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[ CAS No. 1013-88-3 ]

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CAS No. :1013-88-3 MDL No. :MFCD00001760
Formula : C13H11N Boiling Point : 282°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :181.23 g/mol Pubchem ID :136809
Synonyms :

Safety of [ 1013-88-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
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  • Upstream synthesis route of [ 1013-88-3 ]
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[ 1013-88-3 ] Synthesis Path-Upstream   1~17

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  • [ 3060-50-2 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 1, p. 42 - 45[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 1, p. 52 - 55
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  • [ 1013-88-3 ]
  • [ 105-56-6 ]
  • [ 5232-99-5 ]
Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1956, vol. 242, p. 2468
  • 3
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  • [ 6011-14-9 ]
  • [ 70591-20-7 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 13, p. 2663 - 2666
[2] Journal of the American Chemical Society, 1980, vol. 102, # 10, p. 3592 - 3600
[3] Patent: WO2005/28429, 2005, A2, . Location in patent: Page/Page column 61-62
[4] Patent: WO2006/60494, 2006, A1, . Location in patent: Page/Page column 49
[5] Patent: WO2006/60810, 2006, A1, . Location in patent: Page/Page column 72-73
[6] Patent: WO2008/42968, 2008, A2, . Location in patent: Page/Page column 34
[7] Patent: WO2005/74904, 2005, A2, . Location in patent: Page/Page column 63
[8] Patent: WO2010/56877, 2010, A2, . Location in patent: Page/Page column 51-52
[9] Patent: WO2006/34004, 2006, A2, . Location in patent: Page/Page column 62-63
[10] Patent: WO2009/123623, 2009, A1, . Location in patent: Page/Page column 38-39
[11] Patent: WO2006/102535, 2006, A2, . Location in patent: Page/Page column 58
[12] Patent: WO2008/42968, 2008, A2, . Location in patent: Page/Page column 34
[13] Patent: WO2005/74904, 2005, A2, . Location in patent: Page/Page column 63
  • 4
  • [ 1013-88-3 ]
  • [ 151-63-3 ]
  • [ 70591-20-7 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 18, p. 5286 - 5291
  • 5
  • [ 1013-88-3 ]
  • [ 623-33-6 ]
  • [ 69555-14-2 ]
YieldReaction ConditionsOperation in experiment
97% at 20℃; for 18 h; Glycine ethyl ester hydrochloride (1.00 g, 7.16 mmol) was dissolved in dry DCM (40 ml). Benzophenone imine (1.20 ml, 7.16 mmol) was added dropwise. The RM was stirred at rt for 18 h. The RM was filtered through Celite, washed with DCM and the filtrate concentrated in vacuo. The resulting oil was triturated with hexane to give the desired product as a white solid.Y = 97 percent MS ES+: 268.
74% at 20℃; General Procedure A; Preparation of Amino Ester Ketimine from Amino Ester Hydrochloride; Referring to FIG. 6 in the attached drawings, glycine ethyl ester hydrochloride 14b (2.015 g, 14.4 mmol) was suspended in 25 mL dry DCM (dichloromethane) and benzophenone imine (2.42 mL, 14.4 mmol) was added and stirred at room temperature for 8-16 hr. The reaction mixture was filtered, washed with 5 mL DCM and the organic solution was washed 1.x. with H2O and 1.x. with brine (a saturated aqueous solution of sodium chloride). The DCM was dried by filtering over a bed of Hydromatrix brand diatomaceous earth and concentrating to dryness in vacuo. The product 16b, an oil (2.83 g, 74percent), was used without further purification. MS (LC/MS, ESI): 268 (M+H). 1H NMR (300 MHz, CDCl3, δ): 7.5-8.0 (m, 10H), 4.5 (s, 2H), 4.0 (q, 2H), 1.2 (t, 3H). See, O'Donnell et al., J. Org. Chem. 47, 2663 (1982).
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 27, p. 5949 - 5958
[2] Journal of Organic Chemistry, 1982, vol. 47, # 13, p. 2663 - 2666
[3] Patent: WO2018/167468, 2018, A1, . Location in patent: Page/Page column 76
[4] Chemical Communications, 1998, # 16, p. 1679 - 1680
[5] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5841 - 5844
[6] Journal of Chemical Research, Miniprint, 1996, # 11, p. 2768 - 2792
[7] Patent: US6268363, 2001, B1,
[8] Patent: US2010/189644, 2010, A1, . Location in patent: Page/Page column 21
[9] Patent: US5198548, 1993, A,
[10] Chinese Chemical Letters, 2013, vol. 24, # 2, p. 120 - 122
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  • [ 459-73-4 ]
  • [ 69555-14-2 ]
Reference: [1] Patent: WO2011/79114, 2011, A1, . Location in patent: Page/Page column 91
  • 7
  • [ 623-73-4 ]
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  • [ 69555-14-2 ]
Reference: [1] Chemistry Letters, 1994, # 1, p. 81 - 84
  • 8
  • [ 1013-88-3 ]
  • [ 5292-43-3 ]
  • [ 81477-94-3 ]
YieldReaction ConditionsOperation in experiment
99% With N-ethyl-N,N-diisopropylamine In acetonitrile at 70℃; for 16 h; This intermediate was generated by a generic procedure based on that disclosed in US2O1O/0189644 and O’Donnell, Ace. Chem. Res., 37, 506 (2004). A round bottom flask was charged with a stir-bar, diphenylmethanimine (8.6 g, 47.5 mmol), tert-butyl 2-bromoacetate (9.3 g, 47.5 mmol), and acetonitrile (40 mL).The reaction was heated to 70 °C and DIPEA (8.3 mL, 47.5 mmol) was added slowly. The flask was fitted with a reflux condenser and heated at 70 °C for 16 hrs. Analysis of the reaction by HPLC and TLC showed complete conversion of the reactants and the reaction was cooled to room temperature. A solution of 5:3 water/formic acid (1 mL) was added the reaction was concentrated under reduced pressure. Theresultant solid was filtered and washed 2 x 60 mL of a cold solution of3:1 water/ethanol and once with 30 mL of a cold solution of 1:1 water/ethanol. The solid was dried under high vacuum to give tert-butyl 2-((diphenylmethylene)amino)acetate (1-2) as a white solid (14.9 g, 47.0 mmol, 99percent). ‘H NMR (400 MHz, CDC13) ö 7.66 (2H, m), 7.47 (3H, m), 7.41 (1H, t, J=8 Hz), 7.34(1H, t, J=8 Hz), 7.20 (2H, m), 4.13 (2H, s), 1.48 (9H, s), MS (LC/MS) m/z observed295.93, expected 296.16 [M+Hj.
99% With N-ethyl-N,N-diisopropylamine In acetonitrile at 70℃; for 16 h; This intermediate was generated by a generic procedure based on that disclosed in US2010/0189644 and O’Donnell, Acc. Chem. Res.,37,506 (2004). A round bottom flask was charged with a stir-bar, diphenylmethanimine (8.6 g, 47.5 mmol), tert-butyl 2-bromoacetate (9.3 g, 47.5 mmol) and acetonitrile (40 ml). The reaction was heated to 70°C and DIPEA (8.3 ml, 47.5 mmol) was added slowly. The flask was fitted with a reflux condenser and heated at 70°C for 16 hrs. Analysis of the reaction by HPLC and TLC showed complete conversion of the reactants and the reaction was cooled to room temperature. A solution of 5:3 water/formic acid (1) was added the reaction was concentrated under reduced pressure. The resultant solid was filtered and washed 2 x 60 ml of a cold solution of water/ethanol (3:3 (v/v)) and once with 30 ml of a cold solution of water/ethanol (1:1 (v/v)). The solid was dried under high vacuum to give tert-butyl 2-((diphenylmethylene)amino)acetate (I-5) as a white solid (14.9 g, 47.0 mmol, 99percent). H1 NMR (400 MHz, CDCl3) δ 7.66(2H, m), 7.47(3H, m), 7.41(1H, t, J=8 Hz), 7.34(1H, t, J=8 Hz), 7.20(2H, m), 4.13(2H, s), 1.48(9H, s), MS (LC/MS) m/z observed 295.93, expected 296.16 [M+H].
77% With N-ethyl-N,N-diisopropylamine In acetonitrile for 14 h; Reflux General Procedure K; Preparation of Amino Ester Ketimine from α-Bromo AcetateReferring to FIG. 6, benzophenone imine (6.68 mL, 40.0 mmol) and tert-butyl bromoacetate 15c (5.9 mL, 40.0 mmol) were dissolved in 40 mL acetonitrile. DIEA (6.95 mL, 40.0 mmol) was added and the reaction mixture heated to reflux for 14 hr. The reaction mixture was cooled to room temperature, neutralized by the addition of 50percent aqueous acetic acid, and cooled to 0° C. The resulting solids were collected by filtration and then washed with cold ethanol. Product 16c was dried in vacuo to give 9.05 g (77percent) which was used without further purification. MS (LC/MS, ESI): 296 (M+H), 240 (M-tBu+H). 1H NMR (300 MHz, CDCl3, δ): 7.5-8.0 (m, 10H), 4.5 (s, 2H), 1.4 (s, 9H). See, O'Donnell, Acc. Chem. Res. 37, 506 (2004).
77%
Stage #1: With N-ethyl-N,N-diisopropylamine In acetonitrile for 14 h; Reflux
Stage #2: With acetic acid In water; acetonitrile at 20℃;
General Procedure A. Preparation of Amino Ester Ketimine from a-Bromo AcetateAs illustrated in FIG. 1, benzophenone inline (6.68 mL, 40.0 mmol) and tert-butyl bromoacetate 3c (5.9 mL, 40.0 mmol) were dissolved in 40 mL acetonitrile. DIEA (6.95 mL, 40.0 mmol) was added and the reaction mixture heated to reflux for 14 hr. The reaction mixture was cooled to room temperature, neutralized by the addition of 50percent aqueous acetic acid, and cooled to 0° C. The solids were collected by filtration and then washed with cold ethanol. Product 4c was dried in vacuo to give 9.05 g (77percent) which was used without further purification. MS (LC/MS, ESI): 296 (M+H), 240 (M-tBu+H). 1H NMR (300 MHz, CDCl3, δ): 7.5-8.0 (m, 10H), 4.5 (s, 2H), 1.4 (s, 9H). (see O'Donnell, 2004, Acc. Chem. Res. 37, 506)
75% With N-ethyl-N,N-diisopropylamine In acetonitrile Example 1
3.90 g of tert-butyl 2-bromoacetate was dissolved in 20 ml of acetonitrile, and 3.62 g of benzophenone imine and 2.58 g of diisopropylethylamine were added.
The solution was heated under reflux with stirring for 8 h.
The reaction solution was then neutralized with 50percent aqueous acetic acid at room temperature, and an additional 30 ml of water was added.
Upon cooling in an ice bath, the product precipitated out and was filtered off by suction through a sintered glass funnel.
The precipitate was washed with a small amount of cold 90percent ethanol, dried on a filter by suction, and dried over phosphorus pentoxide under vacuum.
In this way 4.45 g (75percent yield) of tert-butyl N(diphenylmethylene)glycinate was obtained (m.p. 114.5° C.).

Reference: [1] Patent: WO2016/15159, 2016, A1, . Location in patent: Page/Page column 56
[2] Patent: US9458192, 2016, B1, . Location in patent: Page/Page column 44-45
[3] European Journal of Organic Chemistry, 2005, # 2, p. 317 - 325
[4] Chemical Communications, 2009, # 2, p. 168 - 170
[5] Patent: US2010/189644, 2010, A1, . Location in patent: Page/Page column 23
[6] Patent: US2012/171116, 2012, A1, . Location in patent: Page/Page column 32
[7] Patent: US2002/62026, 2002, A1,
  • 9
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  • [ 27532-96-3 ]
  • [ 81477-94-3 ]
YieldReaction ConditionsOperation in experiment
83.1% at 20℃; for 20 h; tert-Butyl 2-(diphenymethyleneamino)acetate[0072] A solution of benzophenone imine (106.2 g; 587 mmol) and tert-butyl2-aminoacetate hydrochloride (98.3 g; 587 mmol) in dichloromethane (1 L; HPLC grade) was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between dichloromethane (0.5 L) and water (1.5 L) and the layers were separated. The aqueous phase was extracted with dichloromethane (0.5 L) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a slightly off-white solid. The resulting solid was triturated with n-hexane to give 141 g (83.1percent) of the title product as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.62 (d, 2H, ArH), 7.21-7.42 (m, 6H, ArH), 7.13 (d, 2H, ArH), 4.05 (s, 2H, CH2), 1.41 (s, 9H, C(CH3)3); 13C-NMR (CDCl3, 100 MHz) δ 171.5, 169.8, 139.4, 136.2, 130.4, 128.8, 128.7, 128.6, 128.0.127.7, 81.4, 56.3, 28.1.
Reference: [1] Organic Letters, 2015, vol. 17, # 18, p. 4498 - 4501
[2] Synlett, 2016, vol. 27, # 9, p. 1403 - 1407
[3] Chemistry - A European Journal, 2012, vol. 18, # 12, p. 3773 - 3779
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3515 - 3531
[5] Journal of Organic Chemistry, 1982, vol. 47, # 13, p. 2663 - 2666
[6] Patent: US6410580, 2002, B1,
[7] Patent: US6277987, 2001, B1,
[8] Journal of the American Chemical Society, 2012, vol. 134, # 34, p. 14011 - 14018
[9] Chemistry - A European Journal, 2010, vol. 16, # 4, p. 1153 - 1157
[10] Patent: WO2011/22429, 2011, A2, . Location in patent: Page/Page column 19
[11] Tetrahedron Letters, 2003, vol. 44, # 14, p. 2881 - 2883
[12] Tetrahedron Letters, 2004, vol. 45, # 39, p. 7197 - 7199
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  • [ 6456-74-2 ]
  • [ 81477-94-3 ]
Reference: [1] European Journal of Organic Chemistry, 2003, # 23, p. 4664 - 4678
  • 11
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  • [ 107-59-5 ]
  • [ 81477-94-3 ]
Reference: [1] Journal of Fluorine Chemistry, 2007, vol. 128, # 1, p. 78 - 83
  • 12
  • [ 1013-88-3 ]
  • [ 5680-79-5 ]
  • [ 81167-39-7 ]
YieldReaction ConditionsOperation in experiment
100% at 20℃; for 24 h; To a stirring solution of glycine methyl ester hydrochloride (17.49 g, 139 mmol) in dry dichloromethane (150 mL) under N2 at room temperature was added diphenylimine (25.00 g, 137 mmol) in one portion. The reaction mixture was stirred for 24 h, during which time ammonium chloride precipitated. Water (20 mL) was added and the layers were separated. The organic layer was washed with saturated Na2CO3 solution (2 x 20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered and concentrated by rotary evaporation to give ~ 35 g of a thick light brown syrup (99 percent pure) in ~ 100 percent yield. This was taken on to the next reaction without further purification.
100% at 20℃; for 24 h; To a stirring solution of methyl glycine ester hydrochloride (17.49 g, 139 mmol) in dry dichloromethane (150 mL) under N2 at room temperature was added diphenylimine (25.00 g, 137 mmol) in one portion. The reaction mixture was stirred for 24 h, during which time ammonium chloride precipitated. Water (20 mL) was added and the layers were separated. The organic layer was washed with saturated Na2C03 solution (2 x 20 mL) and brine (20 mL). The organic layer was dried (Na2SC>4), filtered and concentrated by rotary evaporation to give ~35 g of a thick light brown syrup (99percent pure) in ~ 100percent yield. This was taken on to the next reaction without further purification.
92% at 20℃; for 24 h; Benzophenone imine (50.0 g, 0.276 mol) was added in one batch to a solution of glycine methyl ester hydrochloride (39.4 g, 0.314 mol) in 300 mL dichloromethane under stirring, and the resulting reaction solution was stirred at room temperature for 1 day.
The resulting solid was removed by filtration, and the filtrate was washed sequentially with water, sodium carbonate solution and saturated brine, and was concentrated by evaporation to give methyl 2-((diphenylmethylene)amino)acetate (64.2 g) as an oily product, which was solidified after being cooled, and used directly for next step. Yield: 92percent. 1H-NMR (400 MHz, CDCl3): δ= 7.66 (2H, m), 7.45 (4H, m), 7.35 (2H, m), 7.17 (2H, m), 4.22 (2H, s), 3.74 (3H, s).
81% at 25℃; for 24 h; Inert atmosphere To a stirred suspension containing 5.00 g (39.9 mmol) of glycine methyl ester hydrochloride in 20 mL of anhydrous CH2Cl2 was added dropwise 6.70 mL (7.20 g, 39.9 mmol) of benzophenone imine.The milky white mixture was stirred at 25 °C for 24 h under an argon atmosphere. The reaction mixture was filtered and concentrated under diminished pressure. The crude product was crystallized from ether–hexanes to afford 3 as colorless crystals: yield 8.20 g (81percent); silica gel TLC Rf 0.22 (1:9 ethyl acetate−hexanes); 1H NMR (CDCl3) δ 3.73 (s, 3H), 4.21 (s, 2H), 7.15-7.18(m, 2H), 7.30-7.45 (m, 6H) and 7.63-7.66 (m, 2H); 13C NMR (CDCl3)δ 52.0, 55.6, 127.6, 128.1, 128.69,128.75, 128.83, 130.5, 135.9, 139.2, 171.1 and 171.9; mass spectrum (APCI), m/z 254.1182 (M + H)+ (C16H16NO2 requires m/z 254.1181).
81% at 25℃; for 24 h; Inert atmosphere [0067] Methyl 2-(diphenylmethyleneamino)acetate (41). To a stirred suspension containing 5.00 g (39.9 mmol) of glycine methyl ester hydrochloride (40) in 20 mL of anhydrous CH2CI2 was added 6.70 mL (7.20 g, 39.9 mmol) of benzophenone imine drop wise. The white mixture was stirred at 25 °C for 24 h under argon atmosphere. The reaction mixture was filtered and concentrated under diminished pressure. [0068] The crude product was crystallized from ether-hexanes to afford 41 as white crystals; yield 8.20 g (81percent); silica gel TLC R{ 0.22 (1 :9 ethyl acetate-hexanes); XH NMR (CDCI3) δ 3.73 (s, 3H), 4.21 (s, 2H), 7.15-7.18 (m, 2H), 7.30-7.45 (m, 6H) and 7.63-7.66 (m, 2H); 1 C NMR (CDCI3) δ 52.0, 55.6, 127.6, 128.05, 128.69, 128.75, 128.83, 130.5, 135.9, 139.2, 171.1 and 171.9; mass spectrum (APCI), m/z 254.1182 (M + H)+ (Ci6Hi6N02 requires m/z 254.1181).

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[2] Patent: WO2004/5293, 2004, A2, . Location in patent: Page 69-70
[3] Patent: WO2006/23630, 2006, A2, . Location in patent: Page/Page column 39-40; 65
[4] Chemistry - A European Journal, 2012, vol. 18, # 12, p. 3773 - 3779
[5] Organic Process Research and Development, 2018, vol. 22, # 10, p. 1458 - 1460
[6] Patent: EP3257857, 2017, A1, . Location in patent: Paragraph 0084; 0085
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[12] Patent: WO2016/118877, 2016, A1, . Location in patent: Paragraph 0067; 0068
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YieldReaction ConditionsOperation in experiment
100% at 20℃; for 18 h; A 3-necked, 5 L round-bottomed flask was equipped with a mechanical stirrer, a J-KEM temperature probe, and a N2 inlet adapter connected to a bubbler.
The round-bottomed flask was charged with glycine benzyl ester hydrochloride (505.2 g, 2.51 mol, 1.0 equiv.) and CH2Cl2 (3.0 L).
The milky, white reaction mixture was treated with benzophenone imine (471.1 g, 97percent, 2.6 mol, 1.00 equiv.) and an exotherm (+4.5° C.) was observed.
The reaction mixture stirred at 20° C. for 3 h and TLC (50percent ethyl acetate/heptane) showed a trace of starting material.
Additional benzophenone imine (25.0 g, 0.14 mol) was added to the reaction mixture and the mixture was stirred for 15 h at 20° C. TLC confirmed reaction completion.
This mixture was filtered through a short pad of Celite to remove ammonium chloride, and the filter cake was rinsed with CH2Cl2 (1.5 L).
The filtrates were concentrated in vacuo to produce a white solid that was dried in vacuo to give the desired crude product: 878.7 g (106percent); 1H-NMR(DMSO-d6): 7.53-7.25 (m, 13H), 7.12 (dd, 2H), 5.10 (s, 2H), and 4.17 (s, 2H). HPLC Purity: >95percent.
100% at 20℃; for 18 h; Step A; (Benzhvdrylideneamino)-acetic acid benzyl esterA 3-necked, 5 L round-bottomed flask was equipped with a mechanical stirrer, a J-KEM temperature probe, and a N2 inlet adapter connected to a bubbler. The round-bottomed flask was charged with glycine benzyl ester hydrochloride (505.2 g, 2.51 mol, 1.0 equiv.) and CH2CI2 (3.0 L). The milky, white reaction mixture was treated with benzophenone imine (471.1 g, 97percent, 2.6 mol, 1.00 equiv.) and an exotherm (+ 4.5 0C) was observed. The reaction mixture stirred at 20 0C for 3h and TLC (50percent ethyl acetate/heptane) showed a trace of starting material. Additional benzophenone imine (25.0 g, 0.14 mol) was added to the reaction mixture and the mixture was stirred for 15h at 20 0C. TLC confirmed reaction completion. This mixture was filtered through a short pad of Celite to remove ammonium chloride, and the filter cake was rinsed with CH2CI2 (1.5 L). The filtrates were concentrated in vacuo to produce a white solid that was dried in vacuo to give the desired crude product: 878.7 g (106percent); 1H- NMR(DMSOd6): 7.53-7.25 (m, 13H), 7.12 (dd, 2H), 5.10 (s, 2H), and 4.17 (s, 2H). HPLC Purity: > 95percent.
76% at 20℃; for 24 h; Benzophenone imine (100.0 g, 496 mmol) and glycine benzylester hydrochloride (89.9 g, 496 mmol) were combined in CH2Cl2 (250 mL) and the resulting mixture was stirred at ambient temperature for 24 h.
The reaction mixture was filtered to remove precipitated NH4Cl and the filtrate was concentrated under reduced pressure.
The residue was taken up in EtOAc, washed with 1 M NaHCO3, dried with (Na2SO4), and concentrated to give off-white solid.
Recrystallization from hot EtOAc-hexane gives the desired product as colorless plates; Yield: 123.6 g (76percent); Low resolution mass spectroscopy (APCI) m/z 330 [M+H]+; Anal. Calcd for C22H19N1O2: C, 80.22.; H, 5.81; N, 4.25. Found: C, 80.16.; H, 5.77; N, 4.22.
Reference: [1] Patent: US2005/239857, 2005, A1, . Location in patent: Page/Page column 82
[2] Patent: WO2007/49121, 2007, A1, . Location in patent: Page/Page column 15
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2725 - 2731
[4] Patent: US2005/239857, 2005, A1, . Location in patent: Page/Page column 33
[5] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1183 - 1187
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  • [ 81477-91-0 ]
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  • [ 116183-82-5 ]
  • [ 4248-19-5 ]
  • [ 147081-49-0 ]
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[2] Patent: US2002/137747, 2002, A1,
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  • [ 14529-54-5 ]
  • [ 910543-72-5 ]
YieldReaction ConditionsOperation in experiment
54%
Stage #1: With caesium carbonate In 1,4-dioxane at 95℃; for 16 h;
Stage #2: at 20℃; for 1 h;
Stage #3: With sodium hydrogencarbonate In methanol; dichloromethane; water
3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (2)
A 48-mL seal tube equipped with a magnetic stirring bar was charged with benzophenone imine (0.43 g, 2.4 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) (0.51 g, 2.0 mmol), Pd(OAc)2 (0.025 g, 0.040 mmol), rac-BINAP (0.082 g, 0.13 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) in dioxane (15 mL).
After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h.
Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL).
To this was added dichloromethane and the layers were separated.
The aqueous phase was extracted with dichloromethane (3*10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated.
The crude product was dissolved in 1 N HCl/MeOH (3 mL) and stirred for 1 h at room temperature.
Then, to the reaction mixture was added sat. NaHCO3 (10 mL) and dichloromethane (10 mL), and the phases were separated.
The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated.
The crude mixture was purified by column chromatography, gradient 0-10percent MeOH in dichloromethane/ether (1/1), to afford 0.22 g (54percent) of 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (2) as a solid.
Reference: [1] Patent: US2008/153834, 2008, A1, . Location in patent: Page/Page column 21-22
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