* 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.
A mixture of 3-(4-nitrophenoxy)propanoic acid (6.5 g, 30 mmol), concentrated sulfuric acid (30 mL) and phosphorus pentoxide (5.2 g, 37 mmol) is stirred at 60 °C for 3 hours, poured onto ice, stirred for 15 minutes and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a beige solid, 5.5 g (94percent yield) mp 171-173 °C, identified by NMR and mass spectral analyses.
85%
With sulfuric acid In ethyl acetate at 50℃; for 5 h;
A solution of 3-(4-nitrophenoxy)propionic acid (4 g) in concentrated sulphuric acid (40 mL) was heated at 50°C for 5 h. The reaction mixture was poured on ice (400 g) and, after complete melting of the ice, extracted with ethyl acetate (3 x 100 mL). The organic layers were collected, dried over anhydrous magnesium sulphate, filtered, and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate (25 mL) and the solution was supplemented with hexane (75 mL) under stirring. The resulting precipitate was collected by filtration, washed with hexane and dried (yield: 85percent; melting point: 176-178°C.
77.8%
at 65℃; for 3 h;
Mix 3 -(4-nitrophenoxy propanoic acid (6.5 g, 30 mmol) and concentrated H2SO4 (30 mL). Once dissolved, add P205, stir at 65°C for 3 hrs. Cool to room temperature, pour slowly the reaction mixture to ice water (50 mL), stir for 15 min, and extract with EtOAc (100 mLx3). Combine the organic layers, wash with brine (100 mLx2), dry over anhydrous Na2S04, concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=l:l) affords the title compound (4.6 g, 77.8percent). MS: (M-l): 192.2.
77.8%
at 65℃; for 3 h;
Mix 3-(4-nitrophenoxy)propanoic acid (6.5 g, 30 mmol) and concentrated H2SO4 (30 mL). Once dissolved, add P2O5, stir at 65° C. for 3 hrs. Cool to room temperature, pour slowly the reaction mixture to ice water (50 mL), stir for 15 min, and extract with EtOAc (100 mL*3). Combine the organic layers, wash with brine (100 mL*2), dry over anhydrous Na2SO4, concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (4.6 g, 77.8percent). MS: (M-1): 192.2.
70%
at 65℃; for 3 h;
3-(4-nitrophenoxy)propionic acid (8.8 g, 41.7 mmol) was added to a 100 mL reaction flask, and concentrated sulfuric acid (30 mL) was added to stir and dissolve. P2O5 (5.9 g, 41.7 mmol) was added, and the mixture was reacted at 65 ° C for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water (50 mL), and stirred for 15 minutes, and then extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride (100mL × 2), dried over anhydrous sodium sulfate, the obtained crude product was separated and purified by column chromatography and concentrated (silica gel, eluent: ethyl acetate: petroleum ether = 1: 1) to give the title compound (5.6g, 70percent yield).
Reference：
[1] Patent: WO2005/37830, 2005, A1, . Location in patent: Page/Page column 18
[2] Patent: EP2487171, 2012, A1, . Location in patent: Page/Page column 9
[3] Patent: WO2014/418, 2014, A1, . Location in patent: Page/Page column 97
[4] Patent: US2015/197511, 2015, A1, . Location in patent: Paragraph 0450; 0451
[5] Patent: CN108440404, 2018, A, . Location in patent: Paragraph 0075; 0079; 0080; 0081
[6] Journal of the Indian Chemical Society, 1939, vol. 16, p. 639,644
[7] Journal of the American Chemical Society, 1954, vol. 76, p. 5065,5067
[8] Journal of the American Chemical Society, 1954, vol. 76, p. 5065,5067
[9] Yaoxue Xuebao, 1959, vol. 7, p. 189,190[10] Chem.Abstr., 1960, p. 5637
[11] Patent: WO2012/107262, 2012, A1, . Location in patent: Page/Page column 19
[12] Tetrahedron, 2017, vol. 73, # 27-28, p. 3913 - 3922
2
[ 107-94-8 ]
[ 100-02-7 ]
[ 10572-16-4 ]
Yield
Reaction Conditions
Operation in experiment
38.6%
With potassium hydroxide In ethanol; water for 6 h; Reflux
To a 500 mL reaction flask was added p-nitrophenol (15 g, 108 mmol), 3-chloropropionic acid (11.6 g, 108 mmol), and an aqueous solution of ethanol (150 mL) and KOH (20percent, 150 mL); After the reaction mixture was heated to reflux for 6 hours, the mixture was adjusted to pH 1-3, extracted with ethyl acetate (300 mL×3), and the organic phase was washed with saturated aqueous sodium chloride (300 mL×2). Dried over anhydrous sodium sulfate, isolated crude product was purified by chromatography resulting concentrate (silica gel, eluent: ethyl acetate: petroleum ether =1:4) affords the title compound (8.8 g, 38.6percent yield).
25%
Stage #1: With potassium hydroxide In ethanol; water for 2 h; Heating / reflux Stage #2: With hydrogenchloride In ethanol; water at 20℃;
A mixture of 4-nitrophenol (14.0 g., 0.10 mol), 3-chloropropionic acid (10.8 g., 0.10 mol) and potassium hydroxide (11.2 g., 0.20 mol) in water and ethanol is heated at reflux temperature for 2 hours, cooled to ambient temperature, acidified with concentrated HCI to pH -1, and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate. The aqueous bicarbonate phase is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The final ethyl acetate extract is washed with brine, dried over MgS04 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether and hexane to afford the title compound as an off-white crystalline solid, 5.3 g (25percent yield), mp 117-118 °C, identified by NMR and mass spectral analyses.
17.5%
Stage #1: With potassium hydroxide In ethanol; water for 3 h; Reflux Stage #2: With hydrogenchloride In ethanol; water
[00271] Preparation of 46:42 43 44[00272] A mixture of 42 (15g,107.9mmol), 43 (35.1g,325mmol) and KOH(27.3g,488mmol) in 150mL of water and 150mL of EtOH was refluxed for 3h. The result mixture was cooled to room temperature and acidified with concentrated HC1 to pH=l . The aqueous layer was extracted with ethyl acetate(100mLx3). The combined organic layers were washed with saturated NaHC03 solution (100mLx2).The aqueous NaHC03 layer was acidified with concentrated HC1 and extracted with ethyl acetate (100mLx3).The combined EA layers were washed with brine (100mLx2),dried over anhydrous Na2S04 and concentrated. The residue was crystallized from Et20 and hexane to get the desired product 44 (4.0g, 17.5percent) as a white solid. LCMS (M+l)+: 212.
14.9%
With potassium hydroxide In ethanol for 2 h; Reflux
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20percent aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=l-3, extract with EtOAc (300 mLx3), combine the organic layers and wash with brine (300 mLx2), dry over anhydrous Na2S04. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=l :4) affords the title compound (7.5 g, 14.9percent). MS: (M+l): 212.1.
14.9%
With potassium hydroxide In ethanol; water for 2 h; Reflux
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20percent aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=1-3, extract with EtOAc (300 mL*3), combine the organic layers and wash with brine (300 mL*2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (7.5 g, 14.9percent). MS: (M+1): 212.1.
Reference：
[1] Patent: CN108440404, 2018, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078
[2] Patent: WO2005/37830, 2005, A1, . Location in patent: Page/Page column 18
[3] Patent: WO2012/119559, 2012, A1, . Location in patent: Page/Page column 96-97
[4] Patent: WO2014/418, 2014, A1, . Location in patent: Page/Page column 96; 97
[5] Patent: US2015/197511, 2015, A1, . Location in patent: Paragraph 0448; 0449
[6] Journal of the Indian Chemical Society, 1939, vol. 16, p. 639,644
[7] Tetrahedron, 2017, vol. 73, # 27-28, p. 3913 - 3922
3
[ 590-92-1 ]
[ 100-02-7 ]
[ 10572-16-4 ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium hydroxide In water for 5 h; Reflux
A solution of 4-nitrophenol (7 g) in KOH 10percent (70 mL) was supplemented with β-bromopropionic acid (7.6 g) and heated at reflux for 5 hours. After cooling, the mixture was acidified by means of 6N HCl and then extracted with ethyl acetate (3 x 100 mL). The organic layers were collected and extracted with a saturated solution of sodium hydrogenocarbonate (3 x 100 mL). The aqueous layers were mixed together and acidified by means of 6N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 40percent); melting point: 117-118°C.
40%
Stage #1: for 5 h; Reflux Stage #2: With hydrogenchloride In water
A solution of 4-nitrophenol (7 g) in KOH 10percent (70 mL) was supplemented with β- bromopropionic acid (7.6 g) and heated at reflux for 5 hours. After cooling, the mixture was acidified by means of 6N HCI and then extracted with ethyl acetate (3 x 100 mL). The organic layers were collected and extracted with a saturated solution of sodium hydrogenocarbonate (3 x 100 mL). The aqueous layers were mixed together and acidified by means of 6N HCI. The resulting precipitate was collected by filtration, washed with water and dried (yield: 40percent); melting point: 1 17-1 18°C
A mixture of 1c (0.59 g, 3 mmol) and concentreated HCl (5 mL) was refluxed for 2 h and then cooled to 0 °C for 1 h. The resulting solid was collected to yield analytically pure 3c (0.63 g, 98percent) as colorless needles.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypobromite; N-benzyl-N,N,N-triethylammonium chloride; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 0 - 5℃; for 0.5 h;
30g p-nitrophenoxypropanol dissolved in 300ml CH2Cl2;Add 750ml of water and 52.5g of NaHCO3 to the reaction flask and stir to dissolve.Then add 2g KBr, 1.65g benzyl triethylammonium chloride and 600ml NaBrO (10percent);After cooling the reaction solution to 0-5 °C,0.24g of tempo was added and stirred well; p-nitrophenoxypropanol was dropped into the above reaction solution at 0-5°C.After completion of the incubation, the reaction was incubated for 30 minutes. The reaction was complete; the layers were statically separated and the organic layer was separated;The aqueous layer is adjusted to pH 2-3 with concentrated hydrochloric acid.There are a lot of white solids out,After stirring for 1-2 hours, 30 g of product was filtered.
Reference：
[1] Patent: CN107986972, 2018, A, . Location in patent: Paragraph 0014; 0016; 0018; 0019-0020
6
[ 57-57-8 ]
[ 28341-54-0 ]
[ 10572-16-4 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 661
With potassium hydroxide; In ethanol; water; for 6h;Reflux;
To a 500 mL reaction flask was added p-nitrophenol (15 g, 108 mmol), 3-<strong>[107-94-8]chloropropionic acid</strong> (11.6 g, 108 mmol), and an aqueous solution of ethanol (150 mL) and KOH (20%, 150 mL); After the reaction mixture was heated to reflux for 6 hours, the mixture was adjusted to pH 1-3, extracted with ethyl acetate (300 mL×3), and the organic phase was washed with saturated aqueous sodium chloride (300 mL×2). Dried over anhydrous sodium sulfate, isolated crude product was purified by chromatography resulting concentrate (silica gel, eluent: ethyl acetate: petroleum ether =1:4) affords the title compound (8.8 g, 38.6% yield).
25%
A mixture of 4-nitrophenol (14.0 g., 0.10 mol), 3-<strong>[107-94-8]chloropropionic acid</strong> (10.8 g., 0.10 mol) and potassium hydroxide (11.2 g., 0.20 mol) in water and ethanol is heated at reflux temperature for 2 hours, cooled to ambient temperature, acidified with concentrated HCI to pH -1, and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate. The aqueous bicarbonate phase is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The final ethyl acetate extract is washed with brine, dried over MgS04 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether and hexane to afford the title compound as an off-white crystalline solid, 5.3 g (25% yield), mp 117-118 C, identified by NMR and mass spectral analyses.
17.5%
[00271] Preparation of 46:42 43 44[00272] A mixture of 42 (15g,107.9mmol), 43 (35.1g,325mmol) and KOH(27.3g,488mmol) in 150mL of water and 150mL of EtOH was refluxed for 3h. The result mixture was cooled to room temperature and acidified with concentrated HC1 to pH=l . The aqueous layer was extracted with ethyl acetate(100mLx3). The combined organic layers were washed with saturated NaHC03 solution (100mLx2).The aqueous NaHC03 layer was acidified with concentrated HC1 and extracted with ethyl acetate (100mLx3).The combined EA layers were washed with brine (100mLx2),dried over anhydrous Na2S04 and concentrated. The residue was crystallized from Et20 and hexane to get the desired product 44 (4.0g, 17.5%) as a white solid. LCMS (M+l)+: 212.
14.9%
With potassium hydroxide; In ethanol; for 2h;Reflux;
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20% aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=l-3, extract with EtOAc (300 mLx3), combine the organic layers and wash with brine (300 mLx2), dry over anhydrous Na2S04. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=l :4) affords the title compound (7.5 g, 14.9%). MS: (M+l): 212.1.
14.9%
With potassium hydroxide; In ethanol; water; for 2h;Reflux;
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20% aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=1-3, extract with EtOAc (300 mL*3), combine the organic layers and wash with brine (300 mL*2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (7.5 g, 14.9%). MS: (M+1): 212.1.
With potassium hydroxide; In water; for 5h;Reflux;
A solution of 4-nitrophenol (7 g) in KOH 10% (70 mL) was supplemented with beta-<strong>[590-92-1]bromopropionic acid</strong> (7.6 g) and heated at reflux for 5 hours. After cooling, the mixture was acidified by means of 6N HCl and then extracted with ethyl acetate (3 x 100 mL). The organic layers were collected and extracted with a saturated solution of sodium hydrogenocarbonate (3 x 100 mL). The aqueous layers were mixed together and acidified by means of 6N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 40%); melting point: 117-118C.
40%
A solution of 4-nitrophenol (7 g) in KOH 10% (70 mL) was supplemented with beta- <strong>[590-92-1]bromopropionic acid</strong> (7.6 g) and heated at reflux for 5 hours. After cooling, the mixture was acidified by means of 6N HCI and then extracted with ethyl acetate (3 x 100 mL). The organic layers were collected and extracted with a saturated solution of sodium hydrogenocarbonate (3 x 100 mL). The aqueous layers were mixed together and acidified by means of 6N HCI. The resulting precipitate was collected by filtration, washed with water and dried (yield: 40%); melting point: 1 17-1 18C
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