* 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] Advanced Synthesis and Catalysis, 2007, vol. 349, # 4-5, p. 713 - 718
3
[ 5551-11-1 ]
[ 22614-72-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3397 - 3408
4
[ 89-59-8 ]
[ 5551-11-1 ]
Yield
Reaction Conditions
Operation in experiment
54%
With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In N,N-dimethyl-formamide at 135℃; for 48 h;
4-Chloro-1-methyl-2-nitrobenzene (8.5 g, 0.05 mol) was dissolved in dimethylformamide (10 ml).Further, N,N-dimethylformamide dimethyl acetal (18 g, 0.15 mol) was added and stirred, and the mixture was heated to 135 ° C for 48 hours, and the reaction was completed. The temperature was lowered to room temperature, and sodium periodate was slowly added dropwise. 32.1g, 0.15mol) of a mixed solution of water (100ml) and DMF (50ml), keep the temperature below 20 °C; after stirring at room temperature for three hours, the reaction of the plate material is completed; after suction filtration, the filter cake is washed with toluene After the second time; the filtrate separates the organic phase; the organic phase is washed with water, spin-dried through the column, and the mobile phase (petroleum ether: ethyl acetate = 10:1, then petroleum ether: ethyl acetate = 5:1) is washed to give 4 -Chloro-2-nitrobenzaldehyde, (5.00 g, 54percent).
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5113 - 5118
[2] Journal of Organic Chemistry, 2007, vol. 72, # 26, p. 9857 - 9865
[3] Patent: CN108484497, 2018, A, . Location in patent: Paragraph 0045; 0046; 0066; 0067
[4] Patent: DE128727, , ,
[5] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
[6] Organic Preparations and Procedures International, 2006, vol. 38, # 3, p. 325 - 331
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 1596
[8] Patent: WO2005/97800, 2005, A1, . Location in patent: Page/Page column 416-417
[9] Organic Letters, 2011, vol. 13, # 6, p. 1418 - 1421
[10] Synthetic Communications, 2011, vol. 41, # 20, p. 3078 - 3084
[11] Patent: CN108409660, 2018, A,
[12] Patent: CN108409659, 2018, A,
[13] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 6, p. 571
[14] Patent: CN108707112, 2018, A,
5
[ 32989-56-3 ]
[ 5551-11-1 ]
Yield
Reaction Conditions
Operation in experiment
22 g
With sodium periodate In water; N,N-dimethyl-formamide at 20℃; for 4 h;
Add 178g sodium periodate, 580mL water, 288mL DMF to the 2L three-neck bottle.After stirring uniformly, 233 g of the above crude product was directly introduced, and reacted at room temperature for 4 hours to complete the reaction; After suction filtration, the filter cake was washed 3 times with 200 ml of toluene, and the combined filtrate was layered.The aqueous phase was extracted once with 100 mL of toluene;The organic phase is combined, washed three times with water, once with saturated brine, dried and dried, and purified by column chromatography to obtain 22 g of compound 3
22 g
With sodium periodate In N,N-dimethyl-formamide at 20℃; for 4 h;
into a 2L three-neck bottle add 178 g of sodium periodate, 580mL of water, 288mL of DMF, after stirring evenly, directly input 233 g of the aforementioned crude product, normal temperature reaction for 4h to complete the reaction; after suction filtration, the filter cake is washed 3 times with 200 ml of toluene, the combined filtrates are layered, the aqueous phase is extracted once with 100mL of toluene; the organic phases are combined, washed 3 times with water, washed once with saturated brine, dried and dried, purification by column chromatography and then obtained 22 g of compound 3
Reference：
[1] Organic Preparations and Procedures International, 2006, vol. 38, # 3, p. 325 - 331
[2] Organic Letters, 2011, vol. 13, # 6, p. 1418 - 1421
[3] Synthetic Communications, 2011, vol. 41, # 20, p. 3078 - 3084
[4] Patent: CN108409660, 2018, A, . Location in patent: Paragraph 0021; 0031; 0033; 0034
[5] Patent: CN108409659, 2018, A, . Location in patent: Paragraph 0018; 0031
[6] Patent: CN108707112, 2018, A, . Location in patent: Paragraph 0013; 0023-0024; 0026
6
[ 89-59-8 ]
[ 4637-24-5 ]
[ 5551-11-1 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: at 140℃; for 16 h; Stage #2: With sodium periodate In tetrahydrofuran; water at 0 - 20℃; for 5.16667 h;
Example 110; This example concerns the synthesis of Aldehyde 5: To a stirred solution of 2 (5.248 g, 30.59 mmol) in dry DMF (172 mL) was added N,N-dimethylformamide dimethyl acetal (DMFDMA) (13.7 g, 12.0 mL, 88.5 mmol). After heating at 1400C for 16 h, the dark red solution was cooled to 0°C and added slowly, over 20 min via cannula, to a rapidly stirred solution OfNaIO4 (18.7 g, 87.4 mmol) in H2O (69 mL) and DMF (23 mL) at 0°C. The reaction flask was washed with DMF (20 mL) at 0°C and added to NaIO4 mixture. The reaction was stirred at 0°C for 30 min then allowed to warm to rt. After an additional 4 h, the orange solution was filtered and rinsed with PhMe (200 mL). The filtrate was then washed with H2O (2 x 200 mL) and sat. aq. NaCl (2 x 100 mL). The dried (MgSO4) extract was filtered, concentrated in vacuo to a dark red oil, and purified by flash chromatography over silica gel, eluting with 20-50percent EtOAc / Hexanes to give known aldehyde 5 (4.737 g, 25.53 mmol, 84percent). 1H NMR (400 MHz, CDCl3) δ 10.41 (s, IH), 8.13 (d, J- 2.0 Hz, IH), 7.97 (dd, J= 8.3 Hz, IH), 7.78 (dd, J= 2.0, 8.3 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 186.9, 150.1, 140.2, 134.2, 130.9, 129.3, 124.8.
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 42, p. 15742 - 15745
[2] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 11184 - 11188
[3] Advanced Synthesis and Catalysis, 2007, vol. 349, # 4-5, p. 713 - 718
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 19, p. 2751 - 2758
8
[ 32989-56-3 ]
[ 5551-11-1 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 4104 - 4107
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
9
[ 52311-59-8 ]
[ 5551-11-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 1996, vol. 80, # 2, p. 117 - 124
10
[ 1530-56-9 ]
[ 5551-11-1 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1596
11
[ 116435-81-5 ]
[ 5551-11-1 ]
[ 37777-71-2 ]
Reference：
[1] Journal of the Chemical Society, 1938, p. 1841,1844
[2] Journal of the Chemical Society, 1938, p. 1841,1844
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 694[2] Recueil des Travaux Chimiques des Pays-Bas, 1929, vol. 48, p. 1137
14
[ 643-43-6 ]
[ 5551-11-1 ]
Reference：
[1] Journal of the Chemical Society, 1938, p. 1841,1844
15
[ 5551-11-1 ]
[ 7439-89-6 ]
[ 59236-37-2 ]
Yield
Reaction Conditions
Operation in experiment
83%
With hydrogenchloride In ethanol; water; toluene
Method 2 4-Chloro-2-aminobenzaldehyde To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85° C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83percent) as a yellow solid. 1H NMR (CDCl3) δ7.58 (dd, 1H, J=2.1, 8.7 Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz), 9.45 (br s, 2H).
83%
With hydrogenchloride In ethanol; water; toluene
4-Chloro-2-aminobenzaldehyde To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85° C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83percent) as a yellow solid. 1H NMR (CDCl3) δ7.58 (dd, 1H, J=2.1, 8.7 Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz), 9.45 (br s, 2H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6463 - 6466
[2] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 7, p. 1859 - 1861
[3] Chemische Berichte, 1904, vol. 37, p. 1873
[4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
[5] Synthesis, 2010, # 10, p. 1678 - 1686
[6] ACS Combinatorial Science, 2012, vol. 14, # 5, p. 316 - 322
[7] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1311 - 1319
17
[ 5551-11-1 ]
[ 2365-48-2 ]
[ 104795-85-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 24.5 h;
To a solution of 600 mg (3.23 mmol) of 4-chloro-2-nitro-benzaldehyde in DMF (7 ml) were added 559 mg (4.04 mmol) of potassium carbonate and 294 μl (3.23 mmol) of methyl thioglycolate at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then for 24 h at RT. Then the mixture was poured into ice-water and the precipitate was collected by filtration and dissolved in ethyl acetate. The solution was dried (MgSO4) and concentrated to yield 630 mg (86percent) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester as a white solid. 1HNMR (CDCl3, 300 MHz): δ 3.95 (s, 3H), 7.88 (dd, J=8.6 and 1.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 8.02 (s, 1H).To a solution of 630 mg (2.78 mmol) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester in THF (5 ml) were added 6.95 ml of 1N LiOH-solution and the reaction mixture was stirred at RT for 4 h. The pH was then adjusted to 2-3 by addition of 1N HCl and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 579 mg (98percent) of 6-chloro-benzo[b]thiophene-2-carboxylic acid as white solid. MS (ISP) 211.0 (M-H)-.In analogy to example S3 (steps a to b) 139 mg (0.65 mmol) of 6-chloro-benzo[b]thiophen-2-carboxylic acid were converted into 52 mg (0.14 mmol) of (6-chloro-benzo[b]thiophen-2-ylmethyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine. The product was obtained as colorless liquid. MS (ISP) 370.0 (M+H)+.
With hydroxylamine hydrochloride; In pyridine; at 80℃; for 2h;
A mixture OF4-CHLORO-2-NITROBENZALDEHYDE (0.01077 mol) and hydroxylamine hydrochloride (1 : 1) (0. 01184 mol) in pyridine (20ml) was heated on an oil bath for 2 hours at 80 C and then the solvent was evaporated under reduced pressure. The residue was taken up in CH30H/DCM (10/90) and the resulting mixture was extracted with IN HCl and then washed with a NAHCO3 solution and water. The organic layer was separated, dried (MGS04), filtered off and the solvent was evaporated under reduced pressure. The residue was dried (vacuum) at 50C, yielding 1.75 g (81%) of intermediate 71.
With N,N-dimethyl-formamide dimethyl acetal; In N,N-dimethyl-formamide; at 135℃; for 48h;
4-Chloro-1-methyl-2-nitrobenzene (8.5 g, 0.05 mol) was dissolved in dimethylformamide (10 ml).Further, N,N-dimethylformamide dimethyl acetal (18 g, 0.15 mol) was added and stirred, and the mixture was heated to 135 C for 48 hours, and the reaction was completed. The temperature was lowered to room temperature, and sodium periodate was slowly added dropwise. 32.1g, 0.15mol) of a mixed solution of water (100ml) and DMF (50ml), keep the temperature below 20 C; after stirring at room temperature for three hours, the reaction of the plate material is completed; after suction filtration, the filter cake is washed with toluene After the second time; the filtrate separates the organic phase; the organic phase is washed with water, spin-dried through the column, and the mobile phase (petroleum ether: ethyl acetate = 10:1, then petroleum ether: ethyl acetate = 5:1) is washed to give 4 -Chloro-2-nitrobenzaldehyde, (5.00 g, 54%).
4-Chloro-2-nitrobenzaldehyde; [1316] A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) and dimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF (1.2 ml) was heated at 135 C in a sealed tube for 15 h. The reaction mixture was cooled to rt and added dropwise to a 20 C solution ofNaI04 (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After 3 h, the mixture was treated with water (20 ml) and extracted with EtOAc (3 x 15 ml). The extracts were washed with water (3 x 15 ml) and brine (15 ml), and dried over MgS04. After the solid was filtered off and the solvent was removed in vacuo, a brown solid of 4-chloro-2-nitrobenzaldehyde was obtained (J.Org.Chem. 2003, 68, 4104-4107). IH NMR (CDC13, 400 MHz) 5 7.74 - 7.78 (m, 1 H), 7.94 - 7.96 (m, 1 H), 8.11 - 8.12 (m, 1 H), 10.39 (s, 1 H).
With sodium periodate; In water; N,N-dimethyl-formamide; at 20℃; for 4h;
Add 178g sodium periodate, 580mL water, 288mL DMF to the 2L three-neck bottle.After stirring uniformly, 233 g of the above crude product was directly introduced, and reacted at room temperature for 4 hours to complete the reaction; After suction filtration, the filter cake was washed 3 times with 200 ml of toluene, and the combined filtrate was layered.The aqueous phase was extracted once with 100 mL of toluene;The organic phase is combined, washed three times with water, once with saturated brine, dried and dried, and purified by column chromatography to obtain 22 g of compound 3
22 g
With sodium periodate; In N,N-dimethyl-formamide; at 20℃; for 4h;
into a 2L three-neck bottle add 178 g of sodium periodate, 580mL of water, 288mL of DMF, after stirring evenly, directly input 233 g of the aforementioned crude product, normal temperature reaction for 4h to complete the reaction; after suction filtration, the filter cake is washed 3 times with 200 ml of toluene, the combined filtrates are layered, the aqueous phase is extracted once with 100mL of toluene; the organic phases are combined, washed 3 times with water, washed once with saturated brine, dried and dried, purification by column chromatography and then obtained 22 g of compound 3
With sodium periodate; In water; N,N-dimethyl-formamide; at 20℃; for 4h;
Add 178 g of sodium periodate and 580 mL of water to a 2 L three-necked flask.288 mL of DMF, stir well and directly input 233 g of the crude product.The reaction was carried out at room temperature for 4 h to complete the reaction;After suction filtration, the filter cake was washed three times with 200 ml of toluene, and the combined filtrate was separated. The aqueous phase was extracted once with 100 mL of toluene; the organic phase was combined, washed three times with water, once with saturated brine, dried and dried, and purified by column chromatography. 22g compound 3; nuclear magnetic analysis: 1H MR (400MHz, CDCl3) delta (ppm): 10.40 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 4.0 Hz, 1H),That is, as shown in Figure 2.
A solution of methyl lithium (46 mL, 1.4 M in Et2O), was slowly added under argon, at -78C, to a stirred solution of <strong>[5551-11-1]4-chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (10g, 53.9 mmol) in dry tetrahydrofuran (150 mL). After 20 min. at -78C, the reaction mixture was quenched with water (400 mL), extracted twice with ethyl acetate (500 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. Chromatography on silica (EtOAc/CH2Cl2/EtOH, 1:6:1) yielded the title compound (7.2 g, 66%) as yellow oil: 1H NMR (400 MHz, CDCl3) delta 1.56 (d, J = 6.4 Hz, 3H, ArH), 2.40 (br s, 1H, OH), 5.42 (q, J = 6.4 Hz, 1H, CH), 7.63 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H, ArH), 7.82 (d, J = 8.4 Hz, 1H, ArH), 7.92 (d, J = 2.0 Hz, 1H, ArH).
66%
In tetrahydrofuran; diethyl ether; at -78℃; for 0.333333h;
A solution of methyl lithium (46 mL, 1.4 M in Et2O), was slowly added under argon, at -78 C., to a stirred solution of <strong>[5551-11-1]4-chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (10 g, 53.9 mmol) in dry tetrahydrofuran (150 mL). After 20 min. at -78 C., the reaction mixture was quenched with water (400 mL), extracted twice with ethyl acetate (500 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. Chromatography on silica (EtOAc/CH2Cl2/EtOH, 1:6:1) yielded the title compound (7.2 g, 66%) as yellow oil: 1H NMR (400 MHz, CDCl3) delta 1.56 (d, J=6.4 Hz, 3H, ArH), 2.40 (br s, 1H, OH), 5.42 (q, J=6.4 Hz, 1H, CH), 7.63 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 7.82 (d, J=8.4 Hz, 1H, ArH), 7.92 (d, J=2.0 Hz, 1H, ArH).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 24.5h;
To a solution of 600 mg (3.23 mmol) of 4-chloro-2-nitro-benzaldehyde in DMF (7 ml) were added 559 mg (4.04 mmol) of potassium carbonate and 294 mul (3.23 mmol) of methyl thioglycolate at 0 C. The reaction mixture was stirred for 30 min at 0 C. and then for 24 h at RT. Then the mixture was poured into ice-water and the precipitate was collected by filtration and dissolved in ethyl acetate. The solution was dried (MgSO4) and concentrated to yield 630 mg (86%) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester as a white solid. 1HNMR (CDCl3, 300 MHz): delta 3.95 (s, 3H), 7.88 (dd, J=8.6 and 1.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 8.02 (s, 1H).To a solution of 630 mg (2.78 mmol) of 6-chloro-benzo[b]thiophene-2-carboxylic acid methyl ester in THF (5 ml) were added 6.95 ml of 1N LiOH-solution and the reaction mixture was stirred at RT for 4 h. The pH was then adjusted to 2-3 by addition of 1N HCl and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 579 mg (98%) of 6-chloro-benzo[b]thiophene-2-carboxylic acid as white solid. MS (ISP) 211.0 (M-H)-.In analogy to example S3 (steps a to b) 139 mg (0.65 mmol) of 6-chloro-benzo[b]thiophen-2-carboxylic acid were converted into 52 mg (0.14 mmol) of (6-chloro-benzo[b]thiophen-2-ylmethyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine. The product was obtained as colorless liquid. MS (ISP) 370.0 (M+H)+.
With potassium carbonate; In methanol; at 20℃; for 4h;
Example 112; This example concerns the synthesis of Acetylene 8: To a stirred solution of5 (3.667 g, 19.76 mmol), K2CO3 (5.510 g, 39.87 mmol), and MeOH (330 mL) was added diazophosphonate 6 (5.168 g, 26.90 mmol) at rt. After 4 h, the solution was quenched with sat. aq. NaHCO3 (200 mL) and concentrated in vacuo to remove the MeOH. The solution was diluted with EtOAc (200 mL) and washed with H2O (3 x 50 mL), and sat. aq. NaCl (2 x 50 mL). The dried (MgSO4) extract was concentrated in vacuo and purified by flash chromatography over silica gel, eluting with 1% EtOAc/Hexanes, to give 8 (2.870 g, 15.81 mmol, 81%) as a pale yellow solid. MP 68-70C; IR (thin film) 3285, 1555, 1528, 1345, 891, 840, 791, 761 cm"1; 1H NMR (400 MHz, CDCl3) delta 8.09 (d, J = 2.0 Hz, IH), 7.67 (dd, J = 8.4 Hz, IH), 7.60 (dd, J = 8.4, 2.0, IH), 3.59 (s, IH); 13C NMR (75 MHz, CDCl3) delta 150.5, 136.4, 135.3, 133.1, 124.9, 1 15.9, 86.3, 77.6; HRMS (CI+) calcd. for C8H5NO237Cl (M+H) 183.9979, found 183.9980.
A solution of 4-chloro-2-nitro-benzaldehyde (0. 010 rnol) AND N-METHYL-2-PROPEN-L- amine (0.010 mol) in DCM (q. s. ) was stirred for 15 hours at RT, then NaBH (OAC) 3 (0. 011 mol) was added and the reaction mixture was stirred for 3.5 hours at RT. Extra NaBH (OAc) 3 (0.002 mol) was added and the mixture was filtered over silica gel (eluent : DCM). THE SECOND FRACTION WAS REPURIFIED by column chromatography over silica gel and combined with previously obtained 1ST fraction and then the solvent was EVAPORATED. YIELDING 2. 0689 G (86 %) of intermediate 187.
D-proline tert-butyl ester hydrochloride[ No CAS ]
(R)-proline, 1-[(4-chloro-2-nitrophenyl)methyl]-, 1,1-dimethylethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Tetrakis (2-propanolato) titanium (0.010 mol) was added to a solution of D-Proline, 1, 1-dimethylethyl ester, hydrochloride (0.010 mol) and 4-chloro-2-nitro- benzaldehyde (0.010 mol) in DCM (30 ml), then the mixture was stirred for 1 hour at RT and NaBH (OAC) 3 (0. 011 mol) was added. The reaction mixture was stirred for 2 hours at RT and then water was added. The mixture was filtered over a P2 glass filter and washed with DCM, then the organic layer was separated and the aqueous layer was extracted 2 times with DCM. The organic layers were combined, dried, filtered off and the solvent was evaporated, yielding intermediate 150 (used as such in the next reaction step).
beta-alanine, N-[(2-amino-4-chlorophenyl)methyl]-, methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thiophene; potassium fluoride; hydrogen;platinum on activated charcoal; In tetrahydrofuran; methanol; isopropyl alcohol; at 50℃; for 24h;
A mixture of beta-ALANINE, methyl ester, hydrochloride (0.020 mol), 4-chloro-2-nitro- benzaldehyde (0. 010 mol) and potassium fluoride (0.019 mol) in methanol (100 ml) was hydrogenated at 50C for 24 hours with Pt/C (1 g, slurry in THF) as a catalyst in the presence of thiophene solution (1 ml, 4% in 2-propanol). After uptake of H2 (4 equiv.), the reaction mixture was filtered over dicalite, then the filter residue was washed with DCM and the solvent was evaporated. The obtained residue was dissolved in methanol and was used as such in the next reaction step, yielding intermediate 144.
With thiophene; hydrogen;platinum on activated charcoal; In tetrahydrofuran; methanol; ethyl acetate; at 50℃;
A solution of N-methyl-1, 3-dioxolane-2-methanamine (0.020 mol) and 4-chloro-2- nitro-benzaldehyde (0.010 mol) in methanol (200 ML) was hydrogenated at 50C over the weekend with Pt/C (cat. quant., slurry in EtOAc) as a catalyst in the presence of thiophene solution (q. s. , 4 % in THF). After uptake of H2 (4 equiv. ), the reaction mixture was filtered over dicalite and the solvent was evaporated. The residue was purified by RP high-performance liquid chromatography. The product fractions were collected and the organic component of the eluent was evaporated. The PRECIPETATE was filtered off, to give 0.7879 g (31 %) of intermediate 183.
Stepl : (2£)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acidA 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4- chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100 0C. The resultingU dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219g of the desired (2JS)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
With potassium carbonate; In acetic anhydride; at 100℃;
A 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4- chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100 0C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219g of the desired (2£)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
With acetic anhydride; potassium carbonate; at 100℃;
Example 40; 2-[9-chloro-6-(3-hydroxy-3-methylbut-l-yn-l-yl)- lH-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile; Step l; (2£)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid; A 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4- chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100 0C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219g of the desired (2£)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
A 2 L flask equipped with a mechanical stirrer was charged with 183 g of <strong>[5551-11-1]2-nitro-4-chlorobenzaldehyde</strong>, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100 C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219g of the desired (2E)- 2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid
ethyl 3-{2-[bis(methanesulfonyl)-amino]-4-chlorophenyl}acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With triethylamine; In tetrahydrofuran; ethanol; water;
(142-4) Under nitrogen atmosphere, to a solution of the compound of Example 142-3 (500 mg) in EtOH (12 mL) was added tin (II) chloride dihydrate (1.40 g), and the mixture was refluxed for 30 minutes. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution to made it basic, and extracted three times with ethyl acetate. The organic layers were washed with water and a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=5/1) to give an amino compound (201 mg). Under nitrogen atmosphere, the resulting amino compound was dissolved in THF (5.0 mL), and thereto were added NEt3 (300 mul) and methanesulfonylchloride (120 mul) at 0 C., and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate, washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give ethyl 3-{2-[bis(methanesulfonyl)-amino]-4-chlorophenyl}acrylate (229 mg, 31%, 2 steps). 1H NMR (CDCl3, 400 MHz) delta 7.91 (d, 1H, J=16.0 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.50 (dd, 1H, J=1.9, 8.5 Hz), 7.36 (d, 1H, J=1.9 Hz), 6.47 (d, 1H, J=16.0 Hz), 4.27 (q, 2H, J=7.1 Hz), 3.47 (s, 6H), 1.33 (t, 3H, J=7.1 Hz).
With hydrogenchloride; In ethanol; water; toluene;
Method 2 4-Chloro-2-aminobenzaldehyde To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85 C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%) as a yellow solid. 1H NMR (CDCl3) delta7.58 (dd, 1H, J=2.1, 8.7 Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz), 9.45 (br s, 2H).
83%
With hydrogenchloride; In ethanol; water; toluene;
4-Chloro-2-aminobenzaldehyde To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85 C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%) as a yellow solid. 1H NMR (CDCl3) delta7.58 (dd, 1H, J=2.1, 8.7 Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz), 9.45 (br s, 2H).
With potassium carbonate; In pyridine; ethyl acetate;
(1) 5.00 g (27 mmol) of <strong>[5551-11-1]4-chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> was dissolved in 50 ml of pyridine, treated with 3.80 g (40 mmol) of phenol and 7.40 g (54 mmol) of potassium carbonate, and heated at 100 C. for 2.5 hours. Then 5.30 g (67 mmol) of copper (II) oxide was added and the mixture was heated at 120 C. for 15.5 hours. The reaction mixture was concentrated under reduced pressure, treated with ethyl acetate, and filtered to remove insolubles. The filtrate was washed with saturated aqueous sodium carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was subjected to column chromatography on silica gel eluding with hexane-ethyl acetate (97:3) to obtain 4.80 g (yield: 73%) of 2-nitro-4-phenoxybenzaldehyde as a yellow oil. 1H-NMR (300 MHz, CDCl3); delta: 10.48 (1H, s), 7.88 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=7.5 Hz), 7.43 (1H, d, J=7.5 Hz), 7.25 (1H, dd, J=7.4, 7.4 Hz), 7.14 (1H, dd, J=8.4, 1.8 Hz), 7.10 (2H, d, J=8.7 Hz), 7.10 (2H, d, J=8.7 Hz), 6.89 (1H, d, J=1.8 Hz).
With n-butyllithium; pyridinium chlorochromate In tetrahydrofuran; diethyl ether; hexane; dichloromethane; acetic acid
1.a (a)
(a) Ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate To a cooled (-78° C.) solution of ethyl propiolate (8.96 mL, 88.4 mmol) in THF (100 mL) was added n-butyllithium (37.5 mL of 2.37M solution in hexane, 88.9 mmol) dropwise over 70 minutes so as to maintain the internal temperature below -70° C. Additional THF (5 mL) was used to rinse the addition funnel. A solution of 4-chloro-2-nitrobenzaldehyde (14.88 g, 80.2 mmol) in THF (30 mL) was transferred to the addition fiunel and added dropwise is over 47 minutes to maintain the reaction temperature below -70° C. Additional THF (5 mL) was used to rinse the addition funnel. The solution was stirred for 90 minutes at -70° C. and was then warmed to -60° C. glacial acetic acid (18.3 mL, 316 mmol) was quickly added. The solution was allowed to warm to 10° C. over 60 minutes and poured into diethyl ether (900 mL). The resulting solution was washed with saturated aqueous sodium carbonate (2*450 mL) and saturated aqueous sodium chloride (1*450 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator. This product was purified by flash chromatography eluding with ethyl acetate:hexanes (90:10) to give the title compound as red oil (14.73 g, 64.8%). The 4-chloro-2-nitrobenzaldehyde starting material can be prepared as follows: Borane dimethylsulfide (156 mL, 1.55 moles) was added to a stirred solution of 4-chloro-2-nitro-benzoic acid (313.0 g, 1.55 moles) and dry tetrahydrofiuran (2 L) at room temperature under N2 until about 30 mL had been added. The reaction mixture was then heated to gentle reflux. The rest of the borane dimethylsulfide was added dropwise (3 mL/min) with heating to maintain the temperature at gentle reflux. Heating at reflux was continued for 2.5 hours after addition was completed. Additional borane dimethylsulfide (20 mL, 0.2 mole) was added to the reaction mixture and heating was continued for 10 minutes. The reaction mixture was allowed to cool to room temperature and the reaction mixture was concentrated under water aspirator vacuum. The residue was dried under vacuum, then was dissolved in methylene chloride (1.7 L) and the solution was added (15 minutes) to a stirred mixture of pyridinium chlorochromate (375 g, 1.74 moles) and methylene chloride (3 L) under N2. Stirring was continued at room temperature for 0.5 hours, then the reaction mixture was heated at reflux for 1.5 hours. Additional pyridinium chlorochromate (110 g, 0.51 mole) was added and heating at reflux was continued for 1.5 hours. The reaction mixture was allowed to cool to room temperature and diethyl ether (3 L) was added with stirring. The mixture with filtered through CELITE and the pad was flushed with diethyl ether (2*500 mL). The filtrate and wash liquors were combined and filtered twice through silica gel (1200 mL) and (1200 mL). The filtrate was concentrated under water aspirator vacuum. The residue was dried under vacuum to give 4-chloro-2-nitro-benzaldehyde as a yellow powder (247.32 g, 86%).
3-(4-chloro-2-nitro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol;
Step 1: 3-(4-Chloro-2-nitro-benzylamino)-pyrrolidine-1-carboxylic Acid tert-butyl Ester To a solution of 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 mL) was added 4-Chloro-2-nitro-benzaldehyde (1.98 g, 10.7 mmol). The resultant solution was heated at 60 C. overnight. The reaction mixture was cooled to 0 C. and to it was added NaBH4 (629 mg, 10 mmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without further purification. LCMS (retention time=10.28, ES+; 356).
j1585] To a solution of 3-Amino-pyrrolidine-i-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 mE) was added 4-Chloro-2-nitro-benzaldehyde (1.98 g, 10.7 mmol). The resultant solution was heated at 60 C. overnight. The reaction mixture was cooled to 0 C. and to it was added NaI3H4 (629 mg, 10 mmol). Afier 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over Mg504, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without thrther purification. ECMS (retention time=i.28, ES+; 356)
Example 110; This example concerns the synthesis of Aldehyde 5: To a stirred solution of 2 (5.248 g, 30.59 mmol) in dry DMF (172 mL) was added N,N-dimethylformamide dimethyl acetal (DMF»DMA) (13.7 g, 12.0 mL, 88.5 mmol). After heating at 1400C for 16 h, the dark red solution was cooled to 0C and added slowly, over 20 min via cannula, to a rapidly stirred solution OfNaIO4 (18.7 g, 87.4 mmol) in H2O (69 mL) and DMF (23 mL) at 0C. The reaction flask was washed with DMF (20 mL) at 0C and added to NaIO4 mixture. The reaction was stirred at 0C for 30 min then allowed to warm to rt. After an additional 4 h, the orange solution was filtered and rinsed with PhMe (200 mL). The filtrate was then washed with H2O (2 x 200 mL) and sat. aq. NaCl (2 x 100 mL). The dried (MgSO4) extract was filtered, concentrated in vacuo to a dark red oil, and purified by flash chromatography over silica gel, eluting with 20-50% EtOAc / Hexanes to give known aldehyde 5 (4.737 g, 25.53 mmol, 84%). 1H NMR (400 MHz, CDCl3) delta 10.41 (s, IH), 8.13 (d, J- 2.0 Hz, IH), 7.97 (dd, J= 8.3 Hz, IH), 7.78 (dd, J= 2.0, 8.3 Hz, IH); 13C NMR (100 MHz, CDCl3) delta 186.9, 150.1, 140.2, 134.2, 130.9, 129.3, 124.8.
a. To a solution of <strong>[5551-11-1]4-chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (4 g) in dioxane (35 mL), was added 2-(tert-butyldimethylsilanyloxy)propylamine (6.1 g, 1.5 equivalent) in methanol (15 mL) followed by acid acetic (1.9 mL) in methanol (15 mL). After overnight stirring at room temperature, a molar solution of sodium cyanoborohydride in THF (22 mL) was added. After 30 minutes, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford [2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)amine (5.9 g, 77%).
With tin(ll) chloride; In ethanol; at 90℃; for 4h;
<strong>[5551-11-1]4-Chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (3.71 g, 0.02 mol) was dissolved in ethanol (40 ml).Further adding stannous chloride (18.04g, 0.08mol) and ethyl 3,3-diethoxypropionate (9.5g, 0.05mol), and reacting at 90 C for 4 hours, the reaction of the raw materials of the plate is completed; After the solvent was added, ethyl acetate was dissolved, and neutralized to a weak basic with saturated sodium carbonate; filtered, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate, and then the organic layer was combined, and then evaporated to dryness. Ethyl acetate = 10:1, then petroleum ether: ethyl acetate = 5:1) After washing, ethyl 7-chloro-3-quinolinecarboxylate (3.478 g, 74%).
With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium azide; at 0 - 20℃;Sealed tube;
General procedure: Substituted 2-azidobenzaldehydes were prepared by using a protocolreported by Driver et al. in 2011 in one step using the reaction ofcommercially available <strong>[5551-11-1]2-nitrobenzaldehyde</strong>s with sodium azide inHMPA. In a reaction vial dissolved <strong>[5551-11-1]2-nitrobenzaldehyde</strong> (1.0 g,6.62 mmol) in HMPA (10 mL) and sodium azide (0.90 g, 13.9 mmol)was added at 0 C. The reaction was stirred at ambient temperature forovernight. After completion of the reaction, the mixture was dilutedwith ice water and extracted with EtOAc (2×50 mL). The combinedorganic layers were washed with water (3×30 mL) and then driedover anhydrous Na2SO4. The solvent was removed under reducedpressure, and the crude product was purified by column chromatographyas eluent EtOAc: hexanes to afford the desired product.
With tin(II) chloride dihdyrate; In methanol; ethyl acetate; at 25℃; for 20h;
General procedure: A round bottom flask equipped with a magnetic stirrer bar was charged with the 2-nitroacylbenzene (1.00 mmol) in EtOAc-MeOH (1:1; 5 mL). SnCl2.H2O (3.00 mmol) was added and the reaction stirred at room temperature overnight. The reaction was partitioned between DCM (30 mL) and NaHCO3 (20 mL). The aqueous phase was extracted with DCM (3 × 10 mL) and the organic portions combined, washed with H2O (10 mL), saturated aqueous NaCl (10 mL), dried over MgSO4, filtered and reduced in vacuo. The residue was purified by column chromatography (SiO2, hexane/EtOAc) to provide the title compound. General procedure gave the title compound as an orange solid (122 mg, 80%).
With sodium hydroxide; In ethanol; water; at 20℃; for 3h;Inert atmosphere;
General procedure: Compounds 4a to 4f (0.5mmol), substituted aldehydes, and the mixture of ethanol and water (20mL, ethanol: water=3:1, v/v) were added to a three-necked flask. Subsequently, sodium hydroxide (1mL, 1%) was added slowly. After stirring for 3h at room temperature, the reaction was stopped, and the mixture was evaporated under reduced pressure to yield a turbid liquid, which was poured to water (20mL). When the mixture was adjusted at pH 7, a large amount of yellow powder was obtained, and then stirred for 30min. The yellow powder was purified by recrystallization with anhydrous ethanol solvent to yield compounds 5a to 5z, and 6a to 6h.
General procedure: A mixture of dimethylbromosulfoniumbromide (50 mmol) and methyl(triphenylphosphoranylidene) acetate (30 mmol) in CH2Cl2(30 mL) was stirred at r.t. under N2 atmosphere for 1 h. Then, itwas cooled to -78 C.Aldehyde (20 mmol) and NEt3 (160 mmol) were added dropwise. Thereaction mixture was slowly warmed to r.t. over 2 h and continued to stir at r.t.overnight. The resulting mixture was diluted with CH2Cl2 (50mL), and washed with saturatedaqueous Na2SO3. The organic layer was separated, dried over Na2SO4and then concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluted with petroleum/CH2Cl2 to provide 2-bromoacrylates.
7′,9′-bis(4-chloro-2-nitrophenyl)-3-phenyl-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; at 80℃; for 12h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
7′,9′-bis(4-chloro-2-nitrophenyl)-3-(4-methoxyphenyl)-1′,6′,7′,9′-tetrahydro-5H-spiro[isoxazole-4,8′-pyrazolo[3,4-f]quinolin]-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol; at 80℃; for 12h;
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (2.0 mmol), a 1H-indazol-6-amine 2 (1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 9-13 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 4 was collected by filtration without further purification.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate monohydrate; palladium diacetate; In tetrahydrofuran; water; at 40℃;Inert atmosphere;
Step 1: 2-Nitro-4-propenylbenzaldehyde by Suzuki reaction <strong>[5551-11-1]4-Chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (3.200 g; 16.382 mmol; 100.00 mol %), trans-propenylboronic acid (1.610 g; 18.556 mmol; 113.27 mol %) and tripotassium phosphate monohydrate (11.913 g; 49.147 mmol; 300.00 mol %) (mortared) were suspended in 15 ml of tetrahydrofuran and 150.000 mul of water in a 100 ml two-necked flask. The suspension was degassed in vacuo, blanketed with argon, and palladium(II) acetate (47% of Pd) for synthesis (18.390 mg; 0.082 mmol; 0.50 mol %) and 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (34.667 mg; 0.082 mmol; 0.50 mol %) were added in a counterstream of argon. The reaction mixture was stirred at 40 C. and under an argon atmosphere for a few hours. After the reaction, the mixture was filtered, and the filtrate was evaporated to dryness. Chromatographic purification of the residue on silica gel (eluent heptane/EA 11:1) gave 3.000 g of 2-nitro-4-propenyl-benzaldehyde (yield 95.8%, content 100%). MS-FAB (M+H+)=192.0 Rf (polar method): 2.28 min (MS track).
(E)-2-(4-chloro-2-nitrostyryl)benzo[b]thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
General procedure: To a suspension of hexane (5 mL) washed NaH (1.35 g, 28.14mmol) in dry THF (5 mL) at 0 oC under N2 was slowly added the solution of phosphonate ester 15 (4 g, 14.1mmol) in dry THF (5 mL) via syringe and stirred for 15 min. Then, a solution of <strong>[5551-11-1]2-nitrobenzaldehyde</strong> 16a(2.34 g, 15.5 mmol) in dry THF (2 mL) was added and allowed to stir for additional 30 min. After completion(monitored by TLC) of the reaction, it was then poured over crushed ice (100 g) containing Conc. HCl (3 mL),extracted with DCM (3 x 50 mL) and dried (Na2SO4). Removal of solvent in vacuo followed by crystallisation from methanol (10 mL) afforded 2-vinylbenzo[b]thiophene 17a as a bright yellow solid (3.44 g, 87%); mp: 88-90 oC; 1H NMR (300 MHz, CDCl3): delta 7.98 (d, J = 8.1 Hz, 1 H), 7.80-7.77 (m, 1 H), 7.74-7.71 (m, 1 H), 7.60(t, J = 7.8 Hz, 1 H), 7.51 (d, J = 15.6 Hz, 1 H, vinylic -CH), 7.41 (t, J = 7.8 Hz, 1 H), 7.34-7.32 (m, 4 H), 7.27(, J = 6.9 Hz, 1 H) ppm; 13C NMR (75 MHz, CDCl3): delta 147.8, 142.0, 139.9, 139.5, 133.2, 132.3, 128.3, 128.0,127.3, 125.3, 125.2, 124.9, 124.7, 123.8, 122.4 ppm; Anal. Calcd for C16H11NO2S: C, 68.31; H, 3.94; N, 4.98;Found: C, 68.12; H, 3.74; N, 5.22.
(R)-methyl 2-amino-3-(pyridin-2-yl)propanoate hydrochloride[ No CAS ]
[ 5551-11-1 ]
(R)-methyl 2-((4-chloro-2-nitrobenzyl)amino)-3-(pyridin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
To a suspension of Intermediate II.2 (5.5 g, 22 mmol) in MeOH (200 mL) was added triethylamine (6.0 mL, 43 mmol). To this clear solution was added 4-chloro-2- nitrobenzaldehde (4.0 g, 22 mmol), and the resulting mixture was stirred at 23C for 1 h. Sodium cyanoborohydride (1.4 g, 22 mmol) was added followed by acetic acid (2.5 mL, 43 mmol). The reaction mixture was stirred at 23C for 18 h. The mixture was concentrated in vacuo. The crude residue was taken up in EtOAc (100 mL), and washed with 0.5 N NaOH (aq) (1X100 mL). The aqueous phase was then extracted with EtOAc (2X100 mL), and the combined organic extracts were washed with brine (1X100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by FCC (SiO2; elution with 0-5% CH3OH/DCM) to provide 3.8 g (51 %) of 19-1. 1H NMR (400 MHz, CDCl3): dppm 8.50 (m, 1H), 7.88 (m, 1H), 7.60 (td, 1H), 7.43 (m, 2H), 7.17- 7.11 (m, 2H), 4.01 (ABq, 2H), 3.73 (dd, 1H), 3.69 (s, 3H), 3.18 (dd, 1H), 3.03 (dd, 1H), 2.34 (br s, 1H, N-H); LCMS (Method A) tR= 0.89 min, m/z 350.2/352.2 (M+H)+.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; for 24h;
(b) adding 50 g of compound 3 to a 500 mL three-necked flask,50g NBS (ie N-bromosuccinimide),0.3g BPO (ie dibenzoyl peroxide) and 300mL of carbon tetrachloride, the external temperature rise to 90 C, and the reaction for 24h (at this time, TLC showed complete reaction); pour the reaction solution into 500 mL of ice water, adjust the pH to 10 with 2N (equivalent concentration) sodium hydroxide solution, extract the layers, combine the organic phases, and wash with 5% sodium bicarbonate (mass concentration, the same below) solution. Drying, spin drying, column chromatography to obtain 52 g of compound 4 (yield 75%)
With sodium hydride; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 50℃; for 12.5h;Cooling with ice;
(c) adding 10 g of compound 3 to a 250 mL three-necked flask,21.6 g of compound 5 and 100 mL of DME (ie ethylene glycol dimethyl ether), stirred and dissolved,2.3 g of sodium hydrogen (ie, sodium hydride in DMF solution, content 60% by weight) was added under ice water bath conditions.After the addition is completed, the reaction is raised to 50 C for 0.5 h. Raise the temperature for reflux for 2 h,The reaction was cooled to 50 C and the reaction was continued for 10 hours (at this time TLC showed the reaction was completed; water (50 mL) and ethyl acetate (50 mL) were added, and a large amount of solid was precipitated and filtered with suction. The filter cake was beaten with ethanol for 30 min, filtered, and dried to give 8.5 g. Compound 6 (yield 43%)
59%
With sodium hydride; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 50℃; for 12.5h;
(C) into a 250mL three-neck bottle add 10g of compound 3, 21.6g of compound 5 and 100mL of DME (i.e. glycol dimethyl ether), stir and dissolve, under ice water bath conditions add .3g of sodium hydrogen (i.e. sodium hydride DMF solution, the content is 60wt%), after the addition has been completed, the reaction temperature is raised at 50 C for 0.5h, temperature rise for reflux reaction 2h, the reaction is continued at 50 C for 10 hours (TLC showed the reaction has completed; add water (50mL) and ethyl acetate (50mL), a large amount of solid has been precipitated, suction filtration, and the cake is beaten with ethanol for 30 min, suction filtered, and dried and then obtained 8.5 g of compound 6 (yield: 43%); the present invention provides a preparation method of a key intermediate of a drug impurity isomer of depression and a preparation method thereof based on the impurity impurity isomer of a depression drug,It is basically the same as in the first embodiment,The difference is: step (c)Add 3.0g of sodium hydrogen,Finally, 11.5 g of Compound 6 (yield 59%, purity 99.5%) was obtained.
59%
With sodium hydride; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 50℃; for 2.5h;Reflux;
(c) adding 10 g of compound 3 to a 250 mL three-necked flask,21.6 g of compound 5 and 100 mL of DME (ie ethylene glycol dimethyl ether),Stirring and stirring, adding 2.3 g of sodium hydrogen (ie, sodium hydride in DMF solution, content of 60 wt%) under ice water bath.After the addition is completed, the reaction is raised to 50 C for 0.5 h, and the temperature is raised to reflux for 2 h.The reaction was cooled to 50 C and the reaction was continued for 10 hours (at this time TLC showed the reaction was complete;Water (50 mL) and ethyl acetate (50 mL) were added, and a large amount of solid was precipitated and filtered with suction. The filter cake was beaten with ethanol for 30 min, filtered, and dried to give 8.5 g of compound 6 (yield: 43%); (nuclear magnetic of compound 6) The spectrum is shown in Fig. 5. The specific resolution is: 1H NMR (400MHz, CDCl3) delta (ppm): 8.01 (br, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.63 - 7.61 (m, 3H) , 7.47 (d, J = 8.0 Hz, 1H), 7.37-7.32 (m, 2H)).
methyl 3-(4-chloro-2-nitrophenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium t-butanolate; In tetrahydrofuran; at 50℃; for 12h;Schlenk technique; Inert atmosphere;
Phosphate ylide (2.54 g) was added to a Schleck bottle containing 200 mL of tetrahydrofuran under a nitrogen atmosphere, and 0.72 g of sodium t-butoxide was added thereto under stirring, and the mixture was stirred at room temperature for 2 hours, and then 0.93 g was added. <strong>[5551-11-1]4-Chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> was stirred at 50 C for 12 hours.After the reaction, the mixture was filtered, and the filtrate was distilled under reduced pressure.A yellow solid was obtained which was purified by column chromatography eluting eluting eluting eluting
4-chloro-1-(difluoromethyl)-2-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 3.33h;
To a solution of 4- chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong> (705 mg, 3.80 mmol) in dichloromethane (12 mL) was added diethylaminosulfur trifluoride (DAST) (0.653 mL, 4.94 mmol) dropwise over 20 min. The solution was stirred at rt for 3 h and then concentrated under vacuum. The residue was purified with a silica gel flash column, eluting with 0-20% EtOAc in hexane to afford 4-chloro-1-(difluoromethyl)-2-nitrobenzene (756 mg, 3.64 mmol, 96 % yield) as an oil. 1H NMR (400 MHz, chloroform-d) delta 8.12-8.16 (m, 1H), 7.82-7.88 (m, 1H), 7.75 (dd, J=1.76, 8.36 Hz, 1H), 7.18-7.50 (m, 1H).
With nano cellulose OBF2; In ethanol; at 78℃; for 0.25h;Green chemistry;
Nano-cell-OBF2 catalysis (8 mg) was added to a stirred mixtureof an appropriate aromatic aldehyde (1 mmol), 4-hydroxy-6-methyl-2H-pyran-2-one (0.12 g, 1 mmol) andmalononitrile (0.08 g, 1.2 mmol) in EtOH (5 mL). This mixturewas magnetically stirred and refluxed at 78 C for15-27 min. TLC monitored the progress of the reaction (nhexane:ethyl acetate 3:1). Upon the completion of the reaction,the reaction mixture was conventionally filtered off forthe removal the heterogeneous solid nanocatalyst. The filtratewas evaporated under reduced pressure and the crudeproduct was crystallized from hot ethanol to obtain the purecorresponding desired compounds.
92%
With nano-cellulose-OBF2; In ethanol; at 78℃; for 0.25h;Green chemistry;
General procedure: Nano-cell-OBF2 catalysis (8 mg) was added to a stirred mixture of an appropriate aromatic aldehyde (1 mmol), 4-hydroxy-6-methyl-2H-pyran-2-one (0.12 g, 1 mmol) and malononitrile (0.08 g, 1.2 mmol) in EtOH (5 mL). This mixture was magnetically stirred and refluxed at 78 C for 15-27 min. TLC monitored the progress of the reaction (n-hexane: ethyl acetate 3:1). Upon the completion of the reaction, the reaction mixture was conventionally filtered off for the removal the heterogeneous solid nanocatalyst. The filtrate was evaporated under reduced pressure and the crude product was crystallized from hot ethanol to obtain the pure corresponding desired compounds.
tert-butyl 2-[(4-chloro-2-nitrophenyl)methylcyclohexylamino]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 0 - 20℃; for 12h;
tert-butyl 2-[(4-chloro-2-nitro-phenyl)methyl-cyclohexyl-amino]acetate (35) To a stirred suspension of tert-butyl 2-(cyclohexylamino)acetate (34, 556 mg, 2.61 mmol) in CH2Cl2 (13 mL) were added AcOH (0.0782 mL, 13.7 mmol), <strong>[5551-11-1]4-chloro-<strong>[5551-11-1]2-nitrobenzaldehyde</strong></strong> (829 mg, 4.47 mmol), and NaBH(OAc)3 (857 mg, 4.04 mmol) at 0 C. After stirring at ambient temperature for 12 hours, the reaction mixture was diluted with CH2Cl2, quenched with aq. NaHCO3, extracted with CH2Cl2, and washed with brine. The combined organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane/EtOAc = 75:25 to 55:45) provided the title compound (35) as a yellow oil (478 mg, 1.25 mmol, 48%). LCMS: m/z 383 [M + H]+. 1H-NMR (CDCl3) delta: 8.01 (1H, d, J = 8.5 Hz), 7.87 (1H, d, J = 2.4 Hz), 7.54 (1H, dd, J = 8.2, 2.1 Hz), 4.09 (2H, s), 3.24 (2H, s), 2.47-2.47 (1H, m), 1.81-1.77 (4H, br m), 1.43 (9H, s), 1.16-1.06 (6H, br m).
Multi-step reaction with 2 steps
1: iron; ammonium chloride; water / ethanol / 2 h / 60 °C
2: N-Bromosuccinimide / N,N-dimethyl-formamide / 2 h / 20 °C
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