* 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] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1757 - 1763
2
[ 13726-17-5 ]
[ 13726-16-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
With manganese dioxide In dichloromethane; benzene
D. Synthesis of 4-chloro-3-methoxybenzaldehyde To a solution of (4-chloro-3-methoxyphenyl)methan-1-ol (5.08 g, 29.4 mmol) in benzene (120 mL) was added MnO2 (5.65 g, 65 mmol). The reaction mixture was refluxed for 17 hr, chilled, and filtered through Celite, washing the cake with CH2Cl2 (300 mL). The filtrate was concentrated in vacuo to give 4-chloro-3-methoxybenzaldehyde (4.5 g, 89percent).
89%
With manganese dioxide In dichloromethane; benzene
D. Synthesis of 4-chloro-3-methoxybenzaldehyde To a solution of (4-chloro-3-methoxyphenyl)methan-1-ol (5.08 g, 29.4 mmol) in benzene (120 mL) was added MnO2 (5.65 g, 65 mmol). The reaction mixture was refluxed for 17 hr, chilled, and filtered through Celite, washing the cake with CH2Cl2 (300 mL). The filtrate was concentrated in vacuo to give 4-chloro-3-methoxybenzaldehyde (4.5 g, 89percent).
89%
With manganese(IV) oxide In benzine for 17 h; Reflux
D. Synthesis of 4-chloro-3-methoxybenzaldehyde (0202) To a solution of (4-chloro-3-methoxyphenyl)methan-1-ol (5.08 g, 29.4 mmol) in benzene (120 mL) was added MnO2 (5.65 g, 65 mmol). The reaction mixture was refluxed for 17 hr, chilled, and filtered through Celite, washing the cake with CH2Cl2 (300mL). The filtrate was concentrated in vacuo to give 4-chloro-3-methoxybenzaldehyde (4.5 g, 89percent).
87%
With pyridinium chlorochromate In dichloromethane at 20℃; for 3 h; Molecular sieve
[00154] Step 2. A suspension of pyridinium chlorochromate (1.37 g, 6.34 mmol) in dichloromethane (35 mL) was treated with Celite (2.0 g) and stirred at rt. A solution of (4-chloro-3-methoxyphenyl)methanol (730 mg, 4.23 mmol) in dichloromethane (5 mL) was added in one portion, and the resulting mixture was stirred at rt for 3 h. After this time, the mixture was diluted with diethyl ether, and stirred vigorously. The mixture was then filtered through a pad of silica gel and the collected solids were rinsed with additional diethyl ether. The combined filtrates were concentrated under vacuum to provide 4-chloro-3-methoxybenzaldehyde as a pale tan-yellow solid (630 mg, 87percent). 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3 H) 7.41 (dd, J=I.9, 1.8 Hz, 1 H) 7.45 (d, J=2.0 Hz, 1 H) 7.55 (d, J=7.6 Hz, 1 H) 9.95 (s, I H).
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[2] Patent: US2002/77486, 2002, A1,
[3] Patent: US6906063, 2005, B2,
[4] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0202
[5] Tetrahedron Letters, 2005, vol. 46, # 32, p. 5417 - 5419
[6] Patent: WO2010/9069, 2010, A1, . Location in patent: Page/Page column 47
[7] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[8] Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 352 - 358
[9] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[10] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
3
[ 73909-16-7 ]
[ 13726-16-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
With ammonium cerium(IV) nitrate; acetic acid In water at 100℃; for 1.25 h;
Step 2;. 4-Chloro-3- (methyloxy) benzaldehyde; Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1: 1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09g, 19 7 mmol, 1.00 equiv) in 1: 1 HOAc/H2O (100 mL) at 100 °C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H20 and extracted twice with Et20. The combined organic extracts were washed three times with H20, three times with satd. NaHC03, and once with brine. The organic phase was dried over MgS04 and concentrated en vacuo to afford the title compound (3. 00g, 89percent) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7. 57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
Reference：
[1] Patent: WO2005/82890, 2005, A1, . Location in patent: Page/Page column 88
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[4] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[5] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
[6] Patent: EP2314593, 2016, B1,
4
[ 189942-81-2 ]
[ 75-89-8 ]
[ 189942-82-3 ]
[ 13726-16-4 ]
Yield
Reaction Conditions
Operation in experiment
92.4%
Stage #1: at 0℃; Stage #2: With silver carbonate In 2,2,2-trifluoroethanol at 0 - 85℃; for 1.58333 h;
4-Chloro-3-methoxybenzaldehyde bis-(2,2,2-trifluoroethyl)acetal (2); NaH (60percent in mineral oil, 8.06 g, 0.2 mole) was washed 3 times (3.x.30 ml) with hexanes under an argon atmosphere. Two equivalents of 2,2,2-trifluoroethanol (13 ml, 0.18 mole) were slowly added at 0° C., generating hydrogen gas immediately as observed from an attached gas bubbler. The suspended mixture became viscous and the magnetic stirring bar was unable to spin at the end of addition. After the first addition of 13 ml 2,2,2-trifluoroethanol, an additional 2,2,2-trifluroethanol (87 ml) was carefully poured into the reaction vessel down the vessel walls; violent evolution of hydrogen gas occurred several times. Finally, the reaction stirred freely and a milky suspension resulted. 1-Chloro-4-dichloromethyl-2-methoxy-benzene 1 (20.2 g, 89.5 mmole) was added rapidly to the above sodium 2,2,2-trifluoroethoxide suspension through a syringe at 0° C. 2,2,2-Trifluoroethanol (26 ml) was used to rinse the syringe and added to the mixture. Vacuum-dried silver carbonate (49.9 g, 179 mmole) was then added in one portion to the solution. Following immediate removal of the ice bath, the suspended mixture was stirred at room temperature for 5 minutes, then heated at 8085° C. (bath temperature) for 90 minutes. The mixture became viscous again during the reaction. More 2,2,2-trifluoroethanol (54 ml) was added to keep the reaction stirring smoothly. The mixture was cooled and diluted with EtOAc. Some solid was filtered off and rinsed with EtOAc, combining the rinses with the filtrate. After concentration of filtrate, a cloudy oil was obtained. The crude product was partitioned between saturated NaHCO3 solution and 10percent EtOAc/hex, the aqueous layer was extracted two more times with 10percent EtOAc/hex. The combined organic layer was washed with H2O and dried over anhydrous Na2SO4. After concentration of the solution, 32.63 g of a light yellow oil was obtained. The impure product was purified by a silica gel plug filtration (column: 5.x.38 cm), eluting with 04percent EtOAc/hex by gravity to afford 29.18 g (92.4percent) of the TFE acetal 2 as a nearly colorless oil, which solidified in the refrigerator, mp: 29-31° C. TLC (5percent EtOAc/hexanes) showed that 4-chloro-3-methoxybenzaldehyde was the only byproduct. Its spot (rf=0.23) exhibited a nearly similar UV intensity as the TFE acetal 2 (rf=0.40). Based on the excellent yield of the reaction, the TFE acetal 2 apparently had a weak UV activity. IR (CHCl3, cm-1): 2950, 1602, 1590, 1490, 1466, 1412, 1280, 1170, 1120, 1070, 1032, 967 and 870. A very weak absorption of benzaldehyde at 1705 was detected. 1H NMR (CDCl3, ppm): δ 7.41 (1H, dd, J=6.9, 1.8 Hz), 7.027.05 (2H, m), 5.84 (1H, s), 3.803.98 (6H, m), 3.92 (3H, s).
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1757 - 1763
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 543,546
6
[ 16817-43-9 ]
[ 13726-16-4 ]
Reference：
[1] Patent: US2004/102360, 2004, A1,
7
[ 85740-98-3 ]
[ 13726-16-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[3] Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 352 - 358
[4] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[5] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
[6] Patent: EP2314593, 2016, B1,
8
[ 615-74-7 ]
[ 13726-16-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[2] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[3] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
[4] Patent: EP2314593, 2016, B1,
9
[ 67-56-1 ]
[ 104-88-1 ]
[ 13726-16-4 ]
Reference：
[1] Journal of the Indian Chemical Society, 2011, vol. 88, # 5, p. 727 - 730
10
[ 1009-36-5 ]
[ 13726-16-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
11
[ 97-52-9 ]
[ 13726-16-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
12
[ 75-17-2 ]
[ 13726-14-2 ]
[ 13726-16-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
13
[ 13726-16-4 ]
[ 13726-17-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1757 - 1763
[2] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
14
[ 13726-16-4 ]
[ 13726-21-1 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1966, p. 3311 - 3318
With ammonium cerium(IV) nitrate; acetic acid; In water; at 100℃; for 1.25h;
Step 2;. 4-Chloro-3- (methyloxy) benzaldehyde; Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1: 1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09g, 19 7 mmol, 1.00 equiv) in 1: 1 HOAc/H2O (100 mL) at 100 °C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H20 and extracted twice with Et20. The combined organic extracts were washed three times with H20, three times with satd. NaHC03, and once with brine. The organic phase was dried over MgS04 and concentrated en vacuo to afford the title compound (3. 00g, 89percent) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7. 57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
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