallization). The resulting mixture was cooled to 30-350C and stirred for 30 minutes. The reaction mixture was filtered, washed with ethyl acetate (50ml) and dried at 40-500C to yield47.3g of the title compound having purity 99.88% by high performance liquid chromatography.; ExampIe-2; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Isopropyl alcohol (150ml) was added to <strong>[83799-24-0]Fexofenadine</strong> base (5Og) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to2.7-2.8 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred for 15 minutes and was treated with carbon at 25-35C.The filtrate was distilled off under vacuum at 35-400C. To the residue, isopropyl alcohol (25ml) was added followed by addition of ethyl acetate (250ml) at 5O0C. The reaction mixture was heated at 45-5O0C for 3 hours (till complete crystallization). The resulting mixture was cooled to 30-350C and stirred for 30 minutes. The reaction mixture was filtered, washed with ethyl acetate (50ml) and dried at 40-50C to yield 47.5g of the title compound having purity 99.82% by high performance liquid chromatography.; Exampie-7; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Isopropyl alcohol (3.0L) was added to <strong>[83799-24-0]Fexofenadine</strong> base (lkg) at ambient temperature. The reaction mass was stirred and pH was adjusted to 2.5-2.6 with isopropyl alcohol-hydrochloric acid (0.40L) at 25-30C. After checking the clarity of the solution, it was filtered through sparkler and washed with isopropyl alcohol (LOL) which was distilled off completely under vacuum at 35-400C. To the residue, isopropyl alcohol (0.5L) was added followed by addition of ethyl acetate (5.0L) at 35-45C. The reaction mixture was stirred and heated at 45-500C for about lhour (till complete crystallization). The resulting mixture was cooled to 25-3O0C and stirred and centrifuged . The reaction mixture was filtered, washed with ethyl acetate (l.OL) and dried at 40-500C to yield 0.94kg of the title compound having purity 99.76% by high performance liquid chromatography.
	With hydrogenchloride; In methanol; isopropyl alcohol; at 20℃; for 0.25h;pH 2.7 - 2.8;Product distribution / selectivity;	ExampIe-3; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Methanol (150ml) was added to <strong>[83799-24-0]Fexofenadine</strong> base (5Og) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 2.7-2.8 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred for 15 minutes and was filtered to remove any foreign particle. The filtrate was distilled off under vacuum at 35-4O0C. To the residue, methanol (25ml) was added followed by addition of ethyl acetate (250ml) at 5O0C. The reaction mixture was heated at 45-500C for 3 hours (till complete crystallization)^ The resulting mixture was cooled to 30-350C and stirred for 30 minutes. The reaction mixture was filtered, <n="9"/>washed with ethyl acetate (50ml) and dried at 40-500C to yield 44g of the title compound.
	With hydrogenchloride; In ethanol; isopropyl alcohol; at 20℃; for 0.25h;pH 2.8 - 2.9;Product distribution / selectivity;	ExampIe-4; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Ethanol (150ml) was added to <strong>[83799-24-0]Fexofenadine</strong> base (5Og) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 2.8-2.9 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred for 15 minutes and was filtered to remove any foreign particle. The filtrate was distilled off under vacuum at 35-4O0C. To the residue, ethanol (25ml) was added followed by addition of ethyl acetate (250ml) at 5O0C. The reaction mixture was heated at 25-5O0C for 3 hours (till complete crystallization). The resulting mixture was cooled to 30-350C and stirred for 30 minutes. The reaction mixture was filtered, washed with ethyl acetate (50ml) and dried at 40-500C to yield 46g of the title compound.
	With hydrogenchloride; In isopropyl alcohol; acetone; at 20℃; for 0.25 - 0.5h;pH 1.1 - 1.7;Product distribution / selectivity;	Example-5; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Acetone (150ml) was added to <strong>[83799-24-0]Fexofenadine</strong> base (50g) at ambient temperature The reaction mass was stirred for 15 minutes and pH was adjusted to 1.6-1.7 with isopropyl alcohol-hydrochloric acid. Reaction mixture was further stirred for 15 minutes and was filtered to remove any foreign particle followed by washing with minimum amount of acetone. The' filtrate was stirred for 1 hour at ambient temperature. Ethyl acetate (300ml) was added to it and the reaction mixture was stirred at 25-350C for 3 hours (till complete crystallization). The resulting mixture was cooled to 0-5 0C and was stirred for 1.5 hours. The reaction mixture was filtered and washed with ethyl acetate (15ml) and dried at 50-600C to yield 47.5g of the title compound having purity 99.89% by high performance liquid chromatography.; Example-6; Preparation of anhydrous <strong>[83799-24-0]Fexofenadine</strong> hydrochloride; Acetone (129ml) was added to <strong>[83799-24-0]Fexofenadine</strong> base (43 g) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 1.1-1.2 with isopropyl alcohol-hydrochloric acid. Reaction mixture was further stirred for 30 minutes, filtered to remove any foreign particle followed by washing with minimum amount of acetone. The filtrate was stirred for 1 hour at ambient temperature. It was followed by addition of Ethyl acetate (258ml) and stirring at 25-35C for 3 hours (till complete crystallization). The resulting mixture was cooled to 0-5 0C for about 1.5 hours. The reaction mixture was filtered and washed with ethyl acetate ( 13ml) and dried at 50-600C to yield 41.3g of the title compound having purity 99.78% by high performance liquid chromatography.

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39
[ 138452-21-8 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; for 0.0333333h;	A 100 ml round-bottom flask, equipped with magnetic stirrer, is loaded with 10 g (18.6 mmoles) of fexofenadine hydrochloride and 50 ml of methanol, to obtain a clear solution. Afterwards, 2.5 ml of triethylamine (1.81 g; 17.9 mmoles) are added. After about 2 minutes, a precipitate forms which is filtered off, washed with methanol and dried at room temperature, thereby affording 8.9 g (17.7 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in FIG. 1.
	With acetic acid; triethylamine; In methanol; for 0.0333333h;	A 100 ml round-bottom flask, equipped with magnetic stirrer, is loaded with 10 g (18.6 mmoles) of fexofenadine hydrochloride and 50 ml of methanol, to obtain a clear solution. Afterwards, 5 ml of triethylamine (3.63 g; 35.9 mmoles) are added thereto, then acetic acid is added to acidify again the mixture. After about 2 minutes, a precipitate forms which is filtered off, washed with methanol and dried under vacuum at room temperature, thereby affording 7.9 g (15.8 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in FIG. 2.
	With triethylamine; In acetone; acetonitrile; at 60℃;Product distribution / selectivity;	A 100 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 10 g of fexofenadine hydrochloride (18.6 mmoles), 30 ml of acetone and 20 ml of acetonitrile. The mixture is warmed to a temperature of 60 C. under stirring, to obtain a suspension. Afterwards, 2.5 ml of triethylamine (1.81 g; 17.9 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed first with the same acetone-acetonitrile mixture as used in the preparation, then with only acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50 C., thereby affording 8.1 g (16.2 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in FIG. 3.

	With N-butylamine; In acetone;Heating / reflux;Product distribution / selectivity;	A 50 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 5 g of fexofenadine hydrochloride (9.32 mmoles) and 25 ml of acetone. The mixture is refluxed under stirring, to obtain a suspension. Afterwards, 0.9 ml of butylamine (0.68 g; 9.32 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed with acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50 C., thereby affording 4.1 g (8.21 mmoles) of Fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in FIG. 3.
	With tributyl-amine; In acetone;Heating / reflux;Product distribution / selectivity;	A 50 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 5 g of fexofenadine hydrochloride (9.32 mmoles) and 25 ml of acetone. The mixture is refluxed under stirring, to obtain a suspension. Afterwards, 2.22 ml of tributylamine (1.73 g; 9.32 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed with acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50 C., thereby affording 3.5 g (7 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure one spectrum with peaks characteristics as substantially reported in FIG. 3.
	With triethylamine; In methanol; for 0.0333333h;	A 100 ml round-bottom flask, equipped with magnetic stirrer, is loaded with 10 g (18.6 mmoles) of fexofenadine hydrochloride and 50 ml of methanol, to obtain a clear solution. Afterwards, 2.5 ml of triethylamine (1.81 g; 17.9 mmoles) are added. After about 2 minutes, a precipitate forms which is filtered off, washed with methanol and dried at room temperature, thereby affording 8.9 g (17.7 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure 1.
	With triethylamine; In acetone; acetonitrile; at 60℃;	A 100 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 10 g of fexofenadine hydrochloride (18.6 mmoles), 30 ml of acetone and 20 ml of acetonitrile. The mixture is warmed to a temperature of 60C under stirring, to obtain a suspension. Afterwards, 2.5 ml of triethylamine (1.81 g; 17.9 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed first with the same acetone-acetonitrile mixture as used in the preparation, then with only acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50C, thereby affording 8.1 g (16.2 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure 3.
	With N-butylamine; In acetone;	A 50 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 5 g of fexofenadine hydrochloride (9.32 mmoles) and 25 ml of acetone. The mixture is refluxed under stirring, to obtain a suspension. Afterwards, 0.9 ml of butylamine (0.68 g; 9.32 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed with acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50C, thereby affording 4.1 g (8.21 mmoles) of Fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure 3.
	With tributyl-amine; In acetone;	A 50 ml round-bottom flask, equipped with magnetic stirrer, reflux condenser and thermometer, is loaded with 5 g of fexofenadine hydrochloride (9.32 mmoles) and 25 ml of acetone. The mixture is refluxed under stirring, to obtain a suspension. Afterwards, 2.22 ml of tributylamine (1.73 g; 9.32 mmoles) are added thereto. From the resulting clear solution, a precipitate immediately forms which is filtered off and repeatedly washed with acetone. Finally the solid product is dried in a static dryer under vacuum at a temperature of 50C, thereby affording 3.5 g (7 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure one spectrum with peaks characteristics as substantially reported in figure 3.
		A 100 ml round-bottom flask, equipped with magnetic stirrer, is loaded with 10 g (18.6 mmoles) of fexofenadine hydrochloride and 50 ml of methanol, to obtain a clear solution. Afterwards, 5 ml of triethylamine (3.63 g; 35.9 mmoles) are added thereto, then acetic acid is added to acidify again the mixture. After about 2 minutes, a precipitate forms which is filtered off, washed with methanol and dried under vacuum at room temperature, thereby affording 7.9 g (15.8 mmoles) of fexofenadine free base. XRPD analysis of the product shows that it is a novel crystalline form of fexofenadine free base, substantially characterised by the peaks as reported in Figure 2.
	at 65 - 80℃; for 16h;	Methanol (120 ml), water (6 ml), and 32% HCl solution (10 g) were added to a reactor. The solution was cooled to negative 50C under agitation. Fexofenadine base (40g) was added to the reactor. Agitation was continued until full dissolution was obtained. The solution was cooled under agitation to -120C. The suspension was stirred for 2 to 16 hours at -120C. The product was filtered. Pure fexofenadine HCl Form XVI was obtained. The resulting wet cake of fexofenadine HCl Form XVI was dried under vacuum (10 mmHg) at a temperature of 650C to 8O0C. After 16 hours of drying, pure fexofenadine Form XVI was obtained.

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Yield	Reaction Conditions	Operation in experiment
87%		Step j: 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid Dissolve N-methoxy-N-methyl-2-(4-{1-hydroxy-4-[4-hydroxydiphenylmethyl)-piperidine-1-yl]-butyryl}-phenyl)-isobutyramide (8.35 g, 15.33 mmol) in isopropanol (50 mL) and add potassium hydroxide (8.63 g, 153.7 mmol). Heat to reflux for 2 hours, add additional potassium hydroxide (4.35 g, 77.5 mmol) and heat at reflux for an additional 16 hours. Cool to room temperature, treat with concentrated HCl by dropwise addition until pH=3. Dilute with water (100 mL), stir vigorously for 2 hours, add ethyl acetate (30 mL) and stir for 1 hour. Filter to give the title compound (7.15 g, 87%) as an off-white solid. MS (CI, CH4) m/e 502 (M+ +1), 107. Anal. Calcd for C32 H39 NO4.HCl.2.6H2 O: C, 65.70; H, 7.61; N, 2.39; Found: C, 65.25; H, 7.70; N, 2.36.
		EXAMPLE 7 Preparation of 4-[4-[4-(Hydroxydiphenylmethyl)-1-Piperidinyl]-1-Hydroxybutyl]-alpha,alpha-Dimethylphenylacetic Acid (Fexofenadine) 10.9 g of crude Example 6 product is heated at reflux with 7.8 ml 10M NaOH, 17.6 ml water and 55 ml methanol for 3.5 h. After cooling, the mixture is taken to pH 5 with acetic acid and diluted with 30 ml water. The precipitated solid is cooled for 1 h, filtered, washed with water and dried in vacuum.
		Other illustrative examples of compounds prepared by the process of the present invention are as follows: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; n-pentyl 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; ...

		Illustrative examples of compounds prepared by the process of the present invention are as follows: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; n-pentyl 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; ...
		Illustrative examples of compounds of the present invention are as follows: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzeneacetic acid; 5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; n-pentyl 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; ethyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetate; ...
		Illustrative examples of compounds of this invention are the following: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzene acetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzene acetic acid, 4-[4-[4-(diphenylmethylene-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzene acetic acid, 5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxypentyl]-alpha,alpha-dimethylbenzeneacetic acid, 3-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxypropyl]-alpha,alpha-dimethylbenzeneacetic acid, ...
		Illustrative examples of compounds prepared by the process of the present invention are as follows: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3 -hydroxybenzeneacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzeneacetic acid; ...
	In methanol; butanone; at 20℃; for 3.5 - 9h;Heating / reflux;Purification / work up;	f) Purification of FexofenadineFexofenadine (40 Kg) thus isolated from the above step was charged to about 60 to 100 Ltr of a mixture of methanol in methylethyl ketone in volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol in methylethyl ketone was 0.4 to 2.0, specifically about 0.4 to 0.6. The reaction mass was refluxed for about 10 minutes to 2 hours, more particularly between about 20 minutes to 40 minutes. After the said time reaction mass was cooled to room temperature followed by stirring for another 1 hour at room temperature. The reaction mixture was centrifuged. The same treatment was repeated twice followed by treatment with dimethyl formamide-methanol and water.Three times treated fexofenadine base in the above step was charged to about 120 to 180 Ltr of a mixture of methanol in DMF volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol was 0.4 to 2.0. More particularly, the volume ratio of methanol in DMF was about 0.4 to 0.6. The reaction mixture was refluxed for about 10 minutes to 2 hours, more particularly between about 30 minutes to 1.5 hours. After the said time reaction mixture was cooled to room temperature and centrifuged.The wet cake obtained in the above process was taken in water and heated to 50 to 1000C, more particularly between 65 to 850C. The mixture was stirred for about 1 hour and cooled to room temperature. The centrifuged material was centrifuged and dried in fluid bed dryer at 60 to 8O0C for about 5 to 7 hours. Fexofenadine Base (para isomer) having total impurities not more than 1.0% and having moisture content in the range of 2.5 to 6.0% was obtained after employing these purification steps.EXAMPLE 4Fexofenadine Base PurePurification40 Kg of Crude Fexofenadine Base was charged to a mixture of 30 Ltr methanol and 60 Lr methylethyl ketone. The reaction mass was refluxed for 30 minutes followed by cooling to room temperature. Stirring of the reaction mixture was done at room temperature for 1 hour and was centrifuged the material. Sample was submitted for loss on drying and impurity profile.Note: The above purification process was repeated twice and finally material was given the treatment with dimethylformamide and methanol followed by water to meet the impurity profile.Dimethylformamide - Methanol treatmentFexofenadine base obtained after third purification was treated with a mixture of 100 Ltr dimethylformamide and 50 Ltr methanol and heated at reflux for an hour. Then cooled to room temperature and centrifuged.The wet cake obtained above was suspended in 300 Ltr potable water and heated to 70 to 750C temperature. The material was stirred for an hour and then cooled to room temperature. Centrifuged the material and dried in fluid bed dryer (FBD) at 60 to 8O0C for 5 to 7 hours. Moisture content = 2.0 to 5.0%. HPLC Purity = 99%. Yield = 25 Kg.
		f) Purification of FexofenadineFexofenadine (40 Kg) thus isolated from the above step was charged to about 60 to 100 Ltr of a mixture of methanol in methylethyl ketone in volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol in methylethyl ketone was 0.4 to 2.0, specifically about 0.4 to 0.6. The reaction mass was refluxed for about 10 minutes to 2 hours, more particularly between about 20 minutes to 40 minutes. After the said time reaction mass was cooled to room temperature followed by stirring for another 1 hour at room temperature. The reaction mixture was centrifuged. The same treatment was repeated twice followed by treatment with dimethyl formamide-methanol and water.Three times treated fexofenadine base in the above step was charged to about 120 to 180 Ltr of a mixture of methanol in DMF volume ratio of 0.3 to 5.0. More particularly, the volume ratio of methanol was 0.4 to 2.0. More particularly, the volume ratio of methanol in DMF was about 0.4 to 0.6. The reaction mixture was refluxed for about 10 minutes to 2 hours, more particularly between about 30 minutes to 1.5 hours. After the said time reaction mixture was cooled to room temperature and centrifuged.The wet cake obtained in the above process was taken in water and heated to 50 to 1000C, more particularly between 65 to 850C. The mixture was stirred for about 1 hour and cooled to room temperature. The centrifuged material was centrifuged and dried in fluid bed dryer at 60 to 8O0C for about 5 to 7 hours. Fexofenadine Base (para isomer) having total impurities not more than 1.0% and having moisture content in the range of 2.5 to 6.0% was obtained after employing these purification steps.EXAMPLE 4Fexofenadine Base PurePurification40 Kg of Crude Fexofenadine Base was charged to a mixture of 30 Ltr methanol and 60 Lr methylethyl ketone. The reaction mass was refluxed for 30 minutes followed by cooling to room temperature. Stirring of the reaction mixture was done at room temperature for 1 hour and was centrifuged the material. Sample was submitted for loss on drying and impurity profile.Note: The above purification process was repeated twice and finally material was given the treatment with dimethylformamide and methanol followed by water to meet the impurity profile.Dimethylformamide - Methanol treatmentFexofenadine base obtained after third purification was treated with a mixture of 100 Ltr dimethylformamide and 50 Ltr methanol and heated at reflux for an hour. Then cooled to room temperature and centrifuged.The wet cake obtained above was suspended in 300 Ltr potable water and heated to 70 to 750C temperature. The material was stirred for an hour and then cooled to room temperature. Centrifuged the material and dried in fluid bed dryer (FBD) at 60 to 8O0C for 5 to 7 hours. Moisture content = 2.0 to 5.0%. HPLC Purity = 99%. Yield = 25 Kg.
		Illustrative examples of compounds of this invention are the following: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dim ethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzene acetic acid, ...
		Illustrative examples of compounds of this invention are the following: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dim ethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dim ethylbenzeneacetic acid, 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzene acetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-2-hydroxybenzene acetic acid, 4-[4-[4-(diphenylmethylene-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethyl-3-hydroxybenzene acetic acid, 5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxypentyl]-alpha,alpha-dimethylbenzeneacetic acid, 3-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxypropyl]-alpha,alpha-dimethylbenzeneacetic acid, ...

41
racemic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid [ No CAS ]
[ 1082649-95-3 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone;	EXAMPLE 4A (R)-(+)-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid Well dried racemic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid (8.00 g., 15.9 mmole) and (+)-di-para-toluoyltartaric acid monohydrate (6.45 g, 16.0 mmole) were dissolved together in 50 ml of acetone by heating at ca. 55 C. After cooling in a refrigerator set to 4 C. for 3 days, the precipitated crystals were collected by filtration to yield the diastereomeric salt comprising (+)-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid associated with (2S,3S)-(+)-di-para-toluoyltartaric acid (7.53 g, 107% chemical yield, 74% de).

Reference： [1]Patent: US2003/78429,2003,A1

Yield	Reaction Conditions	Operation in experiment
72%		EXAMPLE 8 Preparation of Fexofenadine (7) Sodium hydroxide (2.4 g, 0.06 mols) and sodium borohydride (0.8 g; 0.02 mols) are added to a solution of compound (6) (20.5 g; 0.04 mols) in methanol (100 ml) and water (30 ml). The mixture is heated at 50 C. for 4 hours, then cooled to room temperature and added with acetone (5 ml). After 30 minutes, 36% hydrochloric acid (12.4 g; 0.122 mols) is added. The resulting suspension is heated to 45 C. to complete dissolution, then is slowly cooled to 0 C. The resulting solid is filtered, washed with water (2*30 ml) and dried under vacuum at 60 C., to obtain Fexofenadine hydrochloride (15.5 g; 72% yield). 1H NMR(CD3OD, TMS) delta (ppm): 1.52 (s, 6H); 1.78 (m, 8H); 2.90 (m, 5H); 3.48 (d, 2H); 4.62 (t, 1H); 7.1-7.6 (aromatics, 14H).

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 0 - 60℃; for 3h;Heating / reflux;Purification / work up;	<strong>[83799-24-0]Fexofenadine</strong> (43.Og) obtained in Step-1 was slurred in ethanol (95%, 215ml) and was refluxed for 3 hours. Thereafter reaction mixture was cooled to 0-50C, filtered, washed with ethanol and dried at 50-600C to obtain 40.8 g of title compound having purity 99.78 % by HPLC, meta impurity 0.07% and keto impurity is not detected.

44
[ 64-18-6 ]
[ 83799-24-0 ]
[ 1133879-72-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water; at 25 - 30℃; for 1 - 2h;Product distribution / selectivity;	Example 1: Preparation of <strong>[83799-24-0]fexofenadine</strong> formate: To a mixture of <strong>[83799-24-0]fexofenadine</strong> (100 g) in tetrahydrofuran (2 It), formic acid (85 %, 11.1 g) was added and stirred for one hour at 25-30 0C. The precipitated <strong>[83799-24-0]fexofenadine</strong> formate salt was filtered, washed with tetrahydrofuran, and dried to obtain 97 g of title compound. Example 4: Preparation of <strong>[83799-24-0]fexofenadine</strong> formate: To a mixture of <strong>[83799-24-0]fexofenadine</strong> (450 g) in tetrahydrofuran ( 6.75 It), formic acid (85 %,.49.6 g) was added and stirred for 2 hours at 25-30 0C. The precipitated solid was filtered, washed with tetrahydrofuran (900 ml) and dried at 60-65 0C under vacuum to obtain 450 g of title compound.Tetrahydrofuran (4.5 It) was added to compound obtained above and refluxed for 2 hours. Reaction mixture was cooled to 25-30 0C and filtered. The Resulting product was washed with tetrahydrofuran (900 ml) and dried at 60-65 0C under vacuum to obtain 415 g of title compound.
	In dichloromethane; at 25 - 30℃; for 12h;Product distribution / selectivity;	Example 3: Preparation of <strong>[83799-24-0]fexofenadine</strong> formate: To a mixture of <strong>[83799-24-0]fexofenadine</strong> (50 g) in dichloromethane (250 ml) was added formic acid (99 %, 4.82 g) and stirred for 12 hours at 25-30 0C. The precipitated formate salt was filtered, washed with dichloromethane, and dried to obtain 49 g of title compound.
	In tetrahydrofuran; at 25 - 30℃; for 1h;Product distribution / selectivity;	Example 2: Preparation of <strong>[83799-24-0]fexofenadine</strong> formate: To a mixture of <strong>[83799-24-0]fexofenadine</strong> (100 g) in tetrahydrofuran (2 It), formic acid (99 %, 9.64 g) was added and stirred for one hour at 25-30 0C. The precipitated product was filtered, washed with tetrahydrofuran, and dried to obtain 97 g of title compound.

Reference： [1]Patent: WO2009/34582,2009,A2 .Location in patent: Page/Page column 8, 9
[2]Patent: WO2009/34582,2009,A2 .Location in patent: Page/Page column 9
[3]Patent: WO2009/34582,2009,A2 .Location in patent: Page/Page column 9

45
ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate hydrochloride [ No CAS ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step f: 4-[4[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid; According to the described procedure of Carr et al., United States Patent No. 4,254,129, to a solution of 0.6 g of ethyl 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-hydroxybutyl]-a,a-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3 1/2 hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanolbutanone to give 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic acid, M.P. 195-197C.

Reference： [1]Patent: EP1091938,2010,B1 .Location in patent: Page/Page column 30

46
[ 50679-08-8 ]
[ 83799-24-0 ]
2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methyl-propanol [ No CAS ]

Reference： [1]Journal of Molecular Catalysis B: Enzymatic,2010,vol. 67,p. 172 - 178

47
[ 185066-40-4 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

48
[ 98-82-8 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303
[2]Patent: CN104557671,2018,B

49
C₃₈H₅₃NO₄Si [ No CAS ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

50
[ 1313731-46-2 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

51
[ 1313731-47-3 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

52
[ 70289-38-2 ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303
[2]Patent: CN104557671,2018,B

53
4-(4'-(hydroxy(diphenyl)methyl)piperidin-1-yl)-1-(4-isopropylphenyl)butan-1-ol [ No CAS ]
[ 83799-24-0 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 2296 - 2303

54
2-[4-[4-[4-[hydroxyl(diphenyl)methyl]-1-piperidinyl]butanoyl]phenyl]-2-methylpropanoic acid sodium salt [ No CAS ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
		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.

Reference： [1]Patent: US2011/190504,2011,A1 .Location in patent: Page/Page column 2

55
methyl 4-(1-cyano-1-methylethyl)-benzoate [ No CAS ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[2]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[3]Organic process research and development,2010,vol. 14,p. 1464 - 1468

56
[ 1252902-28-5 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468

57
[ 1308679-43-7 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[2]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[3]Organic process research and development,2010,vol. 14,p. 1464 - 1468

58
[ 394222-37-8 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[2]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[3]Organic process research and development,2010,vol. 14,p. 1464 - 1468

59
[ 76469-88-0 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[2]Organic process research and development,2010,vol. 14,p. 1464 - 1468
[3]Organic process research and development,2010,vol. 14,p. 1464 - 1468

60
[ 394222-36-7 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468

61
[ 1352802-40-4 ]
[ 83799-24-0 ]

Reference： [1]Patent: WO2011/158262,2011,A1

62
[ 32454-35-6 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2012/309973,2012,A1
[2]Patent: EP2532644,2012,A1

63
[ 71-43-2 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2012/309973,2012,A1
[2]Patent: EP2532644,2012,A1
[3]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155

64
[ 162096-54-0 ]
[ 83799-24-0 ]

Reference： [1]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155

65
[ 76811-97-7 ]
[ 83799-24-0 ]

Reference： [1]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155
[2]Patent: CN103333100,2016,B

66
[ 169280-26-6 ]
[ 83799-24-0 ]

Reference： [1]Research on Chemical Intermediates,2013,vol. 39,p. 2149 - 2155

67
[ 394222-31-2 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1
[2]Patent: US2013/237709,2013,A1

68
[ 1451149-71-5 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1
[2]Patent: US2013/237709,2013,A1

69
[ 1451149-72-6 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1
[2]Patent: US2013/237709,2013,A1

70
[ 1451149-73-7 ]
[ 83799-24-0 ]

Yield	Reaction Conditions	Operation in experiment
9 g		EXAMPLE 16 Preparation of fexofenadine In a reaction flask, 10 g 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methyl-propanoic acid (0.018 mol), 30 ml methanol and 2 g hydrochloric acid 37% solution (0.018 mol) were charged, the reaction mixture was heated to 25 C. and kept under these conditions for one hour. At the end of the reaction, 5.0 g sodium hydroxide 30% solution in water (0.038 ml) and 0.4 g sodioborohydride (0.010 mol) were charged, the temperature was brought to 40 C. and the reaction mixture was kept under these conditions for ten hours. At the end of the reaction, the temperature was brought to 13 C. and 1.2 g acetic acid (0.02 mol) and 10 ml water were charged. The is 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 9 g fexofenadine.

Reference： [1]Patent: US2013/237709,2013,A1 .Location in patent: Paragraph 0120

71
[ 1451149-74-8 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1
[2]Patent: US2013/237709,2013,A1

72
[ 1451149-70-4 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1
[2]Patent: US2013/237709,2013,A1
[3]Patent: US2013/237709,2013,A1

73
[ 115-46-8 ]
[ 394222-31-2 ]
[ 83799-24-0 ]

Reference： [1]Patent: US2013/237709,2013,A1

74
[ 394222-38-9 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468

75
[ 169032-17-1 ]
[ 83799-24-0 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1464 - 1468

76
[ 3081-61-6 ]
[ 83799-24-0 ]
L-theanine fexofenadine cocrystal [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; isopropyl alcohol;	0.330 g of fexofenadine (0.658 mmol) and 0.1 19 g of L-<strong>[3081-61-6]theanine</strong> (0.683 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 17a, while the FTIR spectrum is shown in Figure 17b. The DSC melting endotherm of the product was characterized by a peak maximum at 206C.

Reference： [1]Patent: WO2016/144590,2016,A1 .Location in patent: Paragraph 00149

77
[ 2901-13-5 ]
[ 83799-24-0 ]

Reference： [1]Patent: CN103333100,2016,B

78
[ 1448311-89-4 ]
[ 83799-24-0 ]

Reference： [1]Patent: CN103333100,2016,B

79
[ 458-37-7 ]
[ 83799-24-0 ]
fexofenadine curcuminate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca.25%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 24h;	FEX 4 (26.9 mg; 54 mumol) was dissolved in acetonitrile(2 mL). To this solution, CUR 3 (18.6 mg; 50 mumol) wasadded followed by addition of BOP (23 mg; 52 mumol) alongwith 0.1 mL triethylamine. The solution turned brightorange and was stirred at room temperature for 24 h. Thereaction solvent was removed and the residue was taken upin dichloromethane and washed with saturated sodiumbicarbonate. The organic layer was dried and purified onpreparative silica gel TLC using 9:1 dichloromethanemethanolto provide pure 9 in >90% purity with anapproximate yield of 25%. Mass spectra (m/z, %): 875 ([M+ Na]+, 30%). NMR (CDCl3, 600 MHz) delta 7.62 (2 H, m), 7.50 (2 H, m), 7.33-7.39 (14 H, m), 7.23 (2 H, m), 7.11(2 H, m), 6.51 (2 H, d, J = 15.7 Hz), 5.24 (1 H, s), 4.64(1 H, d,), 3.81 (3 H, s), 3.79 (3 H, s), 3.50 (2 H, m), 3.01(3 H, m), 2.93 (2 H, m), and 1.63-1.77 (14 H, m).
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 24h;	<strong>[83799-24-0]Fexofenadine</strong> curcuminate 9: <strong>[83799-24-0]Fexofenadine</strong> 4 (26.9 mg; 54 mumol) was dissolved in acetonitrile (2 mL). To this solution, curcumin 3 (18.6 mg; 50 mumol) was added followed by addition of BOP (23 mg; 52 mumol) along with 0.1 mL triethylamine. The solution turned bright orange and was stirred at room temperature for 24 hours. The reaction solvent was removed and the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried and purified on preparative silica gel TLC using 9:1 dichloromethane-methanol to provide 9 in >90% purity with an approximate yield of 25%. Mass spectra (m/z, %): 875 ([M+Na]+, 30%). NMR (CDCl3, 600 MHz) delta 7.62 (2H, m), 7.50 (2H, m), 7.33-7.39 (14H, m), 7.23 (2H, m), 7.11 (2H, m), 6.51 (2H, d, J=15.7 Hz), 5.24 (1H, s), 4.64 (1H, d,), 3.81 (3H, s), 3.79 (3H, s), 3.50 (2H, m), 3.01 (3H, m), 2.93 (2H, m), 1.63-1.77 (14H, m).

Reference： [1]Medicinal Chemistry Research,2018,vol. 27,p. 1634 - 1646
[2]Patent: US2020/171016,2020,A1 .Location in patent: Paragraph 0018; 0160

80
ethyl 3-methoxy-4-(1′-aminobutyryloxy)cinnamate [ No CAS ]
[ 83799-24-0 ]
C₄₈H₆₀N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 24h;	FEX 4 (13 mg; 26 mumol) was dissolved in acetonitrile(2 mL). To this solution, amine 7 (10 mg; 34 mumol) wasadded followed by addition of BOP (15 mg; 34 mumol) alongwith 0.1 mL triethylamine. The mixture was stirred at roomtemperature for 24 h. The reaction solvent was removed andthe residue was taken up in dichloromethane and washedwith saturated sodium bicarbonate. The organic layer wasdried and purified on preparative silica gel TLC using 9:1dichloromethane-methanol to provide 11 mg (~54% yield)of pure amide in >95%. Mass spectra (m/z, %): 777 ([M +H]+, 55%). This amide was taken in methanol (0.5 mL) intowhich 0.5 mL of 1 N sodium hydroxide was added. Thereaction mixture was heated at 60 oC for 30 min. Thereaction was quenched with water and extracted withdichloromethane. The organic extract was purified on preparativesilica gel TLC using 1:1 dichloromethane-methanol to provide pure 8.

Reference： [1]Medicinal Chemistry Research,2018,vol. 27,p. 1634 - 1646

81
[ 169280-04-0 ]
[ 83799-24-0 ]

Reference： [1]Patent: CN104557671,2018,B

82
[ 169280-21-1 ]
[ 83799-24-0 ]

Reference： [1]Patent: CN104557671,2018,B

83
C₁₈H₂₅N₅ [ No CAS ]
[ 83799-24-0 ]
C₅₀H₆₂N₆O₃ [ No CAS ]

Reference： [1]Patent: US2020/171016,2020,A1 .Location in patent: Paragraph 0020; 0164

84
C₁₈H₂₅N₅O [ No CAS ]
[ 83799-24-0 ]
C₅₀H₆₂N₆O₄ [ No CAS ]

Reference： [1]Patent: US2020/171016,2020,A1 .Location in patent: Paragraph 0021; 0164

85
C₂₀H₂₉N₅O₂ [ No CAS ]
[ 83799-24-0 ]
C₅₂H₆₆N₆O₅ [ No CAS ]

Reference： [1]Patent: US2020/171016,2020,A1 .Location in patent: Paragraph 0022; 0164

86
C₁₆H₂₃NO₄ [ No CAS ]
[ 83799-24-0 ]
C₄₈H₆₀N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca.54%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 24h;	<strong>[83799-24-0]Fexofenadine</strong>-(3-methoxy-4-(1'-aminobutyryloxy)cinnamic acid 8: <strong>[83799-24-0]Fexofenadine</strong> 4 (13 mg; 26 mumol) was dissolved in acetonitrile (2 mL). To this solution, amine 7 (10 mg; 34 mumol) was added followed by addition of BOP (15 mg; 34 mumol) along with 0.1 mL triethylamine. The mixture was stirred at ambient temperature for 24 hours. The reaction solvent was removed and the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried and purified on preparative silica gel TLC using 9:1 dichloromethane-methanol to provide 11 mg (?54% yield) of pure amide in >95%. Mass spectra (m/z, %): 777 ([M+H]+, 55%). This amide was taken in methanol (0.5 mL) into which 0.5 mL of 1N sodium hydroxide was added. The reaction mixture was heated at 60 C. for 30 mins. The reaction was quenched with water and extracted with dichloromethane. The organic extract was purified on preparative silica gel TLC using 1:1 dichloromethane-methanol to provide pure 8. Mass spectra (m/z, %): 749 ([M+H]+, 20%). 1H NMR (CDCl3, 600 MHz) delta ppm: 7.62 (d, 2H, J=15.9 Hz), 7.50 (m, 4H), 7.28-7.35 (br, 8H), 7.20-7.13 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.36 (d, 1H, J=15.9 Hz), 4.09 (br, 2H), 3.82 (s, 3H, OCH3), 3.50 (m, 2H), 3.11 (br, 2H), 3.01 (m, 3H), 2.93 (m, 2H), 1.90-2.05 (br, 4H), 1.72 (br, 8H), 1.52 (6H, m).

Reference： [1]Patent: US2020/171016,2020,A1 .Location in patent: Paragraph 0017; 0159

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CAS No. :	83799-24-0	MDL No. :	MFCD00871892
Formula :	C₃₂H₃₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RWTNPBWLLIMQHL-UHFFFAOYSA-N
M.W :	501.66	Pubchem ID :	3348
Synonyms :		Chemical Name :	2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid

Num. heavy atoms :	37
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.41
Num. rotatable bonds :	10
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	151.59
TPSA :	81.0 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.22 cm/s

Log Po/w (iLOGP) :	4.17
Log Po/w (XLOGP3) :	3.01
Log Po/w (WLOGP) :	4.7
Log Po/w (MLOGP) :	3.86
Log Po/w (SILICOS-IT) :	5.65
Consensus Log Po/w :	4.28

[ CAS No. 83799-24-0 ] {[proInfo.proName]}

Quality Control of [ 83799-24-0 ]

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Physicochemical Properties

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[ 83799-24-0 ] Synthesis Path-Downstream 1~86

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[ 83799-24-0 ]

Precautionary Statements-General

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Inquiry

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-4.55
Solubility :	0.0143 mg/ml ; 0.0000284 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.38
Solubility :	0.0211 mg/ml ; 0.0000421 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-8.1
Solubility :	0.00000396 mg/ml ; 0.0000000079 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.31

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed

[ CAS No. 83799-24-0 ] {[proInfo.proName]}

Quality Control of [ 83799-24-0 ]

Related Doc. of [ 83799-24-0 ]

Product Details of [ 83799-24-0 ]

Calculated chemistry of [ 83799-24-0 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 83799-24-0 ]

Application In Synthesis of [ 83799-24-0 ]

[ 83799-24-0 ] Synthesis Path-Downstream 1~86

Similar Product of [ 83799-24-0 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 83799-24-0 ]