2-Methyl-1-phenylpropan-2-amine (Phentermine) by Asch

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54 reactions in Reaxys

2018-06-23 10h:17m:01s (UTC)

H 2N

1. Query

Search as: Product, As drawn, No mixtures ))

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OH H 2N

H 2N

Rx-ID: 393643 View in Reaxys 1/54 Yield

Conditions & References

41 %

1 : Synthesis of 1e P (677 mg, 22 mmol) was slowly added to the solution of ld (1.5 g, 9.1 mmol) in HI (22 mE 45percent in water) at room temperature. The mixture was stirred at 135° C. overnight, and then cooled to room temperature. Water (100 mE) was added to the above mixture, which was filtered. Saturated aqueous Na25203 solution (100 mE) was added to the filtrate and was made basic with 40percent NaOH (20 mE). The resulting mixture was extracted with ethyl acetate (100 mEx3). The combined ethyl acetate layer was washed with water and dried over anhydrous Na2504 and evaporated. The residue was purified by silica column chromatography (DCM: MeOH30:1, v:v) to provide R’ (0.55 g, 41percent yield). With phosphorus, hydrogen iodide in water, T= 135 °C Patent; HELSINN HEALTHCARE SA; Giuliano, Claudio; Daina, Antoine; Pietra, Claudio; (254 pag.); US2017/275301; (2017); (A1) English View in Reaxys With phosphorus, hydrogen iodide Zenitz; Macks; Moore; Journal of the American Chemical Society; vol. 70; (1948); p. 955 View in Reaxys

H N

H 2N

Rx-ID: 8622327 View in Reaxys 2/54 Yield

Conditions & References With acetic acid, thiourea in ethanol, Time= 10h, Heating, Substitution Jirgensons; Kauss; Kalvinsh; Gold; Synthesis; nb. 12; (2000); p. 1709 - 1712 View in Reaxys 5.D :A mixture of the chloroacetamide from Step C above (12.2 g, 54.2 mmol), thiourea (2.7 g, 65 mmol) and acetic acid (10.6 mL, 0.325 mol) in absolute ethanol (60 mL) was heated to reflux to 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2*75 mL). The combined organic fractions were washed with brine (5*50 mL), dried over MgSO4 and evaporated in vacuo. Distillation under high vacuum provided the free amine (bp 125° C.at;6 Torr). This crude material was dissolved in Et&2O

and 4 mL of 4N HCl in 1,4-dioxane was added.

Filtration of the white precipitate provided the desired compound as its hydrochloric acid salt. With acetic acid, thiourea in ethanol, Time= 16h, Heating / reflux Patent; Andersen, Denise Lyn; Chang, Catherine H.; Falsey, James R.; Frohn, Michael J.; Hong, Fang-Tsao; Liao, Hongyu; Liu, Longbin; Lopez, Patricia; Retz, Daniel Martin; Rishton, Gilbert M.; Rzasa, Robert M.; Siegmund, Aaron; Tadesse, Seifu; Tamayo, Nuria; Tegley, Christopher M.; US2006/69110; (2006); (A1) English View in Reaxys With acetic acid, thiourea in ethanol, Time= 10h, T= 80 °C Yuan, Ming; Chen, Li; Wang, Junwei; Chen, Shenjie; Wang, Kongchao; Xue, Yongbo; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui; Organic Letters; vol. 17; nb. 2; (2015); p. 346 - 349 View in Reaxys 0.567 g

With acetic acid, thiourea in ethanol, Time= 10h, Reflux

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Mancinelli, Andrea; Alamillo, Carla; Albert, Joan; Ariza, Xavier; Etxabe, Haizea; Farràs, Jaume; Garcia, Jordi; Granell, Jaume; Quijada, F. Javier; Organometallics; vol. 36; nb. 4; (2017); p. 911 - 919 View in Reaxys

H 2N

Rx-ID: 15714823 View in Reaxys 3/54 Yield

Conditions & References Reaction Steps: 2 1: 78 percent / AcOH; H2SO4 / 5 h / 20 °C 2: thiourea; AcOH / ethanol / 10 h / Heating With sulfuric acid, acetic acid, thiourea in ethanol, 1: Ritter reaction / 2: Substitution Jirgensons; Kauss; Kalvinsh; Gold; Synthesis; nb. 12; (2000); p. 1709 - 1712 View in Reaxys Reaction Steps: 3 1: 79 percent / H2SO4, AcOH / Ambient temperature; The reagents were added at 0 gradC, then stirring overnight at room temperature. 2: 1. 20percent NaOH, 2. HCl gas / 1.220 gradC, 24h; 3: by neutralization With hydrogenchloride, sodium hydroxide, sulfuric acid, acetic acid Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys Reaction Steps: 2 1: 15.2 g / H2SO4 / acetic acid / 12 h / Ambient temperature 2: aq. KOH / 24 h / 200 °C With potassium hydroxide, sulfuric acid in acetic acid Timberlake, Jack W.; Alender, Jeff; Garner, Archie W.; Hodges, Melvin L.; Oezmeral, Cenan; et al.; Journal of Organic Chemistry; vol. 46; nb. 10; (1981); p. 2082 - 2089 View in Reaxys Reaction Steps: 2 1: acetic acid; sulfuric acid 2: aq. NaOH solution With sodium hydroxide, sulfuric acid, acetic acid Ritter; Kalish; Journal of the American Chemical Society; vol. 70; (1948); p. 4048; Organic Syntheses; vol. 44; (1964); p. 44,45 View in Reaxys Reaction Steps: 2 1.1: sulfuric acid; acetic acid / 20 - 65 °C 1.2: pH > 11 2.1: potassium hydroxide / ethylene glycol / 8 h / Reflux With sulfuric acid, acetic acid, potassium hydroxide in ethylene glycol Patent; Pathway Therapeutics Inc.; US2012/252802; (2012); (A1) English View in Reaxys Reaction Steps: 2 1: trifluoroacetic acid / 9 h / 50 °C 2: thiourea; acetic acid / ethanol / 10 h / 80 °C With acetic acid, thiourea, trifluoroacetic acid in ethanol Yuan, Ming; Chen, Li; Wang, Junwei; Chen, Shenjie; Wang, Kongchao; Xue, Yongbo; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui; Organic Letters; vol. 17; nb. 2; (2015); p. 346 - 349

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View in Reaxys Reaction Steps: 2 1: sulfuric acid; acetic acid / 0 - 20 °C 2: acetic acid; thiourea / ethanol / 10 h / Reflux With sulfuric acid, acetic acid, thiourea in ethanol, 1: |Ritter Amidation Mancinelli, Andrea; Alamillo, Carla; Albert, Joan; Ariza, Xavier; Etxabe, Haizea; Farràs, Jaume; Garcia, Jordi; Granell, Jaume; Quijada, F. Javier; Organometallics; vol. 36; nb. 4; (2017); p. 911 - 919 View in Reaxys

H 2N

Rx-ID: 46359128 View in Reaxys 4/54 Yield

Conditions & References Reaction Steps: 3 1: sodium methylate / methanol / 20 °C 2: zinc; hydrogenchloride / ethanol; water / 4 h / 70 °C 3: hydrogen iodide; phosphorus / water / 135 °C With hydrogenchloride, phosphorus, hydrogen iodide, sodium methylate, zinc in methanol, ethanol, water Patent; HELSINN HEALTHCARE SA; Giuliano, Claudio; Daina, Antoine; Pietra, Claudio; (254 pag.); US2017/275301; (2017); (A1) English View in Reaxys HO

H 2N

N O

Rx-ID: 46359182 View in Reaxys 5/54 Yield

Conditions & References Reaction Steps: 2 1: zinc; hydrogenchloride / ethanol; water / 4 h / 70 °C 2: hydrogen iodide; phosphorus / water / 135 °C With hydrogenchloride, phosphorus, hydrogen iodide, zinc in ethanol, water Patent; HELSINN HEALTHCARE SA; Giuliano, Claudio; Daina, Antoine; Pietra, Claudio; (254 pag.); US2017/275301; (2017); (A1) English View in Reaxys

H 2N

Rx-ID: 39305530 View in Reaxys 6/54 Yield

Conditions & References Reaction Steps: 4 1: sulfuric acid / 50 °C 2: tetrahydrofuran / 2 h / 0 - 25 °C 3: trifluoroacetic acid / 9 h / 50 °C 4: thiourea; acetic acid / ethanol / 10 h / 80 °C With sulfuric acid, acetic acid, thiourea, trifluoroacetic acid in tetrahydrofuran, ethanol Yuan, Ming; Chen, Li; Wang, Junwei; Chen, Shenjie; Wang, Kongchao; Xue, Yongbo; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui; Organic Letters; vol. 17; nb. 2; (2015); p. 346 - 349 View in Reaxys

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H 2N

Rx-ID: 39305535 View in Reaxys 7/54 Yield

Conditions & References Reaction Steps: 3 1: tetrahydrofuran / 2 h / 0 - 25 °C 2: trifluoroacetic acid / 9 h / 50 °C 3: thiourea; acetic acid / ethanol / 10 h / 80 °C With acetic acid, thiourea, trifluoroacetic acid in tetrahydrofuran, ethanol Yuan, Ming; Chen, Li; Wang, Junwei; Chen, Shenjie; Wang, Kongchao; Xue, Yongbo; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui; Organic Letters; vol. 17; nb. 2; (2015); p. 346 - 349 View in Reaxys 2

Na +

O–

H 2N

OH OH

O–

H O

H 2N

OH HO

Rx-ID: 28025768 View in Reaxys 8/54 Yield 94.2 %

Conditions & References 1 : Example 1 Preparation of Phentermine Pamoate Phentermine HCl (37.3 g) was suspended in USP H2O (700.0 g) and stirred to achieve a solution (0.05 g/g) and a pH 5.3. The solution was transferred to a metered addition funnel. A solution of disodium pamoate (45.0 g) was prepared by dissolving in USP water (902.0 g) to give a clear solution at a pH 10.4. The solution was adjusted to about pH 9.4 with 0.2N HCl and clarified by solution filtration. At 20° C., the Phentermine HCl solution was added to the stirred disodium pamoate solution at a controlled rate over about 2.5 hours and the addition funnel rinsed with USP H2O (20.0 g) into the reaction mixture. The mixture was stirred for 1 h then warmed to 70° C. where more precipitation was observed. The mixture was heated from about 70° C. to 95° C. over about 1 h then cooled. Solids were collected by filtration and washed with USP H2O (3×200 g) and dried on a vacuum Büchner for about 3 h. The solids collected (83.5 g) were transferred to a drying oven (50-55° C., vacuum/N2 sweep) and dried about 48 h to give Phentermine Pamoate (64.7 g, 94.2percent). The pamoate was characterized by DSC (FIG. 1), FTIR (FIG. 4) and PXRD (FIG. 7). With hydrogenchloride in water, Time= 4.5h, T= 20 - 95 °C Patent; King, Clifford Riley; Bristol, David W.; English, Michael L.; US2014/178480; (2014); (A1) English View in Reaxys

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H N

H 2N

Rx-ID: 2086324 View in Reaxys 9/54 Yield 66 %

Conditions & References With potassium hydroxide in water, Time= 24h, T= 220 °C Wannagat, U.; Damrath, V.; Harder, U.; Monatshefte fuer Chemie; vol. 125; nb. 11; (1994); p. 1159 - 1170 View in Reaxys With potassium hydroxide, Time= 24h, T= 200 °C Timberlake, Jack W.; Alender, Jeff; Garner, Archie W.; Hodges, Melvin L.; Oezmeral, Cenan; et al.; Journal of Organic Chemistry; vol. 46; nb. 10; (1981); p. 2082 - 2089 View in Reaxys Reaction Steps: 2 1: 1. 20percent NaOH, 2. HCl gas / 1.220 gradC, 24h; 2: by neutralization With hydrogenchloride, sodium hydroxide Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys With potassium hydroxide in ethylene glycol, Reflux Hoenke, Christoph; Bouyssou, Thierry; Tautermann, Christofer S.; Rudolf, Klaus; Schnapp, Andreas; Konetzki, Ingo; Bioorganic and Medicinal Chemistry Letters; vol. 19; nb. 23; (2009); p. 6640 - 6644 View in Reaxys 13 :To a mixture of 2-methyl-1-phenyl-2-propanol (1.5 g, 10 mmol) and acetonitrile (3 mL) in acetic acid (15 mL) was added concentrated sulfuric acid (3 mL) dropwise at room temperature. The mixture was stirred at 65° C. for 3 hours and then poured into ice-water (ca. 200 mL). The aqueous solution was basified with saturated aqueous sodium hydroxide until pH>11. The suspension was stirred for further 0.5 hour, and then the precipitated solid was filtered and washed with water. The white solid was air-dried to give N-(2-methyl-1-phenylpropan-2-yl)acetamide (1.5 g, 78percent yield), which was used for the next step without further purification.A mixture of N-(2-methyl-1-phenylpropan-2-yl)acetamide (191 mg, 1.00 mmol) and potassium hydroxide (1 g) in ethylene glycol (10 mL) was refluxed for 8 hours. The mixture was diluted with ice-water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 2-methyl-1-phenylpropan-amine (200 mg) as a brown oil, which was used for the next step without further purification.Compound A14 was synthesized according to the procedure for compound A22, substituting the crude 2-methyl-1-phenylpropan-amine in place of 1-(4-fluorophenyl)-2-methylpropan-2-amine. The product was purified by preparative HPLC to give compound A14 (30 mg, 13percent yield for 2 steps) as a white solid: 96.4percent purity (HPLC); MS m/z: 480.3 (M+1); 1H NMR (CDCl3, 500 MHz) δ 8.39 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.65 (t, JHF=54.0 Hz, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.16-7.10 (m, 2H), 5.15 (s, 1H), 4.01-3.75 (m, 8H), 3.22 (s, 2H), 1.49 (s, 6H) ppm. Stage 1: With potassium hydroxide in ethylene glycol, Time= 8h, Reflux Stage 2: With water Patent; Pathway Therapeutics Inc.; US2012/252802; (2012); (A1) English View in Reaxys

H 2N

O N O

Rx-ID: 2086949 View in Reaxys 10/54 Yield 98 %

Conditions & References With 10% palladium on activated charcoal, hydrogen in methanol, Time= 24h, T= 40 °C

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Gildner, Peter G.; Gietter, Amber A. S.; Cui, Di; Watson, Donald A.; Journal of the American Chemical Society; vol. 134; nb. 24; (2012); p. 9942 - 9945 View in Reaxys 79 %

With phosphate buffer, potassium chloride in ethanol, T= 30 °C , cotrolled potential electrolysis, cathod: Hg, vs. SCE Ohmori, Hidenobu; Furusako, Shoji; Kashu, Mieko; Ueda, Chihiro; Masui, Masaichiro; Chemical & Pharmaceutical Bulletin; vol. 32; nb. 9; (1984); p. 3345 - 3353 View in Reaxys Reaction Steps: 2 1: 98 percent / citrate buffer (pH 4.2), KCl / ethanol / 30 °C / cotrolled potential electrolysis, cathod: Hg, vs. S.C.E. 2: 57 percent / citrate buffer (pH 4.0), KCl / ethanol / 30 °C / cotrolled potential electrolysis, cathod: Hg, vs. SCE With citrate buffer, potassium chloride in ethanol Ohmori, Hidenobu; Furusako, Shoji; Kashu, Mieko; Ueda, Chihiro; Masui, Masaichiro; Chemical & Pharmaceutical Bulletin; vol. 32; nb. 9; (1984); p. 3345 - 3353 View in Reaxys

H 2N

Rx-ID: 33530902 View in Reaxys 11/54 Yield

Conditions & References Reaction Steps: 2 1: 2-(2,6-dimethylphenyl)amine-4-(2,6-dimethylphenyl)imine-2-pentene; copper(I) bromide; sodium t-butanolate / cyclohexane / 48 h / 60 °C / Inert atmosphere 2: 10% palladium on activated charcoal; hydrogen / methanol / 24 h / 40 °C With 2-(2,6-dimethylphenyl)amine-4-(2,6-dimethylphenyl)imine-2-pentene, 10% palladium on activated charcoal, hydrogen, copper(I) bromide, sodium t-butanolate in methanol, cyclohexane Gildner, Peter G.; Gietter, Amber A. S.; Cui, Di; Watson, Donald A.; Journal of the American Chemical Society; vol. 134; nb. 24; (2012); p. 9942 - 9945 View in Reaxys

H 2N Cl

Rx-ID: 29555741 View in Reaxys 12/54 Yield

Conditions & References 75 :Intermediate 75; 2-Methyl-1 -phenyl-2-propanamine; DPPA (16.87 g, 61.31 mmol) was added with external cooling to a stirred solution of 2,2- dimethyl-3-phenylpropanoic acid (10.21 g, 57.30 mmol) and triethylamine (6.20 g, 61.3 mmol) in dry toluene (100 ml_). A slightly exothermic reaction commenced and was completed after about 1 hour. The reaction mixture was stirred for an additional 1 hour at room temperature, followed by refluxing for 3 hours. The solution was cooled and washed with water (3 X 100 ml_), and the toluene phase was separated, dried over Na2SO4, and evaporated in vacuum. A mixture of 15percent hydrochloric acid (20 ml.) and acetic acid (20 ml.) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (4 X 50 ml_), and the aqueous was concentrated in vacuum to afford the HCI salt of the title compound (5.21 g) as a white solid. LC-MS (ES) m/z = 150 [M+H]+. Stage 1: With diphenyl phosphoryl azide, triethylamine in toluene, Time= 5h, Reflux, Cooling Stage 2: With hydrogenchloride, acetic acid in water, T= 20 °C Patent; GLAXOSMITHKLINE LLC; AXTEN, Jeffrey, Michael; BLACKLEDGE, Charles, William; BRADY, Gerald, Patrick; FENG, Yanhoug, G.; GRANT, Seth, W.; MEDINA, Jesus, Rahul; MILLER, William, H.; ROMERIL, Stuart, P.; WO2010/59658; (2010); (A1) English View in Reaxys

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DPPA (16.87 g, 61.31 mmol) was added with external cooling to a stirred solution of 2,2- dimethyl-3-phenylpropanoic acid (10.21 g, 57.30 mmol) and triethylamine (6.20 g, 61.3 mmol) in dry toluene (100 ml_). A slightly exothermic reaction commenced and was completed after about 1 hour. The reaction mixture was stirred for an additional 1 hour at room temperature, followed by refluxing for 3 hours. The solution was cooled and washed with water (3 X 100 ml_), and the toluene phase was separated, dried over Na2SO4, and evaporated in vacuum. A mixture of 15percent hydrochloric acid (20 ml.) and acetic acid (20 ml.) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted withEtOAc (4 X 50 ml_), and the aqueous was concentrated in vacuum to afford the HCI salt of the title compound (5.21 g) as a white solid. LC-MS (ES) m/z = 150 [M+H]+. Stage 1: With diphenylphosphoranyl azide, triethylamine in toluene, T= 20 °C , Reflux Stage 2: With hydrogenchloride, water, acetic acid, T= 20 °C Patent; GLAXOSMITHKLINE LLC; AXTEN, Jeffrey, Michael; BRADY, Gerald, Patrick, Jr.; GALLAGHER, Timothy, Francis; HEERDING, Dirk, A.; MEDINA, Jesus, Raul; ROMERIL, Stuart, Paul; WO2010/120854; (2010); (A1) English View in Reaxys

H 2N

H N S O

Rx-ID: 29701981 View in Reaxys 13/54 Yield

Conditions & References With piperidine in N,N-dimethyl-formamide, T= 25 °C Ishibashi, Yoshitaka; Miyata, Kengo; Kitamura, Masato; European Journal of Organic Chemistry; nb. 22; (2010); p. 4201 4204 View in Reaxys 2H 2H

H 2N

NH 2 2 2HH 2H 2H 2H

Rx-ID: 27953475 View in Reaxys 14/54 Yield

Conditions & References With hydrogen, water-d2, 10 wt. % palladium on activated carbon, 10% platinum on carbon, Time= 24h, T= 180 °C Ito, Nobuhiro; Watahiki, Tsutomu; Maesawa, Tsuneaki; Maegawa, Tomohiro; Sajiki, Hironao; Synthesis; nb. 9; (2008); p. 1467 - 1478; Art.No: F03608SS View in Reaxys 2

Na +

O–

H 2N

OH OH

O–

H O

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H 2N 2

OHHO

Rx-ID: 28046913 View in Reaxys 15/54 Yield 94.2 %

Conditions & References 1 :Example 1; Preparation of Phentermine PamoatePhentermine HCl (37.3 g) was suspended in USP H2O (700.0 g) and stirred to achieve a solution (0.05 g/g) and a pH 5.3. The solution was transferred to a metered addition funnel. A solution of disodium pamoate (45.0 g) was prepared by dissolving in USP water (902.0 g) to give a clear solution at a pH 10.4. The solution was adjusted to about pH 9.4 with 0.2N HCl and clarified by solution filtration. At 20° C., the Phentermine HCl solution was added to the stirred disodium pamoate solution at a controlled rate over about 2.5 hours and the addition funnel rinsed with USP H2O (20.0 g) into the reaction mixture. The mixture was stirred for 1 h then warmed to 70° C. where more precipitation was observed. The mixture was heated from about 70° C. to 95° C. over about 1 h then cooled. Solids were collected by filtration and washed with USP H2O (3.x.200 g) and dried on a vacuum Buchner for about 3 h. The solids collected (83.5 g) were transferred to a drying oven (50-55° C., vacuum/N2 sweep) and dried about 48 h to give Phentermine Pamoate (64.7 g, 94.2percent). The pamoate was characterized by DSC (FIG. 1), FTIR (FIG. 4) and PXRD (FIG. 7). With hydrogenchloride in water, Time= 4.5h, T= 20 - 95 °C Patent; Bristol, David William; King, Clifford Riley; Mitchener, JR., Joseph Pike; Audia, Vicki Haynes; US2008/293695; (2008); (A1) English View in Reaxys

H 2N

H N

Rx-ID: 10246308 View in Reaxys 16/54 Yield 99 % Spectr.

Conditions & References With trifluorormethanesulfonic acid, [CpRu(IV)(δ-C3H5)(2-quinolinecarboxylato)]PF6 in methanol, Time= 0.5h, T= 30 °C Tanaka, Shinji; Saburi, Hajime; Murase, Takanori; Yoshimura, Masahiro; Kitamura, Masato; Journal of Organic Chemistry; vol. 71; nb. 12; (2006); p. 4682 - 4684 View in Reaxys

H 2N

H 2N Cl

Rx-ID: 23770584 View in Reaxys 17/54 Yield

Conditions & References 5.D :A mixture of the chloroacetamide from Step C above (12.2 g, 54.2 mmol), thiourea (2.7 g, 65 mmol) and acetic acid (10.6 mL, 0.325 mol) in absolute ethanol (60 mL) was heated to reflux to 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2*75 mL). The combined organic fractions were washed with brine (5*50 mL), dried over MgSO4 and evaporated in vacuo. Distillation under high vacuum provided the free amine (bp 125° C.at;6 Torr). This crude material was dissolved in Et&2O

and 4 mL of 4N HCl in 1,4-dioxane was added.

Filtration of the white precipitate provided the desired compound as its hydrochloric acid salt. With hydrogenchloride in 1,4-dioxane, diethyl ether

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Patent; Andersen, Denise Lyn; Chang, Catherine H.; Falsey, James R.; Frohn, Michael J.; Hong, Fang-Tsao; Liao, Hongyu; Liu, Longbin; Lopez, Patricia; Retz, Daniel Martin; Rishton, Gilbert M.; Rzasa, Robert M.; Siegmund, Aaron; Tadesse, Seifu; Tamayo, Nuria; Tegley, Christopher M.; US2006/69110; (2006); (A1) English View in Reaxys

H 2N

H N

P O O

Rx-ID: 8690702 View in Reaxys 18/54 Yield

Conditions & References With hydrogenchloride in tetrahydrofuran, water, Time= 168h, T= 20 °C Gajda; Koziara; Napieraj; Sikora; Zwierzak; Polish Journal of Chemistry; vol. 74; nb. 10; (2000); p. 1385 - 1387 View in Reaxys

H 2N O

Rx-ID: 24295807 View in Reaxys 19/54 Yield

Conditions & References 37 : EXAMPLE 37: EXAMPLE 37: Preparation of N-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-phenylethylamine Hydrochloride, Compound 56 STR37 Using the method of Example 5, supra, 1,2-epoxy-3-phenoxypropane (600 mg, 4 mmol) and 1,1-dimethyl-2-phenylethylamine (596 mg, 4 mmol) yielded the title compound: GC/EI-MS, m/z (rel. int.) 284 (M+1, 1), 208 (100), 162 (1), 133 (7), 91 (27), 77 (15), 70 (22). Patent; NPS Pharmaceuticals, Inc.; SmithKline Beecham, Corp.; SmithKline Beecham, PLC; US6022894; (2000); (A) English View in Reaxys

H 2N

Rx-ID: 2740687 View in Reaxys 20/54 Yield

Conditions & References in ethanol, water, Time= 6h, Heating, Yield given Zwierzak, Andrzej; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 75; nb. 1-4; (1993); p. 51 - 54 View in Reaxys

O O

H 2N

S HO

Rx-ID: 18936070 View in Reaxys 21/54 Yield

Conditions & References Reaction Steps: 3 1: Me3SiN3, BF3*Et2O / benzene / 24 h / Ambient temperature 2: 4 h / 30 - 35 °C

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3: ethanol; H2O / 6 h / Heating With trimethylsilylazide, boron trifluoride diethyl etherate in ethanol, water, benzene Zwierzak, Andrzej; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 75; nb. 1-4; (1993); p. 51 - 54 View in Reaxys

H 2N

O O

S HO

Rx-ID: 18946068 View in Reaxys 22/54 Yield

Conditions & References Reaction Steps: 2 1: 4 h / 30 - 35 °C 2: ethanol; H2O / 6 h / Heating in ethanol, water Zwierzak, Andrzej; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 75; nb. 1-4; (1993); p. 51 - 54 View in Reaxys

H 2N

Rx-ID: 6713021 View in Reaxys 23/54 Yield

Conditions & References Shetty; Journal of Organic Chemistry; vol. 26; (1961); p. 3002 View in Reaxys Patent; Manufactures J.R.Bottu; FR1551268; (1968); ; vol. 72; nb. 12418s; (1970) View in Reaxys Marquardt; Edwards; The Journal of organic chemistry; vol. 37; nb. 11; (1972); p. 1861 - 1863 View in Reaxys Christol et al.; Bulletin de la Societe Chimique de France; (1961); p. 2317 View in Reaxys Patent; Wallace and Tiesnan; GB910789; (1963); ; vol. 59; nb. 2712; (1963) View in Reaxys STR61 TRANYLCYPROMINE ANILERIDINE PHENTERMINE Patent; University of Florida; US4771059; (1988); (A) English View in Reaxys

O O

H O

H 2N

N P

Rx-ID: 2235875 View in Reaxys 24/54 Yield 37 %

Conditions & References With water in ethanol, Time= 8h, Heating Koziara, Anna; Zwierzak, Andrzej; Tetrahedron Letters; vol. 28; nb. 51; (1987); p. 6513 - 6516 View in Reaxys

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H 2N Cl

Rx-ID: 2653804 View in Reaxys 25/54 Yield

Conditions & References With hydrogenchloride, triethyl phosphite in dichloromethane, 1.) room temp., overnight, 2.) room temp., overnight, Yield given Koziara, Anna; Osowska-Pacewicka, Krystyna; Zawadzki, Stefan; Zwierzak, Andrzej; Synthesis; nb. 5; (1987); p. 487 489 View in Reaxys

H 2N Cl

Rx-ID: 20385537 View in Reaxys 26/54 Yield

Conditions & References Reaction Steps: 2 1: SnCl4, trimethylsilyl azide / CH2Cl2 / 144 h / 15 - 20 °C 2: 1.) triethyl phosphite, 2.) gas HCl / CH2Cl2 / 1.) room temp., overnight, 2.) room temp., overnight With hydrogenchloride, trimethylsilylazide, tin(IV) chloride, triethyl phosphite in dichloromethane Koziara, Anna; Osowska-Pacewicka, Krystyna; Zawadzki, Stefan; Zwierzak, Andrzej; Synthesis; nb. 5; (1987); p. 487 489 View in Reaxys

H 2N

O HO

S HO

Rx-ID: 21594250 View in Reaxys 27/54 Yield

Conditions & References Reaction Steps: 3 1: BF3*Et2O / benzene / 24 h / 20 - 30 °C 2: 78 h / 25 - 30 °C 3: 37 percent / H2O / ethanol / 8 h / Heating With boron trifluoride diethyl etherate, water in ethanol, benzene Koziara, Anna; Zwierzak, Andrzej; Tetrahedron Letters; vol. 28; nb. 51; (1987); p. 6513 - 6516 View in Reaxys

O N

H 2N

N N

Rx-ID: 21596685 View in Reaxys 28/54 Yield

Conditions & References Reaction Steps: 2 1: 78 h / 25 - 30 °C 2: 37 percent / H2O / ethanol / 8 h / Heating With water in ethanol Koziara, Anna; Zwierzak, Andrzej; Tetrahedron Letters; vol. 28; nb. 51; (1987); p. 6513 - 6516 View in Reaxys

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H 2N

Rx-ID: 3579782 View in Reaxys 29/54 Yield

Conditions & References With hydrogenchloride, hydrogen, 10 wt. % palladium on activated carbon in ethanol, T= 50 °C , p= 760Torr , Yield given Baldwin, Jack E.; Adlington, Robert M.; Newington, Ian M.; Journal of the Chemical Society, Chemical Communications; nb. 2; (1986); p. 176 - 178 View in Reaxys

H 2N Cl

aq.-ethanolic KOH

Rx-ID: 19033247 View in Reaxys 30/54 Yield

Conditions & References Reaction Steps: 3 1: 100 percent 2: trifluoroacetic acid / 25 °C 3: conc. aq. HCl, H2 / 10percent Pd/C / ethanol / 50 °C / 760 Torr With hydrogenchloride, hydrogen, trifluoroacetic acid, 10 wt. % palladium on activated carbon in ethanol Baldwin, Jack E.; Adlington, Robert M.; Newington, Ian M.; Journal of the Chemical Society, Chemical Communications; nb. 2; (1986); p. 176 - 178 View in Reaxys

H 2N Cl

Rx-ID: 19052010 View in Reaxys 31/54 Yield

Conditions & References Reaction Steps: 2 1: trifluoroacetic acid / 25 °C 2: conc. aq. HCl, H2 / 10percent Pd/C / ethanol / 50 °C / 760 Torr With hydrogenchloride, hydrogen, trifluoroacetic acid, 10 wt. % palladium on activated carbon in ethanol Baldwin, Jack E.; Adlington, Robert M.; Newington, Ian M.; Journal of the Chemical Society, Chemical Communications; nb. 2; (1986); p. 176 - 178 View in Reaxys

H 2N

Cl 2

NH 2

Rx-ID: 2324675 View in Reaxys 32/54 Yield

Conditions & References With hydrogenchloride, phosphoric acid, sodium nitrite, 1.) MeOH, 3 h, reflux, water, Yield given. Multistep reaction

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Leclerc; Decker; Schwartz; Arzneimittel-Forschung/Drug Research; vol. 35; nb. 9; (1985); p. 1357 - 1367 View in Reaxys

H 2N

H N

Rx-ID: 2588815 View in Reaxys 33/54 Yield

Conditions & References With hydrogenchloride in methanol Buchowiecki, Wieslaw; Grosman-Zjawiona, Zofia; Zjawiony, Jordan; Tetrahedron Letters; vol. 26; nb. 9; (1985); p. 1245 1248 View in Reaxys O

H 2N

O N N

Rx-ID: 19069256 View in Reaxys 34/54 Yield

Conditions & References Reaction Steps: 2 1: 1.) H2, 2.) HCl / 1.) 10percent Pd/C / 1.) ethanol, 8 h, reflux 2: 1.) NaNO2, 37percent HCl, 2.) H3PO4 / 1.) MeOH, 3 h, reflux, water With hydrogenchloride, phosphoric acid, hydrogen, sodium nitrite, 10 wt. % palladium on activated carbon Leclerc; Decker; Schwartz; Arzneimittel-Forschung/Drug Research; vol. 35; nb. 9; (1985); p. 1357 - 1367 View in Reaxys

H 2N

O N O

Rx-ID: 19077499 View in Reaxys 35/54 Yield

Conditions & References Reaction Steps: 3 1: 74 percent / Na, EtOH / 12 h / Heating 2: 1.) H2, 2.) HCl / 1.) 10percent Pd/C / 1.) ethanol, 8 h, reflux 3: 1.) NaNO2, 37percent HCl, 2.) H3PO4 / 1.) MeOH, 3 h, reflux, water With hydrogenchloride, ethanol, phosphoric acid, hydrogen, sodium, sodium nitrite, 10 wt. % palladium on activated carbon Leclerc; Decker; Schwartz; Arzneimittel-Forschung/Drug Research; vol. 35; nb. 9; (1985); p. 1357 - 1367 View in Reaxys

H N

H 2N

Rx-ID: 2102442 View in Reaxys 36/54 Yield 57 %

Conditions & References With citrate buffer, potassium chloride in ethanol, T= 30 °C , cotrolled potential electrolysis, cathod: Hg, vs. SCE

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Ohmori, Hidenobu; Furusako, Shoji; Kashu, Mieko; Ueda, Chihiro; Masui, Masaichiro; Chemical & Pharmaceutical Bulletin; vol. 32; nb. 9; (1984); p. 3345 - 3353 View in Reaxys O

H N

H 2N Cl

Rx-ID: 2086323 View in Reaxys 37/54 Yield

Conditions & References With hydrogenchloride, sodium hydroxide, 1.220 gradC, 24h;, Multistep reaction Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys

H 2N

H 2N Cl

Rx-ID: 2427013 View in Reaxys 38/54 Yield

Conditions & References by neutralization Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys O H N

N Cl

OH H 2N

H N

Rx-ID: 3491655 View in Reaxys 39/54 Yield

Conditions & References T= 37 °C , metabolism Dell; Donik; Jacobi; Kamp; Arzneimittel-Forschung/Drug Research; vol. 30; nb. 7; (1980); p. 1138 - 1144 View in Reaxys

H 2N Cl

Rx-ID: 20827683 View in Reaxys 40/54 Yield

Conditions & References Reaction Steps: 2 1: 79 percent / H2SO4, AcOH / Ambient temperature; The reagents were added at 0 gradC, then stirring overnight at room temperature. 2: 1. 20percent NaOH, 2. HCl gas / 1.220 gradC, 24h; With hydrogenchloride, sodium hydroxide, sulfuric acid, acetic acid

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Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys

H 2N

Mg Cl

Rx-ID: 20861292 View in Reaxys 41/54 Yield

Conditions & References Reaction Steps: 3 1: 61 percent 2: 79 percent / H2SO4, AcOH / Ambient temperature; The reagents were added at 0 gradC, then stirring overnight at room temperature. 3: 1. 20percent NaOH, 2. HCl gas / 1.220 gradC, 24h; With hydrogenchloride, sodium hydroxide, sulfuric acid, acetic acid Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys

H 2N Mg Cl

Rx-ID: 20861294 View in Reaxys 42/54 Yield

Conditions & References Reaction Steps: 4 1: 61 percent 2: 79 percent / H2SO4, AcOH / Ambient temperature; The reagents were added at 0 gradC, then stirring overnight at room temperature. 3: 1. 20percent NaOH, 2. HCl gas / 1.220 gradC, 24h; 4: by neutralization With hydrogenchloride, sodium hydroxide, sulfuric acid, acetic acid Dube, Michael F.; Timberlake, Jack W.; Tetrahedron; vol. 36; (1980); p. 1753 - 1756 View in Reaxys O

H 2N

1,1,-Dimethyl-2-phenyl-ethylamine

O O

Rx-ID: 25282303 View in Reaxys 43/54 Yield

Conditions & References 13 : Methyl 3-benzyloxy-5-[(2-(1,1 dimethyl-2-phenylethylamino)1-hydroxyethyl]-benzoate. EXAMPLE 13 Methyl 3-benzyloxy-5-[(2-(1,1 dimethyl-2-phenylethylamino)1-hydroxyethyl]-benzoate. The 3-benzyloxy-5-carboxyphenylglyoxal (120 mmoles) was dissolved in MeOH (1 l.) and cooled to 0°. 1,1,-Dimethyl-2-phenyl-ethylamine (100 g, 0.67 moles) was added at 0° and the resulting mixture was stirred at 0° for 1 hr. before addition of KBH4 (12.2 g, 228 mmoles) over a period of 2 hrs. portionwise. The resultant mixture was allowed to react at room temperature for 18 hours before it was evaporated to a residual glass. The residue was acidified with 6N HCl (l l.) and extracted with CHCl3 (1 l.). Addition of ether to the CHCl3 extract gave the 1,1-dimethyl-2-phenylethylamine HCl as a white precipitate which was removed by filtration. With KBH4 in methanol

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Patent; Warner-Lambert Company; US4018825; (1977); (A) English View in Reaxys O

H N

H 2N

Rx-ID: 377468 View in Reaxys 44/54 Yield

Conditions & References With sodium hydroxide Ritter; Kalish; Journal of the American Chemical Society; vol. 70; (1948); p. 4048; Organic Syntheses; vol. 44; (1964); p. 44,45 View in Reaxys With hydrogenchloride Moed et al.; Recueil des Travaux Chimiques des Pays-Bas; vol. 74; (1955); p. 919,922 View in Reaxys NH 2 H 2N

H 2N

Rx-ID: 387090 View in Reaxys 45/54 Yield

Conditions & References With hypophosphoric acid, sodium nitrite Hass; Bender; Journal of the American Chemical Society; vol. 71; (1949); p. 3482,3485 View in Reaxys

H 2N

NH 2

Rx-ID: 455243 View in Reaxys 46/54 Yield

Conditions & References With hypophosphoric acid, sodium nitrite Kornblum; Iffland; Journal of the American Chemical Society; vol. 71; (1949); p. 2137,2138,2140 View in Reaxys O O

O N

H 2N

Rx-ID: 22082478 View in Reaxys 47/54 Yield

Conditions & References Reaction Steps: 2 1: Raney nickel; ethanol / 60 °C / 58840.6 Torr / Hydrogenation 2: aqueous hypophosphoric acid; sodium nitrite With ethanol, nickel, hypophosphoric acid, sodium nitrite Hass; Bender; Journal of the American Chemical Society; vol. 71; (1949); p. 3482,3485

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View in Reaxys Cl H 2N

O N O

Rx-ID: 22106218 View in Reaxys 48/54 Yield

Conditions & References Reaction Steps: 3 1: sodium ethylate solution 2: Raney nickel; ethanol / 60 °C / 58840.6 Torr / Hydrogenation 3: aqueous hypophosphoric acid; sodium nitrite With ethanol, sodium ethanolate, nickel, hypophosphoric acid, sodium nitrite Hass; Bender; Journal of the American Chemical Society; vol. 71; (1949); p. 3482,3485 View in Reaxys Reaction Steps: 3 1: 2-nitro-propane; ethanolic sodium ethylate solution / 25 °C 2: Raney nickel; ethanol / 60 °C / 58840.6 Torr / Hydrogenation 3: aqueous hypophosphoric acid; sodium nitrite With ethanol, 2-nitropropane, sodium ethanolate, nickel, hypophosphoric acid, sodium nitrite Hass; Bender; Journal of the American Chemical Society; vol. 71; (1949); p. 3482,3485 View in Reaxys

H 2N

Rx-ID: 22034758 View in Reaxys 49/54 Yield

Conditions & References Reaction Steps: 2 1: acetic acid; sulfuric acid 2: aq. NaOH solution With sodium hydroxide, sulfuric acid, acetic acid Ritter; Kalish; Journal of the American Chemical Society; vol. 70; (1948); p. 4048; Organic Syntheses; vol. 44; (1964); p. 44,45 View in Reaxys

H 2N

Rx-ID: 22036057 View in Reaxys 50/54 Yield

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H 2N

2-amino-2-methyl-1-phenyl-propanol-(1)-hydrochloride

Rx-ID: 6713022 View in Reaxys 51/54 Yield

Conditions & References With thionyl chloride, beim Hydrieren des erhaltenen (+-)-2-Chlor-1.1-dimethyl-2-phenyl-aethylamin-hydrochlorids an Palladium in Aethanol Patent; Merrell Co.; US2408345; (1942) View in Reaxys

H 2N

H N

Rx-ID: 327876 View in Reaxys 52/54 Yield

Conditions & References With calcium hydroxide, water, T= 230 °C Mentzer; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 213; (1941); p. 581,583 View in Reaxys

H 2N

Rx-ID: 22047352 View in Reaxys 53/54 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: calcium hydroxide; water / 230 °C With calcium hydroxide, diethyl ether, water Mentzer; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 213; (1941); p. 581,583 View in Reaxys

H 2N

Rx-ID: 22053335 View in Reaxys 54/54 Yield

Conditions & References Reaction Steps: 2 1: aqueous potassium hypobromite 2: calcium hydroxide; water / 230 °C With calcium hydroxide, potassium hypobromite, water Mentzer; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 213; (1941); p. 581,583 View in Reaxys Reaction Steps: 3 1: aqueous potassium hypobromite 2: diethyl ether 3: calcium hydroxide; water / 230 °C

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With calcium hydroxide, potassium hypobromite, diethyl ether, water Mentzer; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 213; (1941); p. 581,583 View in Reaxys

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