* 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.
Reference：
[1] Chemical Communications, 1997, # 11, p. 1067 - 1068
[2] Tetrahedron, 1981, vol. 37, p. 781 - 787
2
[ 3068-00-6 ]
[ 453-20-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 100℃; for 20 h;
Example 1; Instead of PEG-400 and the para-toluenesulfonic acid catalyst used in ComparativeExample 1, dioxane and a strong acid ion exchange resin (Amberlyst 15, H+ form) containing a sulfonic acid group were used in equal amounts. Then, the reaction was conducted using a batch type reactor under conditions of atmospheric pressure and 1000C for 20 hours. The reaction yield was 96 molpercent.
91.3%
at 160 - 180℃;
To a 500 ml_ flask, 1 ,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 equ.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 equ.) were added. The solution was heated to 160-180 °C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3percent yield): bp 86-88 °C (23 mmHg) 1H NMR (400 MHz, CDCI3) δ 4.43-4.42 (1 H, t), 3.95-3.67 (4H, m), 3.08- 3.07 (1 H, d), 2.07-1.82 (2H, m). GCMS m/z 88 (M+).
91.3%
at 160 - 180℃;
To a 500 ml_ flask, 1 ,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 equ.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 equ.) were added. The solution was heated to 160-180 °C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3percent yield): bp 86-88 °C (23 mmHg) 1H NMR (400 MHz, CDCI3) δ 4.43-4.42 (1 H, t), 3.95-3.67 (4H, m), 3.08- 3.07 (1 H, d), 2.07-1.82 (2H, m). GCMS m/z 88 (M+).
91.3%
at 160 - 180℃;
Example 1 Preparation of 3-OH-tetrahydrofuran (II) To a 500 mL flask, 1,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 eq.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 eq.) were added. The solution was heated to 160-180° C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3percent yield).
85%
at 120℃; for 12 h;
Comparative Example 1; 304 g of racemic 1,2,4-butanetriol, 304 g of polyethyleneglycol (Average MW=400 g/mol, hereinafter referred to as 'PEG-400'), and 41.6 g of para-toluenesulfonic acid were fed into a batch type reactor equipped with a distilling apparatus and then stirred. While the reaction pressure was reduced to 10 torr or less, and the temperature of the reactor was slowly increased to 12O0C, the reaction was conducted for 12 hours. During the reaction, tetrahydrofuran was distilled and separated using the distilling apparatus provided at the upper portion of the reactor, thus yielding tetrahydrofuran having 98percent or more purity at a yield of 85 molpercent.
77%
at 90℃;
To 5L of the reaction flask,1.06 kg (10 mol) of 1,2,4-butanetriol was added, 19 g (0.1 mol) of p-toluenesulfonic acid monohydrate was added as a catalytic amount under the stirring ,and heated to be completely dissolved in 1,2,4-butanetriol. The temperature was reduced to 90 ° C under reduced pressure (1.6 kPa) and the 80 to 90 ° C fractions were collected using a distillation apparatus to give 3-hydroxy tetrahydrofuran as a colorless liquid. The collected 3-hydroxy tetrahydrofuran was dissolved in an appropriate amount of anhydrous dichloromethane, dried over molecular sieves and filtered, and the dichloromethane was distilled off under reduced pressure to obtain 678 g of anhydrous 3-hydroxy tetrahydrofuran , yield 77percent.
63%
With toluene-4-sulfonic acid In benzene for 6 h; Reflux; Dean-Stark
Building block B31 : 3-(methylamino)tetrahydrofuran-3-carbonitrile B31 a) tetrahydrofuran-3-ol To a stirred solution of butane-1 ,2,4-triol (1.0 g, 9.0 mmol) in benzene (10 mL) was added p-toluenesulphonic acid (179 mg, 0.9 mmol) and refluxed under Dean-stark apparatus for 6 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was concentrated and purification by column chromatography (silica gel, 4percent MeOH in DCM) provided the titled compound (0.3 g, 36percent). 1 H NMR (400 MHz, DMSO-d6): δ 4.79 (d, J = 3.4 Hz, 1 H), 4.29 - 4.26 (m, 1 H), 3.74 - 3.62 (m, 3H), 3.47 - 3.44 (m, 1 H), 1 .90 - 1.86 (m, 1 H), 1.71 - 1.70 (m, 1 H).
76.35 %Chromat.
at 130℃; for 2 h;
A mixture of 1.00 grams of 1,2,4 butanetriol and 62 milligrams of bismuth triflate was reacted under vacuum (200 torr) at 130° C. for 2 hours. The resulting residue was cooled to room temperature. A sample analyzed by gas chromatography indicated that the residue contained 12.56percent (by weight) of the starting butane-1,2,4-triol and 76.35percent (by weight) of the desired tetrahydrofuran-3-ol.
Reference：
[1] Patent: WO2005/121111, 2005, A1, . Location in patent: Page/Page column 33
[2] Patent: WO2005/121111, 2005, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2007/81065, 2007, A1, . Location in patent: Page/Page column 6
[4] Patent: WO2005/121111, 2005, A1, . Location in patent: Page/Page column 31; 34
[5] Patent: WO2005/121111, 2005, A1, . Location in patent: Page/Page column 33-34
[6] Green Chemistry, 2012, vol. 14, # 6, p. 1749 - 1758
[7] Patent: WO2014/139080, 2014, A1, . Location in patent: Page/Page column 7
[8] Patent: WO2014/140017, 2014, A1, . Location in patent: Page/Page column 6
[9] Patent: US2014/275579, 2014, A1, . Location in patent: Paragraph 0027
[10] Patent: WO2007/81065, 2007, A1, . Location in patent: Page/Page column 5
[11] Patent: CN106957287, 2017, A, . Location in patent: Paragraph 0040
[12] Patent: WO2013/128421, 2013, A1, . Location in patent: Page/Page column 94
[13] Journal of the American Chemical Society, 1958, vol. 80, p. 364
[14] Justus Liebigs Annalen der Chemie, 1955, vol. 596, p. 1,112
[15] Justus Liebigs Annalen der Chemie, 1955, vol. 596, p. 1,112
[16] Journal of the American Chemical Society, 1957, vol. 79, p. 3455
[17] Tetrahedron, 1989, vol. 45, # 22, p. 7099 - 7108
[18] Green Chemistry, 2009, vol. 11, # 1, p. 48 - 52
[19] Journal of Chemical and Engineering Data, 2009, vol. 54, # 9, p. 2666 - 2668
[20] Patent: WO2013/52393, 2013, A1, . Location in patent: Paragraph 00181
[21] Patent: WO2013/52394, 2013, A1, . Location in patent: Paragraph 00265
[22] Org. Synth. Coll. Vol., 1963, vol. IV, p. 534
[23] Patent: US2017/121258, 2017, A1, . Location in patent: Paragraph 0077
[24] Green Chemistry, 2018, vol. 20, # 3, p. 634 - 640
3
[ 627-27-0 ]
[ 453-20-3 ]
Reference：
[1] Chemical Communications, 1998, # 4, p. 463 - 464
[2] Annales de Chimie (Cachan, France), 1911, vol. <8>24, p. 330[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1056
[4] Journal of Catalysis, 1999, vol. 182, # 2, p. 349 - 356
4
[ 4358-64-9 ]
[ 453-20-3 ]
Yield
Reaction Conditions
Operation in experiment
10 %Chromat.
With 5-nonanol; methyltrioxorhenium(VII) In dodecane; benzene at 140℃; for 45 h; Sealed tube
General procedure: CH3ReO3 (0.036 mmol), Glycol (0.36 mmol) and and 0.022 mmol dodecane (internal standard), 5-nonanol (0.68 mmol) were mixed in anhydrous benzene (2 mL) in a 1.5 mL thick walled glass tube fitted with Teflon screw-cap/plunger (Ace Glass), and a spin bar was added. The reaction mixture was heated at 90-150 °C in a preheated oil bath for 24-95 h. The mixture was cooled to room temperature, and an aliquot removed for GC-MS analysis.
With t-butyl bromide In acetonitrile for 1 h; Reflux
General procedure: To asolution of the PMB ether (1 mmol) in acetonitrile (10 mL), t-BuBr (1.1 equiv)was added and stirred at reflux. After completion of the reaction (monitored byTLC), it was concentrated under reduced pressure and the resulting crude wasdissolved in ethyl acetate (50 mL) and washed with saturated sodiumhydrogenocarbonate (25 mL). The aqueous layer was extracted with ethylacetate (2 5 mL) and the combine organic layer was washed with brinesolution, dried (MgSO4), concentrated under reduced pressure and the residuewas purified by column chromatography (silica gel, EtOAc, cyclohexane) toafford the corresponding alcohol.
Reference：
[1] Annales de Chimie (Cachan, France), 1911, vol. <8>24, p. 330[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1056
[3] Annales de Chimie (Cachan, France), 1911, vol. <8>24, p. 330[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1056
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1582 - 1589
22
[ 3068-00-6 ]
[ 96-22-0 ]
[ 453-20-3 ]
[ 149716-35-8 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 3, p. 634 - 640
23
[ 1708-29-8 ]
[ 453-20-3 ]
[ 98869-92-2 ]
[ 98869-94-4 ]
[ 98869-93-3 ]
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, # 5, p. 1459 - 1465
24
[ 1191-99-7 ]
[ 453-20-3 ]
[ 110-63-4 ]
[ 627-27-0 ]
[ 18826-95-4 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1582 - 1589
25
[ 285-69-8 ]
[ 453-20-3 ]
Reference：
[1] Journal of the Chemical Society, 1959, p. 248,254
26
[ 7124-17-6 ]
[ 453-20-3 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1057[2] Annales de Chimie (Cachan, France), 1911, vol. <8>24, p. 351
27
[ 7124-16-5 ]
[ 453-20-3 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 150, p. 1057[2] Annales de Chimie (Cachan, France), 1911, vol. <8>24, p. 351
28
[ 7124-16-5 ]
[ 453-20-3 ]
[ 90325-06-7 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1909, vol. 149, p. 297
29
[ 3068-00-6 ]
[ 105-58-8 ]
[ 453-20-3 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 3455
Reference：
[1] Justus Liebigs Annalen der Chemie, 1955, vol. 596, p. 160,180
32
[ 22929-52-8 ]
[ 453-20-3 ]
Reference：
[1] Journal of the Chemical Society, 1959, p. 248,254
[2] Proceedings of the National Academy of Sciences of the United States of America, 2015, vol. 112, # 51, p. E7065 - E7072
33
[ 1121-62-6 ]
[ 67-56-1 ]
[ 7664-93-9 ]
[ 453-20-3 ]
[ 109-87-5 ]
[ 145873-44-5 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 5335
[2] Zhurnal Obshchei Khimii, 1955, vol. 25, p. 2071,2079;engl.Ausg.S.2025,2032
34
[ 7647-01-0 ]
[ 3068-00-6 ]
[ 453-20-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1955, vol. 596, p. 160,180
35
[ 7124-16-5 ]
[ 7732-18-5 ]
[ 453-20-3 ]
[ 3068-00-6 ]
[ 90325-06-7 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1909, vol. 149, p. 297
36
[ 453-20-3 ]
[ 22929-52-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at -5 - 20℃; for 1 h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at -5 - 20℃; for 1 h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at -5 - 20℃; for 1 h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
79%
With pyridinium chlorochromate In dichloromethane at 20℃;
Description 20 : Dihydro-3(2H)-furanone; A mixture of 3-hydroxytetrahydrofuran (3.0 g, 0.034 mol) and pyridinium chlorochromate (14.7 g, 0.068 mol) in DCM (100 ml) was stirred at room temperature overnight. The title product was obtained by pouring the crude product through a silica pad using ethyl acetate as the eluent. The title product was obtained from 2 elutions (2.29 g; 79percent). 1H NMR (CDCI3) δ: 2.50 (2H, t), 3.87 (2H, s), 4.26 (2H, t).
60%
With acetic acid; pyridinium chlorochromate In dichloromethane at 20℃; Molecular sieve; Inert atmosphere
Pyridinium chlorochromate (6.5 g, 30 mmol, 1.5 equiv) was dissolved in 100 ml DCM at rt. Tetrahydro-3-furanol (1.6 ml, 20 mmol, 1 equiv) was added dropwise. 4 A molecular sieves (16 g) and glacial acetic acid (2 ml) were respectively added. The reaction mixture was stirred at rt overnight. A generous amount of Celite ® 545 was added and the solvent was removed by reduced pressure. The residue was then passed through a Celite ® 545 plug (10percent dichloromethane/diethyl ether) and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10percent dichloromethane/diethyl ether) to afford 3.45 (60percent yield). Spectral data correspond to that reported.24 1H NMR (400 MHz, CDCI3): δ 4.24 (t, J = 7.3 Hz, 2 H), 3.86 (s, 2 H), 2.48 (t, J = 7.3 Hz, 2 H).
Reference：
[1] Patent: WO2014/139080, 2014, A1, . Location in patent: Page/Page column 8; 9
[2] Patent: WO2014/140017, 2014, A1, . Location in patent: Page/Page column 7
[3] Patent: US2014/275579, 2014, A1, . Location in patent: Paragraph 0033
[4] Patent: WO2006/67430, 2006, A1, . Location in patent: Page/Page column 50
[5] Patent: WO2018/132905, 2018, A1, . Location in patent: Paragraph 00420-00422
[6] Journal of Organic Chemistry, 1989, vol. 54, # 6, p. 1249 - 1256
[7] Tetrahedron, 1991, vol. 47, # 34, p. 6975 - 6982
[8] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 5-6, p. 261 - 266
[9] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 13, p. 1629 - 1634
[10] Tetrahedron, 2004, vol. 60, # 46 SPEC. ISS., p. 10411 - 10418
[11] Patent: WO2006/28545, 2006, A2, . Location in patent: Page/Page column 229
[12] Patent: WO2013/52393, 2013, A1, . Location in patent: Paragraph 00182
[13] Patent: WO2013/52394, 2013, A1, . Location in patent: Paragraph 00266
[14] Patent: WO2013/128421, 2013, A1, . Location in patent: Page/Page column 94; 95
[15] Patent: WO2006/101434, 2006, A1, . Location in patent: Page/Page column 83; 84
37
[ 19098-31-8 ]
[ 453-20-3 ]
[ 61266-70-4 ]
Reference：
[1] Tetrahedron Letters, 1980, vol. 21, p. 3051 - 3054
[2] Tetrahedron, 1982, vol. 38, # 14, p. 2139 - 2146
[3] Tetrahedron, 1982, vol. 38, # 14, p. 2139 - 2146
[4] Angewandte Chemie - International Edition, 1999, vol. 38, # 13-14, p. 2012 - 2014
[5] Angewandte Chemie - International Edition, 1999, vol. 38, # 13-14, p. 2012 - 2014
With 1H-imidazole; iodine; triphenylphosphine In dichloromethaneReflux; Inert atmosphere
Mixture of 3-hydroxy tetrahydrofuran (8.8g, 0.1mol) in dichloromethane (200 mL) were added successively triphenylphosphine (52.4g, 0.2mol), imidazole (13.6g, 0.2mol) and iodine (50.7g, 0.2 mol), the reaction solution in N2Protection under reflux overnight, 0.2MNa2S2O3(30 mL) to quench the reaction, the organic layer was separated, aqueous phase extracted with dichloromethane The combined organic phases were extracted three times, dried over anhydrous MgSO4Dried, filtered, and concentrated to give a wet, yellow solid, the solid was added to pentane (100 mL) was stirred 2h, the insoluble solid was filtered to give the desired product (18.6 g of, 94percent yield) after the filtrate was concentrated.
Reference：
[1] Patent: CN103965174, 2016, B, . Location in patent: Paragraph 0171; 0173-0175
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6170 - 6174
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 3, p. 933 - 937[4] Angew. Chem., 2012, vol. 125, # 3, p. 967 - 971,5
With formic acid; phosphotungstic acid hydrate; dihydrogen peroxide In dichloromethane; water at 120℃;
1-14 Example 1
General procedure: The microchannel reactor uses the CS200 silicon carbide microchannel of Shandong Haomai Chemical Technology Co., Ltd.The liquid holding volume is 100ml, equipped with a double plunger pump for feeding,Set the temperature of the high and low temperature integrated circulation machine to 50°C.Mix 3-buten-1-ol with dichloromethane to form a 20% raw material solution,Then add phosphotungstic acid catalyst, the added amount of phosphotungstic acid is 0.2% of 3-buten-1-ol;Mix 30% hydrogen peroxide, formic acid, and distilled water into an oxide material in a volume ratio of 5:4:1;Inject the raw material stream and the oxide material at a molar ratio of 1:1.5 into the CS200 type microchannel reactor through the Prominent slurry pump and the high-pressure constant-flow plunger metering pump respectively.The total liquid flow rate is 2ml/min, and it can stay in the microreactor for 50 minutes. It is cooled by a coil at the outlet and washed with sodium sulfite for gas phase analysis.The product was qualitatively analyzed by the retention time of the product on the chromatogram. The analysis was performed on the Shimadzu 2010PLUS gas chromatograph equipped with an autosampler AOC-20. Gas chromatographic quantitative conditions: CP-Wax 58 (FFAP, 25m×0.25mm×0.2μm, Chrompack) is selected as the chromatographic column;The temperature of the vaporization chamber is 250°C (split ratio 1:30); the temperature of the FID detector is 280°C;Keep the temperature of the column oven at 60 for 1 min, then increase to 250 at a rate of 20/min and keep it for 5 min;Pneumatic control: N2 1mL/min(column), H2 30mL/min, air 300mL/min, makeup N2 29mL/min.
82%
With titanium silicate; dihydrogen peroxide In various solvent(s) at 24.9℃; for 18h;
With barium permanganate at -5℃;
82 % Chromat.
With molecular sieve; dihydrogen peroxide In iso-butanol for 18h; Ambient temperature;
strong acid ion exchange resin (Amberlyst 15, H+ form); In 1,4-dioxane; at 100℃; under 760.051 Torr; for 20h;Product distribution / selectivity;
Example 1; Instead of PEG-400 and the para-toluenesulfonic acid catalyst used in ComparativeExample 1, dioxane and a strong acid ion exchange resin (Amberlyst 15, H+ form) containing a sulfonic acid group were used in equal amounts. Then, the reaction was conducted using a batch type reactor under conditions of atmospheric pressure and 1000C for 20 hours. The reaction yield was 96 mol%.
91.3%
With toluene-4-sulfonic acid; at 160 - 180℃;
To a 500 ml_ flask, 1 ,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 equ.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 equ.) were added. The solution was heated to 160-180 C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3% yield): bp 86-88 C (23 mmHg) 1H NMR (400 MHz, CDCI3) delta 4.43-4.42 (1 H, t), 3.95-3.67 (4H, m), 3.08- 3.07 (1 H, d), 2.07-1.82 (2H, m). GCMS m/z 88 (M+).
91.3%
With toluene-4-sulfonic acid; at 160 - 180℃;
To a 500 ml_ flask, 1 ,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 equ.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 equ.) were added. The solution was heated to 160-180 C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3% yield): bp 86-88 C (23 mmHg) 1H NMR (400 MHz, CDCI3) delta 4.43-4.42 (1 H, t), 3.95-3.67 (4H, m), 3.08- 3.07 (1 H, d), 2.07-1.82 (2H, m). GCMS m/z 88 (M+).
91.3%
With toluene-4-sulfonic acid; at 160 - 180℃;
Example 1 Preparation of 3-OH-tetrahydrofuran (II) To a 500 mL flask, 1,2,4-trihydroxybutane (III, 159 g, 1.5 mol, 1 eq.) and p-toluenesulfonic acid monohydrate (1.5 g, 8.72 mmol, 0.006 eq.) were added. The solution was heated to 160-180 C. Reaction was monitored by GC. The resulting mixture was purified by fractional distillation to give 3-OH-tetrahydrofuran as colorless oil (120.5 g 91.3% yield).
85%
toluene-4-sulfonic acid; In PEG-400; at 120℃; under 10 Torr; for 12h;Product distribution / selectivity;
Comparative Example 1; 304 g of racemic 1,2,4-butanetriol, 304 g of polyethyleneglycol (Average MW=400 g/mol, hereinafter referred to as 'PEG-400'), and 41.6 g of para-toluenesulfonic acid were fed into a batch type reactor equipped with a distilling apparatus and then stirred. While the reaction pressure was reduced to 10 torr or less, and the temperature of the reactor was slowly increased to 12O0C, the reaction was conducted for 12 hours. During the reaction, tetrahydrofuran was distilled and separated using the distilling apparatus provided at the upper portion of the reactor, thus yielding tetrahydrofuran having 98% or more purity at a yield of 85 mol%.
77%
With toluene-4-sulfonic acid; at 90℃;
To 5L of the reaction flask,1.06 kg (10 mol) of 1,2,4-butanetriol was added, 19 g (0.1 mol) of p-toluenesulfonic acid monohydrate was added as a catalytic amount under the stirring ,and heated to be completely dissolved in 1,2,4-butanetriol. The temperature was reduced to 90 C under reduced pressure (1.6 kPa) and the 80 to 90 C fractions were collected using a distillation apparatus to give 3-hydroxy tetrahydrofuran as a colorless liquid. The collected 3-hydroxy tetrahydrofuran was dissolved in an appropriate amount of anhydrous dichloromethane, dried over molecular sieves and filtered, and the dichloromethane was distilled off under reduced pressure to obtain 678 g of anhydrous 3-hydroxy tetrahydrofuran , yield 77%.
63%
With toluene-4-sulfonic acid; In benzene; for 6h;Reflux; Dean-Stark;
Building block B31 : 3-(methylamino)tetrahydrofuran-3-carbonitrile B31 a) tetrahydrofuran-3-ol To a stirred solution of butane-1 ,2,4-triol (1.0 g, 9.0 mmol) in benzene (10 mL) was added p-toluenesulphonic acid (179 mg, 0.9 mmol) and refluxed under Dean-stark apparatus for 6 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was concentrated and purification by column chromatography (silica gel, 4% MeOH in DCM) provided the titled compound (0.3 g, 36%). 1 H NMR (400 MHz, DMSO-d6): delta 4.79 (d, J = 3.4 Hz, 1 H), 4.29 - 4.26 (m, 1 H), 3.74 - 3.62 (m, 3H), 3.47 - 3.44 (m, 1 H), 1 .90 - 1.86 (m, 1 H), 1.71 - 1.70 (m, 1 H).
With toluene-4-sulfonic acid; at 180℃; for 2h;
[00181] Step 1 : To neat butane- 1 ,2,4-triol (300 g, 2.83 mol) was added 4-methylbenzenesulfonic acid (10 g, 58 mmol). The reaction mixture was heated to 180C. After 2 hours, the reaction mixture was cooled to ambient temperature and tetrahydrofuran-3-ol was afforded by distillation of the mixture under reduced pressure (10 mm Hg; the product fraction was collected at 46C).
With toluene-4-sulfonic acid; at 180℃; for 2h;
To neat butane- 1 ,2,4-triol (300 g, 2.83 mol) was added 4- methylbenzenesulfonic acid (10 g, 58 mmol). The reaction mixture was heated to 180C. After 2 hours, the reaction mixture was cooled to ambient temperature and tetrahydrofuran-3-ol was afforded by distillation of the mixture under reduced pressure (10 mm Hg; the product fraction was collected at 46C).
76.35%Chromat.
With bismuth(lll) trifluoromethanesulfonate; at 130℃; under 200 Torr; for 2h;
A mixture of 1.00 grams of 1,2,4 butanetriol and 62 milligrams of bismuth triflate was reacted under vacuum (200 torr) at 130 C. for 2 hours. The resulting residue was cooled to room temperature. A sample analyzed by gas chromatography indicated that the residue contained 12.56% (by weight) of the starting butane-1,2,4-triol and 76.35% (by weight) of the desired tetrahydrofuran-3-ol.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; In dichloromethane; at -5 - 20℃; for 1h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; In dichloromethane; at -5 - 20℃; for 1h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; In dichloromethane; at -5 - 20℃; for 1h;
To a 1 L flask, 3-tetrahydrofuran (3-OH-THF, 60.6 g, 0.68 mol, 1 equ.) was charged, followed by DCM (620 mL) and TEMPO(1.08 g, 0.0069 mol, 0.01 equ.) The solution was cooled to -5 °C. To which TCCA (159.6 g, 0.68 mol, 1 equ.) was added in portions controlling the tern- perature around -5 °C to 0 °C. The resulting mixture was allowed to warm to rt and monitored by GC-MS, Reaction was finished in 1 h to give 95percent yield (GC areapercent).
79%
With pyridinium chlorochromate; In dichloromethane; at 20℃;
Description 20 : Dihydro-3(2H)-furanone; A mixture of 3-hydroxytetrahydrofuran (3.0 g, 0.034 mol) and pyridinium chlorochromate (14.7 g, 0.068 mol) in DCM (100 ml) was stirred at room temperature overnight. The title product was obtained by pouring the crude product through a silica pad using ethyl acetate as the eluent. The title product was obtained from 2 elutions (2.29 g; 79percent). 1H NMR (CDCI3) delta: 2.50 (2H, t), 3.87 (2H, s), 4.26 (2H, t).
60%
With acetic acid; pyridinium chlorochromate; In dichloromethane; at 20℃;Molecular sieve; Inert atmosphere;
Pyridinium chlorochromate (6.5 g, 30 mmol, 1.5 equiv) was dissolved in 100 ml DCM at rt. Tetrahydro-3-furanol (1.6 ml, 20 mmol, 1 equiv) was added dropwise. 4 A molecular sieves (16 g) and glacial acetic acid (2 ml) were respectively added. The reaction mixture was stirred at rt overnight. A generous amount of Celite ® 545 was added and the solvent was removed by reduced pressure. The residue was then passed through a Celite ® 545 plug (10percent dichloromethane/diethyl ether) and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10percent dichloromethane/diethyl ether) to afford 3.45 (60percent yield). Spectral data correspond to that reported.24 1H NMR (400 MHz, CDCI3): delta 4.24 (t, J = 7.3 Hz, 2 H), 3.86 (s, 2 H), 2.48 (t, J = 7.3 Hz, 2 H).
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 3.5h;
Pyridinium chlorochromate (85.8 g, 3.5 eq) was added in portions over a period of 5 minutes to a solution of 3-hydroxytetrahydrofuran (10.02 g, 1.0 eq) in dichloromethane (115 mL). The reaction mixture was stirred at ambient temperature for 3.5 hours and then applied directly to a column of silica gel (325 g). The column was eluted with diethyl ether. The fractions containing product were combined and the solvent was removed by atmospheric distillation to provide 5.22 g of tetrahydrofuran-3-one
With pyridinium chlorochromate; In dichloromethane; at 40℃; for 16h;
00182] Step 2: To a solution of tetrahydrofuran-3-ol (92.5 g, 1.05 mol) indichloromethane (2000 mL) was added pyridinium chlorochromate (454 g, 2.10 mol) and silicon gel (500 g). The reaction mixture was heated to 40°C. After 16 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude residue. The residue was purified via chromatography on silica gel (methanol/DCM, linear gradient) to afford dihydrofuran-3(2H)-one.
With silica gel; pyridinium chlorochromate; In dichloromethane; at 40℃; for 16h;
To a solution of tetrahydrofuran-3-ol (92.5 g, 1.05 mol) indichloromethane (2000 mL) was added pyridinium chlorochromate (454 g, 2.10 mol) and silica gel (500 g). The reaction mixture was heated to 40°C. After 16 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude residue. The residue was purified via chromatography on silica gel (methanol/DCM, linear gradient) to afford dihydrofuran-3(2H)-one.
With pyridinium chlorochromate; In dichloromethane; at 0 - 20℃;
b) dihydrofuran-3(2H)-one To a stirred solution of tetrahydrofuran-3-ol (3.0 g, 34 mmol) as obtained in step a) in DCM (60 mL) was added pyridiniumchloro chromate (14.65 g, 68 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was filtered through celite and the filtrate was washed with water, brine, drier over anhydrous Na2S04 and concentrated. The crude product (2.5 g) was used in the next step without further purification.
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 20℃; for 2h;Molecular sieve;
Tetrapropylammonium perruthenate (TPAP, 20 mg, 0.057 mmol) was added to a mixture of tetrahydrofuran-3-ol (616 mg, 7.0 mmol), N-methylmorphorine N-oxide (NMO, 11 mmol), activated molecular sieve powder (3.5 g) in dichloromethane (30 mL) at room temperature, the reaction mixture was stirred at room temperature for 2 h, then filtered through a short pad of Celite under reduced pressure. The EPO <DP n="85"/>dichloromethane solution ( 20 mL) of dihydrofuran-3(2H)-one was used as a stock solution (0.3 M).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 4h;
Step 1. 4-tert-Butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene To a solution of <strong>[3279-07-0]4-tert-butyl-2-nitrophenol</strong> (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stir at room temp. for 4 h. The resulting mixture was diluted with Et2O (50 mL) and washed with a saturated NH4Cl solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc/70% hexane) to yield the desired ether as a yellow solid (1.3 g, 91%): 1H-NMR (CHCl3) delta 1.30 (s, 9H), 2.18-2.24 (m, 2H), 3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52 (dd, J=2.6, 8.8 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H).
91%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 4h;
To a solution of <strong>[3279-07-0]4-tert-butyl-2-nitrophenol</strong> (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stir at room temp. for 4 h. The resulting mixture was diluted with Et2O (50 mL) and washed with a saturated NH4Cl solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash cromatography (30% EtOAc/70% hexane) to yield the desired ether as a yellow solid (1.3 g, 91%):
91%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 4h;
A2. General Method for the Synthesis of Tetrahydrofuranyloxyanilines; [] Step 1.4-tert-Butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene: To a solution of <strong>[3279-07-0]4-tert-butyl-2-nitrophenol</strong> (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stir at room temp. for 4 h. The resulting mixture was diluted with Et2O (50 mL) and washed with a saturated NH4Cl solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash cromatography (30% EtOAc/70% hexane) to yield the desired ether as a yellow solid (1.3 g, 91%): 1H-NMR (CHCl3) delta 1.30 (s, 9H), 2.18-2.24 (m, 2H), 3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52 (dd, J=2.6, 8.8 Hz, 1H), 7.81 (d,J=2.6 Hz, 1H).
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 20h;
Compound 108: 3-(2-Fluoro-6-nitro-phenoxy)-tetrahydro-furan2-Fluoro-6-nitro-phenol (1.0 g, 6.37 mmol, 1.0 eq) was dissolved in DCM (10 ml) and 3-hydroxy-tetrahydrofuran (0.56 g, 6.37 mmol, 1.0 eq), triphenylphosphine (2.0 g, 7.64 mmol, 1.2 eq), and diazodiethyldicarboxylate (1.22 g, 7.01 mmol, 1.2 eq) were added sequentially. The reaction was stirred at room temperature for 20 hours. The reaction mixture was filtered and the solvent removed in vacuo from the filtrate. The resultant residue was purified by column chromatography using 1 %DCM/MeOH as eluent to give the title compound (0.99 g, 4.35 mmol, 68%). 1H NMR indicates desired compound in ca. 95% purity.
Step 1 4-tert-Butyl-1-(3-tetrahydrofuranyloxy)-2-nitrobenzene To a solution of <strong>[3279-07-0]4-tert-butyl-2-nitrophenol</strong> (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stir at room temp. for 4 h. The resulting mixture was diluted with Et2O (50 mL) and washed with a saturated NH4Cl solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash cromatography (30% EtOAc/70% hexane) to yield the desired ether as a yellow solid (1.3 g, 91%): 1H-NMR (CHCl3) delta 1.30 (s, 9H), 2.18-2.24 (m, 2H), 3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52 (dd, J=2.6, 8.8 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H).
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 25 - 30℃; for 20h;Industry scale; Inert atmosphere;
Example 1Preparation of Crude BT MixtureA crude BT mixture was prepared by dissolving (1 kg, 6.17 mol) of dimethyl malate in 1 L of methanol. Granular sodium borohydride (466 g, 12.3 mol) was suspended in 3.2 L of THF (GC grade, stabilized with 250 ppm BHT) in a 10 L, jacketed reactor with an overhead paddle-type stirrer. A slow nitrogen purge was maintained over the sodium borohydride suspension. The dimethyl malate/methanol solution was added to the sodium borohydride suspension over a four-hour time period, while maintaining the reaction temperature at less than or equal to approximately 30 C. with a recirculating cold water bath. Mild gassing was observed over the course of the addition and during the ensuing reaction. The reaction mixture was stirred at 25 C.-30 C. for 16 hours. As the reaction progressed, the sodium borohydride granules were consumed and the reaction mixture became a homogeneous solution. However, the reaction mixture became increasingly viscous. The increased viscosity resulted in foaming of the reaction mixture, as hydrogen is slowly evolved during the reaction. The reaction mixture was continually stirred to control the foaming.To reduce the viscosity, 500 ml of methanol was added to the reaction mixture, followed by the addition of 1 L of a methanolic hydrochloric acid solution (37% aqueous HCl in 1 L methanol) to quench the reaction. Mild gassing was observed during the initial stage of the quench process, and the temperature was maintained below 35 C. A heavy white precipitate formed, and the mixture was stirred for 1 hour. At this point, the pH of the reaction mixture was between 6 and 8. The reaction mixture was filtered, and precipitated sodium salts (sodium chloride and sodium borate) were washed with three 500 ml portions of methanol. The solvent was removed from the combined filtrates by evaporating the solvent under reduced pressure (rotovap bath temperature 40 C.-45 C.) to concentrate the crude BT. Additional salts precipitated during the concentration, and were filtered.The crude BT mixture obtained after the concentration was a viscous, clear, pale-yellow liquid. The mass of the crude BT mixture corresponded to greater than 100% yield and included BT, dissolved borate species, and solvent. The organic purity of the crude BT mixture, as measured by gas chromatography (GC), was greater than 98%. The organic purity refers to the purity of organic species in the crude BT mixture but does not include inorganic species. Since the organic purity of the crude BT mixture only accounts for organic species, the crude BT mixture was not substantially pure because the boron content of the crude BT mixture was 11%-16% by weight, as determined by inductively coupled plasma (ICP) analysis.As necessary, the crude BT mixture was passed through a thin bed (100 g-150 g) of Amberlite IRN-78 ion-exchange resin. The resin was washed with methanol to recover additional crude BT. At this point, the crude BT mixture had a pH of between 7 and 8. To prevent the BT from cyclizing, the pH of the crude BT mixture is maintained between 6 and 10. The neutralized, crude BT mixture was concentrated on a rotovap (bath temperature 90 C.-95 C.) to constant weight. The boron content of the crude BT mixture, as determined by ICP analysis, was 2% by weight to 3% by weight. The mass of the crude BT mixture was 85 g-95 g. At 3% boron, the crude BT mixture included between 2.6 g and 2.8 g (0.24 mol-0.26 mol) of boron.
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 16.16h;
Example 18; 4-(3-(5-Fluoroisoindoline-2-carboxamido)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3 ,4-b]indole- 1 -carboxamide; 1. 6-(Tetrahydrofuran-3 -ylox - 1H-indole; To a mixture of <strong>[2380-86-1]1H-indol-6-ol</strong> (2.00 g, 15.02 mmol), tetrahydrofuran-3-ol (1.46 nL, 18.0 mmol), and triphenylphosphine (4.33 g, 16.52 mmol) in dichloromethane (80 mL) at 0 C was added diisopropyl diazene- 1 ,2-dicarboxylate (3.49 mL, 18.03 mmol) over 10 min. The mixture was stirred at room temperature for 16 hr. The starting indole and desired product were detected in a ratio of 3:2. The dark mixture was diluted with CH2C12 (80 mL), washed with IN NaOH (50 mL), water (50 mL), and brine (50 mL). The organic solution was dried over anhydrous MgSO4. The desired product (0.642 g, 3.16 mmol, 21.03% yield) was isolated as viscous oil by ISCO (300 g silica gel, solid loading, 10-50% ethyl acetate/hexane).
With EL-14 lipase; In hexane; at 4℃; for 16h;Enzymatic reaction;
General procedure: Lipase enzyme lyophilized powder (2 mg), was added to a solution of the substrate (13.3 mumol) in the reaction solvent (0.5 mL), followed by addition of a solution of vinyl acetate (66.5 mumol) in the reaction solvent (0.5 mL). The reactions were shaken at 150 rpm at 30 C for an appropriate amount of time. The reactions were filtered through anhydrous magnesium sulfate and analyzed directly by chiral GC or evaporated, redissolved in iso-propyl alcohol (HPLC grade) and analyzed by chiral HPLC. The screening results are summarized in Table 2 and Table 3.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane;Reflux; Inert atmosphere;
Mixture of 3-hydroxy tetrahydrofuran (8.8g, 0.1mol) in dichloromethane (200 mL) were added successively triphenylphosphine (52.4g, 0.2mol), imidazole (13.6g, 0.2mol) and iodine (50.7g, 0.2 mol), the reaction solution in N2Protection under reflux overnight, 0.2MNa2S2O3(30 mL) to quench the reaction, the organic layer was separated, aqueous phase extracted with dichloromethane The combined organic phases were extracted three times, dried over anhydrous MgSO4Dried, filtered, and concentrated to give a wet, yellow solid, the solid was added to pentane (100 mL) was stirred 2h, the insoluble solid was filtered to give the desired product (18.6 g of, 94% yield) after the filtrate was concentrated.
With 5-nonanol; methyltrioxorhenium(VII); In dodecane; benzene; at 140℃; for 45h;Sealed tube;
General procedure: CH3ReO3 (0.036 mmol), Glycol (0.36 mmol) and and 0.022 mmol dodecane (internal standard), 5-nonanol (0.68 mmol) were mixed in anhydrous benzene (2 mL) in a 1.5 mL thick walled glass tube fitted with Teflon screw-cap/plunger (Ace Glass), and a spin bar was added. The reaction mixture was heated at 90-150 C in a preheated oil bath for 24-95 h. The mixture was cooled to room temperature, and an aliquot removed for GC-MS analysis.
5-nitro-2-((tetrahydrofuran-3-yl)oxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium tert-butylate; In N,N-dimethyl-formamide; tert-butyl alcohol; at 27 - 40℃; for 6h;
To a stirred solution of <strong>[369-36-8]2-fluoro-5-nitroaniline</strong> 61 ( 2.0 g, 12.8 mmol) & tetrahydrofuran-3-ol (1.4 g, 16.65 mmol) in t-BuOH (20 ml) & DMF (4 ml) was dropwise added potassium tert Buoxide (1M in t-BuOH) (46 ml, 46.12 mmol) at RT was stirred at RT for 2h, Reaction mixture was warmed to 40C for 4h, reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with EtOAc and washed with brine solution. The organic phase was dried and concentrated to get crude material. The crude material was purified by flash column chromatography (Si02), eluting with 40 % EtOAc in hexane to get 5-nitro-2-((tetrahydrofuran-3-yl) oxy) aniline as brown liquid (1.0 g, 35% yield). ?HNMR (400 MHz, CDCI3): oe 7.66-7.63 (dd, 1H), 7.57-7.56 (m, 1H), 6.73 (d, lH), 5.05-5.04 (m, 1H), 4.13-3.94 (m, 6H), 2.35-2.26 (m, 2H), MS: 225.03 (M+H)
226 mg
To a stirred solution of 3-hydroxy tetrahydrofuran (203mg) in DMF (lOml) at 0C, NaH (92mg) was added slowly. After the mixture was stirred at 0-5C for 30 minutes, the compound 124a (3 00mg) in DMF was added dropwised. Then the reaction mixture was stirred with warmingnaturally to the room temperature. The reaction was complete detected by TLC (PE:EA=1 :1) after4 hours. Then lSml H20 was added to the solution. Afterwards, the mixture was extracted by EA(lSmlX2). The combined organic phase was combined and washed with aqueous solution ofNaC1 and dried over Na2SO4 and concentrated under reduced pressure to give crude Compound124b. The crude product was purified by column chromatography to give 226mg Compound124b.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 2h;
100 EXAMPLE 100 Preparation of Compound 235
10492] To a solution of 235-1 ( 1.82 g, 10.0 mmol), tetrahydrofuran-3-ol (880 mg, 10.0 mmol) and PPh3 (2.62 g, 10.0 mmol) in THF (30 mL) at 0 °C was added DIAD (2.02 g, 10.0 mmol) dropwise. The mixture was stirred at 0 °C for 2 h, and the reaction was then quenched with sat. NaHC03 solution. The aqueous layer was extracted by DCM (3x). The combined organic layers were dried over MgSC>4, filtered and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel to give 235-2 (2.4 g, 89.6%).
With triethylamine; In acetonitrile; at 20℃; for 2h;
To a solution of (3RS)-3-hydroxy-tetrahydrofuran (0.459 mL, 5.62 mmol) in MeCN (33.3 mL) was added TEA (1.56 mL; 11.2 mmol) and DSC (4.545 g; 16.9 mmol). The reaction mixture wasstirred at rt for 2h. The reaction mixture was concentrated to dryness and the residue was diluted with EtOAc (50 mL). The org. layer washed with 1M aq. citric acid (3x20 mL), water (30 mL), brine (30 mL), dried over MgSO,, filtered and evaporated to dryness. The evaporation residue waspurified by CC (Hexane-EA-MeOH gradient) to afford the title compound (1.28 g; 99% yield) as a colorlessoil. 1H NMR (DMSO-ds) 6: 5.41 (m, 1H); 3.79-3.87 (m, 3H); 3.76 (td, J = 4.5, 8.6 Hz, 1H); 2.82 (s, 4H); 2.27 (m, 1H); 2.03 (m, 1H).
30.8%
With triethylamine; In acetonitrile; at 20℃; for 18h;
To a solution oftetrahydrofuran-3-ol(0.1 g, 1.135 mmol) inacetonitrile(5 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.436 g, 1.703 mmol) andTEA(0.237 mL, 1.703 mmol). The reaction mixture was allowed to stir at rt for 18 h. The solvent was removed and the reaction mixture was diluted with DCM, washed with 10% NaHCO3, brine, dried over Na2SO4and concentrated to afford2,5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl) carbonate(0.08 g,0.349 mmol,30.8%yield).1H NMR (DMSO-d6, delta=2.50 ppm, 400 MHz): delta 5.44-5.38 (m, 1H), 3.88-3.65 (m, 5H), 2.82 (s, 3H), 2.31-2.21 (m, 1H), 2.07-1.98 (m, 1H).
30.8%
With triethylamine; In acetonitrile; at 20℃; for 18h;
To a solution of tetrahydrofuran-3-ol (0.1 g, 1.135 mmol) in acetonitrile (5 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.436 g, 1.703 mmol) and TEA (0.23 7 mL, 1.703 mmol). The reaction mixture was allowed to stir at rt for 18 h.The solvent was removed and the reaction mixture was diluted with DCM, washed with 10% NaHCO3 , brine, dried over Na2SO4 and concentrated to afford 2,5- dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl) carbonate (0.08 g, 0.349 mmol, 30.8 % yield). ?H NMR (DMSO-d6, oe = 2.50 ppm, 400 MHz): oe 5.44 - 5.38 (m, 1 H), 3.88 - 3.65 (m, 5 H), 2.82 (s, 3 H), 2.31 -2.21 (m, 1 H), 2.07- 1.98 (m, 1 H).
12.I Step Γ
Step Γ. To a solution of 3-hydroxytetrahydrofuran (200 mg, 1.55 mmol) in DCM (5 mL) was added Ms20 (539 mg, 3.10 mmol) and pyridine (367 mg, 4.65 mmol) at -10 °C. After stirred at room temperature overnight, the reaction mixture was diluted with DCM (10 mL), washed with saturated NaHC03, dried over anhydrous Na2S04, and evaporated to dryness under reduced pressure to give tetrahydrofuran-3-yl methanesulfonate 35 in 89% yield (285 mg).
89%
With pyridine In dichloromethane at -10 - 20℃;
12.I Step I:
To a solution of 3-hydroxytetrahydrofuran (200 mg, 1.55 mmol) in DCM (5 mL) was added Ms20 (539 mg, 3.10 mmol) and pyridine (367 mg, 4.65 mmol) at-10 °C. After stirred at room temperature overnight, the reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO3, dried over anhydrous Na2504, and evaporated to dryness under reduced pressure to afford tetrahydrofuran-3-yl methanesulfonate 35 in 89% yield (285 mg).
N-(2-methoxy-5-nitro-4-(tetrahydrofuran-3-yloxy)phenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 g
4ml of tetrahydrofuran was dissolved 3-hydroxy 50mlTHF added 60% NaH (1.1g), at room temperature the reaction 0.5h, cooled to 10 , the N- (4- fluoro-2-methoxy-5-nitrophenyl yl) -4- (1-methyl -1H- indol-3-yl) pyrimidin--2- (2g) was added to the reaction system, the reaction temperature was raised naturally 5h, TLC detection material to complete the reaction. 30 and concentrated to dryness under reduced pressure, 500ml of water was added, a large number of orange solid was precipitated, vacuum filtration, the filter cake washed with copious water and dried to give N- (2- methoxy-5-nitro-4- (tetrahydrofuran - 3- yloxy) phenyl-4- (1-methyl -1H- indol-3-yl) pyrimidin-2-amine (1g).
(2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
Intermediate 36: (2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate
Intermediate 36: (2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate A mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (2.5 g, 12.3 mmol), diisopropylethylamine (3.18 g, 4.3 mL, 24.6 mmol), 1-hydroxybenzotriazole hydrate (2.26g, 14.76 mmol), EDC (2.83 g, 14.76 mmol), and tetrahydrofuran-3-ol (10.84 g, 9.97 mL, 123 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (50 mL). The organic phase was washed with 1M hydrochloric acid (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried and evporated to give the title compound (3.07 g, 11.23 mmol, 91 % yield), as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 5.30-5.34 (m, 1H), 5.00-5.04 (m, 1H), 4.16-4.22 (m,1H), 3.92-3.94 (m, 1H), 2.12-2.22 (m, 1H). 1.93-2.03 (m, 1H), 1.78-1.84 (m, 1H), 1.60-1.69 (m, 1H), 1.43 (s, 9H), 0.92 (t, J = 12.0 Hz, 3H).
(2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43.7%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h;
Intermediate 48: (2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3- methylbutanoate A solution of <strong>[102507-13-1](S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid</strong> (250 mg, 1.072 mmol) in tetrahydrofuran (5 mL) was treated with triphenylphosphine (309 mg, 1.18 mmol) and diisopropyl azodicarboxylate (238 mg, 229 muL, 1.18 mmol). The mixture was stirred at room temperature for 5 minutes then tetrahydrofuran-3-ol (472 mg, 434 muL, 5.36 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (15 mL). The solution was washed with water (2x10 mL) and brine (10 mL).The organic phase was dried and evaporated. The residue was chromatographed [40% ethyl acetate/hexane] to give the title compound (142 mg, 0.468 mmol, 43.7 % yield) as a colourless oil. 1H NMR (400 MHz, CDCl3) delta ppm 5.33-5.44 (m, 2H), 4.14-4.20 (m, 1H), 3.83-3.97 (m, 4H), 2.13-2.25 (m, 1H), 2.00-2.12 (m, 1H), 1.44 (s, 9H), 1.26-1.29 (m, 6H).
3-(3-methoxy-4-nitrophenoxy)tetrahydrofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.8%
With diethylazodicarboxylate; In tetrahydrofuran; at 0 - 25℃; for 16.0h;Inert atmosphere;
<strong>[16292-95-8]3-methoxy-4-nitrophenol</strong> (1.0 g, 5.91 mmol),Hydroxytetrahydrofuran (0.52 g, 5.91 mmol) and(1.86 g, 7.09 mmol) was dissolved in dry THF (40 mL)The reaction was purged with nitrogen and reduced to 0 & lt; 0 &A solution of diethyl azodicarboxylate (1.5 g, 8.8 mmol) was slowly added dropwise,After the addition was completed, the reaction solution was transferred to the reaction at 25 C for 16 hours.After completion of the reaction, the reaction mixture was concentrated and the residue was purified by column chromatography (PE: EA = 8: 1) to give the title compound (1.2 g, yield 84.8%).
3-hydroxytetrahydrofuran (869.00 jiL, 10.56 mmol) was diluted in THF (33.5 mL). Then, the solution was cooled to 0 C and LiHMDS (10.00 mL, 10.56 mmol) was added. After 30 mi <strong>[1480-87-1]2-fluoro-3-nitropyridine</strong> (1.50 g, 10.56 mmol) was quickly added and the reaction mixture was stirred overnight allowing the temperature to reach rt. Thereaction mixture was mixed with another batch (from 100 mg of 2-fluoro-3- nitropyridine) and partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated to afford 2.03 g of intermediate 54 (91% yield) which was directly engaged in the next steps without any further treatment.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;
Preparation of (±)-7-bromo-5-chloro-l-(tetrahydrofuran-3-yl)-lH-pyrazolo[4,3-b] pyridine
Diisopropyl azodicarboxylate (254 mI, 1.29 mmol) was dropwise added to an ice cold solution of 7-bromo-5-chloro-lH-pyrazolo[4,3-b]pyridine (200 mg, 0.860 mmol), tetrahydrofuran-3-ol (racemic) (91 mg, 83 mI, 1.032 mmol) and triphenylphosphine (338 mg, 1.291 mmol) in THF (4 mL). After stirring at ice bath temperature over approx. 15 minuntes, the reaction mixture was allowed to reach room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo. Ethyl acetate was added and the mixture was washed with aqueous NaOH (IN) and brine, dried over Na2S04 and concentrated in vacuo. The crude material was purified via flash chromatography on silica gel (etyl acetate/heptane) to afford the title compound.
With potassium <i>tert</i>-butylate In tetrahydrofuran at 60℃; for 3h;
6-amino-4-methoxynicotinonitrile (9b)
General procedure: 8 (1g, 7.3 mmol) was added to a solution of t-BuOK(1.47 g, 13.1 mmol) in MeOH (20 mL). The reaction mixture stirred at 60 °C and stirred for 3 h. The cooled reaction mixture was concentrated. The resulting crude product was purified by silica gel chromatography (SiO2, petroleum ether/EtOAc stepwise elution, 2:1 to 1:1) to afford 9b as an white solid (780 mg72%).1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 5.96 (s, 1H), 3.92 (s, 3H).
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