* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium tetrahydroborate In methanol at 20℃; for 1 h;
The 2a (0.5mmol) was dissolved in 0.5mL of methanol,At room temperature was slowly added NaBH 4 (2.0mmol),Mixture was stirred at room temperature 1h.Added 2mL saturated NH 4Cl solution.The solvent was removed by distillation under reduced pressure.The residue was added 5mLNaOH (1N),With 5mLCH 2Cl 2 and extracted four times.The organic phase was collected and dried over anhydrous sodium sulfate,And concentrated to give the crude product.The crude product after column chromatography product 2b.Yield: 90percent.
Reference：
[1] Patent: CN103992236, 2016, B, . Location in patent: Paragraph 0051;0054; 0055
[2] Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1687 - 1689
2
[ 877-50-9 ]
[ 42142-52-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With sodium tetrahydroborate In acetic acid at 5 - 10℃; for 3.5 h;
Example 2 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one with NaBH4 in HOAc. [0031] Acetic acid was used instead of methanol in combination with sodium borohydride under mild conditions for the reduction of 3-(methylamino)-1-phenyl-2-propen-1-one. Sodium borohydride (6 equivalents) was slowly added to a 0.25 M solution of 3-(methylamino)-1-phenyl-2-propen-1-one (Formula 3), in glacial acetic acid at 5-10° C. after stirring for 3 hours at room temperature followed by the usual work-up, the target aminoalcohol was isolated with a 77percent yield (Table 1, entry 1). The effectiveness of this method may be due to the enhanced activity of both carbonyl and azomethyne groups under acidic conditions. [0032] In a particular example, NaBH4 (800 mg, 21.0 mmol) was added in portions to a vigorously stirred solution of 3-(methylamino)-1-phenyl-2-propen-1-one (600 mg, 3.7 mmol) in glacial HOAc (15 mL) over a period of 30 min at 5-10° C. The reaction mixture was stirred for another 30 min at the same temperature, and then for 3 hours at room temperature. Work-up was done using 4 M aqueous sodium hydroxide (60 mL) that was added dropwise under water/ice bath cooling (the pH of the resulting solution was about 12). The resulting mixture was extracted with EtOAc (3.x.70 mL), washed with H2O (50 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave 470 mg (77percent) of 2 as yellow oil. [0033] A similar transformation was also achieved by the use of a mixture of sodium metal (6 equiv.), isopropanol and tetrahydrofuran (Table 1, entry 2) under the conditions of the electron transfer reduction reported recently for a similar reaction of a series of enaminones. Unfortunately, the yield was only 55percent; and the reduction product contained some impurities that were difficult to remove. [TABLE-US-00001] TABLE 1 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one. Entry Reducing agent Isolated Yield (percent) 1 NaBH4, HOAc 77 2 Na, i-PrOH 55 [0034] The new convenient approach leading to the racemic mixture of 3-(methylamino)1-phenyl-1-propanol compliments existing methods. However, unlike some previous routes, the new method takes advantage of using one reduction step only.
55%
With sodium; isopropyl alcohol In tetrahydrofuran
Example 2 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one with NaBH4 in HOAc. [0031] Acetic acid was used instead of methanol in combination with sodium borohydride under mild conditions for the reduction of 3-(methylamino)-1-phenyl-2-propen-1-one. Sodium borohydride (6 equivalents) was slowly added to a 0.25 M solution of 3-(methylamino)-1-phenyl-2-propen-1-one (Formula 3), in glacial acetic acid at 5-10° C. after stirring for 3 hours at room temperature followed by the usual work-up, the target aminoalcohol was isolated with a 77percent yield (Table 1, entry 1). The effectiveness of this method may be due to the enhanced activity of both carbonyl and azomethyne groups under acidic conditions. [0032] In a particular example, NaBH4 (800 mg, 21.0 mmol) was added in portions to a vigorously stirred solution of 3-(methylamino)-1-phenyl-2-propen-1-one (600 mg, 3.7 mmol) in glacial HOAc (15 mL) over a period of 30 min at 5-10° C. The reaction mixture was stirred for another 30 min at the same temperature, and then for 3 hours at room temperature. Work-up was done using 4 M aqueous sodium hydroxide (60 mL) that was added dropwise under water/ice bath cooling (the pH of the resulting solution was about 12). The resulting mixture was extracted with EtOAc (3.x.70 mL), washed with H2O (50 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave 470 mg (77percent) of 2 as yellow oil. [0033] A similar transformation was also achieved by the use of a mixture of sodium metal (6 equiv.), isopropanol and tetrahydrofuran (Table 1, entry 2) under the conditions of the electron transfer reduction reported recently for a similar reaction of a series of enaminones. Unfortunately, the yield was only 55percent; and the reduction product contained some impurities that were difficult to remove. The new convenient approach leading to the racemic mixture of 3-(methylamino)1-phenyl-1-propanol compliments existing methods. However, unlike some previous routes, the new method takes advantage of using one reduction step only.
Reference：
[1] Patent: US5892117, 1999, A,
[2] Patent: US5892117, 1999, A,
[3] Patent: US5892117, 1999, A,
[4] Patent: US5998627, 1999, A,
[5] Patent: US5998627, 1999, A,
[6] Patent: US5998627, 1999, A,
[7] Patent: US5760243, 1998, A,
[8] Patent: US5760243, 1998, A,
[9] Patent: US5760243, 1998, A,
6
[ 18776-12-0 ]
[ 74-89-5 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[2] Chem. Zentralbl., 1907, vol. 78, # II, p. 1086
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3101 - 3108
[4] Patent: WO2014/46544, 2014, A1, . Location in patent: Page/Page column 12-13; 23
7
[ 98-86-2 ]
[ 42142-52-9 ]
Reference：
[1] Synthetic Communications, 2006, vol. 36, # 13, p. 1923 - 1926
[2] Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1687 - 1689
[3] Organic Process Research and Development, 2014, vol. 18, # 7, p. 875 - 885
[4] Patent: CN103992236, 2016, B,
8
[ 62872-58-6 ]
[ 74-89-5 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[2] Chinese Journal of Chemistry, 2011, vol. 29, # 3, p. 504 - 510
[3] Letters in Drug Design and Discovery, 2011, vol. 8, # 3, p. 268 - 275
9
[ 936-59-4 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[3] Chinese Journal of Chemistry, 2011, vol. 29, # 3, p. 504 - 510
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 3, p. 268 - 275
10
[ 18776-12-0 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3854 - 3862
[2] Chinese Journal of Chemistry, 2011, vol. 29, # 3, p. 504 - 510
[3] Letters in Drug Design and Discovery, 2011, vol. 8, # 3, p. 268 - 275
11
[ 108606-85-5 ]
[ 74-89-5 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 32, p. 6121 - 6127
12
[ 104-55-2 ]
[ 42142-52-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 32, p. 6121 - 6127
13
[ 27152-62-1 ]
[ 42142-52-9 ]
Reference：
[1] Chemical and pharmaceutical bulletin, 1963, vol. 11, # 8, p. 1049 - 1054
14
[ 42142-52-9 ]
[ 82248-59-7 ]
Reference：
[1] Patent: WO2015/1565, 2015, A2,
[2] Patent: CN106916074, 2017, A,
[3] Patent: CN108929236, 2018, A,
With hydrogenchloride; potassium hydroxide In sulfolane; water; toluene
EXAMPLE 1 Preparation of N-methyl-3-[(4-trifluoromethyl)phenoxy]-3-phenyl propylamine hydrochloride (fluoxetine hydrochloride) A mixture of N-methyl-3-hydroxy-3-phenyl propylamine (MPHA, 75 gm), potassium hydroxide (150 gm) and poly (ethylene glycol)-6000 (30 gm) was charged to sulfolane (150 ml) at 90-95° C. Stirred and charged 1-chloro-4-trifluoromethylbenzene (90 gm) at 90-95° C. The reaction mixture so obtained was further stirred for about 45 minutes at 120-125° C. After the reaction was over, the reaction mixture was cooled to 20-25° C., water (990 ml) and toluene (990 ml) were added to it. Charged hydrochloric acid (300 ml) to it slowly, stirred it vigorously, and the toluene layer was separated. Toluene (900 ml) was recovered under vacuum at 60-65° C. to get crude fluoxetine hydrochloride and is crystallized from ethyl acetate to afford the pure product (134 gm, 95.7percent) of purity (by HPLC) more than 99percent.
Reference：
[1] Patent: US2003/50508, 2003, A1,
17
[ 42142-52-9 ]
[ 98-56-6 ]
[ 56296-78-7 ]
Reference：
[1] Patent: US5225585, 1993, A,
18
[ 42142-52-9 ]
[ 127-19-5 ]
[ 98-56-6 ]
[ 202122-33-6 ]
[ 56296-78-7 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 7, p. 875 - 885
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;
The 2a (0.5mmol) was dissolved in 0.5mL of methanol,At room temperature was slowly added NaBH 4 (2.0mmol),Mixture was stirred at room temperature 1h.Added 2mL saturated NH 4Cl solution.The solvent was removed by distillation under reduced pressure.The residue was added 5mLNaOH (1N),With 5mLCH 2Cl 2 and extracted four times.The organic phase was collected and dried over anhydrous sodium sulfate,And concentrated to give the crude product.The crude product after column chromatography product 2b.Yield: 90%.
Example 2 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one with NaBH4 in HOAc. [0031] Acetic acid was used instead of methanol in combination with sodium borohydride under mild conditions for the reduction of 3-(methylamino)-1-phenyl-2-propen-1-one. Sodium borohydride (6 equivalents) was slowly added to a 0.25 M solution of 3-(methylamino)-1-phenyl-2-propen-1-one (Formula 3), in glacial acetic acid at 5-10 C. after stirring for 3 hours at room temperature followed by the usual work-up, the target aminoalcohol was isolated with a 77% yield (Table 1, entry 1). The effectiveness of this method may be due to the enhanced activity of both carbonyl and azomethyne groups under acidic conditions. [0032] In a particular example, NaBH4 (800 mg, 21.0 mmol) was added in portions to a vigorously stirred solution of 3-(methylamino)-1-phenyl-2-propen-1-one (600 mg, 3.7 mmol) in glacial HOAc (15 mL) over a period of 30 min at 5-10 C. The reaction mixture was stirred for another 30 min at the same temperature, and then for 3 hours at room temperature. Work-up was done using 4 M aqueous sodium hydroxide (60 mL) that was added dropwise under water/ice bath cooling (the pH of the resulting solution was about 12). The resulting mixture was extracted with EtOAc (3×70 mL), washed with H2O (50 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave 470 mg (77%) of 2 as yellow oil. [0033] A similar transformation was also achieved by the use of a mixture of sodium metal (6 equiv.), isopropanol and tetrahydrofuran (Table 1, entry 2) under the conditions of the electron transfer reduction reported recently for a similar reaction of a series of enaminones. Unfortunately, the yield was only 55%; and the reduction product contained some impurities that were difficult to remove. [TABLE-US-00001] TABLE 1 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one. Entry Reducing agent Isolated Yield (%) 1 NaBH4, HOAc 77 2 Na, i-PrOH 55 [0034] The new convenient approach leading to the racemic mixture of 3-(methylamino)1-phenyl-1-propanol compliments existing methods. However, unlike some previous routes, the new method takes advantage of using one reduction step only.
55%
With sodium; isopropyl alcohol; In tetrahydrofuran;
Example 2 Reduction of 3-(Methylamino)-1-phenyl-2-propen-1-one with NaBH4 in HOAc. [0031] Acetic acid was used instead of methanol in combination with sodium borohydride under mild conditions for the reduction of 3-(methylamino)-1-phenyl-2-propen-1-one. Sodium borohydride (6 equivalents) was slowly added to a 0.25 M solution of 3-(methylamino)-1-phenyl-2-propen-1-one (Formula 3), in glacial acetic acid at 5-10 C. after stirring for 3 hours at room temperature followed by the usual work-up, the target aminoalcohol was isolated with a 77% yield (Table 1, entry 1). The effectiveness of this method may be due to the enhanced activity of both carbonyl and azomethyne groups under acidic conditions. [0032] In a particular example, NaBH4 (800 mg, 21.0 mmol) was added in portions to a vigorously stirred solution of 3-(methylamino)-1-phenyl-2-propen-1-one (600 mg, 3.7 mmol) in glacial HOAc (15 mL) over a period of 30 min at 5-10 C. The reaction mixture was stirred for another 30 min at the same temperature, and then for 3 hours at room temperature. Work-up was done using 4 M aqueous sodium hydroxide (60 mL) that was added dropwise under water/ice bath cooling (the pH of the resulting solution was about 12). The resulting mixture was extracted with EtOAc (3×70 mL), washed with H2O (50 mL), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave 470 mg (77%) of 2 as yellow oil. [0033] A similar transformation was also achieved by the use of a mixture of sodium metal (6 equiv.), isopropanol and tetrahydrofuran (Table 1, entry 2) under the conditions of the electron transfer reduction reported recently for a similar reaction of a series of enaminones. Unfortunately, the yield was only 55%; and the reduction product contained some impurities that were difficult to remove. The new convenient approach leading to the racemic mixture of 3-(methylamino)1-phenyl-1-propanol compliments existing methods. However, unlike some previous routes, the new method takes advantage of using one reduction step only.
Into a 1L three-necked RB flask was charged 100GR of N-methyl-N- (3-hydroxy-3- phenyl) propylamine and 300ML of toluene. Ethyl acrylate (62gr) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65C and maintained for 7HRS. The reaction mixture was cooled to 40C and toluene distilled off under vaccum to get the title compound (160GR) of formula-XIV (X = H, R = Et) as syrup. IR (neat): 3243, 3062,3028, 2980,2953, 2846,2808, 1730,1453, 1371,1322, 1199,1127, 1093,1043, 763, and 702CM-I. 1H-NMR (300MHZ, CDC13) : 7.18-7. 40 (m, 5H, ar. H); 6.14 (br. s, 1H, exch. with D20,-CH (OH) -); 4.89 (t, J = 5.9Hz, 1H,-CH (OH) -); 4.16 (q, J = 7. 0HZ, 2H, - OCH2CH3); 2.47-2. 84 (m, 6H, 3 X-CH2-) ; 2.30 (s, 3H,-NCH3) ; 1.78-1. 87 (m, 2H,-CH2- ) ; 1. 26 (t, J = 7.3Hz, 3H,-OCH2CH3).
Into a 1L three-necked. RB flask was charged 100GR of N-methyl-N- (3-hydroxy-3- phenyl) propylamine and 300ML of toluene. Methyl acrylate (57GR) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65C and maintained for 7hrs. The reaction mixture was cooled to 40C and toluene distilled off under vaccum. The residue was dissolved in isopropyl ether (150ML) and stirred for LHR, filtered off the crystals to get 140gr (92%) of white crystalline solid of the formula-XIV (X = H, R = Me). M. P. 41-42C. IR (KBr) : 3125,2946, 2967,1734, 1437,1373, 1325,1202, 1182, 1142,1066, 1016,943, 859, 800, 768, and 703CM'I. IH-NMR (300MHZ, CDCI3) : 7.23- 7.40 (m, 5H, ar. H); 6.10 (br. s, exch. with DzO, 1H,-CH (OH)-) ; 4.90 (t, J = 5. 90HZ, 1H,- CH (OH) -) ; 3. 71 (s, 3H,-C02CH3) ; 2.50-2. 53 (m, 6H, 3 x-CH2-); 2. 31 (s, 3H, -NCH3) ; 1.79-1. 88 (m, 2H,-CH2-).
Example 2 r3-(lH-Indol-3-yl)-3-phenyl-propyl1-methyl-amine (Alternate Procedure) The synthetic procedure of Example 2 is outlined in Scheme E below. SCHEME E Step Trifluoro-acetic acid 3-fmethyl-(2,2,2-trif).uoro-acety].')-ammo1-l-phenLyl-propyl ester; 3-Methylamino-l-phenyl-propan-l-ol (1.65 g, 10 mmole) was dissolved in methylene chloride (5 ml), and trifluoroacetic anhydride (5 g, 23.8 mmole) was added in portions. Following the brief exotherm which caused the solvent to boil, the mixture was evaporated to dryness and azeotroped twice with methylene chloride and once with toluene to remove any excess anhydride. The residue was taken up in methylene chloride, applied to a short silica gel column, and eluted with 3: 7 ethyl acetate : hexane. The product thus isolated was pumped dry to afford trifluoro-acetic acid 3-[methyl-(2,2,2- triffuoro-acetyl)-arnino]-1-phenyl-propyl ester, which was used in the following step without further purification.
With potassium tert-butylate; In N,N-dimethyl acetamide; at 50 - 110℃; for 7 - 9h;Product distribution / selectivity;
To a solution of N-methy-3-phenyl-3-hydroxy phenylpropylamine (25 g, 0.15 mole) in N,N-dimethylacetamide and potassium tertiary butoxide (19 g, 0.17 mole) at 50-60C was charged 2-flourotoluene (50 g, 0.45 mole) and the mixture was heated to 105-110C and maintained for 7-9 hours. After the completion of the reaction (as monitored by TLC) there were charged water (250 ml) followed by dichloromethane (250 ml) and the mixture was stirred for 10-15 minutes. The organic layer was separated from the aqueous layer, and the aqueous layer was extracted with dichloromethane (2x50 ml). The combined organic layer was subjected to distillation to obtain a thick residue. The obtained residue was further purified by preparing its oxalate salt. The crude residue was charged into acetone (240 ml) followed by the addition of oxalic acid, petroleum ether (240 ml) was charged, and the mixture was stirred for 1-5 hours at 0-5C. Filtering the obtained solid and washing with a mixture of acetone and petroleum ether in a 1:1 ratio (100 ml) resulted in the recovery of atomoxetine oxalate. Yield 55% and HPLC purity 98.35%.
With potassium tert-butylate; In hexamethylphosphorus triamide; at 50 - 110℃; for 19 - 20h;Product distribution / selectivity;
To a solution of N-methy-3-phenyl-3-hydroxy phenylpropylamine (25 g, 0.15 mole) in hexamethylphosphorous triamide and potassium tertiary butoxide (19 g, 0.17 mole) at 50-60C was charged 2-flourotoluene (50 g, 0.45 mole) and the contents of the reaction were heated to 105-110C. The reaction was maintained for 19-20 hours. After the completion of the reaction (checked by TLC) there were charged water (250 ml) followed by toluene (250 ml) and the mixture was stirred for 10-15 minutes. The aqueous and organic layers were separated, then the aqueous layer was extracted with toluene (2x75 ml). Thecombined organic layer was washed with water (3x75 ml) and then subjected to distillation to obtain a thick residue. The residue was dissolved in acetone (150 ml) followed by adding oxalic acid and isopropyl ether (200 ml) and the mixture was stirred for 1-1.5 hours at 0-5C, then the obtained solid was separated by filtration and washing with isopropyl ether (100 ml) resulting in the oxalate of atomoxetine. Yield 62.4% and HPLC purity 95.4%.
250 milliliters of N,N-dimethylacetamide was taken into round bottom flask to which 115.3 grams of potassium tertiary butoxide, 100 grams of N-Methyl-3-phenyl-3-(o-tolyloxy)propylamine and 100 grams of 2-fluorotoulene were added,followed by heating to 120 to 130C for about 12 to 14 hours. Solvent was distilled from the above reaction mass under vacuum below 118 to 122C, followed by the addition of 500 milliliters of methanol and 300 milliliters of a 45-50 percent by weight sodium hydroxide solution. The reaction mass was transferred into an autoclave and then heated to a temperature of 105 to 110C for about 6 to 7 hours. The solvent was totally distilled off under vacuum at a temperature below 80C, then 1 liter of demineralised water and 1 liter of toluene were added, followed by cooling to 0 to 5C and adjusting the pH to a value between 8 and 9 with dilute hydrochloric acid. The above reaction mass was stirred for about 15 to 30 minutes to separate the organic and aqueous layers and the aqueous layer was extracted with 400 milliliters of toluene followed by stirring for about 5 to 10 minutes. Organic and aqueous layers were separated and the combined organic layers were washed with 400 milliliters of dimineralised water. The organic layer was taken into a round bottom flask followed by complete distillation under vacuum below 80C and then cooled to 25 to 35C. 1.3 liters of acetone and 64.2 grams of oxalic acid were added to the round bottom flask followed by stirring for about 45 to 60 minutes. The solid mass that was obtained was filtered and washed with 520 milliliters of acetone, and then slurried in 700 milliliters of acetonitrile in a round bottom flask and stirred for about 30 to 45 minutes. The solid mass was isolated by filtration and washed with 200 milliliters of acetonitrile, followed by drying at 50 to 60C for 4 to 5 hours under vacuum to afford atomoxetine oxalate.
To a solution of 25 g of N-methyl-3-phenyl-3-hydroxyphenyl propylamine in N,N-dimethylacetamide and 19 g. of potassium f-butoxide at 50-600C was charged 50 g of 2-flourotoluene, then the mixture was heated to 120-1300C and maintained over a period of about 12 to 14 hours followed by distillation of the reaction mass under vacuum at a temperature below 1200C. The reaction mass was cooled to 40 to 500C, 500 ml of methanol and 300 ml of a 45-50% by weight aqueous sodium hydroxide solution were added, and the mixture was heated in an autoclave to a temperature of about 90 to 120C, or 100-110C, for 5-20 hours or 6-7 hours. After the completion of the reaction, as monitored by thin layer chromatography ("TLC"), the solvent was distilled at a temperature below 8O0C, 250 ml of water followed by 250 ml of dichloromethane were charged to the residue and the mixture was stirred for 10-15 minutes. The organic layer was separated from the aqueous layer, and the aqueous layer was extracted with 100 ml of dichloromethane. The combined organic layers were subjected to distillation to obtain a thick residue. The obtained residue was further purified by preparing its oxalate salt: the crude residue was charged into acetone (240 ml) followed by the addition of 12.5 g oxalic acid, petroleum ether (240 ml) was charged, and the mixture was stirred for 1-5 hours at 0-5C. Filtering the obtained solid and washing with a mixture of 100 ml of acetone and petroleum ether in a 1 :1 ratio resulted in the recovery of (+/-)-atomoxetine oxalate Form Il with a yield of 55% and HPLC purity of 98.35 area-%.; 250 milliliters of N.N-dimethylacetamide was taken into round bottom flask to which 115.3 grams of potassium f-butoxide, 100 grams of N-Methyl-3-phenyl-3- (o-tolyloxy) propylamine and 100 grams of 2-fluorotoulene were added, followed by heating to 120 to 1300C for about 12 to 14 hours. Solvent was distilled from the above reaction mass under vacuum below 118 to 1220C, followed by the addition of 500 milliliters of methanol and 300 milliliters of a 45-50% by weight aqueous solution of sodium hydroxide. The reaction mass was transferred into an autoclave and then heated to a temperature of 105 to 11O0C for about 6 to 7 hours. The solvent was totally distilled off under vacuum at a temperature below 8O0C, then 1 liter of water and 1 liter of toluene were added, followed by cooling to 0 to 5C and adjusting the pH to a value between 8 and 9 with dilute hydrochloric acid. The above reaction mass was stirred for about 15 to 30 minutes, the organic and aqueous layers were separated, and the aqueous layer was extracted with 400 milliliters of toluene followed by stirring for about 5 to 10 minutes. Organic and aqueous layers were separated and the combined organic layers were washed with 400 milliliters of water. The organic layer was taken into a round bottom flask followed by complete distillation under vacuum below 80C and then cooled to 25 to 35C. 1.3 liters of acetone and 64.2 grams of oxalic acid dihydrate were added to the above reaction mass followed by stirring for about 45 to 60 minutes. The solid mass that was obtained was filtered and washed with 520 milliliters of acetone. The wet solid was transferred into a round bottom flask followed by the addition of 700 milliliters of acetonitrile and stirring for about 30 to 45 minutes. The resulting slurry was filtered and washed with 200 milliliters of acetonitrile followed by drying at 50 to 6O0C for 4 to 5 hours under vacuum to afford crystalline (+/-)-atomoxetine oxalate having Form II
With potassium tert-butylate; In N,N,N,N,N,N-hexamethylphosphoric triamide; at 50 - 110℃; for 19 - 20h;Product distribution / selectivity;
To a solution of 25 g N-methyl-3-phenyl-3-hydroxyphenyl propylamine in hexamethylphosphorous triamide and 19 g potassium f-butoxide at 50-600C was charged 50 g of 2-flourotoluene and the mixture was heated to 105-1100C. The reaction was maintained for 19-20 hours. After the completion of the reaction (monitored by TLC) there were charged 250 ml of water followed by 250 ml toluene and the mixture was stirred for 10-15 minutes. The aqueous and organic layers were separated, then the aqueous layer was extracted with (2*75 ml) toluene. The combined organic layer was washed with (3x75 ml) water and then subjected to distillation to obtain a thick residue. The residue was dissolved in 150 ml of acetone followed by adding of 12.5 g oxalic acid and 200 ml of isopropyl ether and the mixture was stirred for 1-1.5 hours at 0-50C, then the obtained solid was separated by filtration and washed with isopropyl ether (100 ml) resulting in the (+/-)-atomoxetine oxalate with yield 62.4% and a purity of 95.4 area-% by HPLC.
a [3-(2-Chloro-5-nitrophenoxy)-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester This was prepared by the method of Example 2 using alpha-[2-(methylamino)ethyl]benzenemethanol and 2-chloro-5-nitrophenol. MS APCI+ve m/z 321/323 [(M-Boc+H)+].
EXAMPLE 7 2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65-70 C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried (K2 CO3) and concentrated to give N-methyl-3-phenyl-3-hydroxy-propyl-amine.
palladium-carbon; In ethanol;
EXAMPLE 10 2-Methyl-5-phenylisoxazolidine (54.3 g, 333 mmol) and Pd/C (2.7 g) in EtOH (55.0 g) are heated to 60-80 C. in a 300-mL, stirred (700 rpm), Hastalloy autoclave which is kept pressurized to 55 psig with H2 for 5 hours. After cooling, the mixture is filtered and the EtOH removed in vacuo to give N-methyl-3-phenyl-3-hydroxypropylamine.
palladium-carbon; In ethanol;
EXAMPLE 8 2-Methyl-5-phenylisoxazolidine (12.6 g, 77.3 mmol) in EtOH (134 g) is mixed with 5% Pd/C (1.2 g) in a glass pressure reactor. The reactor is warmed to 40-50 C. and the pressure maintained at 40 psig with H2 until the pressure becomes constant (ca. 24 hours). The mixture is filtered through Celite and the solvent is removed to give N-methyl-3-phenyl-3-hydroxypropylamine.
In acetic acid;
EXAMPLE 11 2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65-70 C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried (K2 CO3) and concentrated to give N-methyl-3-phenyl-3-hydroxypropyl-amine.
palladium-carbon; In ethanol;
EXAMPLE 12 2-Methyl-5-phenylisoxazolidine (12.6 g, 77.3 mmol) in EtOH (134 g) is mixed with 5% Pd/C (1.2 g) in a glass pressure reactor. The reactor is warmed to 40-50 C. and the pressure is maintained at 40 psig with H2 until the pressure becomes constant (ca. 24 hours). The mixture is filtered through Celite and the solvent is removed to give N-methyl-3-phenyl-3-hydroxypropylamine.
palladium-carbon; In H2; ethanol;
EXAMPLE 14 2-Methyl-5-phenylisoxazolidine (54.3 g, 333 mmol) and Pd/C (2.7 g) in EtOH (55.0 g) are heated to 60-80 C. in a stirred (700 rpm) 300-mL Hastalloy autoclave which is kept pressurized to 55 psig with H2 for 5 hours. After cooling, the mixture is filtered and the EtOH removed in vacuo to give N-methyl-3-phenyl-3-hydroxypropylamine.
In acetic acid;
EXAMPLE 3 2-Methyl-5-phenylisoxazolidine (2.0 g, 12.3 mmol) and Zn powder (1.2 g, 18.3 mmol) in 10 molar aqueous acetic acid are heated to 65-70 C. for 4 hours. Additional Zn powder (0.4 g, 6.1 mmol) is added and heating is continued for one more hour. The reaction mixture is neutralized with sodium hydroxide and extracted with chloroform. The extract is dried K2 CO3) and concentrated to give N-methyl-3-phenyl-3-hydroxypropylamine.
palladium-carbon; In ethanol;
EXAMPLE 4 2-Methyl-5-phenylisoxazolidine (12.6 g, 77.3 mmol) in EtOH (134 g) is mixed with 5 Pd/C (1.2 g) in a glass pressure reactor. The reactor is warmed to 40-50 C. and the pressure maintained at 40 psig with H2 until the pressure becomes constant (ca. 24 hours). The mixture is filtered through Celite and the solvent is removed to give N-methyl-3phenyl-3-hydroxypropylamine.
palladium-carbon; In ethanol;
EXAMPLE 6 2-Methyl-5-phenylisoxazolidine (54.3 g, 333 mmol) and Pd/C (2.7 g) in EtOH (55.0 g) are heated to 60-80 C. in a 300-mL, stirred (700 rpm), Hastalloy autoclave which is kept pressurized to 55 psig with H2 for 5 hours. After cooling, the mixture is filtered and the EtOH removed in vacuo to give N-methyl-3-phenyl-3-hydroxypropylamine.
With potassium hydroxide; tetra(n-butyl)ammonium hydrogen sulfate; In sulfolane; water;
EXAMPLE 12 N-Methyl-3-phenyl-3-hydroxypropylamine (49.8 g, 302 mmol), 4-chlorobenzotriflouride (60.0 g, 332 mmol), powdered 87% KOH (22.0 g, 341 mmol), and tetrabutylammonium hydrogen sulfate (0.5 g, 1.5 mmol) and sulfolane (47 g) are combined and heated to 150 C. under a nitrogen condenser for 24 hours. More 4-chlorobenzotriflouride (11.0 g, 61 mmol) and KOH (3.0 g, 47 mmol) are added and heating is continued for 48 hours. After cooling, water (300 mL) is added, and the aqueous solution is extracted with ether (3*100 mL) and the combined extracts are washed with water (2*100 mL). The ether solution is dried (K2 CO3). The ether is removed in vacuo and the product is distilled (125-130 C., 0.5 mm Hg) to give N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]propylamine.
Example 3 Preparation of Fluoxetine Free Base [0035] To a 3.0 L round bottom flask is added 24.5 g (0.148 mol) of the aminoalcohol and this is dissolved in 215 mL of DMSO. To this solution is added 5.72 g (0.238 mol) of sodium hydride (washed with hexanes). The solution is heated to 60 C. for 1 hour. To this dark orange solution is added 50 mL of 4-chlorobenzotrifluoride (0.374 mol). The reaction mixture is heated to 115 C. for 6 hours. The reaction is allowed to cool to room temperature and then 1.0 L of water is added to quench the reaction. The reaction mixture is extracted with ethyl ether (2 times 500 mL), followed by two extractions using toluene (2 times 500 mL). The organic layers are combined and washed twice with brine. The aqueous layer is separated and the organic layer dried, filtered and rotoevaporated to yield 60.3 g of crude material. This crude material was purified by column chromatography (silica gel) using 5% methanol:methylene chloride as the eluent. Yield of pure fluoxetine free base is typically about 55%.
With potassium hydroxide; tetra(n-butyl)ammonium hydrogen sulfate; In sulfolane; water;
EXAMPLE 16 N-Methyl-3-phenyl-3-hydroxypropylamine (49.8 g, 302 mmol), 4-chlorobenzotrifluoride (60.0 g, 332 mmol), powdered 87% KOH (22.0 g, 341 mmol), and tetrabutylammonium hydrogen sulfate (0.5g, 1.5 mmol) and sulfolane (47 g) are combined and heated to 150 C. under a nitrogen condenser for 24 hours. More 4-chlorobenzotrifluoride (11.0 g, 61 mmol) and KOH (3.0 g, 47 mmol) are added and heating is continued for 48 hours. After cooling, water (300 mL) is added, and the aqueous solution is extracted with ether (3*100 mL) and the combined extracts are washed with water (2*100 mL). The ether solution is dried (K2 CO3). The ether is removed in vacuo and the product is distilled (125-130 C., 0.5 mm Hg) to give N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]propylamine.
With 1-methyl-pyrrolidin-2-one; In water;
EXAMPLE 2 N-Methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine 150 ml of N-methylpyrrolidone and 18.5 g (0.152 mol) of potassium t-butoxide were transferred into a N2 -gas secured reaction vessel and mixed for 15 minutes. To the mixture was added 25 g (0.1 52 mol) of 1-phenyl-3-N-methylaminopropan-1-ol, and 36.0 g (0.199 mol) of 1-chloro-4-trifluoromethylbenzene and mixing was continued for 6 hours at 80 C. The solution was cooled to 25 C. and 300 ml of water was added. After that, the solution was extracted twice with 200 ml of toluene. The toluene layers were combined and washed five times with 100 ml of water, and evaporated into dryness. 42 g (90% of the theoretical) of a pure N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine base was obtained as an evaporation residue. The base was transformed in a well-known manner into fluoxetine hydrochloride in almost a quantitative yield. M.P.=154-155 C. Analysis: 1 H-NMR (CDCl3) 7.4 (doublet 2H); 7.3 (multiplet 5H); 6.9 (doublet 2H): 5.3 (two doublets 1H): 2.7 (triplet 2H); 2.4 (singlet 3H); 2.2 (multiplet 1H); 2.0 (multiplet 1H); 1.4 (singlet 1H).
With 1-methyl-pyrrolidin-2-one; In water; toluene;
EXAMPLE 4 N-Methyl-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine A mixture of 4.0 g (0.0357 mol) potassium t-butoxide, ml of N-methylpyrrolidone, 5.0 g (0.0303 mol) of 1-phenyl-3-N-methylaminopropan-1-ol, and 7.4 g (0.0410 mol) of 1-chloro-4-trifluoromethylbenzene was heated to 40 C. and stirred for 8 hours at 40 C. The mixture was then cooled to 20-25 C. and 40 ml of toluene and water were added. The combined toluene-phases were washed four times with 20 ml of water. Toluene was evaporated under reduced pressure yielding 5.06 g of the product. Analysis: 1 H-NMR (CDCl3): 7.4 (doublet 2H); 7.3 (multiplet 5H); 6.9 (doublet 2H); 5.3 (two doublets 1H); 2.7 (triplet 2H); 2.4 (singlet 3H); 2.2 (multiplet 1H); 2.0 (multiplet 1H); 1.4 (singlet 1H).
With 1-methyl-pyrrolidin-2-one; In water; toluene;
EXAMPLE 5 N-Methyl-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine A mixture of 4.0 g (0.0357 mol) potassium t-butoxide, 30 ml of N-methylpyrrolidone, 5.0 g (0.0303 mol) of 1-phenyl-3-N-methylaminopropan-1-ol and 7.4 g (0.0410 mol) of 1-chloro-4-trifluoromethylbenzene was heated to 140 C. and the reaction mixture was agitated at this temperature for 3 hours. The mixture was then cooled to 20-25 C. and 40 ml of toluene and 60 ml of water were added. The layers were separated and water-phase was extracted with 40 ml of toluene. The combined toluene-phases were washed four times with 20 ml of water. Toluene was evaporated under reduced pressure yielding 7.19 g of the product. Analysis: 1 H-NMR (CDCl3): 7.4 (doublet 2H): 7.3 (multiplet 5H): 6.9 (doublet 2H); 5.3 (two doublets 1H); 2.7 (triplet 2H); 2.4 (singlet 3H); 2.2 (multiplet 1H); 2.0 (multiplet 1H); 1.4 (singlet 1H).
In water; toluene;
EXAMPLE 3 N-Methyl-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine A mixture of 8.0 g (0.0713 mol) potassium t-butoxide, 60 ml of dimethylsufoxide, 10 g (0.0606 mol) of 1-phenyl-3-N-methylaminopropan-1-ol, and 14.8 g (0.0820 mol) of 1-chloro-4-trifluoromethylbenzene was heated to 80 C. and stirred for 4,5 hours at 80 C. The mixture was then cooled to 20-25 C. and 80 ml of toluene and 120 ml of water were added. The layers were separated and water-phase was extracted with 80 ml of toluene. The combined toluene-phases were washed four times with 40 ml of water. Toluene was evaporated under reduced pressure yielding 18.86 g the product. Analysis: 1 H-NMR (CDl3): 7.4 (doublet 2H); 7.3 (multiplet 5H); 6.9 (doublet 2H); 5.3 (two doublet 1H); 2.7 (triplet 2H); 2.4 (singlet 3H); 2.2 (multiplet 1H); 2.0 (multiplet 1H); 1.4 (singlet 1H).
2b (6.6mmol) were dissolved DMSO (2mL) at,The reaction solution was added NaH (9.9mmol),At 55 under N 2 and stirred 30min. 4-Chlorobenzotrifluoride (9.9mmol) was dissolved in a mixture of 2.9 g of 1.0mLDMSO, Was heated to 90 deg.] C for 1 hour.After cooling to room temperature was added NaOH10mL (2N),Toluene was extracted 3 times,The extracts were combined,After concentrating the compound 2.
EXAMPLE 3 N-Methyl-gamma-{4-[(trifluoromethyl)thio]phenoxy}benzenepropanamine ethanedioate To a suspension of 2 g of a 60% sodium hydride mineral oil dispersion and 25 ml of N,N-dimethylacetamide were added a solution of 8.26 g of alpha-[2-(methylamino)ethyl]benzenemethanol in 75 ml of N,N-dimethylacetamide over a 30-minute period. After stirring for one hour, the mixture was heated at 50-60 C. for 30 minutes. p-Bromophenyl trifluoromethyl sulfide (12.85 g) was added and the mixture heated at 100 C. for 2.5 hours. After cooling, the mixture was stirred at room temperature overnight. The solution was poured into 250 ml of cold water and extracted three times with diethyl ether. The combined ether extracts were washed first with water, then with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated in vacuo. The resulting oil was purified by high pressure liquid chromatography over silica gel eluding with methylene/chloride/methanol/ammonium hydroxide (100:5:1). The appropriate fractions were combined and evaporated to provide 1.59 g of the title product base as an oil. The oxalate salt was made in warm ethyl acetate and the resulting product crystallized from isopropanol to provide 1.64 g of the title product as colorless crystals, m.p. 173-174 C. (with decomposition). Analysis calculated for C19 H20 F3 NO5 S: Theory: C, 52.90; H, 4.67; N, 3.25; Found: C, 53.20; H, 4.80; N, 3.08.
N-(3-hydroxy-3-phenylpropyl)-N-methylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 5℃; for 1.58333h;
50 g of N-methyl-3-phenyl-3-hydroxy propyl amine and 250 ml of dichloromethane were placed into a round bottom flask followed along with 50.5 EPO <DP n="26"/>ml of triethylamine and the mixture was cooled to a temperature of about 0 to 50C, then 260 ml of acetyl chloride was added slowly in a dropwise manner for a period of about 35 minutes and the reaction mass was maintained for about 1 hour at the same temperature. 500 ml of water were added to the reaction mass and the aqueous and organic layers were separated, followed by washing the organic layer with water. The organic layer was separated and subjected to distillation at a temperature of about 450C for about 50 minutes. To the residue 275 ml of ethyl acetate were added and the mixture was cooled to a temperature of about 50C with stirring. The solid was isolated by filtration and washed with 100 ml of ethyl acetate, subjected to suction drying, and finally dried at a temperature of about 600C.Melting Range: 55-62C.IR : 3234 (Ar- CH), 295028 (AIi -CH), and 3234 (OH) cm"1. 1 H NMR: (DMSO-d6, 200 MHz): delta 7.37 (m, 1 H), delta 7.3 (m, 1 H), delta 7.2 (m, 1 H), delta 7.35 (m, 1 H), delta 5.3 (dd, 1 H), delta 4.54 (d, OH), delta 3.42 (d, 2H), delta 1.8beta(s, 3H), delta 1.8(s, 2H).13C NMR: (DMSO-d6, 200 MHz): delta 128, 128, 125.6, 125.6, 126.7, 145.8, 146, 71.7, 46. MS: m/z 208 (100%, M+).
100.0 g of N-methyl-3-phenyl-3-hydroxy propyl amine, 87 g of fluorbenzene, 115.3 g of potassium tertiary butoxide, and 250 ml of dimethyl acetamide were taken into a round bottom flask and heated to a temperature of about 1200C. with stirring for about 11 to 12 hours, heating was stopped and the stirring was continued over a period of about 10 hours. The above reaction mass was transferred into round bottom flask along with the addition of 500 ml of methanol and 300 ml of a 45-50% by weight aqueous solution of sodium hydroxide and subjected to stirring with simultaneous heating to a temperature of about 1100C, then was cooled to a temperature of about 320C, and the reaction mass was taken into another round bottom flask and subjected to distillation to a temperature of about 650C followed by the addition of 1000 ml of water to the contents in the flask and cooling to a temperature of about 0 to 50C. pH of the reaction mass was adjusted with 300 ml of 5% aq. hydrochloric acid and 1000 ml of toluene were added with stirring. The aqueous and organic layers were separated and the aqueous layer was extracted with 1000 ml of toluene. Both organic layers were combined and washed with 800 ml of water. The organic layer was subjected to distillation to a temperature of about 650C. and to the residue 568 ml of acetone were added followed by stirring and cooling to a temperature of about 50C, and formed solid was filtered and washed with acetone. The solid mass was suction dried for about 10 minutes and finally dried at a temperature about 500C.Melting Range: 165 to 1700 C.IR: 3067 (Ar- CH), 2846 (AIi -CH), 1597, 1497 (Ar C=C bending), and 1236 (Ar C-O-C) crtauT1.1 H NMR: (DMSO-d6, 200 MHz): delta 7.41 (d, 1 H J= 8.4), delta 7.34 (m, 1 H), delta 7.27 (m, 1 H), delta 7.34 (m, 1 H), delta 7.40 (d, 1 H J= 8.4), delta 5.3 (dd, 1 H J = 4.4, 8.0), delta 6.74 (d, 1 H J = 7.6), delta 6.97 (t, 1 H J = 7.6), 8 6.7.5 (t, 1 H J = 7.4), 8 7.11 (d, IH J = 7.2), delta 3.0 (m, 2H). EPO <DP n="25"/>13C NMR: (DMSO-d6, 200 MHz): delta 125.8, 128.5, 126.2, 128.5, 125.8, 140.8, 75.6, 155.0, 112.9, 127.7, 120.2, 130.4, 125.8, 34.1 , 45.1 , and 32.2. MS: m/z 242 (100%, M+1)EXAMPLE 11
With hydrogen;5% PdCl2 on carbon; In water; ethyl acetate; at 55 - 57℃; under 2206.72 - 2574.5 Torr; for 1h;
1200 liters of water were placed into a reactor along with 400 kg of N- Methyl-N-benzyl-2-benzoyl ethamine hydrochloride. 19.2 kg of 5% PdC^ on carbon was suspended in 40 liters of water and the solution was set aside. 1200 liters of ethyl acetate were added to the mixture containing water and N-Methyl-N- EPO <DP n="23"/>benzyl-2-benzoyl ethamine hydrochloride, followed by the addition of the above- prepared 5% PdCl2 suspension along with 50 liters of water under a nitrogen atmosphere. Hydrogen pressure of about 3.0 to 3.5 kg/cm2 was applied to the reaction mass at a temperature of about 55 to 570C. Hydrogen pressure was removed and the reaction mass was maintained for about 1 hour and than cooled to a temperature of about 35 to 370C under a nitrogen atmosphere of about 0.5 to 1.0 kg/cm2. The reaction mass was filtered through a leaf filter and transferred into another reactor, stirred for about 10 to 15 minutes and allowed to settle for about 20 to 30 minutes. The aqueous layer was separated and extracted with 400 liters of toluene by stirring the mixture and then allowing the layers to separate, then the aqueous layer was removed. 172 kg of a 45-50% by weight aqueous solution of sodium hydroxide were added to the organic layer and stirred for 15 to 20 minutes, the layers were allowed to settle, the aqueous layer was separated, and the sodium hydroxide treatment was repeated. The organic layer was transferred into a reactor and heated to a temperature of about 75 to 90 C, allowed to settle for about 15 to 30 minutes and the water was removed. The reaction mass was heated to reflux and the water removed from the reaction mass azeotropically under reflux below 1200C. The solvent was distilled completely under vacuum below 1000C for about 1 hour, and finally at a temperature of about 80 to 850C to produce the product. Melting Range: 50-600C.IR : 3067, 3030 (Ar- CH), 2965, 2946 (AIi -CH), 1483 (Ar C=C bending), and 1235 (Ar C-O-C) cm-1. 1H NMR: (DMSO-d6, 200 MHz): delta 7.39 (m, 1 H), delta 7.27 (m, 1 H), delta 7.22 (m, 1H), delta 7.25 (m, 1 H), delta 7.32 (m, 1 H J= 8.4), delta 4.94 (dd, 1 H) delta 1.8 (m, 2H), 2.8(m, 2H), delta . 2.4(s, 3H).13C NMR: (DMSO-d6, 200 MHz): delta 127, 127, 125.8, 125.8, 126.4, 71.7, 48.9, , 36.8, 36.0.MS: m/z 166 (100%, M+1).
N-(2-fluorophenylmethyl)-3-hydroxy-N-methyl-3-phenylpropylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
EXAMPLE 3 N-(2-fluorophenylmethyl)-3-hydroxy-N-methyl-3-phenylpropylamine A mixture of 3-hydroxy-N-methyl-3-phenylpropylamine (8.3 g, 50 mM), 2,2,6,6-tetramethylpiperidine (8.4 ml, 50 mM), o-fluorobenzyl chloride (7.25 g, 50 mM) and acetonitrile (100 ml) was stirred for 24 hours at ambient temperature. The resulting precipitate was removed by filtration, the precipitate washed with acetonitrile and the combined filtrate and washings evaporated under reduced pressure. The residue was partitioned between 2 N hydrochloric acid (100 ml) and ether (100 ml), the aqueous layer basified and extracted with ether (2*100 ml). The ether extract was dried and the solvent removed under reduced pressure to yield an oil (10.3 g). Distillation gave the title compound b.p. 160-2 C./0.6 mbar. Found: C, 74.4; H, 7.3; N, 5.4%; C17 H20 FNO requires: C, 74.7; H, 7.4; N, 5.1%.
N-[(5-Chloro-2-fluorophenyl)methyl]-N-methyl-3-hydroxy-3-phenylpropylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
A solution of 5-chloro-2-fluorobenzyl bromide (10.5 g) in acetonitrile (100 ml) was added dropwise to a mixture of N-methyl-3-hydroxy-3-phenylpropylamine (7.7 g), 2,2,6,6-tetramethylpiperidine (8 ml) and acetonitrile (100 ml). After 12h the mixture was filtered, and filtrate evaporated and the residue chromatographed on silica (Woelm Grade 1) using ether as eluant to give the title compound as an oil (10.5 g), b.p. 160/0.5 mm. (Found: C, 66.1; H, 6.2; N, 4.1%; C17 H19 ClFNO requires: C, 66.3; H, 6.2; N, 4.55%).
N-methyl-3-phenyl-3-(2-methylthiophenoxy)propylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With HCl (g); NaH; In water; dimethyl sulfoxide; ethyl acetate;
Step B A 1 L jacketed flask was charged with NaH (60 % oil dispersion, 31.7 g, 0.792 mol), potassium benzoate (13.0 g, 0.0809 mol), and DMSO (133.6 mL). To this vessel was added a solution N-methyl-3R-hydroxy-3-phenylpropylamine (133.6 g, 0.809 mol) in 133.6 mL DMSO over 45 minutes followed by a 66.8 mL DMSO rinse. The resulting mixture stirred for 10 minutes. To this vessel was added 2-fluorothioanisole (126.5 g, 0.890 mol) followed by an additional rinse with 66.8 mL of DMSO. The reaction mixture was heated to 65C and stirred for 18.8 hours. The reaction was then cooled to room temperature and added to a quench solution consisting of 0.9 L of H2O and 0.7 L EtOAc followed by an additional rinse with 0.23 L H2O and 0.18 L EtOAc. The layers were separated and the aqueous layer was extracted with 0.38 L EtOAc. The combined EtOAc layers were washed with 0.67 L each of H2O and saturated aqueous NaCl. The EtOAc layer was dried over Na2SO4and filtered. The Na2SO4was washed with 0.13 L EtOAc. The filtrate was cooled to approximately 0C and HCl (g) (29.52 g) was added. The thick slurry thus formed was stirred an additional 30 minutes and the crystals were collected by filtration, washed with 0.27 L of cold EtOAc, and placed in a vacuum oven at 35-40C. G (233.1 g) was recrystallized from EtOH (0.700 L) which provided 188.3 g of N-methyl3R-(2-methylthiophenoxy)-3-phenylpropylamine hydrochloride in 99.6 % ee. 1H NMR (CDCl3): delta 9.64 (br s, 2 H), 7.40-7.20 (m, 5H), 7.15-7.05 (m, 1H), 6.95-6.82 (m, 2H), 6.65-6.55 (m, 1H), 5.45 (dd, 1H), 3.32-3.18 (m, 2H), 2.66 (t, 3H), 2.56-2.42 (m, 5H). Calcd. for C17H22ClNOS:
Example 2; Preparation of N-Methyl-3-f2-methylphenoxyVbenzenepropanamine hydrochloride; A 100ml flask was flushed for 15 min with N2 and subsequently charged with 1O g (60.5 mmol) N-methyl-3-hydroxy-3-phenylpropylamine, 15,3 g (72 mmol) potassium phosphate and 1.14 g copper iodide (6.0 mmol, 10 mol-%). 40 ml of toluene followed by 7.7 ml (60 mmol) of 2-iodotoluene were added to the mixture and the suspension was heated to reflux for 20 h. After cooling to room temperature, the suspension was filtered and the residue was washed with 20 ml of toluene. 30 ml of water was added to the filtrate and the mixture was stirred for 15 min at room temperature. The phases were separated and 30 ml of water was added to the toluene phase. The aqueous phase was brought to pH 1 with 30 % HCl. The phases were stirred and separated. The aqueous phase was brought to pH 12 with aqueous NaOH followed by addition of 30 ml toluene. The mixture was heated to 50 C and the phases were separated. The toluene phase was evaporated giving 7.4 g of an oil. EPO <DP n="17"/>5,8 g of the residue was dissolved in 18ml of toluene, warmed to 80 0C and 11,1 g of 7.7 % HCl-ethyl acetate solution was added dropwise to the solution. After 15 min stirring at reflux temperature the solution was cooled to 0 0C with a rate of 10-15 C/h. The precipitate was collected and dried under reduced pressure at 40 C over night. Yield 5.0 g (17.1 mmol, 75 %).The crystals obtained in the before mentioned crystallization were combined with 17 ml of toluene and heated to reflux, causing all solids to dissolve. Upon cooling to room temperature, 4,3 g (86 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected after filtration and drying at about 50 C under reduced pressure.; Example 4; Preparation of N-Methyl-3 -(2-methylphenoxyVbenzenepropanamine hydrochloride; A 100 ml flask was flushed for 15 min with N2 and subsequently charged with 1O g (60.5 mmol) N-methyl-3-hydroxy-3-phenylpropylarnine, 15,3 g (72 mmol) potassium phosphate and 604 mg copper(I)chloride (6.0 mmol, 10 mol-%). 40 ml of toluene followed by 8.4 ml (66 mmol) of 2-iodotoluene was added to the mixture and the suspension was heated to reflux for 26 h. After cooling to room temperature, the suspension was filtered and the residue washed with 20 ml of toluene. 30 ml of water was added to the filtrate and the mixture was stirred for 15 min at room temperature. The phases were separated and 30 ml of water was added to the toluene phase. The aqueous phase was brought to pH 1 with 30 % HCl. The mixture was stirred and the phases were separated. The aqueous phase was brought to pH 12 with aqueous NaOH followed by addition of 30ml toluene. The mixture was heated to 50 C and the phases were separated. The toluene phase was evaporated giving 7.4 g of an oil.5,8 g of the residue was dissolved in 18ml of toluene, warmed to 80 0C and 11,1 g of 7.7 % HCl-ethyl acetate solution was added dropwise to the solution. After 15 min stirring at reflux temperature the solution was cooled to 0 C with a rate of 10-15 C/h. The precipitate was collected and dried under reduced pressure at 40 C over night. Yield 5.0 g (17.1 mmol, 75 %).The crystals obtained in the before mentioned crystallization were combined with 17 ml of toluene and heated to reflux, causing all solids to dissolve. Upon cooling to room EPO <DP n="19"/>temperature, 4,3 g (86 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected after filtration and drying at about 50 C under reduced pressure.
85%
Example 3; Preparation of N-Methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride; A 10 ml flask was subsequently filled with I g (6.1 mmol) N-methyl-3-hydroxy-3- phenylpropylamine, 2.6 g (12.2 mmol) potassium phosphate and 0.11 g copper iodide (0.6 mmol, 10 mol-%) under a flow of nitrogen. 15 ml of acetonitrile and 1.17 g 2- iodotoluene (9.2 mmol) were added to the mixture and the suspension was heated to reflux temperature. After heating for about 3O h the mixture was cooled to room temperature. The mixture was filtrated and the residue washed with 15 ml acetonitrile. The organic phase was evaporated and redissolved in 30 ml toluene. 15 ml water was added and the aqueous phase was brought to pH 1 with 30 % aq. HCl. The phases were separated and the aqueous phase was brought to pH 12 with aqueous KOH. 10 ml of toluene was added and the mixture was stirred for 15 min, after which the phases were separated. The combined toluene phases were evaporated giving 1.6 g of an oil.The oil was dissolved in 5 ml of toluene and heated to reflux temperature. 1,85 g of 12 %-HCl-ethyl acetate was added and the solution was cooled to room temperature. After filtration and drying of the residue under reduced pressure at 50 C 1.3 g EPO <DP n="18"/>(4.5 mmol, 71 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected.Recrystallization of the received solids from 4 ml of MEBK gave 1.1 g (85 %) of N- methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride after drying under reduced pressure at 50 C.
A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2-iodotoluene (0.59 g, 2.7 mmol), cupric sulfate (0.06 g), cesium carbonate (0.65 g, 2.0 mmol) and xylenes (0.5 mL) was stirred under nitrogen at 130-140 C. until reaction completion as determined by 1H NMR. The reaction mixture was cooled to room temperature and filtered, washed with toluene. The filtrate was washed with 5% aqueous ammonia solution and water. The organic layer was evaporated to dryness and the residue dissolved in ethyl acetate (5 mL). A 20% HCl solution in isopropanol (0.5 g) was added and the resulting suspension stirred at 0-5 C., filtered, and washed with more ethyl acetate to give 0.22 g of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride (Tomoxetine hydrochloride) as an off-white solid. 1H NMR spectrum of the product is identical to that of Example 5.
Example 7; A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2- iodotoluene (0.59 g, 2.7 mmol), cupric sulfate (0.06 g), cesium carbonate (0.65 g, 2.0 mmol) and xylenes (0.5 ml_) was stirred under nitrogen at 130- 1400C until reaction completion as determined by 1H NMR. The reaction mixture was cooled to room temperature and filtered, washed with toluene. The filtrate was washed with 5% aqueous ammonia solution and water. The organic layer was evaporated to dryness and the residue dissolved in ethyl acetate (5 ml_). A 20% HCI solution in isopropanol (0.5 g) was added and the resulting suspension stirred at 0-50C, filtered, and washed with more ethyl acetate to give 0.22 g of N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine hydrochloride (Tomoxetine hydrochloride) as an off- EPO <DP n="23"/>white solid. 1H NMR spectrum of the product is identical to that of Example 5.
(3R)-methyl-3-hydroxy-3-phenylpropylamine (S)-mandelate salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
In acetic acid methyl ester; at 50℃; for 0.5h;Product distribution / selectivity;
Preparation of (RVN-methyl-3-(2-memylphenoxyVbenzenepropanamine hydrochloride; A 3L vessel was charged with 165.2g N-methyl-3-hydroxy-3-phenylpropylamine and 68.5 g (S)-(+)-mandelic acid. 1240ml methyl acetate was added and the clear solution was heated to 50 C for 30 min. The mixture was then cooled to 10 C and stirred for 2 h at this temperature. Filtration of the suspension followed by drying under reduced pressure at 50 0C over night gave 108.7 g (76 %) of (3i?)-methyl-3-hydroxy-3- phenylpropylamine-(5)-mandelate salt with an enantiomeric excess of 94% as determined by chiral HPLC analysis.
75%
In ethyl acetate; at 50℃; for 0.5h;Product distribution / selectivity;
(3R)-methyl-3-hydroxy-3-phenylpropylamine-(S)-mandelate salt; :A 5L vessel was charged with 165,2 g N-methyl-3-hydroxy-3-phenylpropylamine and 68.5 g (S)-(+)-mandelic acid. 3300 ml ethyl acetate was added and the clear solution heated to 50 C for 30 min. The mixture was then slowly cooled to 20 C and stirred for 12 h at this temperature. Filtration of the suspension followed by drying under reduced pressure at 50 0C over night gave 107.5 g (75 %) of (3R)-methyl-3-hydroxy-3- phenylpropylamine-(S)-mandelate salt with an enantiomeric excess of 83 % as determined by chiral HPLC analysis. EPO <DP n="15"/>A 3L reaction vessel was charged with 105 g of the above-mentioned (3R)-methyl-3- hydroxy-3-phenylpropylamine-(S)-mandelate, 1340 ml of acetone and 420 ml of MTBE. The mixture was heated to 50 0C causing all solids to dissolve. Upon slow cooling to room temperature and continued stirring for 12 h, 82 g of (3R)-methyl-3-hydroxy-3- phenylpropylarnine-(S)-mandelate with an enantiomeric purity of 99.5% was obtained after drying at reduced pressure at about 50C over night.
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h;
Step 1. 3-Chloro-N-methyl-3-phenylpropan-1 -amine hydrochloride. (0306) To a solution of 3-(methylamino)-1 -phenylpropan-1 -ol (5 g, 30.3 mmol) in DCM (20 mL) at 0 C, thionyl chloride (2.46 mL, 33.3 mmol) in DCM (7 mL) was added. The solution was allowed to reach r.t. and stirred for 2 h. The solvent was removed under reduced pressure to give the title compound as white solid (6.67 g, quant, yield).
88%
With thionyl chloride; In dichloromethane; at 20℃; for 1.5 - 2.5h;
Stage a) - Activation of the hydroxyl; Preparation of a compound of formula III; EXAMPLE 1; N-methyl-3-pheny 1-3 -hydroxy-propylamine (10Og; O.betaOmoles) is loaded while being stirred at room temperature into methylene chloride (400ml), obtaining a solution. A solution Of SOCl2 (52.7ml; 0.73moles) is dripped in about 30 minutes <n="10"/>into methylene chloride (100ml), and the resulting liquid is stirred at room temperature for l-2h. The vacuum solvent is evaporated at 400C until a solid residue is attained. Acetone (400ml) is added; the suspension is left to stir for 30 minutes and the solvent is removed by vacuum evaporation. Acetone (500ml) is once again added; the suspension is reflux heated (56C) for Ih, then it is cooled to room temperature and left stirring for Ih. The solid is filtered, washing the panel with acetone (100ml) and it is dried in a 500C oven so to obtain the compound of formula XV (117.6g; 88% yield).
88%
With thionyl chloride; In dichloromethane; at 20℃;
Stage a)-Activation of the HydroxylPreparation of a Compound of Formula IIIExample 1 N-methyl-3-phenyl-3-hydroxy-propylamine (100 g; 0.60 moles) is loaded while being stirred at room temperature into methylene chloride (400 ml), obtaining a solution. A solution of SOCl2 (52.7 ml; 0.73 moles) is dripped in about 30 minutes into methylene chloride (100 ml), and the resulting liquid is stirred at room temperature for 1-2 h. The vacuum solvent is evaporated at 40 C. until a solid residue is attained. Acetone (400 ml) is added; the suspension is left to stir for 30 minutes and the solvent is removed by vacuum evaporation. Acetone (500 ml) is once again added; the suspension is reflux heated (56 C.) for 1 h, then it is cooled to room temperature and left stirring for 1 h. The solid is filtered, washing the panel with acetone (100 ml) and it is dried in a 50 C. oven so to obtain the compound of formula XV (117.6 g; 88% yield).
3-[2-(4-fluorophenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acrylic acid[ No CAS ]
(2E)-N-methyl-N-(3-hydroxy-3-phenylpropyl)-3-[1-methyl-2-(4-fluorophenyl)-1H-indol-3-yl]acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(2E)-3-[1-methyl-2-(4-fluorophenyl)-1H-indol-3-yl]acrylic acid (30 mg) was dissolved in dimethylformamide (3 ml) and PS(polystyrene)-carbodiimide (0.88 mmol/g, 174 mg) and 1-hydroxybenzotriazole (21 mg) were added, followed by stirring for 30 minutes. Then, alpha-[2-(methylamino)ethyl]benzyl alcohol (19 mg) was added and the mixture was stirred overnight. To the reaction solution was added PS-trisamine (4.50 mmol/g, 100 mg), followed by stirring for another one hour. The reaction solution was filtered and the filtrate was concentrated. The resulting residue was purified by LC-MS to obtain the objective product (29 mg). Positive ion ESI-MS m/z: 443[M+H]+
9,10-dihydro-9-oxoacridine-4-carbonyl chloride[ No CAS ]
[ 1250437-72-9 ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium carbonate; In N,N-dimethyl-formamide; for 0.2h;Microwave irradiation;
General procedure: 0.030 mole) appropriate N-methyl-3-phenyl-3-substitutedpropylamine 9, 18, 11 and 1.4g of anhydrous potassium carbonatein 50 ml of DMF was irradiated with MW at 350WMW intensity for 14 min. After completion of reaction, thework-up was done in a manner similar to the conventionalmethod.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
Example 15,5'-Diallyl-2'-[3-(methylamino)-1 -phenylpropoxy1biphenyl-2-ol hydrochloride; Triphenylphosphine (0.074 g, 0.281 mmol) was dissolved in dry toluene (1 .5 ml_) and the solution cooled down to 0 C. A solution of DEAD (~40% in toluene, 129 muIota_, 0.281 mmol) was added dropwise and the mixture was stirred for 5 min. a-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.037 g, 0.225 mmol), followed by the addition of magnolol (0.050 g, 0.187 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and washed with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (S1O2, EtOAc/MeOH 0- 20%). The desired compound was obtained as a yellow solid in 55% yield (0.046 g, 0.102 mmol). 1H NMR (400 MHz, CD3OD) 5 7.34 - 7.18 (m, 5H), 7.10 (dd, J = 8.2, 2.1 , 1 H), 7.01 - 6.87 (m, 4H), 6.72 (d, J = 8.4, 1 H), 6.10 - 5.80 (m, 2H), 5.40 (dd, J = 8.4, 3.9, 1 H), 5.06 (m, 4H), 3.37 (d, J = 6.7, 2H), 3.26 (d, J = 6.6, 2H), 3.13 - 2.93 (m, 2H), 2.56 (s, 3H), 2.20 - 2.01 (m, 2H).13C NMR (101 MHz, CD3OD) delta 154.10, 153.90, 141 .81 , 139.55, 139.13, 134.47, 132.96, 132.80, 132.77, 130.47, 130.14, 129.84, 129.49, 129.20, 128.16, 127.27, 1 16.99, 1 16.04, 1 15.95, 1 15.90, 80.05, 48.20, 40.51 , 40.40, 35.59, 33.99.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
Example 1 5,5'-Diallyl-2'-[3-(methylamino)-1-phenylpropoxy]biphenyl-2-ol hydrochloride Triphenylphosphine (0.074 g, 0.281 mmol) was dissolved in dry toluene (1.5 mL) and the solution cooled down to 0 C. A solution of DEAD (?40% in toluene, 129 muL, 0.281 mmol) was added dropwise and the mixture was stirred for 5 min. alpha-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.037 g, 0.225 mmol), followed by the addition of magnolol (0.050 g, 0.187 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and washed with 10% aqueous HCl (x3). The combined organic fractions were dried (MgSO4), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (SiO2, EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 55% yield (0.046 g, 0.102 mmol). 1H NMR (400 MHz, CD3OD) delta 7.34 - 7.18 (m, 5H), 7.10 (dd, J = 8.2, 2.1, 1H), 7.01 - 6.87 (m, 4H), 6.72 (d, J = 8.4, 1H), 6.10 - 5.80 (m, 2H), 5.40 (dd, J = 8.4, 3.9, 1H), 5.06 (m, 4H), 3.37 (d, J = 6.7, 2H), 3.26 (d, J = 6.6, 2H), 3.13 - 2.93 (m, 2H), 2.56 (s, 3H), 2.20 - 2.01 (m, 2H). 13C NMR (101 MHz, CD3OD) delta 154.10, 153.90, 141.81, 139.55, 139.13, 134.47, 132.96, 132.80, 132.77, 130.47, 130.14, 129.84, 129.49, 129.20, 128.16, 127.27, 116.99, 116.04, 115.95, 115.90, 80.05, 48.20, 40.51, 40.40, 35.59, 33.99.
Example 4 '-Diallyl-2'-[3-(methylamino)-1 -phenylpropoxy1biphenyl-4-ol hydrochloride; Triphenylphosphine (0.740 g, 2.81 mmol) was dissolved in dry toluene (15 mL) and the solution was cooled down to 0 C. A solution of DEAD (~40% in toluene, 1 .29 mL, 2.81 mmol) was added dropwise and the mixture was stirred for 5 min. a-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.372 g, 2.25 mmol), followed by the addition of honokiol (0.5 g, 1 .87 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and washed with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (S1O2, EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 5% yield (0.043 g, 0.095 mmol), and the product described in Example 8 was also isolated. 1H NMR (200 MHz, CDCI3) delta 7.42 - 6.76 (m, 10H), 6.54 (d, J = 8.4, 1 H), 6.20 - 5.74 (m, 2H), 5.23 - 4.92 (m, 5H), 3.46 (d, J = 6.7, 2H), 3.29 (d, J = 6.6, 2H), 3.06 - 2.10 (m, 7H). 13C NMR (101 MHz, CDCI3) delta 154.38, 152.43, 139.95, 137.56, 136.97, 133.52, 131 .49, 131.21 , 130.91 , 129.81 , 129.12, 128.67, 128.33, 128.05, 127.27, 125.77, 1 16.14, 1 15.90, 1 14.48, 79.83, 47.09, 39.48, 34.59, 34.40, 33.53.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;Product distribution / selectivity;
Example 5; mL) and the solution was cooled down to 0 C. A solution of DEAD (~40% in toluene, 1 .29 mL, 2.81 mmol) was added dropwise and the mixture was stirred for 5 min. a-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.372 g, 2.25 mmol), followed by the addition of honokiol (0.5 g, 1 .87 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and washed with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (S1O2, EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 12% yield (0.100 g, 0.265 mmol), and the product described in Example 6 was also isolated. 1H NMR (400 MHz, CDCI3) delta 7.34 - 7.16 (m, 7H), 7.07 (dd, J = 8.4, 2.1 , 1 H), 7.00 - 6.88 (m, 2H), 6.63 (d, J = 8.6, 1 H), 6.07 - 5.84 (m, 2H), 5.33 (s, 1 H), 5.13 - 4.94 (m, 4H), 3.45 (d, J = 6.3, 2H), 3.29 (d, J = 6.7, 2H), 3.01 (t, J = 7.3, 2H), 2.56 - 2.24 (m, 5H).13C NMR (101 MHz, CDCI3) 5 154.63, 151 .64, 140.38, 138.27, 137.26, 132.32, 131 .45, 130.77, 130.69, 129.41 , 129.34, 128.98, 128.58, 128.42, 128.13, 126.21 , 1 16.38, 1 16.32, 1 15.91 , 1 13.64, 77.87, 46.83, 39.85, 35.19, 35.13, 33.56, 21 .50, 14.65.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
B.5,5'-Diallyl-2-ethoxy-2'-[3-(methylamino)-1 -phenylpropoxy1biphenylhydrochloride; Triphenylphosphine (0.334 g, 1 .273 mmol) was dissolved in dry toluene (4 mL) and the solution cooled down to 0 C. A solution of DEAD (-40% in toluene, 590 mu, 1 .273 mmol) was added dropwise and the mixture was stirred for 15 min. a- [2-(Methylamino)ethyl]benzyl alcohol was then added (0.168 g, 1 .017 mmol), followed by the dropwise addition of a solution of 5,5'-diallyl-2'-ethoxybiphenyl- 2-ol (0.250 g, 0.849 mmol) in dry toluene (1 mL). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and extracted with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (S1O2, hexane/EtOAc 0-100% followed by EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 16% yield (0.062 g, 0.140 mmol). 1H NMR (400 MHz, CD3OD) delta 7.44 - 7.24 (m, 6H), 7.21 (dd, J = 8.3, 2.3 Hz, 1 H), 7.1 1 - 7.02 (m, 2H), 6.99 - 6.89 (m, 2H), 6.67 (d, J = 8.4 Hz, 1 H), 6.10 - 5.85 (m, 2H), 5.29 (dd, J = 7.7, 4.6 Hz, 1 H), 5.17 - 4.95 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H), 3.41 (d, J = 6.7 Hz, 2H), 3.28 (d, J = 6.7 Hz, 2H), 2.99 - 2.81 (m, 2H), 2.50 (s, 3H), 2.1 1 - 1 .99 (m, 2H), 1 .24 (t, J = 7.1 , 3H).13C NMR (101 MHz, CD3OD) delta 156.23, 154.14, 141 .80, 139.22, 139.09, 134.00, 133.95, 132.69, 132.57, 130.51 , 130.39, 129.95, 129.70, 129.44, 129.26, 129.09, 127.1 1 , 1 15.96, 1 15.80, 1 15.73, 1 15.05, 79.64, 66.26, 47.74, 40.39, 40.24, 35.45, 33.73, 15.36.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
Triphenylphosphine (0.334 g, 1.273 mmol) was dissolved in dry toluene (4 mL) and the solution cooled down to 0 C. A solution of DEAD (~40% in toluene, 590 muL, 1.273 mmol) was added dropwise and the mixture was stirred for 15 min. a-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.168 g, 1.017 mmol), followed by the dropwise addition of a solution of 5,5'-diallyl-2'-ethoxybiphenyl-2-ol (0.250 g, 0.849 mmol) in dry toluene (1 mL). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and extracted with 10% aqueous HCI (x3). The combined organic fractions were dried (MgSO4), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (SiO2, hexane/EtOAc 0-100% followed by EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 16% yield (0.062 g, 0.140 mmol). 1H NMR (400 MHz, CD3OD) delta 7.44 - 7.24 (m, 6H), 7.21 (dd, J = 8.3, 2.3 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.99 - 6.89 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 6.10 - 5.85 (m, 2H), 5.29 (dd, J = 7.7, 4.6 Hz, 1H), 5.17 - 4.95 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H), 3.41 (d, J = 6.7 Hz, 2H), 3.28 (d, J = 6.7 Hz, 2H), 2.99 - 2.81 (m, 2H), 2.50 (s, 3H), 2.11 - 1.99 (m, 2H), 1.24 (t, J = 7.1, 3H). 13C NMR (101 MHz, CD3OD) delta 156.23, 154.14, 141.80, 139.22, 139.09, 134.00, 133.95, 132.69, 132.57, 130.51, 130.39, 129.95, 129.70, 129.44, 129.26, 129.09, 127.11, 115.96, 115.80, 115.73, 115.05, 79.64, 66.26, 47.74, 40.39, 40.24, 35.45, 33.73, 15.36.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
B.5,5'-Diallyl-2-methoxy-2'-[3-(methylamino)-1 -phenylpropoxy1biphenyl hydrochloride; Triphenylphosphine (0.140 g, 0.535 mmol) was dissolved in dry toluene (3 mL) and the solution cooled down to 0 C. A solution of DEAD (-40% in toluene, 210 muIota_, 0.535 mmol) was added dropwise and the mixture was stirred for 5 min. a- [2-(Methylamino)ethyl]benzyl alcohol was then added (0.071 g, 0.428 mmol), followed by the addition of 5,5'-diallyl-2'-methoxybiphenyl-2-ol (0.100 g, 0.356 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and extracted with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (S1O2, hexane/EtOAc 0-100% followed by EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 14% yield (0.023 g, 0.048 mmol).1H NMR (400 MHz, CD3OD) delta 7.38 - 7.16 (m, 6H), 7.04 (dd, J = 15.1 , 5.2, 2H), 6.91 (d, J = 9.7, 2H), 6.66 (d, J = 8.1 , 1 H), 6.10 - 5.80 (m, 2H), 5.30 (dd, J = 7.8, 4.6, 1 H), 5.18 - 4.92 (m, 4H), 3.79 (s, 3H), 3.40 (d, J = 6.7, 2H), 3.27 (d, J = 6.6, 2H), 2.89 (dd, J = 1 1 .9, 7.0, 2H), 2.48 (s, 3H), 2.17 - 2.01 (m, 2H).13C NMR (101 MHz, CD3OD) delta 157.16, 154.30, 141 .98, 139.39, 139.21 , 134.15, 134.13, 133.78, 132.73, 132.60, 130.42, 130.1 1 , 129.88, 129.39, 129.21 , 127.20, 1 16.08, 1 15.89, 1 15.66, 1 12.95, 79.46, 56.78, 47.84, 40.49, 40.40, 35.69, 33.89.
With triphenylphosphine; diethylazodicarboxylate; at 0 - 80℃; for 17h;Product distribution / selectivity;
Triphenylphosphine (0.140 g, 0.535 mmol) was dissolved in dry toluene (3 mL) and the solution cooled down to 0 C. A solution of DEAD (?40% in toluene, 210 muL, 0.535 mmol) was added dropwise and the mixture was stirred for 5 min. alpha-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.071 g, 0.428 mmol), followed by the addition of 5,5'-diallyl-2'-methoxybiphenyl-2-ol (0.100 g, 0.356 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and extracted with 10% aqueous HCl (x3). The combined organic fractions were dried (MgSO4), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (SiO2, hexane/EtOAc 0-100% followed by EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 14% yield (0.023 g, 0.048 mmol). 1H NMR (400 MHz, CD3OD) delta 7.38 - 7.16 (m, 6H), 7.04 (dd, J = 15.1, 5.2, 2H), 6.91 (d, J = 9.7, 2H), 6.66 (d, J = 8.1, 1H), 6.10 - 5.80 (m, 2H), 5.30 (dd, J = 7.8, 4.6, 1H), 5.18 - 4.92 (m, 4H), 3.79 (s, 3H), 3.40 (d, J = 6.7, 2H), 3.27 (d, J = 6.6, 2H), 2.89 (dd, J = 11.9, 7.0, 2H), 2.48 (s, 3H), 2.17 - 2.01 (m, 2H). 13C NMR (101 MHz, CD3OD) delta 157.16, 154.30, 141.98, 139.39, 139.21, 134.15, 134.13, 133.78, 132.73, 132.60, 130.42, 130.11, 129.88, 129.39, 129.21, 127.20, 116.08, 115.89, 115.66, 112.95, 79.46, 56.78, 47.84, 40.49, 40.40, 35.69, 33.89.
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 0 - 80℃; for 17h;
Example 4 3,5'-Diallyl-2'-[3-(methylamino)-1-phenylpropoxy]biphenyl-4-ol hydrochloride Triphenylphosphine (0.740 g, 2.81 mmol) was dissolved in dry toluene (15 mL) and the solution was cooled down to 0 C. A solution of DEAD (~40% in toluene, 1.29 mL, 2.81 mmol) was added dropwise and the mixture was stirred for 5 min. a-[2-(Methylamino)ethyl]benzyl alcohol was then added (0.372 g, 2.25 mmol), followed by the addition of honokiol (0.5 g, 1.87 mmol). The solution was stirred at 0 C for 1 h and at 80 C for 16 h. The crude mixture was diluted with EtOAc and washed with 10% aqueous HCI (x3). The combined organic fractions were dried (MgS04), filtered, and evaporated to dryness. The resulting syrup was purified by column chromatography (SiO2, EtOAc/MeOH 0-20%). The desired compound was obtained as a yellow solid in 5% yield (0.043 g, 0.095 mmol), and the product described in Example 8 was also isolated. 1H NMR (200 MHz, CDCl3) delta 7.42-6.76 (m, 10H), 6.54 (d, J = 8.4, 1H), 6.20 - 5.74 (m, 2H), 5.23 - 4.92 (m, 5H), 3.46 (d, J = 6.7, 2H), 3.29 (d, J = 6.6, 2H), 3.06 - 2.10 (m, 7H). 13C NMR (101 MHz, CDCl3) delta 154.38, 152.43, 139.95, 137.56, 136.97, 133.52, 131.49, 131.21, 130.91, 129.81, 129.12, 128.67, 128.33, 128.05, 127.27, 125.77, 116.14, 115.90, 114.48, 79.83, 47.09, 39.48, 34.59, 34.40, 33.53.
1,3-bis(3-methyl-6-phenyl-1,3-oxazinan-2-yl)propane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
In ethyl acetate; at 10 - 20℃;Inert atmosphere;
A three neck 50 mL round bottom flask equipped with a stir bar, thermocouple, addition funnel capped with nitrogen inlet and condenser is charged with 3-(methylamino)-l- phenylpropan-l-ol (100%, 8.26 g, 0.05 mols, 2.0 equivalents) and dissolved in 15 mL of ethylacetate. The flask is cooled to approximately 10 C under ice/water bath. Once the temperature is reached, glutaraldehyde (50%, 5.0 g, 0.025 mols, 1.0 equivalents) is added drop wise over a period of 5-10 minutes. The reaction temperature is maintained by cooling the bath and by controlled addition of glutaraldehyde. After complete addition of glutaraldehyde, the reaction can still be stirred. However, as the reaction mixture warms to room temperature the reaction mixture becomes opaque and solids start forming. The reaction is stopped and the solid filtered through a Buchner funnel and washed thoroughly with pentane. The white powder is dried under vacuum for 1 h. This process results in 1.5 g of white solid (8% yield). The material does not elute in the GC and therefore is characterized by LC-MS. The LC-MS analysis confirms the presence of (1) l,3-bis(3-methyl-6-phenyl-l,3- oxazinan-2-yl)propane and CI-LC/MS shows [M+H] = 395.
With triethylamine; In tetrahydrofuran; ethyl acetate;
- METHOD B: tert-Butyl 3-hydroxy-3-phenylpropyl(methyl)carbamate 3-(Methylamino)-1-phenylpropan-1-ol (5.0 g, 30.3 mmol) was dissolved in 80 mL of THF and cooled to 0 C. Et3N (5.0 mL, 36.4 mmol) and Boc2O (7.3 g, 33.3 mmol) were successively added and the mixture was stirred at room temperature for 20 h. Then, the reaction mixture was diluted in EtOAc and successively washed with sat. aq. NH4Cl solution (3x) and brine (3x). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to afford 7.9 g (29.78 mmol, 98% yield) of a colorless oil identified by 1H-NMR as tert-butyl 3-hydroxy-3-phenylpropyl(methyl)carbamate which was used in the next step without further purification.
A 500 mL three-necked flask was charged with Compound I (50.0 g, 0.3 mol)Dimethyl sulfoxide (AR, 250 mL),Potassium hydroxide (84.9 g, 1.5 mol),Heated and stirred,Temperature control 110 stirring 1h,Compound II(99.9 g, 0.9 mol) was added dropwise to the reaction system,Continue to control temperature 110 reaction, TLC monitoring reaction was complete, stop the reaction. reaction The system was cooled to room temperature, the reaction system was added ethyl acetate 500mL and water 500ml,Stir well and let stand to separate the organic phase,1L washed the organic phase twice,The organic phase is dried over anhydrous sodium sulphate,Suction filtration,Collect filtrate to 3L single-mouth bottle,1150 mL of an ethyl acetate solution of oxalic acid (38.1 g, 0.3 mol)Filter cake was collected by suction filtration,40 blasting to give white-like solid 88.5g,The solid was dissolved in 885 ml of ethanol,Heated to reflux 1h,Cooled to room temperature and suction filtered,The filter cake was dried by air at 40 C to obtain a qualified product 80.3g, yield 76.8%.
76.8%
Compound I (50.0 g, 0.3 mol) was sequentially added to a 500 mL three-necked flask. Dimethyl sulfoxide (AR, 250 mL) and potassium hydroxide (84.9 g, 1.5 mol) were added, heated and stirred at 120 C for 1 h. Compound II (99.9 g, 0.9 mol) was added dropwise to the reaction system, temperature of the reaction was controlled to 120C, the reaction was monitored by TLC and the reaction was stopped. The reaction system was cooled to room temperature. 500 mL of ethyl acetate and 500 ml of water were added to the reaction system, stirred well and the organic phase was separated and allowed to stand. The organic phase was washed twice with 1L. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected in a 3L single-mouth bottle. 1150 mL of oxalic acid (38.1 g, 0.3 mol) in ethyl acetate was added, the filter cake was collected by suction filtration and dried at 40C to obtain 88.5 g of an off-white solid. The solid was dissolved in 885 ml of ethanol, refluxed for 1 h, the temperature was dropped to room temperature and suction-filtered. The filter cake was dried by blasting at 40 C to obtain 80.3 g of qualified product, and the yield was 76.8%.
430 g
To a stirred solution of potassium hydroxide (254.6gm) in toluene (1000ml), dimethyl sulphoxide ( 1750ml) and 3-methylamino- l -phenyl- 1 -propanol (250gm) were added at ambient temperature followed by addition of 2-fluoro toluene (499.75gm) into the reaction mass. The reaction mass was heated up to the temperature at 126-128C for 8-9 hours with azeotropic distillation to remove water, cooled to ambient temperature and water ( 1750ml) was added into it. The reaction mass'was stirred and the layers were separated. The aqueous layer extracted with toluene and washed with water. The organic layers were combined. To a stirred organic layer, oxalic acid solution {oxal ic acid.2H20 (195gm) + isopropylalcohol (750ml)} was added and further stirred for 1 hour. The reaction mass was then filtered at ambient temperature and washed with toluene (2 x 250ml) followed by washing with isopropyl alcohol (2 x 250ml). The product was suck dried and further dried in vacuuo at 65-70C for 2-3 hours to give 425-430 gm of title compound.HPLC purity: >99%Isomeric impurity:N-Methyl-3-phenyl-3-(w-tolyloxy)propan-l -amine oxalate 0.5-1.0%,N-MethyI-3-phenyl-3-(p-tolyloxy)propan- 1 -amine oxalate 1 .0-2.0%.
5-(ethoxymethylene)thiazolidine-2,4-dione[ No CAS ]
(Z)-5-(((3-hydroxy-3-phenylpropyl)(methyl)amino)methylene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: To a suspension of 1 (100 mg, 0.58 mmol) in acetonitrileand triethylamine was added 2 amines 2.14-2.19(0.5 mmol) in one lot. The reaction mixture was stirred at room temperature for 15-20 min, and the completion of thereaction was monitored by TLC. The precipitated solidswere filtered under vacuum and dried to obtain the purecompounds (3.14-3.29) in quantitative yields.
3-[4-[2-(tert-butyldimethylsilyloxy)ethyl]phenoxy]-N-methyl-3-phenylpropan-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.03 g
With triphenylphosphine; diethylazodicarboxylate; In toluene; at 20℃; for 40h;
3-[4-[2-(tert-Butyldimethylsilyloxy)ethyl]phenoxy]-N-methyl-3-phenylpropan-1-amine (0284) (0285) Triphenylphosphine (3.0 g, 11.4 mmol), 4-[2-(tert-butyldimethylsilyloxy)ethyl]phenol (2.40 g, 9.52 mmol) and 3-(methylamino)-1-phenylpropan-1-ol (1.88 g, 11.40 mmol) were dissolved in toluene (55 mL). A solution of DEAD (40% in toluene, 5.2 mL, 11.4 mmol) was added dropwise at room temperature and the mixture was stirred for 16 h. Then, additional triphenylphosphine (1.5 g, 5.7 mmol) and DEAD (40% in toluene, 2.6 mL, 5.7 mmol) were consecutively added and the mixture was stirred for additional 8 h. A third addition of triphenylphosphine (0.75 g, 2.9 mmol) and DEAD (40% in toluene, 1.3 mL, 2.9 mmol) was performed and the mixture was stirred for additional 16 h. The crude was then evaporated to dryness under vacuum and purified by flash chromatography (SiO2, from 100% EtOAc to 25% MeOH in EtOAc) to afford 2.03 g of a pale yellow oil. 1H-NMR analysis allowed the identification of 3-[4-[2-(tert-butyldimethylsilyloxy)ethyl]phenoxy]-N-methyl-3-phenylpropan-1-amine despite the presence of some minor impurities. (0286) 1H NMR (400 MHz, CD3OD) delta 7.38-7.19 (m, 5H), 6.99 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.77 (ddd, J=8.8, 3.0, 1.8 Hz, 2H), 5.27 (dd, J=8.1, 4.8 Hz, 1H), 3.72 (t, J=7.1 Hz, 2H), 2.79-2.61 (m, 5H), 2.36 (s, 3H), 2.21-2.10 (m, 1H), 2.06-1.95 (m, 1H), 0.82 (s, 9H), -0.10 (s, 3H), -0.12 (s, 3H).
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