* 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] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4790 - 4793
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 6, p. 1455 - 1459
[3] Tetrahedron Letters, 2002, vol. 43, # 41, p. 7303 - 7306
3
[ 352-70-5 ]
[ 446-33-3 ]
[ 446-34-4 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
4
[ 591-09-3 ]
[ 352-70-5 ]
[ 446-33-3 ]
[ 446-34-4 ]
Reference：
[1] Bl. Soc. Sci. Lett. Lodz, 1952, vol. 3, # 15, p. 4[2] Chem.Abstr., 1955, p. 203
5
[ 578-46-1 ]
[ 446-34-4 ]
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 8, p. 2376 - 2377
6
[ 352-70-5 ]
[ 446-33-3 ]
[ 446-34-4 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448 - 8454
7
[ 352-70-5 ]
[ 446-34-4 ]
Reference：
[1] Chemische Berichte, 1929, vol. 62, p. 1804
[2] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
8
[ 591-09-3 ]
[ 352-70-5 ]
[ 446-33-3 ]
[ 446-34-4 ]
Reference：
[1] Bl. Soc. Sci. Lett. Lodz, 1952, vol. 3, # 15, p. 4[2] Chem.Abstr., 1955, p. 203
9
[ 446-34-4 ]
[ 452-81-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
10
[ 446-34-4 ]
[ 825-98-9 ]
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
11
[ 446-34-4 ]
[ 452-80-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[2] Acta Chemica Scandinavica (1947-1973), 1955, vol. 9, p. 1079,1083
[3] Bl.Soc.Sci.Lett.Lodz, 1952, vol. <3>3, # 15, p. 6
[4] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
[5] Journal of Medicinal Chemistry, 2000, vol. 43, # 26, p. 5017 - 5029
12
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Reference：
[1] Patent: US4243819, 1981, A,
13
[ 446-34-4 ]
[ 108-24-7 ]
[ 326-67-0 ]
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
14
[ 446-34-4 ]
[ 5081-36-7 ]
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
15
[ 446-34-4 ]
[ 455-87-8 ]
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[2] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
16
[ 446-34-4 ]
[ 403-21-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium dichromate; sulfuric acid In acetic acid at 120℃; for 2 h;
2-Fluoro-4-methyl-l-nitro-benzene (1.0 g, 12.9 mmol) was added portion- wise to a suspension of potassium dichromate (5.04 g, 17.16 mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid (3.6 mL). The reaction mixture was heated to 1200C for 2 h and then allowed to cool to ambient temperature. The reaction was quenched with crushed ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-fluoro-4-nitro-benzoic acid (1.9 g, 83percent) as a white solid.
82.9%
With potassium permanganate In ethyl acetate
Reference Example 39 An aqueous solution (50 mL) containing 3-fluoro-4-nitrotoluene (2.0 g, 12.9 mmol) and potassium permanganate (4.07 g, 25.8 mmol) was heated under reflux for 15 hours. The reaction solution was cooled and then aqueous phase was washed with ethyl acetate. The aqueous phase was acidified with 4 N aqueous hydrochloric acid solution, and the precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate five times. The crystals collected by filtration were dissolved in ethyl acetate, and combined with the ethyl acetate extraction solution. The ethyl acetate layer combined was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, to obtain 3-fluoro-4-nitrobenzoic acid (1.07 g, 82.9percent) as pale yellow crystals. 1H-NMR(CDCl3)δ:8.01-8.06(1H,m),8.12-8.18 (1H,m) ppm FABMS:186(M+1)
68%
With sodium dichromate; sulfuric acid In water at 0 - 90℃; for 4.3 h;
(a) Synthesis of 3-fluoro-4-nitrobenzoic acid Sodium dichromate (6.50 g, 21.8 mmol) was added to a suspension of 3-fluoro-4-nitrotoluene (2.50 g, 16.0 mmol) in water (19 ml) under ice-cooling, and concentrated sulfuric acid (14.7 ml) was added dropwise thereto at 6°C over a period of 2 hours. After completion of the dropwise addition, an ice-water bath was removed and the mixture obtained was allowed to stand for 20 minutes until its temperature became room temperature. Thereafter, the mixture was heated and then stirred at 90°C for 2 hours. After completion of the reaction, water (50 ml) was poured into the reaction mixture under ice-cooling, and the resulting mixture was stirred at room temperature for a while. This mixture was extracted twice with ethyl acetate and then the organic layer was washed three times with a 2N-aqueous sodium hydroxide solution. The aqueous layer was acidified with 6N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated and the crude product thus obtained was purified by a silica gel column chromatography (eluent: chloroform/methanol = 8/2) to obtain 3-fluoro-4-nitrobenzoic acid (2.00 g, 68percent).
58%
With potassium permanganate In water for 6 h; Heating / reflux
Stage 1: 3-fluoro-4-nitrobenzoic acid A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2*300 ml). The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield). NMR (1H, 400 MHz, DMSO-d6): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
58%
Stage #1: With potassium permanganate In water for 6 h; Reflux Stage #2: at 0℃;
EXAMPLE A1; N,N-bis(3-methylbutyl)-11-oxo-5-(3-piperidin-1-ylpropyl)-5,11-dihydrothieno[3',2':4,5]pyrimido[1,2-a]benzimidazole-7-carboxamide hydrochloride; Stage 1: 3-fluoro-4-nitrobenzoic acid; A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2.x.300 ml). The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield).NMR (1H, 400 MHz, DMSO-d6): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
58%
With potassium permanganate In water for 6 h; Heating / reflux
Stage 1: 3-fluoro-4-nitrobenzoic acid A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 l) is heated to reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2*300 ml). The aqueous phase is acidified with an aqueous solution of concentrated hydrochloric acid (12N) then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield). NMR 1H (400 MHz, DMSO-d6): δ7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
24%
With sodium dichromate; sulfuric acid In water at 90 - 100℃; for 1 - 2 h;
Concentrated H2SO4 (190 mL) was added dropwise to a cooled solution of 3-fluoro-4- nitrotoluene (161.2 mmol, 25 g) and sodium dichromate dihydrate (225.6 mmol, 67.2 g) in water (200 mL). The addition was carried out while maintaining the temperature of the reaction mixture below 10 [C.] Once the addition was complete, the solution was refluxed at 100 [C] for approximately 2 h. The reaction mixture was cooled to room temperature, diluted with H20 (200 mL) and the product extracted with ethyl acetate. The organic extracts were combined and extracted with a solution of 2N sodium hydroxide. The basic phase was acidified with concentrated [HC1] to afford (65.9 mmol, 12.2 g) as an off-white solid precipitate (yield: 40.8percent). The precipitate was further purified by recrystallization from an ethanol/water mixture to afford 3-fluoro-4- nitrobenzoic acid as white crystals.To a solution [OF 3-FLUORO-4-NITROTOLUENE] (22.45 g, 144.7 mmol) and sodium dichromate dihydrate (60.38 g, 202.6 mmol) in water at [0 C] was added concentrated sulfuric acid (140 mL) dropwise over 3 h. When the addition was complete, the solution was allowed to warm to room temperature over [1] h, and then brought to 90 C for 1 h. The mixture was allowed to cool to room temperature, diluted with 300 mL water and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts were concentrated down to 300 mL and extracted with [1] N NaOH (3 x 250 mL). The aqueous extracts were acidified with 6 N [HC1] and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over [MGS04] and concentrated to give a gummy solid. Trituration with hexane gave the [3-FLUORO-4-NITROBENZOIC] acid as a solid that was collected by filtration (6.51 g, 24percent).
68%
With Na2Cr2O7; sulfuric acid In sodium hydroxide; water
Example 8 Synthesis of 3-Fluoro-4-[3-Pentyl-3-(5,5,8,8-Tetramethyl-5,6,7,8-Tetrahydro-Naphthalen-2-yl)-Ureido]-Benzoic Acid A solution of 3-fluoro-4-nitrotoluene (2 g, 12.82 mmole) in 13 mL water, containing 5.72 g of Na2Cr2O7, was treated dropwise with 14.2 mL of concentrated sulfuric acid, stirred at room temperature for one hour and then diluted with 20 mL of water. The mixture was filtered and the recovered solid was gently heated in 50 mL 2percent sodium hydroxide solution. The resulting solution was cooled and filtered and the filtrate was acidified with concentrated HCl. The aqueous phase was extracted with two 100 mL portions of ethyl acetate, the combined extracts were washed with 100 mL of aqueous saturated sodium chloride solution, dried over MgSO4, filtered and concentrated in vacuo to give 1.6 g (68percent) of 3-fluoro-4-nitrobenzoic acid as a yellow solid.
Reference：
[1] Patent: WO2009/130481, 2009, A1, . Location in patent: Page/Page column 145
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1729 - 1744
[3] Patent: EP1820799, 2007, A1,
[4] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 60-61
[5] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1386 - 1391
[6] Patent: EP1500643, 2005, A1, . Location in patent: Page 39
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1043 - 1046
[8] European Journal of Medicinal Chemistry, 1999, vol. 34, # 3, p. 225 - 234
[9] Patent: US2005/65179, 2005, A1, . Location in patent: Page/Page column 9
[10] Patent: US2009/209531, 2009, A1, . Location in patent: Page/Page column 5
[11] Patent: US2006/281784, 2006, A1, . Location in patent: Page/Page column 8
[12] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4345 - 4359
[13] Patent: US4483986, 1984, A,
[14] Patent: WO2004/14905, 2004, A1, . Location in patent: Page 157; 157
[15] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[16] Journal of Medicinal Chemistry, 1983, vol. 26, # 8, p. 1193 - 1196
[17] Patent: US2003/158226, 2003, A1,
[18] Patent: US5624957, 1997, A,
17
[ 51632-16-7 ]
[ 446-34-4 ]
[ 69409-98-9 ]
Reference：
[1] Patent: US4243819, 1981, A,
18
[ 446-34-4 ]
[ 160538-51-2 ]
Yield
Reaction Conditions
Operation in experiment
29.2%
Stage #1: at 5 - 10℃; for 3 h; Stage #2: for 0.25 h; Stage #3: for 0.25 h; Heating / reflux
Preparation of Compound 5, Sodium Salt; [0057] Sulfuric acid (14.5 mL) was slowly added to a solution of 3-fluoro-4-nitrotoluene (10.0 g, 64 mmol) in acetic acid (75 mL) at 5° C. Cromium trioxide (17.92 g, 180 mmol) was added slowly over 1 hour. The reaction was kept below 10° C. for an additional 2 hours and then poured into ice water (700 mL) and the resulting yellow solids filtered off. The solids were stirred in 2percent NaHCO3 for 15 minutes, filtered, dried in vacuo, then heated to reflux for 15 minutes in a solution of: water (60 mL), concentrated HCl (40 mL), and ethanol (11 mL). The yellow solids were isolated by filtration, 3.16 g 4-nitro-2-fluorobenzaldehyde (29.2percent yield).
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 21, p. 7223 - 7226
[2] Patent: US2003/216589, 2003, A1, . Location in patent: Page/Page column 6
[3] Tetrahedron Letters, 1994, vol. 35, # 45, p. 8465 - 8468
19
[ 446-34-4 ]
[ 185629-31-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 4, p. 1043 - 1046
With NBS; 2,2'-azobisisobutyronitrile In Carbon tetrachloride for 8h; Irradiation;
58%
With potassium bromate; sodium dihydrosulfite In dichloromethane; water monomer for 10 - 16h;
39.1; 175.1
In a 2 L of round bottle flask was placed 3-fluoro-4-nitrotoluene (7.2 g) in 700 mL of dichloromethane. To this was added 500 mL of water and then potassium bromate (31 g), followed by adding sodium hydrosulfite (32 g) from a funnel dropwise as a solution in 200 mL of water during the period of 16 h. The reaction was transferred to a separatory funnel and washed with Na2S203 aq NaHC03 and water. The organic phase was dried over MgS04, filtered and evaporated to produce an oil. The oil was put in the freezer over the weekend to give crude yellow precipitate (10.55 g). The crude product was purified with a column (125 g silica gel), eluting with EtOAc in hexanes (from 0 to 20%) to give 3.2 g of white precipitate (58% yield). ¹H NMR (CD2Cl2) : No. 8.05(t, 1H), 7.35 (m, 2H), 4.5 (s, 2H).; Step 1: Preparation of 1-(3-fluoro-4-nitrobenzylbromide) In a 3 L round bottom flask 3-fluoro-4-nitrotoluene (10 g, 64 mmol) was dissolved in methylene chloride (1 L). To the solution, 500 mL of water was added, followed by potassium bromate (43 g, 257 mmol). Sodium hydrosulfite (53 g) in 500 mL of water was added dropwise to the reaction mixture over 10 h. The organic layer was separated, washed and concentrated. The crude product was purified on silica gel column using 0 to 20% EtOAc/hexanes as eluent to furnish 9.7 g (64%) of the desired product.
57%
With NBS; 2,2'-azobisisobutyronitrile In DCE Heating;
57.3%
With NBS; 2,2'-azobisisobutyronitrile In Carbon tetrachloride at 95℃; for 24h;
54%
With NBS; dibenzoyl peroxide In Carbon tetrachloride Heating;
47%
With NBS; benzoic acid anhydride In Carbon tetrachloride Heating / reflux;
D.1 3-FLUORO-4-NITROBENZYL bromide
In the step D-1, to a solution of 3-fluoro-4-nitrotoluene (4.83 g) in carbon tetrachloride (50 ML) were added N-bromosuccinimide (NBS, 12.6 g) and benzoyl peroxide (0.45 g). The mixture was refluxed overnight and additional NBS (6.3 g) and benzoyl peroxide (0.15 g) were added to reflux for another 10 hours. After cooling, the reaction mixture was passed through a filter paper to remove resulting precipitates, that were washed with chlorofolm (50 ml). The filtrates were combined and washed with saturated sodium thiosulfite water solution and brine, successively. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1 to 5/1) to obtain 3- fluoro-4-nitrobenzyl bromide as a yellow oil (3. 43 g, 47%).
1.1 Procedure A.
Step 1: Preparation of 4-(bromomethyl)-2-fluoronitrobenzene. A stirred suspension of N-bromosuccinimide (NBS, 24.0 g, 136 mmol) and 3-fluoro-4-nitrotoluene (12.1 g, 78 mmol) in 1,2-dichoroethane (DCE, 250 mL) is irradiated with a 650 watt sunlamp for 1 h. For the first 60 min, the temperature of the solution is maintained between 0 and 25° C. with external cooling; most of the NBS dissolves during this time. The cooling bath is then removed and irradiation is continued for 15 min so as to complete the reaction. The DCE is evaporated under reduced pressure and the residual oil is partitioned between ether (150 ML) and water (100 mL). The product is chromatographed on silica gel to give a first fraction of 19.9 g of material, a 3:2 mixture of the title compound and 4-(bromomethyl)-2-fluoro-1-nitrobenzene. A second fraction of the pure title compound (3.4 g) is obtained, and this is recrystallized from ether/hexane. Physical characteristics: mp 46-49° C. Anal. Calcd for C7H5BrFNO2: C, 35.93; H, 2.15; N, 5.99. Found: C, 35.83; H, 1.95; N, 5.81. 1H NMR (CDCl3) δ 4.48, 7.28-7.38, and 8.08.
With NBS; 2,2'-azobisisobutyronitrile In 1,2-dichloro-ethane at 80℃; Inert atmosphere;
1.Q
4-(bromomethyl)-2-fluoro-1-nitrobenzene. To a stirred solution of 2-fluoro-4-methyl-1- nitrobenzene(5 g, 32.231 mmol, 1 equiv.) in DCE (41.50 g, 13.13 equiv.) was added NBS (100 mg, 2 equiv.) and AIBN (0.64 g, 3.868 mmol, 0.12 equiv.) in portions at 80 C under nitrogen atmosphere. The crude product was used as-is.
With NBS; 2,2'-azobisisobutyronitrile In 1,2-dichloro-ethane at 80℃; Inert atmosphere;
1 4-(bromomethyl)-2-fluoro-1-nitrobenzene
To a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (5 g, 32.231 mmol, 1 equiv) in DCE (41.50 g, 13.13 equiv) was added NBS (100 mg, 2 equiv) and AIBN (0.64 g, 3.868 mmol, 0.12 equiv) in portions at 80 °C under nitrogen atmosphere. The crude product was used as-is.
With NBS; 2,2'-azobisisobutyronitrile In 1,2-dichloro-ethane at 80℃; Inert atmosphere;
1 4-(bromomethyl)-2-fluoro-1-nitrobenzene
To a stirred solution of 2-fluoro-4-methyl-1-nitrobenzene (5 g, 32.231 mmol, 1 equiv) in DCE (41.50 g, 13.13 equiv) was added NBS (100 mg, 2 equiv) and AIBN (0.64 g, 3.868 mmol, 0.12 equiv) in portions at 80 °C under nitrogen atmosphere. The crude product was used as-is.
Preparation of Compound 5, Sodium Salt; [0057] Sulfuric acid (14.5 mL) was slowly added to a solution of 3-fluoro-4-nitrotoluene (10.0 g, 64 mmol) in acetic acid (75 mL) at 5 C. Cromium trioxide (17.92 g, 180 mmol) was added slowly over 1 hour. The reaction was kept below 10 C. for an additional 2 hours and then poured into ice water (700 mL) and the resulting yellow solids filtered off. The solids were stirred in 2% NaHCO3 for 15 minutes, filtered, dried in vacuo, then heated to reflux for 15 minutes in a solution of: water (60 mL), concentrated HCl (40 mL), and ethanol (11 mL). The yellow solids were isolated by filtration, 3.16 g 4-nitro-2-fluorobenzaldehyde (29.2% yield).
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 65℃; for 18h;
17.1
A solution of 3-fluoro-4-nitrotoluene (Aldrich, 4.65 gr, 30 mmole), 4-amino-1-benzyl-piperidine (Aldrich, 6.1 ml, 30 mmole), K2CO3 (6.63 gr, 48 mmole) in dimethylformamide (50 ml) was stirred at 65° C. under N2 for 18 hours. After cooling to room temperature the mixture was poured into water (200 ml)-dichloromethane (350 ml). The aqueous layer was extracted with dichloromethane (two times 70 ml) and the combined organic layers were washed with water (two times 50 ml), dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol (97:3) as the eluent. After concentration in vacuo the pure product was obtained as a yellow oily substance (9.1 gr, 28 mmole, 93% yield).
7.64 g
With potassium carbonate In N,N-dimethyl-formamide at 70℃;
With sodium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 15h;
Ethyl-4-amino-i-piperidine-carboxylate (18.3 g, 106 mmol) was added to a stirred suspension of 3-fluoro-4-nitrotoluene (15.Og g, 97 mmol), sodium carbonate (10.3 g, 97 mmol) and potassium iodide (0.16 g, 0.97 mmol) in dimethylformamide (150 ml_). The mixture was heated to 50 0C, stirred for 15 hours and then allowed to cool. The reaction mixture was diluted with water (200 ml_) and ethyl acetate (200 ml_). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 200 ml_). The organic extracts were combined, extracted with a 10% aqueous solution of citric acid (250 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with dichloromethane and then ethyl acetate/hexane (7:8) to give the title compound (25.0 g, 84 % yield) as a yellow solid. (Rf: 0.3 (ethyl acetate/hexane 7:8))
84%
With sodium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 15h;
Ethyl-4-amino-i-piperidine-carboxylate (18.3 g, 106 mmol) was added to a stirred suspension of 3-fluoro-4-nitrotoluene (15.Og g, 97 mmol), sodium carbonate (10.3 g, 97 mmol) and potassium iodide (0.16 g, 0.97 mmol) in dimethylformamide (150 ml_). The mixture was heated to 50 0C, stirred for 15 hours and then allowed to cool. The reaction mixture was diluted with water (200 ml.) and ethyl acetate (200 ml_). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 200 ml_). The organic extracts were combined, extracted with a 10% aqueous solution of citric acid <n="59"/>(250 ml_), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with dichloromethane and then ethyl acetate/hexane (7:8) to give the title compound (25.0 g, 84 % yield) as a yellow solid. (Rf: 0.3 (ethyl acetate/hexane 7:8))
1,1-dimethylethyl 4-[(5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
A stirred solution of 3-fluoro-4-nitrotoluene (1 Og, 0.064mol) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, O.OdeltaOmol) followed by 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.3g, 0.064mol) and then heated at 9O0C for 18hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under vacuum. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%). 1H NMR delta (CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
A stirred solution of 3-fluoro-4-nitrotoluene (1Og, 0.064mole) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, O.OdeltaOmole) followed by 1 ,1-dimethylethyl 4-amino-1 -piperidinecarboxylate (11.3g, 0.064mole) and then heated at 9O0C for 18hrs. The mixture was concentrated under reduced pressure and the residue treated with 10% Na2CO3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under reduced pressure. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%). 1H NMR delta(CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
Description 1.; 1,1-Dimethylethyl 4-[(5-methyl-2-nitrophenyl)amino]-1- piperidinecarboxylate (D1)); A stirred solution of 3-fluoro-4-nitrotoluene (10g, 0.064mole) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, 0.080mole) followed by 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 1.3g, 0.064mole) and then heated at 9O0C for 18hrs. The mixture was concentrated under <n="51"/>vacuum and the residue treated with 10% Na2CC>3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under vacuum. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%).1H NMR delta (CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
A stirred solution of 3-fluoro-4-nitrotoluene (1 Og, 0.064mole) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, O.OdeltaOmole) followed by 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.3g, 0.064mole) and then heated at 9O0C for 18hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under vacuum. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%).1H NMR delta (CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
Description 1. 1 ,1-Dimethylethyl 4-[(5-methyl-2-nitrophenyl)amino]-1- piperidinecarboxylate (D1))A stirred solution of 3-fluoro-4-nitrotoluene (1 Og, 0.064mole) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, 0.080mole) followed by 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 1.3g, 0.064mole) and then heated at 90 0C for 18hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under vacuum. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%). 1H NMR delta (CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 18h;
Description 1.; 1,1-Dimethylethyl 4-[(5-methyl-2-nitrophenyl)amino]-1- piperidinecarboxylate (D1)); A stirred solution of 3-fluoro-4-nitrotoluene (10g, 0.064mole) in dimethylformamide (40ml) at room temperature under argon was treated with diisopropylethylamine (14ml, 0.080mole) followed by 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 1.3g, 0.064mole) and then heated at 9O0C for 18hrs. The mixture was concentrated under <n="51"/>vacuum and the residue treated with 10% Na2CC>3 solution (100ml) and extracted with dichloromethane (2 x 150ml). The combined extract was washed with water (150ml), dried (Na2SO4) and concentrated under vacuum. The residue was treated with Et2O (200ml) and allowed to stand overnight. The crystals which had formed were filtered off, washed with Et2O and dried to afford the title compound as an orange solid (16g, 74%).1H NMR delta (CDCI3, 400MHz): 1.45-1.65 (2H, m), 1.48 (9H, s), 2.00-2.10 (2H, m), 2.35 (3H, s), 3.00-3.15 (2H, m), 3.62-3.72 (1 H, m), 3.92-4.12 (2H, br m), 6.46 (1 H, dd), 6.63 (1 H, s), 8.07 (1 H, d), 8.15 (1 H, d).
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 160℃; for 4h; Heating / reflux;
44.1
To a suspension of m-fluoro-p-nitrotoluene (4.1 g,. 26.4 mmol) and K2CO3 (11 g, 79.5 mmol) in dry DMF (75 mL) under a nitrogen atmosphere was added p-bromothiophenol (5 g, 26.4 mmol) in single portion. The suspension was heated to reflux at 160° C. for 4 h then allowed to cool to RT. The mixture was then filtered through silica gel. The filtrated was concentrated and purified by flash chromatography on silica gel (ethyl acetate/hexanes 10% to 50%) to yield 156a (6.8 g, 79%) an orange oil.
tert-butyl [3-methyl-3-(5-methyl-2-nitro-phenyl-amino)-butyl]-carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide at 20℃;
A
A) tert-butyl[3-methyl-3-(5-methyl-2-nitro-phenylamino)-butyl]-carbamate: 2.0 g (12.9 mmol) 3-fluoro-4-nitro-toluene, 2.6 g (13.0 mmol) tert-butyl (3-amino-3-methyl-ambient temperature in 20 mL DMF. The solvent is distilled off and the residue is combined with ethyl acetate. The mixture is washed repeatedly with water, dried with sodium sulphate and the solvent is eliminated. Yield 4.8 g, mass spectroscopy: [M+H]+=338.
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
a
2.0 g (12.9 mmol) 3-fluoro-4-nitro-toluene, 2.6 g (13.0 mmol) tert-butyl (3-amino-3-methyl-butyl)-carbamate and 2.3 g (16.8 mmol) potassium carbonate are stirred overnight at ambient temperature in 20 mL DMF. The solvent is distilled off and the residue is combined with ethyl acetate. The mixture is washed repeatedly with water, dried with sodium sulphate and the solvent is eliminated. 4.8 g yellow oil. Mass spectroscopy: [M+H]+=338.
α-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate[ No CAS ]
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; ethanol;
(2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.) To a mixture of 5.15 mmole of alpha-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate (6.44 mmole), 4 ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of <strong>[51632-16-7]m-phenoxybenzyl bromide</strong>. The reaction is stirred overnight at RT. The reaction is poured into 5% sodium hydroxide/ether, extracted with water (2*) and then washed with water (2*), dried over sodium sulfate and rotoevaporated under vacuum. The crude product is subjected to preparatory TLC eluding with 10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine. nmr (CDCl3) delta 0.98 [d, 3, J-7 Hz, CH(CH3)2 ], 1.02 [d, 3, J=7 Hz, CH(CH3)2 ], 2.22 STR20 and 5.13 ppm (s, 2, ArCH2 O). IR (neat)) 1734 cm-1 (C=O).
N-(2,4-dinitrophenyl)valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 38 to yield the m-phenoxybenzyl ester of N-(2,4-dinitrophenyl)valine. This procedure is repeated using 3-fluoro-4-nitrotoluene in place of 2-fluoro-4-nitrotoluene to prepare 2-fluoro-4-trifluoromethylaniline, which is converted into N-(2-fluoro-4-trifluoromethylphenyl)valine and then esterified to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, MS m/e 461.1 (M+).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 110℃;
Description 5; . tert-Butyl 4-methyl-4-(5-methyl-2-nitrophenylamino)piperidine-1- carboxylate (D5); <n="47"/>To a solution of tert-butyl 4-amino-4-methyl-1-piperidinecarboxylate (D4, 3.5g, 16 mmol) in dry N,N-dimethylformamide (30ml) was added potassium carbonate (3.46g, 25mmol) and 3-fluoro-4-nitrotoluene (3.1 1g, 20 mmol) at room temperature and the mixture subsequently stirred overnight at 1 1O0C. The mixture was cooled to room temperature and the mixture was diluted with ethyl acetate (300ml) and washed with water (200ml). The organic phase was dried, filtered, concentrated and purified by silica gel chromatography to give the title compound (3.5g, 61.4%) as yellow solid.1H NMR (CDCI3) delta: 1.39 (9H, s), 1.46 (3H, s), 1.62 (2H, m), 2.04 (2H, d), 2.27 (3H, s), 3.11 (2H, t), 3.71 (2H, m), 6.38 (1 H, d), 6.73 (1 H, s), 8.02 (1 H, d), 8.40 (1 H, s).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48h;
11
To a solution of 3-Fluoro-4-nitrotoluene (1.0 g, 6.5 mmol) in DMF (5 niL) were: 3-Amino- hexanoic acid ethyl ester hydrochloride (1.3g, 6.7 mmol) and DIPEA (2.2 mL, 12.9 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with ethyl acetate and washed with water (x4). The organic phase was then dried over Na2SCH and concentrated. The resulting residue was purified by Combiflash using hexane and ethyl acetate (10% gradient) as an eluent to afford 1.4 g of the desired product as orange oil.
Step 1 : In a similar manner to that described for the preparation of (S)-2-(tert- butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid except the reaction mixture was stirred at 0 C for 4 h, <strong>[1464025-91-9](2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid DCHA</strong> (2.0 g, 5.00 mmol) and 2-fluoro-4-methyl-l -nitrobenzene (1.55 g, 9.99 mmol) were converted to (2S,3S)-2-tert-butoxycarbonylamino-3-(5-methyl-2-nitro-phenoxy)-butyric acid (0.95 g, 53.6 % yield).
Stage #1: (S)-N-(tert-butoxycarbonyl)serine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h;
Stage #2: 2-fluoro-4-methyl-1-nitrobenzene In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h;
Step 1 : (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (5.5 g, 26.8 mmol, Eq: 1.00) was dissolved in DMF (90 mL) at 0 °C and NaH (60 % in mineral oil, 2.57 g, 64.3 mmol, Eq: 2.4) was added in small portionsThe mixture was stirred for 30 min. and 2-fiuoro-4- methyl-1 -nitrobenzene (4.16 g, 26.8 mmol, Eq: 1.00) in DMF (lOmL) was added dropwise. The resulting mixture was stirred for 60 min., diluted with 1.0 M KHS04 and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatagraphy to afford (S)-2-(tert- butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid (7.60 g, 83 %) as red oil.
1-tert-butyl-4-methyl-2-(5-methyl-2-nitrophenoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In N,N-dimethyl-formamide;Reflux;
A reaction flask was taken to dissolve 2-fluoro-4-methyl-1-nitrobenzene (purchased from Shanghai Titan Technology Co., Ltd., 64.46 mmol, 1.0 eq), potassium carbonate (64.46 mmol, 1.0 eq) in 60 mL DMF. ,<strong>[88-60-8]2-tert-Butyl-5-methylphenol</strong> (70.91 mmol, 1.1 eq) was added under reflux, and the temperature was maintained for 2-3 h.After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure,The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 50:1).The product 1-tert-butyl-4-methyl-2-(5-methyl-2-nitrophenoxy)benzene (12.55 g, yield 65%) was obtained as a pale yellow oil.
N-(3-chloro-4-fluorobenzyl)-5-methyl-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
Step A: To a stirred solution of <strong>[72235-56-4]3-chloro-4-fluorobenzylamine</strong> (487 muL, 3.87 mmol, 1.2 eq) in DMF (11 mL) was added potassium carbonate (778 mg, 5.63 mmol, 1.5 eq) at room temperature. After five min, solid 2-fluoro-4-methylnitrobenzene (500 mg, 3.22 mmol, 1 eq) was added at room temperature. The reaction was stirred at room temperature for 18 hours and monitored by LCMS. Upon conversion to the aniline product, the reaction was quenched with 10% aqueous HCl and diluted with water, then extracted with ethyl acetate (×2). The organic phase was washed with water and a brine solution, dried over magnesium sulfate, and concentrated to afford a dark crude solid. The crude N-(3-chloro-4-fluorobenzyl)-5-methyl-2-nitroaniline was used without further purification on the subsequent step.
4,5-dibromo-2-(5-methyl-2-nitrophenyl)-2H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 15h;Large scale;
3- Fluoro-4-nitrotoluene (1367 g, 1 eq.), 4,5-dibromo-2/-/-1 ,2,3-triazole (1999 g, 1 eq.), K2C03 (1340 g, 1.1 eq.) and DMF (1 1 L) is heated to 75 C for 15 h. The reaction mixture is cooled to 22 C and treated with water (18 L). The resulting suspension is filtered, washed with water (4 L). The product is washed with isopropanol (5 L), and dried under reduced pressure to yield a white solid. Yield: 281 1 g, 88%. Purity: 100% a/a (LC-MS method 2). 1H NMR (400 MHz, DMSO) <5: 8.10 (d, J = 8.3 Hz, 1 H), 7.86 (d, J = 1.0 Hz, 1 H), 7.66 (dd, J1 = 0.9 Hz, J2 = 8.3 Hz, 1 H), 2.51 (s, 3 H).
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