* 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] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4116 - 4125
2
[ 5471-82-9 ]
[ 5437-38-7 ]
Yield
Reaction Conditions
Operation in experiment
80.96%
With sodium hydroxide In methanol at 20℃;
To a 250 mL single-necked flask was added 19.5 g of methyl 3-methyl-2-nitrobenzoate,Methanol 50mL, dissolved by adding 10.1percent sodium hydroxide 50mL,Room temperature reaction 4.0 ~ 6.0h, concentrated to remove methanol,Plus dilute hydrochloric acid to adjust the pH of 2 to 3,Filter, dry,To give 14.65 g of a white solid, yield 80.96percent, purity 98.35percent.
Reference：
[1] Patent: CN106496038, 2017, A, . Location in patent: Paragraph 0025; 0027
3
[ 5471-82-9 ]
[ 22223-49-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 10 h;
Methyl 3-methyl-2-nitro benzoate (1g, 5.2mmol) was dissolved in ethanol (40mL) and then 10percent palladium on charcoal (0.1g) was added to the reaction mixture and stirred at rt for 10h. Then the mixture was filtrated, and evaporation of solvent under reduced pressure afforded the light yellow oil product. (0.85g, 99percent); δH (300MHz, CDCl3) 2.18 (3H, s, Me), 3.88 (3H, s, CO2Me), 5.84 (2H, br s, NH2), 6.61 (1H, t, J 7.7Hz, Ph), 7.22 (1H, d, J 7.3Hz, Ph), 7.79 (1H, d, J 7.7Hz, Ph); δC (75MHz, CDCl3) 17.4, 51.5, 110.1, 115.6, 123.0, 129.1, 134.9, 149.0, 169.0.
97.5%
With hydrogen In acetonitrile at 70℃; for 16.5 h;
EXAMPLE 4Preparation of 2-amino-5-chloro-N,3-dimethylbenzamideStep A: Preparation of methyl 2-amino-3-methylbenzoateMethyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5percent Pd/C (Degussa CE 105 XRCAV, 1.0 g), and acetonitrile (300 mL) were combined in a 600-mL pressure vessel. The mixture was heated to 70 °C and hydrogenated at 65 psi (450 kPa) for 8 h. More 5percent Pd/C (1.0 g) was added and hydrogenation was continued at 100 psi (690 kPa) for 8.5 h. Then the reaction mixture was cooled, purged with nitrogen, and filtered through Celite.(R). diatomaceous filter aid, rinsing with acetonitrile (3 x 25 mL). The combined filtrates were partly evaporated to a weight of ~ 160 g, and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed 40.3 wtpercent of the title compound (80.6 g, 97.5percent yield).
Reference：
[1] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
[2] Patent: WO2006/62978, 2006, A1, . Location in patent: Page/Page column 23
[3] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[4] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5629 - 5633
[5] Chemische Berichte, 1907, vol. 40, p. 4413
[6] Patent: US4456471, 1984, A,
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[8] Patent: US2015/111870, 2015, A1, . Location in patent: Paragraph 0685; 0686
4
[ 67-56-1 ]
[ 5437-38-7 ]
[ 5471-82-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 0 - 20℃; for 10 h; Inert atmosphere
Method 1: H2SO4/CH3OH: Concentrated sulfuric acid (1mL) was added to a solution of 2-nitro-3-toluicacid (1g, 5.49mmol) in methanol (4mL) and the reaction mixture was stirred and heated to reflux for 5h. After completion of the reaction (was determined by TLC analysis), the crystalline product was filtered and washed with cold water and dried (0.95g, 89percent). (0020) Method 2: CH3OH/SOCl2: 2-Nitro-3-toluicacid (1g, 5.49mmol) was placed in a round bottom flask (25mL) containing methanol (4mL). The reaction solution was cooled to 0°C and thionyl chloride (1mL, 13.83mmol) was added to the reaction flask. The solution was allowed to warm slowly to rt and was stirred for 10h. After completion of the reaction (was determined by TLC analysis), aqueous sodium hydrogen carbonate (5mL, 5percent) was added and the crystalline product was collected and washed with cold water and then dried. The product 5 was afforded as a white solid (1.05g, 99percent); mp 73–74°C (lit.14b 72–73°C); δH (300MHz, CDCl3) 2.35 (3H, s, Me), 3.88 (3H, s, CO2Me), 7.63 (1H, t, J 7.7Hz, Ph), 7.73 (1H, d, J 7.6Hz, Ph), 7.90 (1H, d, J 7.6Hz, Ph); δC (75MHz, CDCl3) 16.8, 53.5, 122.9, 129.0, 130.7, 131.2, 136.6, 150.2, 164.3.
85%
at 0℃; for 20 h; Heating / reflux
Example 14; 2-Methyl-4-{1-methyl-1-[2-(4-trifluoromethylphenyl)-2H-indazol-7- yll ethylsulfanyl} phenoxyacetic Acid; Step A; Methyl 3-Methyl-2-nitrobenzoate; Add acetyl chloride (20 mL) dropwise to a suspension of commercially available 3-methyl-2-nitro-benzoic acid (13.45 g, 74.25 mmol) in methanol (200 mL) at 0°C, heat to reflux and stir for 20 h. Remove the solvents under reduced pressure and dissolve the residue in ethyl acetate (800 mL). Wash with saturated aqueous NaHC03 solution (200 mL) and brine (150 mL), dry over Na2S04 and remove the solvents under reduced pressure to provide methyl 3-methyl-2-nitrobenzoate as a white solid (12.35 g, 85percent) :'H NMR (CDC13) 8 2.36 (s, 3H), 3.89 (s, 3H), 7.40-7. 51 (m, 2H), 7.84 (m, 1H).
82.2%
at 58℃;
Niraparib The synthesis of intermediate 1 is carried out in two steps, the first step (esterification reaction):The ratio of 3-methyl-2-nitrobenzoic acid and methanol to n (3-methyl-2-nitrobenzoic acid): n (methanol) = 1:Take it182g 3-methyl-2-nitrobenzoic acid,160.2 g of methanol was placed in a flask with a reflux device,Slow heating,After 3-methyl-2-nitrobenzoic acid was completely dissolved in methanol,Add 6mL of concentrated sulfuric acid,The temperature was raised to 58 ° C to carry out the reaction,The product was 3-methyl-2-nitro-methyl formate (Niraparib intermediate 1) and water.The resulting Niraparib intermediate 1 is subjected to the second step (refined extraction):After the esterification reaction is completed,After the temperature of the reaction solution was lowered to room temperature,The pH of the solution was adjusted to neutral with sodium bicarbonate,Separating the oil phase layer in the extraction bottle,With 0.1kg / L sodium bicarbonate solution repeatedly washed to neutral,Dried over anhydrous sodium sulfate to give Intermediate 1 as Niraparib 160.04g, yield 82.2percent.
Reference：
[1] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
[2] Tetrahedron, 2004, vol. 60, # 10, p. 2235 - 2246
[3] Patent: WO2005/66136, 2005, A1, . Location in patent: Page/Page column 87-88
[4] Patent: CN106467513, 2017, A, . Location in patent: Paragraph 0009; 0036; 0037; 0038; 0039
[5] Chemische Berichte, 1907, vol. 40, p. 4413
[6] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1692 - 1695
[7] Patent: WO2009/87381, 2009, A1, . Location in patent: Page/Page column 35
[8] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[9] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7170 - 7185
[10] Patent: WO2007/113596, 2007, A1, . Location in patent: Page/Page column 77
5
[ 99-36-5 ]
[ 5471-82-9 ]
[ 24078-21-5 ]
Reference：
[1] Patent: CN105820054, 2016, A, . Location in patent: Paragraph 0016
[2] Patent: CN106496038, 2017, A, . Location in patent: Paragraph 0025-0026
6
[ 5437-38-7 ]
[ 5471-82-9 ]
Reference：
[1] Patent: US5157119, 1992, A,
7
[ 5437-38-7 ]
[ 77-78-1 ]
[ 5471-82-9 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
Reference：
[1] Journal of the Chemical Society, 1951, p. 2067,2070
[2] Patent: US5466704, 1995, A,
10
[ 5437-38-7 ]
[ 5471-82-9 ]
Reference：
[1] Patent: US5273975, 1993, A,
11
[ 99-04-7 ]
[ 5471-82-9 ]
Reference：
[1] Chemische Berichte, 1907, vol. 40, p. 4413
[2] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
[3] Patent: CN106496038, 2017, A,
12
[ 67-56-1 ]
[ 50424-93-6 ]
[ 5471-82-9 ]
Reference：
[1] Chemische Berichte, 1909, vol. 42, p. 433
13
[ 99-36-5 ]
[ 7697-37-2 ]
[ 5471-82-9 ]
[ 20587-30-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 162
14
[ 5471-82-9 ]
[ 500024-27-1 ]
Reference：
[1] Chemische Berichte, 1907, vol. 40, p. 4413
15
[ 99-36-5 ]
[ 7697-37-2 ]
[ 5471-82-9 ]
[ 20587-30-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 162
16
[ 99-36-5 ]
[ 5471-82-9 ]
[ 24078-21-5 ]
Reference：
[1] Patent: CN105820054, 2016, A, . Location in patent: Paragraph 0016
[2] Patent: CN106496038, 2017, A, . Location in patent: Paragraph 0025-0026
17
[ 5471-82-9 ]
[ 93247-78-0 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 17, p. 5838 - 5845
[2] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1692 - 1695
18
[ 5471-82-9 ]
[ 4637-24-5 ]
[ 93247-78-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 10, p. 4116 - 4125
19
[ 5471-82-9 ]
[ 132874-06-7 ]
Yield
Reaction Conditions
Operation in experiment
41%
With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane for 12 h; Heating / reflux
Step B; Methyl 3-Bromomethyl-2-nitrobenzoate; Heat a mixture of methyl 3-methyl-2-nitrobenzoate (12.34 g, 63.23 mmol), benzoyl peroxide (0.920 g, 3.80 mmol) and N-bromosuccinimide (11.25 g, 63.21 mmol) in carbon tetrachloride (330 mL) at reflux under nitrogen for 12 h. Dilute the cooled mixture with methylene chloride (150 mL), treat with silica gel (30 g) and remove the solvents under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (15: 85), to provide methyl 3-bromomethyl-2- nitrobenzoate (1B) as a pale yellow solid (7.15 g, 41percent) :'H NMR (CDC13) 8 3.91 (s, 3H), 4.46 (s, 2H), 7.58 (t, 1H), 7.74 (dd, 1H), 7.96 (dd, 1H).
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5629 - 5633
[2] Organic Process Research and Development, 2011, vol. 15, # 4, p. 831 - 840
[3] Journal of Organic Chemistry, 1997, vol. 62, # 17, p. 5838 - 5845
[4] Tetrahedron, 2004, vol. 60, # 10, p. 2235 - 2246
[5] Patent: WO2005/66136, 2005, A1, . Location in patent: Page/Page column 88
[6] Tetrahedron Letters, 2002, vol. 43, # 34, p. 5949 - 5952
[7] Patent: US5273975, 1993, A,
[8] Patent: WO2009/87381, 2009, A1, . Location in patent: Page/Page column 35
[9] Patent: US2005/222141, 2005, A1, . Location in patent: Page/Page column 30
[10] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[11] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7170 - 7185
[12] Patent: WO2007/113596, 2007, A1, . Location in patent: Page/Page column 77
20
[ 5471-82-9 ]
[ 132874-06-7 ]
Reference：
[1] Patent: US5216003, 1993, A,
21
[ 5471-82-9 ]
[ 138229-56-8 ]
[ 132874-06-7 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 4, p. 831 - 840
22
[ 5471-82-9 ]
[ 206548-14-3 ]
Reference：
[1] Patent: US2015/111870, 2015, A1,
23
[ 5471-82-9 ]
[ 755752-82-0 ]
Yield
Reaction Conditions
Operation in experiment
12.6 g
With potassium acetate; acetic acid; isopentyl nitrite In 1,2-dichloro-ethane for 24 h; Reflux
Example 9 Compound 16 (20.0g, 0.103mol) in 1,2-dichloroethane was added 100mL, acetic acid 20mL, was added potassium acetate (2.0g, 0.021mol) was dissolved after stirring, isoamyl nitrite (24.1 g of, 0.206 mol), heated to reflux and reacted at this temperature for 24 hours, cooled to room temperature, the reaction was washed with saturated sodium carbonate solution, the solution was evaporated under reduced pressure, 80 mL of ethanol was added to the residual liquid, dropwise under ice after 10mL of concentrated hydrochloric acid was added, and stirred at this temperature for 2 hours, the solid was filtered off to give a pale yellow solid, the resulting solid was added 90 mL of ethyl acetate and saturated sodium carbonate solution was added 100mL, stirred for 1 hour, the organic phase liquid separation, the aqueous phase was washed twice with ethyl acetate (2 * 50mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a pale yellow solid 12.6g.
Reference：
[1] Patent: CN106854176, 2017, A, . Location in patent: Paragraph 0050; 0051
24
[ 5471-82-9 ]
[ 138229-59-1 ]
Yield
Reaction Conditions
Operation in experiment
66.4%
at 40℃;
Take Niraparib Intermediate 1 (0.88 mol) 160g In a Erlenmeyer flask with reflux and stirrer,230 g (2.64 mol) of AMD (activated manganese dioxide) was added,55 mL of 65percent nitric acid (0.6 mol) was slowly added with stirring to 40 ° C,Reflux 5-7h. Hot filter,After standing, the oil phase is separated,With 0.1kg / L sodium bicarbonate solution repeatedly washed to neutral,Dried with anhydrous sodium sulfate,Niraparib Intermediate 2 was 130.98 g,The yield was 66.4percent.
Reference：
[1] Patent: CN106467513, 2017, A, . Location in patent: Paragraph 0009; 0040; 0041; 0042; 0043
[2] Organic Process Research and Development, 2011, vol. 15, # 4, p. 831 - 840
[3] Organic Process Research and Development, 2011, vol. 15, # 4, p. 831 - 840
[4] Patent: CN106749180, 2017, A,
[5] Patent: CN106749181, 2017, A,
[6] Patent: WO2007/113596, 2007, A1,
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 10h;
Methyl 3-methyl-2-nitro benzoate (1g, 5.2mmol) was dissolved in ethanol (40mL) and then 10% palladium on charcoal (0.1g) was added to the reaction mixture and stirred at rt for 10h. Then the mixture was filtrated, and evaporation of solvent under reduced pressure afforded the light yellow oil product. (0.85g, 99%); deltaH (300MHz, CDCl3) 2.18 (3H, s, Me), 3.88 (3H, s, CO2Me), 5.84 (2H, br s, NH2), 6.61 (1H, t, J 7.7Hz, Ph), 7.22 (1H, d, J 7.3Hz, Ph), 7.79 (1H, d, J 7.7Hz, Ph); deltaC (75MHz, CDCl3) 17.4, 51.5, 110.1, 115.6, 123.0, 129.1, 134.9, 149.0, 169.0.
97.5%
With hydrogen;5%-palladium/activated carbon; In acetonitrile; at 70℃; under 3361.55 - 5171.62 Torr; for 16.5h;
EXAMPLE 4Preparation of 2-amino-5-chloro-N,3-dimethylbenzamideStep A: Preparation of methyl 2-amino-3-methylbenzoateMethyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5% Pd/C (Degussa CE 105 XRCAV, 1.0 g), and acetonitrile (300 mL) were combined in a 600-mL pressure vessel. The mixture was heated to 70 C and hydrogenated at 65 psi (450 kPa) for 8 h. More 5% Pd/C (1.0 g) was added and hydrogenation was continued at 100 psi (690 kPa) for 8.5 h. Then the reaction mixture was cooled, purged with nitrogen, and filtered through Celite diatomaceous filter aid, rinsing with acetonitrile (3 x 25 mL). The combined filtrates were partly evaporated to a weight of ~ 160 g, and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed 40.3 wt% of the title compound (80.6 g, 97.5% yield).
With zinc; In water; acetic acid;
EXAMPLE 6 Preparation of 2-methyl-6-methoxycarbonylaniline In this example 0.02 mole of 2-methyl-6-methoxycarbonyl-nitrobenzene in 25 ml of acetic acid was added dropwise to a slurry containing 6.5 g of zinc dust suspended in 25 ml of water at 30-35 C. The resulting exothermic reaction is controlled by maintaining the mixture at about room temperature (about 20-25 C.) through external cooling. The reaction product mixture was filtered to remove the zinc dust and the filtrate, then washed sequentially with methylene chloride and water, and then extracted with methylene chloride. The extract was washed with an aqueous ammonium hydroxide, then with water and filtered through diatomaceous earth. The filtrate was then dried and evaporated affording 2.7 g of the title product as an oil.
With hydrogen; In methanol; at 20℃; for 16h;
Methyl 2-amino-3-methylbenzoateMethyl 3-methyl-2-nitrobenzoate (45.0 g, 230 mmol), methanol (1 L) and Raney Ni (5 g) were added to a 2 L round-bottomed flask. The resultant reaction mixture was stirred under H2 (1 atm, balloon) at room temperature for 16 hours. The suspension was filtered through a pad of Celite and the pad was washed with methanol (500 mL). The filtrate was concentrated to dryness under reduced pressure to afford the title compound.
With N-Bromosuccinimide; Perbenzoic acid; In tetrachloromethane; for 12.0h;Heating / reflux;
Step B; Methyl 3-Bromomethyl-2-nitrobenzoate; Heat a mixture of methyl 3-methyl-2-nitrobenzoate (12.34 g, 63.23 mmol), benzoyl peroxide (0.920 g, 3.80 mmol) and N-bromosuccinimide (11.25 g, 63.21 mmol) in carbon tetrachloride (330 mL) at reflux under nitrogen for 12 h. Dilute the cooled mixture with methylene chloride (150 mL), treat with silica gel (30 g) and remove the solvents under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (15: 85), to provide methyl 3-bromomethyl-2- nitrobenzoate (1B) as a pale yellow solid (7.15 g, 41%) :'H NMR (CDC13) 8 3.91 (s, 3H), 4.46 (s, 2H), 7.58 (t, 1H), 7.74 (dd, 1H), 7.96 (dd, 1H).
35%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 12.0h;Reflux; Inert atmosphere;
Weigh compound 1 (2.34g, 12mmol), dissolve it with 0.2M carbon tetrachloride solution, add benzoyl peroxide (0.17g, 0.72mmol), NBS (2.18g, 14.16mmol), and reflux under nitrogen. 12 hours.After the mixture was cooled to room temperature, the filtrate was concentrated under reduced pressure, 30 mL of water was added, and extracted with EA three times. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow mixture, which was subjected to column chromatography (eluent was Petroleum ether: ethyl acetate = 90: 1) to give Compound 2 (1.15 g, 35%) as a white flocculent solid.
30%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 20.0h;Inert atmosphere;
A mixture of Compound E (5.13 g, 26.3 mmol), benzoyl peroxide (511 mg, 2.11 mmol), and N- bromosuccinamide (14.1 g, 78.8 mmol) in CCU (120 mL) was heated under a nitrogen atmosphere for 20 h. The mixture was cooled to ambient temperature, diluted with dichloromethane and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 10% EtOAc/hexanes (10:90) to yield Compound F (2.14 g, 7.80 mmol) in 30% yield as an off-white solid. NMR (400 MHz, CDCh) delta 7.93 (d, J= 7.7 Hz, 1H), 7.72 (d, J= 7.7 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 4.43 (s, 2H), 3.88 (s, 3H). MS (ES+) m/z: C9H8BrN04 requires 273/275, found 242/244 (M - MeO) 227/229 (M - N02). Physical state: Off-white solid; R/= 0.7 (mobile phase: EtOAc/hexanes, 20:80).
Part B. Methyl 3-(bromomethyl)-2-nitrobenzoate This product was prepared by following the procedure of Example 6, but substituting methyl 3-methyl-2-nitrobenzoate for 8-methylquinoline. The product was purified by chromatography on silica gel and was crystallized from ethyl acetate:hexane; mp 91-95 C.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 12.0h;Reflux;
Step 2: Methyl 3-(bromomethyI)-2-nitrobenzoate (A2); A mixture of (Al) (1.0 eq.), (BzO)2 (0.06 eq.) and NBS (1.18 eq.) in CCl4 (0.2 M, with respect to Al) was heated at reflux under N2 atmosphere for 12 hr. The mixture was cooled to RT, diluted with DCM, concentrated under reduced pressure whilst dry loading onto SiO2. The residue was purified by flash column chromatography on SiO2 using 10:90 EtO Ac/Petroleum ether to yield the desired (A2) as a white solid. 1H NMR (400MHz, CDCl3, 300K) delta 7.93 (1 H, d, J = 7.7 Hz), 7.72 (IH, d, J = 7.7 Hz), 7.57 (IH, t, J = 7.7 Hz), 4.43 (2H, s), 3.88 (3H, s). MS (ES) C9H8BrNO4 requires: 273:275, found: 242:244 (M-MeO)+, 227:229 (M-NO2) +.
With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; at 90.0℃;
Process 2 Bromination Benzoyl peroxide was added to the mixture of methyl 2-nitro-3-methylbenzoate (1.6 g), N-bromosucciimide (2.0g) and benzene (15 mL) and stirred at 90 C. overnight. After removing the solvent, the residue was diluted with ethyl acetate and washed with sodium thiosulfate aqueous solution, 1M sodium hydrate aqueous solution, water and saturated aqueous solution of sodium chloride respectively. Then the obtained substance was concentrated and dried, and the obtained crude material was purified with silica gel column chromatography to obtain methyl 3-bromomethyl-2-nitrobenzoate.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 12.0h;Heating / reflux;
Step 2: Methyl 3-(bromomethyl)-2-nitrobenzoate (A2); A mixture of (Al) (1.0 eq.), (BzO)2 (0.06 eq.) and NBS (1.18 eq.) in CCl4 (0.2 M) was heated at reflux under N2 atmosphere for 12 hr. The mixture was cooled to RT, diluted with DCM, concentrated under reduced pressure whilst dry loading onto SiO2. The residue was purified by flash column chromatography on SiO2 using 10:90 EtO Ac/Petroleum ether to yield the desired (A2) as a white solid. 1H NMR (400MHz, CDCl3, 300K) delta 7.93 (IH, d, J = 7.7 Hz), 7.72 (IH, d, J = 7.7 Hz), 7.57 (IH, t, J = 7.7 Hz), 4.43 (2H, s), 3.88 (3H, s). MS (ES) C9H8BrNO4 requires: 273:275, found: 242:244 (M-MeO)+, 227:229 (M-NO2) +.
An N,N-dimethylformamide solution (50 ml) containing <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (19.5 g, 0.10 mol) and N,N-dimethylformamide dimethylacetal (23.8 g, 0.20 mol) was refluxed for 5 hours. A Dean-Stark trap was attached and refluxing was conducted for a further 5 hours without distilling off low-boiling products. N,N-dimethylformamide dimethylacetal (11.9 g, 0.10 mol) was added and refluxing was conducted for 5 hours. After the disappearance of <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> was confirmed and the reaction mixture was cooled, the mixture was poured into a 10% aqueous HCl solution (300 ml), followed by stirring at room temperature for 1 hour. Extraction with ethyl acetate was conducted. The aqueous layer was made alkaline with an aqueous sodium bicarbonate solution and then extraction with ethyl acetate was conducted. The organic layers obtained were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain methyl 3-formylmethyl-2-nitrobenzoate of liquid state (yield: 21.0 g and 90%).Confirmed data 1H-NMR (CDCl3) delta:9.75 (1H,d), 7.95 (1H,d-d), 7.60 (1H,tri), 7.51 (1H,d-d), 3.91 (3H,s), 3.78 (2H,s) ppm
With sodium tetrahydroborate; In tetrahydrofuran; for 1.5h;Heating / reflux;
Sodium borohydride (19.4 g, 0.51 mol) was added to a tetrahydrofuran solution (250 ml) containing <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (100 g, 0.51 mol). To the mixture being refluxed was dropwise added methanol (49.2 g, 1.54 mol) slowly in 30 minutes. After the dropwise addition, the mixture was refluxed for 1 hour until there was no foaming. After cooling, the mixture was poured into water and extraction with diisopropyl ether was conducted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain light brown crystals of 3-hydroxymethyl-2-nitrotoluene (yield: 80.3 g and 94%, melting point: 41 to 42C). The crystals were made into a tetrahydrofuran solution (350 ml). A sodium hydroxide powder (26.9 g, 0.67 mol) was added to the solution, followed by stirring at room temperature for 1 hour. After a white solid appeared, dimethyl sulfate (90.9 g, 0.72 mol) was dropwise added at 30 C or less in 30 minutes. During the dropwise addition, the system became homogeneous once and then became agar-like. The system was stirred for 2 days in that state and then poured into water. Thereto was added ammonia water (100 g). Stirring was conducted for 1 hour, after which extraction with ethyl acetate was made. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 3-methoxymethyl-2-nitrotoluene of liquid state (87.0 g, 100%, purity: 96%).Confirmed data 1H-NMR (CDCl3) delta:7.41-7.23 (3H,m), 4.49 (2H,s), 3.37 (3H,d), 2.35 (3H,s) ppm
Step 1: Synthesis of Methyl 2-nitro-3-methylbenzoate: 2-Nitro-3-methylbenzoic acid (50 gm) was dissolved in methanol (250 mL) and bubbled with HCl gas until the solution just began to reflux. The reaction mixture was stoppered and allowed to stir at room temperature for three days. The reaction was concentrated to a solid on a rotary evaporator. The solid was then redissolved and reconcentrated from methanol twice. 1H NMR data: CDCl3, TMS 2.36 (s, 3H), 3.89 (s, 3H), 7.49 (m, 2H), 7.87 (d, 1H).
40
[ 5437-38-7 ]
[ 18107-18-1 ]
[ 5471-82-9 ]
Yield
Reaction Conditions
Operation in experiment
In hexane; acetone; for 3h;
Example 21 Synthesis of the Compound of the Following Formula (E-9) which has a Substituent(s) of Example 21 of Table 4 Process 1 Methylesterification 2M hexane solution (4.5 mL) of trimethylsilyldiazomethane was added to the mixture of 2-Nitro-3-methylbenzoic acid (1.6 g) and acetone (15 mL) and stirred for 3 hours. After removing the solvent, the residue was diluted with ethyl acetate and washed with 1M sodium hydrate aqueous solution, water and saturated aqueous solution of sodium chloride respectively. Then the obtained substance was concentrated and dried to obtain methyl 2-nitro-3-methylbenzoate.
2,2'-azobis(2-methylpropionitrile) (AIBN)[ No CAS ]
[ 5471-82-9 ]
[ 132874-06-7 ]
Yield
Reaction Conditions
Operation in experiment
In tetrachloromethane;
Step 2: Synthesis of Methyl 2-nitro-3-bromomethylbenzoate: Methyl 2-nitro-3-methylbenzoate (15.3 gm) was suspended in carbon tetrachloride (45 mL) along with N-bromosuccinimide (15 3 gm) and heated to reflux. 2,2'-Azobis(2-methylpropionitrile) (AIBN) (0.4 gm) was added to the refluxing solution in four equal portions over 48 hours. The reaction was cooled to room temperature, filtered, and concentrated. The residue consisted of a mixture of starting material, desired product, and dibrominated material which were difficult to separate and so were used in the next step without purification.
3-carboxymethyl-β-(N,N-dimethylamino)-2-nitrostyrene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide dimethyl acetal; N,N-dimethyl-formamide;
A. Preparation of (30) where Y is 3-Methoxycarbonyl and Z is Hydrogen A solution of <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (29) (51 g) in N,N-dimethylformamide dimethylacetal (100 ml) and DMF (250 ml) was refluxed for 72 hours. The mixture was allowed to cool to room temperature, and was poured into ice water. The precipitate was filtered off, affording 3-carboxymethyl-beta-(N,N-dimethylamino)-2-nitrostyrene (34 g), a compound of Formula (30), m.p. 124-126 C.
In N,N-dimethyl-formamide dimethyl acetal; N,N-dimethyl-formamide;
A. Preparation of (N) where Y is 3-Methoxycarbonyl and Z is Hydrogen A solution of <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (M) (51 g) in N,N-dimethylformamide dimethylacetal (100 ml) and DMF (250 ml) was refluxed for 72 hours. The mixture was allowed to cool to room temperature, and was poured into ice water. The precipitate was filtered off, affording 3-carboxymethyl-beta-(N,N-dimethylamino)-2-nitrostyrene (34 g), a compound of Formula (N), m.p. 124-126 C.
methyl 2-nitro-3-(2-oxo-n-propyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ISOPROPYLAMIDE; ethyl acetate;
10a Methyl 2-nitro-3-(2-oxo-n-propyl)benzoate A solution of <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (1.5 g) and N,N-dimethylacetamide dimethyl acetal (3 ml) in dimethylacetamide (5 ml) was heated at 140 C. for 3 hours. After evaporation of the solvent, the resulting brown syrup was dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.42 g, 23%). 1 H-NMR(200 MHz,CDCl3) delta: 2.26(3H,s), 3.78(2H,s), 3.90(3H,s), 7.4-7.7(2H,m), 7.91(1H,dd)
Part A. Methyl 3-methyl-2-nitrobenzoate 3-Methyl 2-nitrobenzoic acid (15.0 g) was stirred overnight with methanolic hydrogen chloride (150 mL of 2.2N). The reaction was then refluxed for 3 hours, cooled and filtered to give 9.0 g of methyl 3-methyl-2-nitrobenzoate, mp 72-75 C.
With sodium hydroxide; thionyl chloride; In methanol; water;
EXAMPLE 2 Preparation of Methyl 2-nitro-3-methylbenzoate Thionylchloride (253 mL) was added dropwise to 3 1 methanol at 0-10 C. Toward end of the addition, the temperature was allowed to rise to 20 C. Solid 2-nitro-3-methylbenzoic acid (500 g) was charged in one portion and the reaction mixture was heated to reflux overnight. It was distilled until pot reached 73 C. After cooling to 60 C., 685 mL water was introduced dropwise and the reaction mixture was cooled to 20 C. Upon adding 26 mL water and 125 mL 80% NaOH, the pH was adjusted to 7. The product was collected by filtration and washed with 3*100 mL water and air dried overnight. Yield of methyl 2-nitro-3-methylbenzoate was 503.5 g (93.5%), mp 72 C. 1 H NMR (300 MHz, CDCl3) delta2.38 (s, 3H), 3.90 (s, 3H), 7.50 (m, 2H), 7.88 (m, 1H).
Take Niraparib Intermediate 1 (0.88 mol) 160g In a Erlenmeyer flask with reflux and stirrer,230 g (2.64 mol) of AMD (activated manganese dioxide) was added,55 mL of 65% nitric acid (0.6 mol) was slowly added with stirring to 40 C,Reflux 5-7h. Hot filter,After standing, the oil phase is separated,With 0.1kg / L sodium bicarbonate solution repeatedly washed to neutral,Dried with anhydrous sodium sulfate,Niraparib Intermediate 2 was 130.98 g,The yield was 66.4%.
155 g
To a solution of methyl 3-methyl-2-nitrobenzoate (250 g) in DMF (500 mL) at 25-35C, dimethylformamide dimethyl acetal (DMF -DMA) (621 mL, 4.64 mole) was added. The resulting solution was heated to 130C; and stirred until HPLC/TLC analysis indicated completion of reaction. After completion of the reaction, the reaction mass was cooled to 20-30C; and water (3.0 L) and sodium periodate (493 g) was charged under stirring. The reaction was allowed to heat at 35- 45C under stirring until HPLC/TLC analysis indicated completion of reaction. After completion of the reaction, the reaction mass was cooled to 20-30C, filtered and washed water (500 mL). The wet cake obtained was charged in ethyl acetate (2.0 L), heated to reflux temperature for 1 h, cooled to 60-65C and filtered the inorganic salt (NalCb). Filtrate was concentrated till 2-3 volume (approximately 0.5 L) remains in reactor. The Reaction mass was cooled down to 0-10C by maintaining for 1-3 h. The solid was filtered and washed with chilled ethyl acetate (1 L). The solid material obtained was dried under reduced pressure to afford the titled compound (Yield: 155 g; HPLC Purity: >99.0%). Example 1 (B): Preparation of methyl 3-formyl-2-nitrobenzoate (Compound 10)
To a solution of compound 9 (83.0 g, 0.43 mol) was added 210 mL of DMF,Adding 220 mL of DMF-DMA,After heatingTo 130 C for 18 hours, cooled to room temperature, add water 450mL stirring, a solid precipitation,The solid was filtered off and washed with water. And dried under reduced pressure (45 C) to give 96.3 g of a brown solid
96.3 g
In N,N-dimethyl-formamide; at 130℃; for 18h;
210 mL of DMF was added to Compound 9 (83.0 g, 0.43 mol), and 220 mL of DMF-DMA was added thereto, followed by heatingThe reaction was carried out at 130 C for 18 hours, cooled to room temperature, and 450 mL of water was added with stirring to precipitate a solid. The solid was filtered off and washed with water andDrying under reduced pressure (45 C) gave 96.3 g of a brown solid
With nitric acid; acetic anhydride; at 30℃; for 3h;
4.8 mL of 65% nitric acid (0.07 mol) was added to a 100 mL round bottom flask, 7.6 mL (0.08 mol) of acetic anhydride was added dropwise, and after the reaction was carried out for 0.5 h, 7.6 mL of acetic anhydride and 3.0 g of methyl 3-methylbenzoate (0.02 mol) were mixed and slowly added dropwise to the reaction system. The above operations were carried out under ice-cooling. After the drop, the temperature is raised to 30 C for 3 h. After stopping the reaction, the acetic anhydride, nitric acid and acetic acid are distilled off. The concentrated solution is poured into ice water, stirred, and precipitated with yellow solid. The product was attached to the wall of the flask by dissolving 20 mL of ethyl acetate. The product was dissolved and concentrated to give 3.83 g of a pale yellow liquid in a yield of 98.21%. The content ratio of methyl 3-methyl-2-nitrobenzoate to methyl 3-methyl-4-nitrobenzoate was 72:28 by HPLC analysis. The pale yellow liquid mixture was recrystallized from absolute ethanol to give methyl 3-methyl-2-nitrobenzoate.
With nitric acid; acetic anhydride; In dichloromethane; at 40 - 50℃; for 0.25h;
To a 100 mL round bottom flask was added 2.7 mL of 65% nitric acid (0.04 mol) 3.8 mL (0.04 mol) of acetic Anhydridewas added dropwise , dropwise, after 0.5 h of reaction, 3.8 mL of acetic anhydride, 2.7 mL of dichloromethane,3.0 g of methyl 3-methylbenzoate (0.02 mol) was mixed, Slowly added to the reaction system,The above operations are carried out under ice bath conditions.After dripping, the temperature to 40 ~ 50C reaction 15min, After stopping the reaction,Steamed acetic anhydride and glacial acetic acid,Pour the concentrate into ice water,Stirring, with yellow solid precipitation,The product attached to the wall of the flask was dissolved by addition of 20 mL of ethyl acetate,Separated, concentrated, pale yellow liquid 3.66g, the yield of 93.85%.By HPLC analysis,The methylester ratio of methyl 3-methyl-2-nitrobenzoate to methyl 3-methyl-4-nitrobenzoate was about 66:34.The pale yellow liquid mixture was recrystallized from absolute ethanol to give methyl 3-methyl-2-nitrobenzoate.
With potassium acetate; acetic acid; isopentyl nitrite; In 1,2-dichloro-ethane; for 24h;Reflux;
Example 9 Compound 16 (20.0g, 0.103mol) in 1,2-dichloroethane was added 100mL, acetic acid 20mL, was added potassium acetate (2.0g, 0.021mol) was dissolved after stirring, isoamyl nitrite (24.1 g of, 0.206 mol), heated to reflux and reacted at this temperature for 24 hours, cooled to room temperature, the reaction was washed with saturated sodium carbonate solution, the solution was evaporated under reduced pressure, 80 mL of ethanol was added to the residual liquid, dropwise under ice after 10mL of concentrated hydrochloric acid was added, and stirred at this temperature for 2 hours, the solid was filtered off to give a pale yellow solid, the resulting solid was added 90 mL of ethyl acetate and saturated sodium carbonate solution was added 100mL, stirred for 1 hour, the organic phase liquid separation, the aqueous phase was washed twice with ethyl acetate (2 * 50mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a pale yellow solid 12.6g.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
