* 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 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 17h;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 3h;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) delta 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).
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).
A solution of <strong>[13726-16-4]4-chloro-3-methoxybenzaldehyde</strong> (34 mg) and compound 7 (35 mg) in THF (1 mL) was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (85 mg) was added in one portion. The mixture was stirred at room temperature for another hour and EtOAc (1 mL) was added followed by the addition of saturated aqueous ammonium chloride (1 mL). The aqueous phase was extracted by EtOAc (3 x l mL) and the combined organic extractants was dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound 8 as a white solid (36 mg, 95percent). LCMS: Rf: 3.460 min, M+H+ : 491.
With phosphorus pentachloride; In dichloromethane; at 20℃; for 20.0833h;
1-Chloro-4-dichloromethyl-2-methoxy-benzene (1); Powdered PCl5 (27.45 g, 0.15 mole) was added under argon to <strong>[13726-16-4]4-chloro-3-methoxybenzaldehyde</strong> (16 g, 94.1 mmole) in five portions; an exothermic reaction was noticed and the mixed solids melted. A water bath was used occasionally to maintain the reaction at room temperature. After the addition of PCl5 was completed, the mixture was stirred for 5 minutes, followed by addition of 66 ml CH2Cl2. The resulting white suspension in a yellow solution was stirred overnight at room temperature. TLC after 20 hours showed the reaction was nearly complete; a less polar spot (rf=0.41 in 5percent EtOAc/hex) was the major product. The reaction was quenched cautiously with saturated NaHCO3 solution at 0° C.; the mixture foamed with an exotherm. Powdered NaHCO3 was then added until the aqueous solution became alkaline. A white solid in the organic layer was filtered off and rinsed with CH2Cl2, combining the rinses with the filtrate. The two-phase filtrate was poured into a separatory funnel. After the organic layer separated, the aqueous layer was drained off and extracted twice with CH2Cl2. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4 and concentrated, to yield 23.79 g of a yellow oil. The crude product was purified by a silica gel plug filtration (column: 5.x.38 cm), eluting with 04percent EtOAc/hexanes by gravity. The separation was reasonably good, affording 20.2 g (95.2percent) of the dichloroacetal 1 as a nearly colorless oil. IR (CHCl3, cm-1): 1598, 1590, 1492, 1468, 1415, 1290, 1262, 1068 and 1032. No starting material benzaldehyde absorption at 16901706 was detected. 1H NMR (CDCl3, ppm): delta 7.37 (1H, d J=8.2 Hz, H-5), 7.18 (1H, d, J=2 Hz, H-2), 7.06 (1H, dd, J=8.2, 2 Hz, H-6), 6.67 (1H, s) and 3.96 (3H, s, OMe).
4-chloro-3-methoxybenzaldehyde dichloroacetal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.73 g (87%)
With sodium hydrogencarbonate; benzaldehyde; In dichloromethane;
4-Chloro-3-methoxybenzaldehyde dichloroacetal (1). 4-Chloro-3-methoxybenzaldehyde (1.5 g, 8.8 mmol) was added to PCI5 (2.45 g, 11.8 mmol) under argon and was stirred for 15 min. while heat evolved from the liquefied mixture. Methylene chloride (3 ml) was added and the solution was stirred overnight at room temperature; TLC analysis indicated a trace of UV activity from the starting benzaldehyde remained. Additional CH2 Cl2 (15 ml) and saturated NaHCO3 solution (40 ml) were added and the solution was stirred for 1 hr at room temperature to quench the reaction. The reaction mixture was partitioned between CH2 Cl2 and water, the aqueous layer was washed once with CH2 Cl2 and the combined organic layers were dried over Na2 SO4. The product was recovered after evaporating the solvent under pressure and pumping to dryness on high vacuum. Purification of the oil on silica gel, eluding with 4percent EtOAc/hexanes, yielded 1.73 g (87percent) of dichloroacetal 1 as a light yellow oil. 1 H NMR (CDCl3, ppm): 3.94 (3H, s); 6.65 (1H, s); 7.03 (1H, dd, J=2 Hz, 8 Hz); 7.15 (1H, d, J=2 Hz); 7.35 (1H, d, J=8 Hz)
N-cyclooctyl-3-methoxy-4-chloro-benzylamine-hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 34 Starting from 9.9 g of <strong>[13726-16-4]3-methoxy-4-chlorobenzaldehyde</strong> and 6.35 g of cyclooctylamine, there were obtained according to the method described in Example 1 7.2 g of N-cyclooctyl-3-methoxy-4-chloro-benzylamine-hydrochloride. Melting point 222°-223° C (from ethanol).
pyridin-4-ylcarbinol t-butyldimethylsilyl ether[ No CAS ]
[ 13726-16-4 ]
[ 1352562-70-9 ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; tetrabutyl ammonium fluoride; diisopropylamine; In tetrahydrofuran;
Step 4 1-(4-Chloro-3-methoxyphenyl)-2-pyridin-4-yl-ethane-1,2-diol (19-8) To a stirring solution of diisopropylamine (14.4 mL, 110 mmol) in tetrahydrofuran (400 mL) at -78° C. was added, dropwise, n-butyllithium (44 mL of a 2.5 M solution in tetrahydrofuran). After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (22.3 g, 100 mmol) in tetrahydrofuran (80 mL) was added dropwise and the temperature allowed to rise to -15° C. The solution was again cooled to -78° C. and a solution of <strong>[13726-16-4]4-chloro-3-methoxybenzaldehyde</strong> (19-6) (17 g, 100 mmol) in tetrahydrofuran (60 mL) added dropwise. After the solution was allowed to warm to room temperature, it was poured into saturated aqueous sodium hydrogen carbonate (2 L). The aqueous layer was extracted with ethyl acetate (3*400 mL), the combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran and to this solution was added tetrabutylammonium fluoride (120 mL of a 1.0 M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil chromatographed on silica gel, eluding with 95:5 to 90:10 dichloromethane:methanol to give the title compound as a mixture of diastereomeric diols (19-8) which was used without further purification.
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