* 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.
Step 1 : To a solution of 2-fluoro-4-nitrobenzoic acid (1 g, 5.402 mmol) in MeOH was added H2SO4 (2.9 ml). The reaction mixture was refluxed overnight, and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and washed with a saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated. The crude was purified by column chromatography to afford the pure compound methyl 2-fluoro- 4-nitrobenzoate (1 .05 g, 98 percent).
Reference：
[1] Patent: WO2013/68467, 2013, A1, . Location in patent: Page/Page column 57; 59; 60; 61
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 19, p. 7042 - 7051
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 2, p. 337 - 343
[4] Patent: WO2004/37814, 2004, A1, . Location in patent: Page 166-167
[5] Patent: EP1810969, 2007, A1, . Location in patent: Page/Page column 41
[6] Patent: EP1905769, 2008, A1, . Location in patent: Page/Page column 60
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 169 - 173
2
[ 403-24-7 ]
[ 18107-18-1 ]
[ 392-09-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20℃; for 1.5 h;
471a) Synthesis of Methyl 2-Fluoro-4-nitrobenzoate.To a 500ml round bottom flask, 2-fluoro-4-nitrobenzoic acid (1 1.68g, 63.1mmoles), toluene (200ml) and methanol (30ml) were added, respectively. Trimethylsillyldiazomethane (2M) in diethyl ether (38ml, 76mmoles) was then added dropwise at romm temperature over 30 minutes. The solution was then stired for lhour. The sovents were then removed under vaccum to afford a yellow solid. The residual solvent was co-evaporated with methanol (100ml) to give 12.52g of yellow solid (100percent yield). NMR lH-(DMSO)-I'-8.28 (d, IH, J=7.58Hz), 8.10-8.22 (m, 2H), 3.93 (s, 3H).
Reference：
[1] Patent: WO2008/51547, 2008, A1, . Location in patent: Page/Page column 533
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 12, p. 1657 - 1661
3
[ 186581-53-3 ]
[ 403-24-7 ]
[ 392-09-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 20℃;
Add diazomethane (22.3 mL, 2 M in ether) to a mixture of 2-fluoro-4-nitro benzoic acid (4.14 g) and ether (50 mL). Stir at room temperature overnight. Concentrate under reduced pressure to provide (4.08 g, 92percent) of an oil.
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1993, # 11, p. 921 - 922
5
[ 67-56-1 ]
[ 1427-07-2 ]
[ 392-09-6 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
6
[ 1427-07-2 ]
[ 392-09-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 2, p. 337 - 343
7
[ 403-24-7 ]
[ 392-09-6 ]
Reference：
[1] Helvetica Chimica Acta, 1951, vol. 34, p. 1350,1354
8
[ 392-09-6 ]
[ 73792-08-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
With palladium on activated charcoal; hydrogen In methanol at 23℃; for 2 h;
Step 2: Methyl 2-fluoro-4-nitrobenzoate (1 .05 g, 5.273 mmol) was dissolved in MeOH. Pd/C (105 mg) was added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours under H2. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound methyl 4-amino-2-fluorobenzoate (870 mg, 98 percent).
89%
With ammonium formate In ethanol at 95℃; for 6 h;
Reflux the mixture of 2-fluoro-4-nitro-benzoic acid methyl ester [(0.] 85 g), ammonium formate (1.1 g) and [PD/C] (10percent, 0.32 g) in ethanol (20 mL) at [95C] for 6 hours. Filter over [CELITE0] and concentrate under reduced pressure to provide (0.64 g, 89percent) a gray solid.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 19, p. 7042 - 7051
[2] Patent: WO2013/68467, 2013, A1, . Location in patent: Page/Page column 57; 59; 60; 61
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 2, p. 337 - 343
[4] Patent: WO2004/14900, 2004, A1, . Location in patent: Page 52
[5] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
[6] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2991 - 3013
[7] Patent: EP1810969, 2007, A1, . Location in patent: Page/Page column 41
[8] Patent: EP1905769, 2008, A1, . Location in patent: Page/Page column 60
[9] Patent: WO2011/27106, 2011, A1, . Location in patent: Page/Page column 76
[10] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 4, p. 798 - 814
9
[ 392-09-6 ]
[ 660432-43-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 23℃; for 4 h;
Step 1 : To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (10.0 g, 49.7 mmol, 1 eq.) in methanol (100 mL) was added sodium borohydride (9.40 g, 248.7 mmol, 5 eq.) at RT and stirred for 4h. The methanol was evaporated and the residue was diluted with ethyl acetate (50 mL x 2) washed with water (50 mL) and brine (50 mL). The ethyl acetate layer was dried over Na2S04, evaporated under vacuum to get (2-fluoro-4-nitrophenyl)methanol (8 g, 94percent, off-white solid; TLC system: EtOAc/PE (3:7), Rf: 0.30).
94%
at 23℃; for 4 h;
Step 1 : To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (10.0 g, 49.7 mmol, 1 eq.) in methanol (100 mL) was added sodium borohydride (9.40 g, 248.7 mmol, 5 eq.) at RT and stirred for 4h. The methanol was evaporated and the residue was diluted with ethyl acetate (50 mL x 2) washed with water (50 mL) and brine (50 mL). The ethyl acetate layer was dried over Na2SO4, evaporated under vacuum to get (2-fluoro-4-nitrophenyl)methanol (8 g, 94percent, off-white solid; TLC system: EtOAc/PE (3:7), Rf: 0.30).
2-[3-fluoro-4-(morpholine-4-carbonyl)-phenyl]-6-methyl-4-(3-trifluoromethyl-phenyl)-1,6-dihydro-2<i>H</i>-1,2,5,6,7-pentaaza-<i>as</i>-indacen-3-one[ No CAS ]
2-fluoro-<i>N</i>-[4-(2-hydroxy-ethyl)-phenyl]-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1<i>H</i>-1,2,5,6,7-pentaaza-<i>as</i>-indacen-2-yl]-benzamide[ No CAS ]
With hydrazine hydrate; In ethanol; at 120℃; for 2.0h;Microwave irradiation;
[0625] In two portions of equal size, a total of 2.00 g (10.0mmol) ofmethyl2-fluoro-4-nitrobenzoate and 2.51 g (50.2mmol) of hydrazine monohydrate in 36 ml of ethanol wereheated in a microwave reactor at 120 C. for 2 h. The combinedreaction solutions were diluted with ethyl acetate andwashed with water. The aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases weredried over magnesium sulphate and concentrated underreduced pressure. Yield: 1.66 g (purity 95%, 88% of theory)[0626] LC/MS [Method 11]: R,=0.73 min; MS (ESipos):rnz=I8o (M+Ht,[0627] 1H-NMR (400 MHz, DMSO-d6): o [ppm]=12.4 (s,lH), 11.0 (br. s, lH), 8.21 (d, lH), 7.86 (d, lH), 7.78 (dd, lH).
With hydrazine; In ethanol; for 14.0h;Heating / reflux;
[00310] The crude material, <strong>[392-09-6]2-fluoro-4-nitro-benzoic acid methyl ester</strong>, from above was treated with hydrazine (1.6 mL, 51 mmol) in ethanol under reflux for 14 hrs. After removal of solvent by evaporation, the residue was washed with water. The precipitate product was filtered and dried on the vacuum pump to give the title compound which was used without further purification (4. 0g, 85% for two steps). MS (ES+): M/E= 180.1 (M+H), 178.0 (M-H); LC/Method A/1. 83 min.
1.66 g
With hydrazine hydrate; In ethanol; at 120℃; for 2.0h;Microwave irradiation;
In two portions of equal size, a total of 2.00 g (10.0mmol) of <strong>[392-09-6]methyl 2-fluoro-4-nitrobenzoate</strong> and 2.51 g (50.2 mmol) of hydrazinemonohydrate in 36 ml of ethanol were heated in a microwave reactor at 120 C for2 h. The combined reaction solutions were diluted with ethyl acetate and washedwith water. The aqueous phase was extracted three times with ethyl acetate. Thecombined organic phases were dried over magnesium sulphate and concentratedunder reduced pressure. Yield: 1.66 g (purity 95%, 88% of theory)
Add diazomethane (22.3 mL, 2 M in ether) to a mixture of 2-fluoro-4-nitro benzoic acid (4.14 g) and ether (50 mL). Stir at room temperature overnight. Concentrate under reduced pressure to provide (4.08 g, 92%) of an oil.
With hydrazine; In ethanol; for 17.0h;Heating / reflux;
2-Fluoro-4-nitrobenzoic acid methyl ester (5 g, 25.11 mmol) and hydrazine hydrate (1.34 ml, 27.62 mmol) were dissolved in 250 ml of ethanol and heated under reflux for 11 h. A further 0.26 ml of hydrazine hydrate were added and heated under reflux for a further 6 h, and the mixture was concentrated and ethyl acetate and water were added. The precipitated residue was filtered off with suction and dried. Purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA) resulted in 1.39 g of product, M+H+: 180.05.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 19.0h;Product distribution / selectivity;
471 Ib) Synthesis of 8-Nitro-l-methyl-l , 2,3,4- tetrahydrobenzo[e][l,4]diazepine-5-one. To a 300ml round bottom flask, <strong>[392-09-6]methyl 2-fluoro-4-nitrobenzoate</strong> (12.52, 63 mmoles), N- methyl ethylenediamine (4.82g, 65mmoles), DMF(200ml) and K2CO3 (10.49g, 76mmoles) were added, respectively. The reaction mixture was then heated to 900C for 18 hours. The reaction was cooled to room temperature. The mixture was then poured over ice and stired for one hour. The solid was then filtered and washed with water. The residual water was removed under vaccum overnight. The solid was partitioned with diethyl ether and methanol (9/1). The solid was filtered and washed to afford 9.2Og of bright yellow solid (41.6% yield).NMR l H-(DMSO)-I'- 8.50 (bs, IH), 7.68 (s, 2H), 7.50 (s, IH), 3.23.38 (m, 4H), 2.90(s, 2H)
499a) Synthesis of 2-[(2-Amino-ethyl)-isopropyl-amino]-4-nitro-benzoic acid methyl ester. To a 250ml round btoom flask, <strong>[392-09-6]methyl 2-fluoro-4-nitrobenzoate</strong> (9.0Og, 45.2mmoles), N-isopropyl ethylenediamine (10ml ), and DMF (10ml) was added at room temperature (exotherm to 700C). Upon cooling to room temperature, the content was poured into 300ml ice water. The solid was filtered, washed with cold water, and subsequently washed with cold ethanol. The solid (6.1Og, 49% yield) was dried under vacuum. NMR lH-(DMSO)-I'- 13.42 (bs, IH), 8.80 (bs, 1), 8.63 (s, IH), 8.14 (d, IH), 7.00 (bs, IH), 4.87-4.20 (bm, 2H), 3.90 (s, 3H), 3.46-3.70 (m, 2H), 2.78-2.86 (m, 2H),1.10 (d, 6H, J=6.30Hz)
In 1-methyl-pyrrolidin-2-one; at 140℃; for 0.583333h;Microwave irradiation;
2-morpholino-4-nitrobenzoic acid[00416] A solution of <strong>[392-09-6]methyl 2-fluoro-4-nitrobenzoate</strong> (200 mg, 1.00 mmol) and morpholine (8.04 mmol) in NMP (2.1 mL) was heated at 140 C (microwave) for 35 min. The cooled mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL) and brine (10 ml). The combined aqueous layers were acidified to pH=2 with a 1M solution of HCl in H2O and extracted with DCM (3 x 20 mL). The combined organic layers were dried by passing through a phase cartridge separator and evaporated to dryness affording the title compound as a mixture with morpholine which was used in the next step without further purification.
In 1-methyl-pyrrolidin-2-one; at 140℃; for 0.583333h;Microwave irradiation;
j297j A solution of methyl 2-fluoro-4-nitrobcnzoate (200 rng, 100 mmol) and morpholine (703iL, 8.04 mmol) in NMP (2.1 mL) was heated at 140C rnW) for 35mm. The cooled mixturewas diluted with EtOAc (20 mL) and washed with H20 (10 mL) and brine (10 ml). The combined aqueous layers were acidified to p1-1=2 with a I M solution of HCI in 1I2O and extracted with DCM (3 x 20 rnL). The combined organic layers were dried by passing through a phase cartridge separator and evaporated to dryness to affordthe title compound as a mixturewith morpholine which was used in the next step without further purification.
With hydrazine hydrate; In ethanol; for 4.0h;Reflux;
: Hydrazine hydrate (5 mL, 0.12 mol) was added to a solution of 2-fiuoro-4-nitro-benzoic acid methyl ester (10.5 g, 0.05 mol) in anhydrous EtOH (100 mL). The reaction mixture was heated at reflux for 4 hours. Then, the solvent was evaporated under reduced pressure and the crude intermediate (Jl) was used without purification for the next step.
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