* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70 - -30℃; for 1 h; Stage #2: at -70 - 20℃; for 2.5 h;
To a solution of diisopropylamine (1.1 mL, 8.0 mmol) in THF (10 mL) was added dropwise n-butyllithium 1.6 M hexane solution (5.0 mL, 8.0 mmol) at -30°C, and the mixture was stirred at the same temperature for 30 min. Thereto was added dropwise a solution of (benzyloxy)acetic acid (0.60 g, 3.6 mmol) in THF (5 mL) at -70°C, and the mixture was stirred at the same temperature for 30 min. Further, at the same temperature, 1-bromo-3-chloropropane (3.6 mL, 36 mmol) was added, and the mixture was stirred at the same temperature for 30 min and then at room temperature for 2 hr. The reaction mixture was added to ice-cooled water, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 3 - 4 with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 - 50/50) to give the title compound as a colorless oil (0.28 g, 32percent). 1H NMR (CDCl3) δ: 1. 91 - 2.06 (4 H, m), 3.54 (2 H, t, J=5.1 Hz), 4.08 (1 H, t, J=6.6 Hz), 4.55 and 4.74 (2 H, d, J=11.4 Hz), 7.34 - 7.39 (5 H, m).
With potassium hydroxide In tetrahydrofuran; toluene at 70 - 80℃; Large scale
960 g of tetrahydroffiran and 41 g of toluene were added into a reaction flask. While controlling the temperature of the system at 10-20° C., 534.0 g of potassium hydroxide was added in four portions. Afier the addition of potassium hydroxide was completed, 1371.1 g of benzyl alcohol was added into the system in three portions. 300.1 g of chloroacetic acid was dissolved in 480.5 g of tetrahydrofuran, and the solution of chloroacetic acid in tetrahydrofuran was added dropwise into the above system while maintaining the temperature at 70-80° C. The system was reacted until chloroacetic acid was completely consumed. After cooling the system down, 3.12 Kg of purified water was added and tetrahydroffiran was removed under reduced pressure. The aqueous phase was extracted four times with toluene, and adjusted with hydrochloric acid at 10-20° C. to pH 3. The aqueous phase was extracted twice with methyl tert-butyl ether, and then concentrated to give 421.3 g of benzyloxyacetic acid (compound 3). The yield was 88.3percent, and the GC purity was 99.2percent. H1 NMR (400 MHz, CDCl3) δ: 12.28 (br, 1H),7.34-7.30 (m, 5H), 4.59 (s, 2H), 4.12 (s, 2H).
Reference：
[1] Chemistry - A European Journal, 1999, vol. 5, # 1, p. 121 - 161
[2] Tetrahedron, 2002, vol. 58, # 38, p. 7663 - 7679
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 3, p. 695 - 703
[4] Patent: US2017/190684, 2017, A1, . Location in patent: Paragraph 0065; 0066; 0081
[5] Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3793 - 3798
[6] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3762 - 3765
[7] Zhurnal Obshchei Khimii, 1954, vol. 24, p. 642,645; engl. Ausg. S. 651, 654
[8] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 10, p. 2479 - 2483
[9] Bulletin de la Societe Chimique de France, 1993, vol. 130, # 3, p. 388 - 394
[10] Journal of Organometallic Chemistry, 1997, vol. 530, # 1-2, p. 149 - 158
[11] Journal of the American Chemical Society, 2002, vol. 124, # 42, p. 12426 - 12427
[12] Patent: WO2005/35541, 2005, A1, . Location in patent: Page/Page column 15
[13] Organic and Biomolecular Chemistry, 2012, vol. 10, # 8, p. 1598 - 1601
[14] Patent: WO2013/189980, 2013, A1, . Location in patent: Page/Page column 31
[15] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2305 - 2308
4
[ 79-08-3 ]
[ 100-51-6 ]
[ 30379-55-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 15, p. 4460 - 4468
[2] Tetrahedron Letters, 1987, vol. 28, # 7, p. 797 - 800
[3] European Journal of Organic Chemistry, 2008, # 14, p. 2375 - 2387
[4] European Journal of Organic Chemistry, 2006, # 21, p. 4910 - 4915
[5] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3762 - 3765
[6] Tetrahedron Letters, 1985, vol. 26, # 10, p. 1343 - 1344
[7] Synlett, 1999, # 6, p. 692 - 694
[8] Organic Letters, 2007, vol. 9, # 23, p. 4865 - 4868
[9] Synlett, 2009, # 4, p. 653 - 657
[10] Organic Letters, 2010, vol. 12, # 5, p. 1120 - 1123
[11] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3576 - 3581
[12] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5162 - 5192
5
[ 30379-54-5 ]
[ 30379-55-6 ]
Reference：
[1] Tetrahedron Letters, 1992, vol. 33, # 17, p. 2299 - 2302
[2] Bulletin de la Societe Chimique de France, 1970, p. 4018 - 4023
6
[ 32122-09-1 ]
[ 30379-55-6 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1953, vol. 237, p. 1162
[2] Medicinal Chemistry Research, 2004, vol. 13, # 8-9, p. 660 - 676
[3] Patent: EP569598, 1993, A1,
[4] Organic Letters, 2011, vol. 13, # 21, p. 5762 - 5765
Reference：
[1] Letters in Organic Chemistry, 2016, vol. 13, # 9, p. 652 - 656
16
[ 100-44-7 ]
[ 30379-55-6 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1953, vol. 237, p. 1162
17
[ 20194-18-7 ]
[ 30379-55-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1970, p. 4018 - 4023
18
[ 2785-29-7 ]
[ 105-39-5 ]
[ 30379-55-6 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 1062,1063
19
[ 30379-55-6 ]
[ 19810-31-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5 h;
Example 1(a) Benzyloxy acetyl chloride To benzyloxyacetic acid (10.0 g, 60.0 mmol, 8.6 mL) in dichloromethane (50 mL) was added oxalyl chloride (9.1 g, 72.0 mmol, 6.0 mL) and DMF (30.0 mg, 0.4 mmol, 32.0 μL) and stirred at RT for 3 h. There was initially a rapid evolution of gas as the reaction proceeded but evolution ceased as the reaction was complete. The dichloromethane solution was concentrated in vacuo to give a gum. This gum was treated with more oxalyl chloride (4.5 g, 35.7 mmol, 3.0 mL), dichloromethane (50 mL), and one drop of DMF. There was a rapid evolution of gas and the reaction was stirred for a further 2 h. The reaction was then concentrated in vacuo to afford 11.0 g (quantitative) of Benzyloxy acetyl chloride (1) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 73.6, 74.8, 128.1, 128.4, 128.6, 130.0, and 171.9.
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2 h;
To benzyloxyacetic acid (10.0 g, 60.0 mmol, 8.6 mL) in dichloromethane (50 mL) was added oxalyl chloride (9.1 g, 72.0 mmol, 6.0 mL) and DMF (30.0 mg, 0.4 mmol, 32.0 μ) and stirred at RT for 3 h. There was initially a rapid evolution of gas as the reaction proceeded but evolution ceased as the reaction was complete. The dichloromethane solution was concentrated in vacuo to give a gum. This gum was treated with more oxalyl chloride (4.5 g, 35.7 mmol, 3.0 mL), dichloromethane (50 mL), and one drop of DMF. There was a rapid evolution of gas and the reaction was stirred for a further 2 h. The reaction was then concentrated in vacuo to afford 11.0 g (quantitative) of Benzyloxy acetyl chloride as a gum. The structure was confirmed by 13C NMR (75 MHz, CDC13) 5c 73.6, 74.8, 128.1, 128.4, 128.6, 130.0, and 171.9.
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5 h;
To benzyloxyacetic acid (10.0 g, 60.0 mmol, 8.6 mL) in dichloromethane (50 mL) wasadded oxalyl chloride (9.1 g, 72.0 mmol, 6.0 mL) and DMF (30.0 mg, 0.4 mmol, 32.0μL) and stuffed at RT for 3 h. There was initially a rapid evolution of gas as the reaction proceeded but evolution ceased as the reaction was complete. The dichloromethane solution was concentrated in vacuo to give a gum. This gum was treated with more oxalyl chloride (4.5 g, 35.7 mmol, 3.0 mL), dichloromethane (50 mL), and one drop of DMF.There was a rapid evolution of gas and the reaction was stuffed for a further 2 h. The reaction was then concentrated in vacuo to afford 11.0 g (quantitative) of Benzyloxy acetyl chloride (1) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δc 73.6, 74.8, 128.1, 128.4, 128.6, 130.0, and 171.9.
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5 h;
To benzyloxyacetic acid (10.0 g, 60.0 mmol, 8.6 mL) in dichloromethane (50 mL) was added oxalyl chloride (9.1 g, 72.0 mmol, 6.0 mL) and DMF (30.0 mg, 0.4 mmol, 32.0 μL) and stirred at RT for 3 h. There was initially a rapid evolution of gas as the reaction proceeded but evolution ceased as the reaction was complete. The dichloromethane solution was concentrated in vacuo to give a gum. This gum was treated with more oxalyl chloride (4.5 g, 35.7 mmol, 3.0 mL), dichloromethane (50 mL), and one drop of DMF. There was a rapid evolution of gas and the reaction was stirred for a further 2 h. The reaction was then concentrated in vacuo to afford 11.0 g (quantitative) of Benzyloxy acetyl chloride (1) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 73.6, 74.8, 128.1, 128.4, 128.6, 130.0, and 171.9.
100%
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5 h;
Example 1(a) Benzyloxy Acetyl Chloride (1) (0158) To benzyloxyacetic acid (10.0 g, 60.0 mmol, 8.6 mL) in dichloromethane (50 mL) was added oxalyl chloride (9.1 g, 72.0 mmol, 6.0 mL) and DMF (30.0 mg, 0.4 mmol, 32.0 μL) and stirred at RT for 3 h. There was initially a rapid evolution of gas as the reaction proceeded but evolution ceased as the reaction was complete. The dichloromethane solution was concentrated in vacuo to give a gum. This gum was treated with more oxalyl chloride (4.5 g, 35.7 mmol, 3.0 mL), dichloromethane (50 mL), and one drop of DMF. There was a rapid evolution of gas and the reaction was stirred for a further 2 h. The reaction was then concentrated in vacuo to afford 11.0 g (quantitative) of Benzyloxy acetyl chloride (1) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) bc 73.6, 74.8, 128.1, 128.4, 128.6, 130.0, and 171.9.
Reference：
[1] Patent: US2013/177501, 2013, A1, . Location in patent: Paragraph 0152
[2] Patent: WO2015/7834, 2015, A1, . Location in patent: Page/Page column 17
[3] Patent: WO2015/40087, 2015, A1, . Location in patent: Page/Page column 13; 14
[4] Patent: US9168317, 2015, B2, . Location in patent: Page/Page column 20
[5] Patent: US9314541, 2016, B2, . Location in patent: Page/Page column 21
[6] European Journal of Organic Chemistry, 2017, vol. 2017, # 3, p. 695 - 703
[7] European Journal of Organic Chemistry, 2008, # 14, p. 2375 - 2387
[8] Journal of the American Chemical Society, 2003, vol. 125, # 13, p. 3793 - 3798
[9] European Journal of Organic Chemistry, 2006, # 21, p. 4910 - 4915
[10] European Journal of Organic Chemistry, 2017, vol. 2017, # 38, p. 5789 - 5794
[11] Journal of Organic Chemistry, 1984, vol. 49, # 25, p. 5003 - 5006
[12] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 1, p. 29 - 39
[13] Helvetica Chimica Acta, 1933, vol. 16, p. 1130,1138
[14] Journal of Organic Chemistry, 1961, vol. 26, p. 194 - 197
[15] Journal of Organic Chemistry, 1983, vol. 48, # 26, p. 5221 - 5228
[16] Bulletin de la Societe Chimique de France, 1993, vol. 130, # 3, p. 388 - 394
[17] Tetrahedron Letters, 1994, vol. 35, # 39, p. 7269 - 7272
[18] Synlett, 1999, # 6, p. 692 - 694
[19] Chemistry - A European Journal, 1999, vol. 5, # 1, p. 121 - 161
[20] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 771 - 775
[21] Organic Letters, 2003, vol. 5, # 4, p. 591 - 594
[22] Organic Letters, 2007, vol. 9, # 23, p. 4865 - 4868
[23] Journal of Organic Chemistry, 2008, vol. 73, # 6, p. 2105 - 2113
[24] Synlett, 2009, # 4, p. 653 - 657
[25] Journal of the American Chemical Society, 2008, vol. 130, # 51, p. 17270 - 17271
[26] Synthesis, 2010, # 14, p. 2407 - 2412
[27] Tetrahedron, 2009, vol. 65, # 33, p. 6720 - 6729
[28] Tetrahedron Letters, 2011, vol. 52, # 16, p. 1909 - 1912
[29] Organic Letters, 2011, vol. 13, # 21, p. 5762 - 5765
[30] Organic and Biomolecular Chemistry, 2012, vol. 10, # 8, p. 1598 - 1601
[31] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5162 - 5192
[32] Chemistry - A European Journal, 2017, vol. 23, # 54, p. 13314 - 13318
[33] Chemistry - A European Journal, 2018, vol. 24, # 52, p. 13947 - 13953
[34] Patent: CN107383007, 2017, A, . Location in patent: Paragraph 0006; 0012
[35] Patent: WO2006/103555, 2006, A1, . Location in patent: Page/Page column 101-102
A solution of 2-(benzyloxy)acetic acid (25.0 g, 150 mmol) in MeOH (500 mL) was cooled to 4 0C in an ice-water bath. Thionyl chloride (13.0 mL, 179 mmol) was added drop-wise via an addition funnel at a rate to maintain the temperature below 8 0C. The resulting solution was stirred for 30 min. at 4 0C and 2.5 hr. at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 (200 mL). The aqueous layer was extracted with an additional portion of EtOAc (100 mL) and the organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to afford 27.6 g (92 percent) of methyl 2-(benzyloxy)acetate as a clear, colorless liquid. 1H NMR (OMSO-d6, 400 MHz): δ 7.26-7.41 (m, 5 H), 4.54 (s, 2H), 4.18 (s, 2H), 3.67 (s, 3H).
90%
Stage #1: at 0℃; for 1 h; Stage #2: at 60℃; for 3 h;
[00458] Thionyl chloride (17.2 g) was added to methanol (100 mL ) at 0 °C. After stirring for 1 h, 2-(benzyloxy)acetic acid (111) (8.0 g, 48.2 mmol) was added. The mixture was stirred at 60 °C for 3 h, and concentrated to give methyl 2-(benzyloxy)acetate (112) (Yield 7.8 g, 90percent), which was used in the next step without further purification. LCMS: m/z 181.1 [M+H]+; tR = 0.84 min.
18.1 g
at 70℃; for 2 h;
A mixture of 2- (benzyloxy) acetic acid (20 g) and H2S04 (10 L) in MeOH (200 mL) was stirred at 70°C for 2 hr and evaporated The residue was treated with saturated NaHC03 solution, and extracted with AcOEt. The organic layer was dried over MgS04, passed through silica gel pad and concentrated under reduced pressure to give the title compound (18.1 g) . ""H-NMR (300 MHz, DMSO-d6) δ 3.67 (3H, s) , 4.17 (2H, s) , 4.54 (2H, s) , 7.16-7.54 (5H, m) .
7.9 g
for 16 h; Reflux
2-(benzyloxy)acetic acid (11.5 g, 69.2 mmol) in methanol (69 mL) with a catalytic amount ofconcentrated sulfuric acid was heated under reflux for 16 h. The reaction was cooled to rt andwater and MTBE were added. The aqueous layer was extracted with MTBE and the combinedorganic layers were dried and the solvent removed under reduced pressure to give 7.9 g of themethyl ester.20 1H NMR (500MHz, CDCI3): o = 7.38-7.34 (m, 4H), 7.31 (m, 1 H), 4.63 (s, 2H), 4.11 (s, 2H), 3. 76(s, 3H).
200 g
at 0℃; for 6 h; Inert atmosphere; Reflux
Step A - Synthesis of Intermediate Compound lb To a solution of compound la (200g, 1.2 mol) in dry Methanol (2 L) was added SOCI2 (424 g, 3.6 mol) under 2 at 0 °C, then heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (3 L). The organic phase was washed with NaHCCh (2 L*2), brine, dried over a2S04 and concentrated in vacuo to provide compound lb (200 g) as an oil.
Reference：
[1] Chemistry - A European Journal, 1999, vol. 5, # 1, p. 121 - 161
[2] European Journal of Organic Chemistry, 2006, # 6, p. 1489 - 1498
[3] Patent: WO2010/127272, 2010, A2, . Location in patent: Page/Page column 86; 87
[4] Angewandte Chemie - International Edition, 2014, vol. 53, # 5, p. 1334 - 1337[5] Angew. Chem., 2014, vol. 126, # 5, p. 1358 - 1361
[6] Patent: WO2015/42414, 2015, A1, . Location in patent: Paragraph 00458
[7] Patent: WO2013/27845, 2013, A1, . Location in patent: Paragraph 0444
[8] Patent: WO2013/189980, 2013, A1, . Location in patent: Page/Page column 31
[9] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2305 - 2308
[10] Patent: WO2014/99586, 2014, A1, . Location in patent: Page/Page column 28; 29
[11] Patent: US2014/194431, 2014, A1, . Location in patent: Paragraph 0127-0129
[12] Patent: WO2015/95258, 2015, A1, . Location in patent: Page/Page column 56
[13] Patent: WO2015/89847, 2015, A1, . Location in patent: Page/Page column 34
22
[ 186581-53-3 ]
[ 30379-55-6 ]
[ 31600-43-8 ]
Reference：
[1] Journal of Organometallic Chemistry, 1997, vol. 530, # 1-2, p. 149 - 158
[2] Helvetica Chimica Acta, 1958, vol. 41, p. 768
[3] Synthetic Communications, 1998, vol. 28, # 20, p. 3727 - 3741
[4] Organic Letters, 2012, vol. 14, # 19, p. 5010 - 5013
23
[ 64-17-5 ]
[ 30379-55-6 ]
[ 32122-09-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Inert atmosphere; Reflux
Step 1 A catalytic amount of concentrated sulfuric acid was added to Compound 10a (33.2 g, 0.2 mol) in ethanol (300 mL) solution. The reaction was heated to reflux overnight. The solvent was concentrated, and the resulting residue was dissolved into ethyl acetate, and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain Compound 10b (35 g, Yield 90percent).
90%
With sulfuric acid In ethanolInert atmosphere; Reflux
A catalytic amount of concentrated sulfuric acid was added to Compound lOa (33.2 g, 0.2 mol) in ethanol (300 mE) solution. The reaction was heated to reflux overnight. The solvent was concentrated, and the resulting residue was dissolved into ethyl acetate, and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain Compound lOb (35 g, Yield
Reference：
[1] Patent: EP2754659, 2014, A1, . Location in patent: Paragraph 0168-0170
[2] Patent: US2014/378488, 2014, A1, . Location in patent: Paragraph 0380; 0381; 0382
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 2, p. 437 - 450
[4] Scientia Sinica (English Edition), 1957, vol. 6, p. 279,289[5] Huaxue Xuebao, 1956, vol. 22, p. 542
Step 1 A catalytic amount of concentrated sulfuric acid was added to Compound 10a (33.2 g, 0.2 mol) in ethanol (300 mL) solution. The reaction was heated to reflux overnight. The solvent was concentrated, and the resulting residue was dissolved into ethyl acetate, and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain Compound 10b (35 g, Yield 90%).
90%
With sulfuric acid; In ethanol;Inert atmosphere; Reflux;
A catalytic amount of concentrated sulfuric acid was added to Compound lOa (33.2 g, 0.2 mol) in ethanol (300 mE) solution. The reaction was heated to reflux overnight. The solvent was concentrated, and the resulting residue was dissolved into ethyl acetate, and then washed with saturated aqueous sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain Compound lOb (35 g, Yield
(2) Benzyloxyacetic acid Ethyl benzyloxyacetate (5.20g) was hydrolyzed in the same manner as in Example 2-(2) to give the above-captioned compound (3.65g).
With lithium aluminium tetrahydride In tetrahydrofuran for 1h;
Stage #1: benzyloxyacetic acid With borane-THF In tetrahydrofuran at 0 - 20℃;
Stage #2: With methanol In tetrahydrofuran at 0℃;
124.1 Step 1: 2-(benzyloxy)ethan-1-ol (181)
2-(benzyloxy)acetic acid (319.6 mg, 1.923 mmol) was dissolved in THF (4 mL) and cooled to 0°C.1M borane tetrahydrofuran complex in THF (5.3 mL, 5.30 mmol) was added and the reaction warmed to room temperature overnight. The reaction was cooled to 0°C and quenched with methanol (4 mL). The reaction was concentrated to dryness and reconstituted in MeOH (8.00 mL) and stirred at room temperature overnight. The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc in heptane) to afford 2-(benzyloxy)ethan-1-ol 181 as a clear liquid.1H NMR (400 MHz, CD2Cl2) δ 7.39 - 7.25 (m, 5H), 4.55 (s, 2H), 3.74 -3.67 (m, 2H), 3.62 - 3.53 (m, 2H).
A solution of 2-(benzyloxy)acetic acid (25.0 g, 150 mmol) in MeOH (500 mL) was cooled to 4 0C in an ice-water bath. Thionyl chloride (13.0 mL, 179 mmol) was added drop-wise via an addition funnel at a rate to maintain the temperature below 8 0C. The resulting solution was stirred for 30 min. at 4 0C and 2.5 hr. at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 (200 mL). The aqueous layer was extracted with an additional portion of EtOAc (100 mL) and the organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to afford 27.6 g (92 %) of methyl 2-(benzyloxy)acetate as a clear, colorless liquid. 1H NMR (OMSO-d6, 400 MHz): delta 7.26-7.41 (m, 5 H), 4.54 (s, 2H), 4.18 (s, 2H), 3.67 (s, 3H).
90%
[00458] Thionyl chloride (17.2 g) was added to methanol (100 mL ) at 0 C. After stirring for 1 h, 2-(benzyloxy)acetic acid (111) (8.0 g, 48.2 mmol) was added. The mixture was stirred at 60 C for 3 h, and concentrated to give methyl 2-(benzyloxy)acetate (112) (Yield 7.8 g, 90%), which was used in the next step without further purification. LCMS: m/z 181.1 [M+H]+; tR = 0.84 min.
18.1 g
With sulfuric acid; at 70℃; for 2h;
A mixture of 2- (benzyloxy) acetic acid (20 g) and H2S04 (10 L) in MeOH (200 mL) was stirred at 70C for 2 hr and evaporated The residue was treated with saturated NaHC03 solution, and extracted with AcOEt. The organic layer was dried over MgS04, passed through silica gel pad and concentrated under reduced pressure to give the title compound (18.1 g) . ""H-NMR (300 MHz, DMSO-d6) delta 3.67 (3H, s) , 4.17 (2H, s) , 4.54 (2H, s) , 7.16-7.54 (5H, m) .
7.9 g
With sulfuric acid; for 16h;Reflux;
2-(benzyloxy)acetic acid (11.5 g, 69.2 mmol) in methanol (69 mL) with a catalytic amount ofconcentrated sulfuric acid was heated under reflux for 16 h. The reaction was cooled to rt andwater and MTBE were added. The aqueous layer was extracted with MTBE and the combinedorganic layers were dried and the solvent removed under reduced pressure to give 7.9 g of themethyl ester.20 1H NMR (500MHz, CDCI3): o = 7.38-7.34 (m, 4H), 7.31 (m, 1 H), 4.63 (s, 2H), 4.11 (s, 2H), 3. 76(s, 3H).
200 g
With thionyl chloride; at 0℃; for 6h;Inert atmosphere; Reflux;
Step A - Synthesis of Intermediate Compound lb To a solution of compound la (200g, 1.2 mol) in dry Methanol (2 L) was added SOCI2 (424 g, 3.6 mol) under 2 at 0 C, then heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (3 L). The organic phase was washed with NaHCCh (2 L*2), brine, dried over a2S04 and concentrated in vacuo to provide compound lb (200 g) as an oil.
With thionyl chloride; at 0 - 20℃; for 3h;
To a stirred solution of benzyloxy-acetic acid (5 g, 30.12 mmol) in methanol (100 mL) was added SOCl2 (2.66 mL, 35.8 mmol) at 0 C. The mixture was stirred for 30 min at 0 C., finally at room temperature for 2.5 h. After completion of the reaction, the solvent was evaporated and the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get benzyloxy-acetic acid methyl ester (3) as a crude colorless oil (4.98 g).
With thionyl chloride; at 0℃; for 6h;Inert atmosphere; Reflux;
To a solution of compound la (200g, 1.2 mol) in dry methanol (2 L) was added SOCI2 (424 g, 3.6 mol) under 2 at 0 C, then heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in Ethyl acetate (3 L). The organic phase was washed with NaHCC (2 L*2), brine, dried over Na2S04 and concentrated in vacuo to provide compound lb as an oil.
With thionyl chloride; at 0℃; for 6h;Inert atmosphere; Reflux;
To a solution of compound 1 a (200g, 1.2 mol) in dry methanol (2 L) was addedSOC12 (424 g, 3.6 mol) under N2 at 0C, then heated under reflux for 6 hours. The reactionmixture was concentrated in vacuo and the resulting residue was dissolved in Ethyl acetate (3 L). The organic phase was washed with NaHCO3 (2 Lx2), brine, dried over Na2SO4 and concentrated in vacuo to provide compound lb as an oil.
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h;
66 4-(2-Benzyloxyacetylamino)phenoxyacetic acid methyl ester (66)
To a mixture of 4-aminophenoxyacetic acid methyl ester 15 (20 g, 110.5 mmol) and benzyloxyacetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atm. was added dropwise a solution of 1,3-dicyclohexylcarbodiimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml). The reaction mixture was stirred at room temp. for 12 hrs. The solids were filtered off, the dichloromethane solution was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml), dried over sodium sulphate, and distilled to get crude 66. The crude 66 was purified by column chromatography on silica gel using benzene as eluant to get pure 66 (25 g, 68.9%) as a white powder. M.p: 76-77.5° C. 1H NMR (CDCl3) δ 3.82 (s, 3H, ester), 4.10 (s, 2H, CH2), 4.62 (s, 2H, CH2), 4.66 (s, 2H, CH2), 6.88 (d, 2H, Ar), 7.38 (m, 5H, Ar), 7.46 (d, 2H, Ar), 8.24 (bs, 1H, NH)
Stage #1: benzyloxyacetic acid With pivaloyl chloride; triethylamine In tetrahydrofuran
Stage #2: (S)-4-Benzyl-2-oxazolidinone With triethylamine; lithium chloride
70%
With dmap; pivaloyl chloride; triethylamine In toluene at 75℃; for 16h;
5 (5)-4-benzyl-3-(2-(benzyloxy)acetyl)oxazolidin-2-one 13
To a water bath-cooled suspension of (S)-4- benzyloxazolidin-2-one (4.44 g, 25.1 mmol) in dry toluene (45 (0305) mL) were added subsequently, benzyloxyacetic acid (5.0 g, (0306) 30.1 mmol) and Et3N (8.74 mL, 62.7 mmol). The mixture (0307) became clear and was stirred for 5 min. Then, pivaloyl chloride (0308) (0309) (3.70 mL, 30.1 mmol) was added, followed by DMAP (1.53 g, (0310) 12.5 mmol), and the thick mixture was stirred for 5 min at rt, followed by stirring at 75 °C for 16 h. The mixture was cooled to rt, after which the reaction mixture was washed twice with 1M aqueous HC1 (50 mL, then 25 mL), 0.5M aqueous NaOH (3 x 25 mL) and brine (25 mL), dried over Na2S04 and filtered before concentration under reduced pressure. Purification by flash chromatography (heptane :EtO Ac = 3: 1- 1.5: 1) afforded 13 as a white solid (5.75 g, 70%). NMR (400 MHz, CDC13) δ 7.45-7.27 (m, 8H), 7.23- 7.18 (m, 2H), 4.74-4.66 (m, 5H), 4.31-4.20 (m, 2H), 3.33 (ABdd, J= 13.4, 3.3 Hz, 1H), 2.82 (ABdd, J= 13.4, 9.4 Hz, 1H).
Multi-step reaction with 2 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / dichloromethane / 16 h / 25 °C
2.1: magnesium; ethylene dibromide / tetrahydrofuran / 1 h / 25 °C
2.2: 1 h / 0 °C
Multi-step reaction with 2 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / dichloromethane / 16 h / 25 °C
2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C
2.2: 1 h / -78 °C
Multi-step reaction with 2 steps
1.1: pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 25 °C
2.1: magnesium / tetrahydrofuran; ethylene dibromide / 1 h / 25 °C
2.2: 1 h / 0 °C
Multi-step reaction with 2 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; pyridine / dichloromethane / 16 h / 25 °C
2.1: n-butyllithium / hexane; tetrahydrofuran / 1 h / -78 °C
2.2: 1 h / -78 °C
Stage #1: benzyloxyacetic acid; dimethyl amine With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; chloroform at 20℃; for 16h;
Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 16h;
26 Synthesis of 2-hydroxy-N,N-dimethylacetamide
Diisopropylethylamine (2.10 mL, 12.0 mmol), HBTU (2.74 g, 7.22 mmol), and a solution of dimethylamine in THF (2.0 M, 3.61 mL, 7.22 mmol) were added to a solution of 2-(benzyloxy)acetic acid (1.00 g, 6.02 mmol) in chloroform (30.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 16 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform/methanol). The obtained residue was dissolved in methanol (30.0 mL), and palladium-carbon (10% wet, 0.640 g, 0.602 mmol) was added at room temperature, and the resulting mixture was stirred under hydrogen atmosphere at the same temperature for 16 hours. The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform/methanol) to obtain 2-hydroxy-N,N-dimethylacetamide (0.255 g, 2.47 mmol, 41%) as a colorless oil.
A mixture of compound 4,6-dichloropyridine-2,3- diamine (0.190g, 1.O6mmol, 1.Oeq) and benzyloxyacetic acid (0.354g, 2.l3mmol, 2.Oeq) was heated at 150 °C for 4 hrs. After completion of the reaction, reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. Organic layers were combined, dried over Na2SO4 and concentrated in vacuo to obtain crude product. This was purified by column chromatography and compound was eluted in 6percent ethyl acetate in hexane as eluant to obtain pure10.1 (0.170g, 51.69 percent). MS(ES): m/z 309.51 [M+H]t
methyl 3-(2-(benzyloxy)acetamido)-2-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30 g
With pyridine; methanesulfonyl chloride; In acetonitrile; at 15℃; for 12h;
To a solution of 2-benzyloxyacetic acid (18.7 g, 113 mmol) and methyl 3-amino-2- chlorobenzoate (19.0 g, 102 mmol) in CH3CN (100 mL) were added pyridine (32.4 g, 409 mmol) and MsCl (18.4 g, 161 mmol). The mixture was stirred at 15 C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel chromatography to give methyl 3-(2-(benzyloxy)acetamido)-2-chlorobenzoate (I-485) (30.0 g) as a yellow oil.
N-(2-amino-6-bromophenyl)-2-(benzyloxy)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 18h;Inert atmosphere;
To a mixture of <strong>[1575-36-6]3-bromobenzene-1,2-diamine</strong> (20.0 g, 107 mmol) and 2- (benzyloxy)acetic acid (26.8 g, 161 mmol) in DCM (30 mL) were added T3P (102 g, 160 mmol, 50% purity) and DIPEA (27.6 g, 214 mmo) in one portion at 25 C under N2atmosphere. The mixture was stirred at 25C for 18 h. The reaction mixture was poured into H2O (300 mL). The resulting solution was extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography to afford N-(2-amino-6-bromophenyl)-2-(benzyloxy)acetamide (I-250) (26.0 g, 73% yield) as a yellow oil.
Chemistry
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