There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 1129-28-8 * Storage: {[proInfo.prStorage]}
* 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.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 70℃;
30mL CCl4The 7.9g inter-methylbenzoate was dissolved in dry 100mL three-necked flask, AIBN (azobisisobutyronitrile) 0.23g, 9.36gNBS (bromosuccinimide) three times into the reaction system ( was added in two intervals of about 2-3h), heated to 70 , the reaction from the system during the final yellow to orange to white, TLC tracking (eluent: cyclohexane: ethyl acetate = 5) to be reaction was almost complete, the succinimide was removed by filtration and the unreacted bromosuccinimide, the resultant filtrate rotary evaporated to give 11.5 g of product as a yellow oil, 95percent yield.
94%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethaneReflux
A solution of methyl 3-methylbenzoate (47 g, 0.31 mol) in CCl4 (200 mL) was heated to reflux followed by addition of AIBN (2.6 g) in one portion. After that, NBS (67 g, 0.38 mol) was added carefully to the mixture during 2 h, and then the reaction was refluxed for an additional 5 h. After cooling to r.t. the mixture was filtered and evaporated under vacuum to give methyl 3-(bromomethyl)benzoate (10, 67 g, Yield: 94percent) as a yellowish oil. The obtained oil was then dissolved in triethyl phosphate (130 g, 0.71 mol), heated to 160 °C and kept at this temperature for an additional 10 h. The mixture was concentrated on a rotary evaporator and then purified by flash chromatography(PE:EA = 5:1~PE:EA = 1:3) to give 11 as a yellow oil, which was used without any further purification.
94%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 16 h;
To a solution of methyl 3-methylbenzoate (4.0 g, 26.60 mmol) in CCU (150 mL) was added BS (5.69 g, 31.96 mmol), and the suspension was heated at 80 °C for 5 min and AIBN (2.18 g, 13.30 mmol) was added. The suspension continued to stir at 80 °C for 16 h. The mixture was cooled to RT and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography eluting with EA/petroleum ether from 0percent to 3percent to give methyl 3-(bromomethyl)benzoate (5.7 g, 94percent) as a white oil
91%
With N-Bromosuccinimide In tetrachloromethane at 50℃; for 5 h; Heating / reflux
To a mixture of methyl-m-toluate (180 g, 1.2 mol) and N-bromosuccimide (235 g, 1.32 mol) in CCl4 (2 L) was added in portion benzoyl peroxide (18 g, 0.1 times) at 50° C. The mixture was refluxed for 5 h. Then the mixture was allowed to cool down to 40° C. and the solid was filtered off. The filtrate was concentrated to give methyl 3-(bromomethyl)benzoate (252 g, 91percent) as light yellow liquid.
87%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 70℃; for 4 h;
To a solution of Intermediate BL (5.0g, 33.29 mmol) and benzoyl peroxide (0.4 g, 1.66 mmol) in CC14 (60.0 mL) was added NBS (5.75 g, 33.29 mmol). The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 1percent ethyl acetate in petroleum ether as the eluent to afford Intermediate BM (6.8 g, 87percent) as pale yellow oil. NMR (CDC13): δ 8.07 (s, 1H), 8.00-7.96 (m, 1H), 7.60-7.58 (m, 1H), 7.43 (t, J= 7.67 Hz, 1H), 4.52 (s, 2H), 3.93 (s, 3H).
10%
With N-Bromosuccinimide In cyclohexane for 16 h; Reflux
Synthesis Example 11; Synthesis of Compound 22; Methyl-3-methyl benzoate (1.5 g, 10 mmol) and N-bromosuccinimide (5.34 g, 30 mmol) was suspended in cyclohexane (50 ml). To the suspension, a catalytic amount of hydrogen peroxide was added, and the reaction mixture was heated to reflux for 16 h. The reaction mixture was then filtered, and evaporated to yield 0.231 g (10percent) as a yellow oil. Compound 21 was then formed by coupling methyl 3-bromomethylbenzoate to thionicotinamide intermediate IIa in the manner of Method A to yield 180 mg (45percent) of compound 22 as a crystalline material. ESI-MS m/z=397.1 [M+H]+.
10%
With N-Bromosuccinimide; dihydrogen peroxide In cyclohexane for 16 h; Reflux
Methyl-3-methyl benzoate (1.5 g, 10 mmol) and N-bromosuccinimide (5.34 g, 30 mmol) was suspended incyclohexane (50 ml). To the suspension, a catalytic amount of hydrogen peroxide was added, and the reaction mixturewas heated to reflux for 16 h. The reaction mixture was then filtered, and evaporated to yield 0.231 g (10percent) as a yellowoil. Compound 21 was then formed by coupling methyl 3-bromomethylbenzoate to thionicotinamide intermediate IIa inthe manner of Method A to yield 180 mg (45percent) of compound 22 as a crystalline material. ESI-MS m/z = 397.1 [M+H]+.
Reference：
[1] Organic and Biomolecular Chemistry, 2003, vol. 1, # 14, p. 2506 - 2511
[2] Patent: CN106146413, 2016, A, . Location in patent: Paragraph 0027; 0028
[3] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 7 - 17
[4] Molecules, 2016, vol. 21, # 12,
[5] Patent: WO2018/169777, 2018, A1, . Location in patent: Paragraph 0227
[6] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 9; 21-22
[7] Patent: WO2011/47156, 2011, A1, . Location in patent: Page/Page column 89
[8] Journal of Organic Chemistry, 2002, vol. 67, # 7, p. 2160 - 2167
[9] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[10] Farmaco, Edizione Scientifica, 1987, vol. 42, # 6, p. 409 - 424
[11] Organic Letters, 2013, vol. 15, # 4, p. 917 - 919
[12] Journal of the American Chemical Society, 2010, vol. 132, # 49, p. 17366 - 17369
[13] Chemistry - A European Journal, 2016, vol. 22, # 49, p. 17576 - 17580
[14] RSC Advances, 2013, vol. 3, # 45, p. 23119 - 23127
[15] Collection of Czechoslovak Chemical Communications, 2004, vol. 69, # 12, p. 2239 - 2252
[16] Organometallics, 2015, vol. 34, # 9, p. 1627 - 1634
[17] Patent: US2010/210593, 2010, A1, . Location in patent: Page/Page column 46
[18] Patent: EP2942346, 2015, A1, . Location in patent: Paragraph 0158
[19] Journal of Organic Chemistry, 1959, vol. 24, p. 1952,1954
[20] Journal of Medicinal Chemistry, 1987, vol. 30, # 1, p. 96 - 104
[21] Journal of Organic Chemistry, 1992, vol. 57, # 3, p. 965 - 969
[22] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 2, p. 297 - 304
[23] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3891 - 3904
[24] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 345 - 348
[25] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4667 - 4677
[26] Patent: WO2004/43966, 2004, A1, . Location in patent: Page 49
[27] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 10, p. 3122 - 3125
[28] Patent: EP1577302, 2005, A1, . Location in patent: Page/Page column 116-117
[29] Journal of Medicinal Chemistry, 2009, vol. 52, # 10, p. 3317 - 3327
[30] Angewandte Chemie - International Edition, 2010, vol. 49, # 37, p. 6633 - 6637
[31] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[32] Chemistry - A European Journal, 2015, vol. 21, # 28, p. 10179 - 10184
[33] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 13, p. 1845 - 1854
2
[ 67853-03-6 ]
[ 1129-28-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
With phosphorus tribromide In diethyl ether for 2 h;
To the solution of compound B4 (28 g, 0.168 mol) in 700 mL of Et2O was added PBr3 (17.4 mL, 0.185 mol) dropwise. The solution was stirred for 2 h, and then the reaction was poured into 500 mL of ice-water. The aqueous layer was extracted with Et2O. The combined organic layers were washed with sat. NaHCO3, water, and brine consecutively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give 34 g of compound B5 as an oil (yield: 70percent).
70%
With phosphorus tribromide In diethyl ether
Synthesis of Compound B5: [Show Image] To the solution of compound B4 (28 g, 0.168 mol) in 700 mL of Et2O was added PBr3 (17.4 mL, 0.185 mol) dropwise. The solution was stirred for 2 h, and then the reaction was poured into 500 mL of ice-water. The aqueous layer was extracted with Et2O. The combined organic layers were washed with sat. NaHCO3, water, and brine consecutively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give 34 g of compound B5 as an oil (yield: 70percent).
Reference：
[1] Patent: WO2011/20615, 2011, A1, . Location in patent: Page/Page column 45; 47
[2] Patent: EP2289883, 2011, A1, . Location in patent: Page/Page column 18
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1711 - 1715
[4] Patent: EP1445249, 2004, A1, . Location in patent: Page 136
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 2, p. 476 - 479
[6] Patent: WO2014/121931, 2014, A1, . Location in patent: Page/Page column 26
3
[ 99-36-5 ]
[ 1129-28-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) In dichloromethane at 20℃; for 10 h; Heating / reflux
Example 2: Preparation of Methyl 3-bromomethylbenzoate; To a solution of Methyl 3-methylbenzoate (150 g, I mol) and l,3-Dibromo-5,5-dimethyl hydantoin (DDH) (15O g, 0.52 mol) in dichloromethane (500 ml) was added AIBN (0.1 g, 0.0006 mol) at room temperature and heated under reflux for 1O h. AIBN in 0.1 g lots were added intermittently during reflux to complete the reaction. After completion of the reaction (monitored by TLC), the reaction mixture was poured into cold water (600 ml) and the organic layer was separated. The aqueous layer was extracted again with dichloromethane (200 ml). The combined organic layer was washed with water and dried over anhydrous sodium sulphate and the solvent was removed by distillation. Colorless liquid, 220 g (96 percent yield)Note: The product contains some dibromo derivative also. Benzoyl peroxide could be used as a radical initiator.
Reference example 2 Methyl 3-bromomethylbenzoate 3-Bromomethylbenzoyl chloride (1.96 g, 10.37 mmol) was dissolved in methanol (20 ml), and triethylamine (1.5 ml) was added thereto. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a saturated sodium hydrogencarbonate solution and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.90 g, 10.29 mmol, yield: 97percent) as a colorless oil.
Reference：
[1] Patent: EP1550662, 2005, A1, . Location in patent: Page/Page column 20
[2] Organic and biomolecular chemistry, 2004, vol. 2, # 12, p. 1732 - 1741
5
[ 67-56-1 ]
[ 6515-58-8 ]
[ 1129-28-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 25℃; for 1 h; Reflux
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 °C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0 percent)
94%
at 25℃; for 1 h; Reflux
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25° C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0percent)
With ammonium chloride; zinc In tetrahydrofuran; water for 3 h;
General procedure: To 0.13 g (2 mmol) of Zn metal in 1 mL saturated aqueous NH4Cl solution was added 0.23 g (1 mmol) of 4. Stirring was begun and a solution of the appropriate benzyl bromide (2 mmol) in 2 mL of THF was added via pipette. The reaction vessel was capped and the mixture allowed to stir until the yellow color of 4 was discharged (generally ~3 h). The reaction mixture was filtered through a plug of glass wool into a centrifuge tube. The organic layer was removed. The aqueous layer was washed 2 × 2 mL of THF. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Column chromatography on SiO2 using appropriate mixtures of ethylacetate and hexanes provided the desired compounds.
With 18-crown-6 ether In acetonitrile at 20℃; for 72 h;
(i) Production of methyl 3-(cyanomethyl)benzoate; To a solution of methyl 3-bromobenzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95-->30/70), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (7.0 g, 91percent) as a colorless oil. 1H-NMR (DMSO-d6, 300 MHz) δ 3.88 (3H, s), 4.17 (2H, s), 7.57 (1H, t, J = 7.6 Hz), 7.61 - 7.69 (1H, m), 7.88 - 7.95 (1H, m), 7.97 (1H, br s).
Reference：
[1] Patent: EP2181987, 2010, A1, . Location in patent: Page/Page column 65; 110; 115
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3452 - 3478
[3] Angewandte Chemie - International Edition, 2010, vol. 49, # 37, p. 6633 - 6637
[4] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
[5] Patent: WO2008/156820, 2008, A1, . Location in patent: Page/Page column 59
[6] Patent: WO2016/165014, 2016, A1, . Location in patent: Page/Page column 22
16
[ 143-33-9 ]
[ 1129-28-8 ]
[ 68432-92-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 75℃; for 5 h;
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) arid sodium cyanide (4.33 g, 88.4 mmol) in DMf (25 ml) and water (1 ml) was stirred at 75 °C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined orgaiiics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of colourless oil. NMR: 7.90 (s, I H), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 1; 3-Cγanomethyl-benzoic acid methyl esterA suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g5 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of colourless oil. NMR: 7.90 (s5 IH), 7.86 (d, IH), 7.60 (d, IH)5 7.50 (m5 IH)5 4.10 (s, 2H)5 3.80 (s, 3H); m/z 175.
70%
Stage #1: at 75℃; for 5 h; Stage #2: With water In N,N-dimethyl-formamide
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 χ 100 ml). The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane- EtOAc) to give7.2 g (70percent) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined organics were dried with Na2SC>4(s) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give7.2 g (70percent) of colourless oil. NMR (400 MHz): 7.90 (s, 1H), 7.86 (d, 1H), 7.60 (d, 1H), 7.50 (m, 1H), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 15; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 hours. The reaction mixture was quenched with water (50 ml), extracted with EtOAc (3 x 100 <n="52"/>ml) and the combined organics were dried and concentrated under reduced pressure. The residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of a colourless oil.1HNMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z: 175.
70%
at 75℃; for 5 h;
Method 9; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of niethyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 2 3-Cyanomethyl-benzoic acid methyl ester A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 ° C. for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried with NaCl(sat) and then Na2SO4(s). The solvents were removed under reduced pressure. The resulting residue was purified by column chromatography utilizing an 20 ISCO system (hexane-EtOAc) to give 7.2 g (70percent/o) of colourless oil. NMR: 7.90 (s, 1H); 7.86 (d, 1H); 7.60 (d, 1H); 7.50 (m, 1H); 4.10 (s, 2H); 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 50; 3-Cyanomethylbenzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodiumcyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100ml x 3). The combined organics were dried with Na2SO4(s) and concentrated under reducedpressure. The resulting residue was purified by column chromatography utilizing an ISCOsystem (hexane-EtOAc) to give7.2 g (70percent) of colourless.oil. NMR (400 MHz): 7.90 (s, 1 H),7.86 (d, 1 H), 7.60 (d, 1 H), 7.50 (m, 1 H)3 4.10 (s, 2 H), 3.80 (s, 3 H); m/z 175.
70%
at 75℃; for 5 h;
Method 12; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 0C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of colourless oil. NMR: 7.90 (s, 1Η), 7.86 (d, 1Η), 7.60 (d, 1Η), 7.50 (m, 1Η), 4.10 (s, 2Η), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 6; 3-Cyanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 0C for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined <n="28"/>organics were dried with NaCl(sat) and then Na2S O4(s). The solvents were removed under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
at 75℃; for 5 h;
Method 4; 3-Cyanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 °C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organics were dried with Na2S04(s) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70percent) of a colourless oil.
Step 1: synthesis of methyl 3-(cyanomethyl)benzoate (1)To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2 x 500mL). The combined organic layers were washed with water, brine, dried (Na2S04), filtered and evaporated under reduced pressure to yield methyl 3- (cyanomethyl)benzoate 1 (17g, 89percent). 1H-NMR (400 MHz, CDC13) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
89%
at 20℃;
Step 1: synthesis of methyl 3-(cyanomethyl)benzoate (1) To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2*500 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield methyl 3-(cyanomethyl)benzoate 1 (17 g, 89percent). 1H-NMR (400 MHz, CDCl3) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
85%
at 75℃; for 5 h; Inert atmosphere
A suspension of methyl-3-(bromomethyl)benzoate (0.5 g, 2.18 mmol) and sodium cyanide (0.16 g, 3.27 mmol) in DMF (0.93 mL) and H2O (0.04 mL) was stirred at 75 °C for 5 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with H2O (3×), dried (Na2SO4) and the solvents were evaporated. The residue was purified by column chromatography (silica gel, from 80:20 hexane/EtOAc to 70:30 hexane/EtOAc) to afford 0.324 g (85percent) of a colourless oil identified as methyl 3-(cyanomethyl)benzoate 29b. 1H NMR (400.13 MHz, CDCl3): δ 8.02–8.00 (m, 2H, ArH), 7.56–7.53 (m, 1H, ArH), 7.50–7.46 (m, 1H, ArH), 3.93 (s, 3H, CH3), 3.81 (s, 2H, CH2) ppm. 13C NMR (100.62 MHz, CDCl3): δ 166.3 (s), 132.3 (d), 131.0 (s), 130.5 (s), 129.3 (d), 129.2 (d), 129.1 (d), 117.5 (s), 52.3 (q), 23.4 (t) ppm. HMRS (ESI+): Calcd for C10H10NO2 ([M+H]+), 176.0706; found, 176.0703. IR (NaCl): ν 3003 (w, C–H), 2954 (w, C–H), 2252 (w, CN), 1722 (s, CO), 1439 (m), 1287 (m) cm−1. UV (MeOH): λmax 283, 229 nm.
81%
at 65℃; for 2 h;
Methyl 3-(cyanomethyl)benzoate 15. To a stirring aqueous solution (60 mL) of potassium cyanide (3.62 g, 55.7 mmol) at 65°C was added dropwise methyl 3-(bromomethyl)benzoate 14 (10.2 g, 44.5 mmol) in absolute ethanol (50 mL) over a period of 0.5 h. After addition, the reaction was stirred for 1.5 h at 65°C. The solution was then diluted with absolute ethanol (500 mL), cooled on ice bath, filtered, and concentrated with a rotary evaporator. The crude was treated with chloroform (350 mL), dried over MgS04, filtered, concentrated, and used without further purification. Yield 6.3 g (81percent). 3/4-NMR (CDC13): 3.81 br s (2H, CH2), 3.93 s (3H, CH3); 7.45-7.51 m (1H, CH), 7.53-7.58 m (1H, CH), 7.99-8.04 m (2H, CH).
51%
at 0 - 10℃; for 3.25 h;
To a cold solution of Intermediate BM (7.2 g, 31.44 mmol) in DMSO (35.0 mL) at 0 °C was added a sodium cyanide (3.0 g, 62.88 mmol) portionwise over 15 minutes. After the addition was complete, the reaction mixture was allowed to stir at 10 °C for 3 hours. Ice cold water was added to the reaction mixture (50 mL), and the reaction was extracted with ethyl acetate (3 χ 50 mL), washed with water (2 χ 25 mL) and brine (25 mL), dried over anhydrous Na2S04, and the solvent was removed to afford the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 10percent ethyl acetate in petroleum ether as the eluent to afford Intermediate BN (2.8 g, 51percent) as a pale brown liquid. NMR (CDC13): δ 9.44-9.42 (m, 2H), 8.90-8.78 (m, 2H), 4.63 (s, 3H), 4.49 (s, 2H). Mass (M-H): 174.1.
Reference：
[1] Patent: WO2011/147764, 2011, A1, . Location in patent: Page/Page column 25
[2] Patent: US2013/79341, 2013, A1, . Location in patent: Paragraph 0104
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 2056 - 2067
[4] Patent: WO2012/173784, 2012, A1, . Location in patent: Page/Page column 28-29
[5] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[6] Patent: WO2011/47156, 2011, A1, . Location in patent: Page/Page column 89
[7] Patent: US2009/275583, 2009, A1, . Location in patent: Page/Page column 30
18
[ 151-50-8 ]
[ 1129-28-8 ]
[ 68432-92-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 18-crown-6 ether In acetonitrile for 24 h; Heating / reflux
To methyl 3-bromomethyl-benzoate (25.28 g, 0.11 mol) in acetonitrile (230 ml) is added potassiumcyanide (14.3 g, 0.22 mmol) and 18-crown-6 (1.00 g, 2.6 mmol) and the mixture is heated to reflux for24 h. After filtration, the crude product is transferred to the next step without any further purification.Yield: 18.5 g (96 percent)
68%
at 60℃;
a) methyl 3-(cyanomethyl)benzoateA slurry of methyl 3-(bromomethyl)benzoate (4.0 g, 17.5 mmol) and potassium cyanide (1.2 g, 18.4 mmol) in ethanol (40 ml) was heated at 60 °C over night, filtrated and evaporated. The residue was purified using column chromatography on SiO2 affording 2.1 g (68percent) of the title compound.1H NMR (399.988 MHz, CDC13) δ 8.06 - 7.98 (m, 2H), 7.56 (d, J= 8.0 Hz, IH), 7.51 - 7.46 (m, IH), 3.94 (s, 3H), 3.82 (s, 2H)
Reference：
[1] Patent: WO2006/589, 2006, A1, . Location in patent: Page/Page column 56-57
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 25, p. 4030 - 4052
[3] Organic and biomolecular chemistry, 2004, vol. 2, # 12, p. 1732 - 1741
[4] Patent: WO2007/30061, 2007, A1, . Location in patent: Page/Page column 83
Stage #1: at 20 - 50℃; for 2 h; Inert atmosphere Stage #2: With water; potassium hydroxide In methanol at 50℃; for 1.5 h; Stage #3: With hydrogenchloride In methanol; water at 20℃;
a) 3-(Methoxymethyl)benzoic acid; To a solution of methyl 3-(bromomethyl)benzoate (1129-28-8, 1.05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74 g, 13.8 mmol). The suspension was stirred at 50° C. for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50° C. for 1.5 hr.After cooling to rt aqueous HCl was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as a colorless oil (749 mg, 96percent). LCMS RtB=2.47 min; [M+H]+=167.0]
96%
Stage #1: at 20 - 50℃; for 2 h; Inert atmosphere Stage #2: With water; potassium hydroxide In methanol at 50℃; for 1.5 h; Stage #3: With hydrogenchloride In methanol; water at 20℃;
Building Block B3.1: 4-Bromomethyl-5-(3-methoxymethyl-phenyl)-oxazole a) 3-(Methoxymethyl)benzoic acid To a solution of methyl 3-(bromomethyl)benzoate, 1.05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74 g, 13.8 mmol). The suspension was stirred at 50° C. for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50° C. for 1.5 hr.After cooling to rt aqueous HCl was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as colorless oil (749 mg, 96percent). LCMS RtB=2.47 min; [M+H]+=167.0]
96%
Stage #1: at 50℃; for 2 h; Stage #2: With water; potassium hydroxide In methanol at 50℃; for 1.5 h; Stage #3: With hydrogenchloride In methanol; water at 20℃;
To a solution of methyl 3-(bromomethyl)benzoate, 1 .05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74g, 13.8 mmol). The suspension was stirred at 50 °C for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50 °C for 1 .5 hr.After cooling to rt aqueous HCI was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as colorless oil (749 mg, 96percent). LCMS RtB = 2.47 min; [M+H]+ = 167.0]
With diisobutylaluminium hydride In toluene at 0 - 20℃; for 2 h; Inert atmosphere
Step A: To a stirred solution of methyl 3-(bromomethyl)benzoate (5 g, 21.8 mmol) in toluene (50 mL) was added DABAL-H (43.6 ml, 43.6 mmol) in an ice bath. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with 1 N HCl, extracted with EtOAc and water. The organic layer was dried over anhydrous Na2S04 and concentrated to afford (3-(bromomethyl)phenyl)methanol (4.0 g, 19.9 mmol, 91percent yield) as a colorless oil.
91%
With diisobutylaluminium hydride In toluene at 0℃; for 2 h;
To a stirred solution of methyl 3-(bromomethyl)benzoate (5 g, 21.8 mmol) in toluene (50 mL) was added DABAL-H (43.6 ml, 43.6 mmol) in an ice bath. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with 1 N HC1, extracted with EtOAc and water. The organic layer was dried over anhydrous Na2S04 and concentrated to afford (3-(bromomethyl)phenyl)methanol (4.0 g, 19.9 mmol, 91percent yield) as a colorless oil.
68%
With diisobutylaluminium hydride In toluene at -30℃; for 2.5 h;
To a solution of methyl 3-(bromomethyl)benzoate (0.5 g, 2.2 mmol) dissolved in dry toluene (10 mL), cooled to -30°C, 1M solution of DIBAL-H in toluene (4.3 mL, 4.4 mmol) was dropped. The reaction mixture was stirred at -30°C for 2.5h and then allowed to warm to ambient temperature. The reaction mixture was quenched with methanol, filtered, extracted with ethyl acetate, washed with aqueous sodium bicarbonate solution, then brine, dried over sodium sulfate, and evaporated under reduced pressure giving 3-bromomethylbenzyl alcohol (0.3 g); yield 68percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5867 - 5872
29
[ 110-91-8 ]
[ 1129-28-8 ]
[ 67451-81-4 ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium hydroxide In methanol; dichloromethane
EXAMPLE 14 3-Morpholin-4-yl-methyl-benzoic Acid Commercially available methyl 3-bromomethyl benzoate (5 g, 22 mmole) was dissolved in dichloromethane (20 mL) and morpholine (3.93 mL, 45 mmol) was added. The solution was allowed to stir for 12 h, and filtered. The solvent of the filtrate was removed under reduced pressure. The resulting crude ester was dissolved in methanol, and sodium hydroxide (4.6 mL of 5N solution) was added. The solution was stirred overnight at 40° C. for 12 h. The solvent was partially removed under reduced pressure. The crude was acidified, dichloromethane was added and the solution was cooled in ice. After one hour, it was filtered, to provide the title product (2.3 g, 41percent) as the white solid hydrochloride salt: 1H-NMR (DMSO-d6) δ13.1 (bs, 1H), 11.8 (bs, 1H), 8.14 (s, 1H), 7.92 (m, 2H), 7.65 (t, J=4 Hz, 1H), 4.39 (bs, 2H), 3.91(m, 4H), 3.12 (m, 4H). MS (EI-NEG):[M+]221; Anal.RP-HPLC: 99percent purity.
Reference：
[1] Patent: US6355633, 2002, B1,
30
[ 1129-28-8 ]
[ 67451-81-4 ]
Reference：
[1] Patent: WO2018/169777, 2018, A1,
31
[ 1129-28-8 ]
[ 775304-60-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1708 - 1716
To a solution of methyl 3- (bromomethyl)benzoate (0.5 g, 2.18 mmol) in ether (10 mL), at 0 °C was added dropwise methylmagnesium bromide (3M in Et20, 2.18 mL, 6.55 mmol). The reaction mixture was warmed up to 45 °C and stirred for 2 h, and then poured into an ice-cooled saturated aq. solution of NH4CI and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by Si02gel chromatography (8percent to 60percent EtOAc/Hexanes) to give 2-(3-(bromomethyl)phenyl)propan-2-ol as a clear oil (202 mg, 40percent). MS (ES+) Ci0H13BrO requires: 229, found: 229/231 [M+H]+.
With N-Bromosuccinimide In acetonitrile at 20℃; for 0.25h; Irradiation;
95%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 70℃;
1.3 (3) 3-bromomethyl-benzoic acid methyl ester (IV)
30mL CCl4The 7.9g inter-methylbenzoate was dissolved in dry 100mL three-necked flask, AIBN (azobisisobutyronitrile) 0.23g, 9.36gNBS (bromosuccinimide) three times into the reaction system ( was added in two intervals of about 2-3h), heated to 70 , the reaction from the system during the final yellow to orange to white, TLC tracking (eluent: cyclohexane: ethyl acetate = 5) to be reaction was almost complete, the succinimide was removed by filtration and the unreacted bromosuccinimide, the resultant filtrate rotary evaporated to give 11.5 g of product as a yellow oil, 95% yield.
94.3%
With N-Bromosuccinimide In Carbon tetrachloride for 6h; Reflux;
94%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride Reflux;
3.1.2. Synthesis of Methyl 3-((Diethoxyphosphoryl)methyl)benzoate (11)
A solution of methyl 3-methylbenzoate (47 g, 0.31 mol) in CCl4 (200 mL) was heated to reflux followed by addition of AIBN (2.6 g) in one portion. After that, NBS (67 g, 0.38 mol) was added carefully to the mixture during 2 h, and then the reaction was refluxed for an additional 5 h. After cooling to r.t. the mixture was filtered and evaporated under vacuum to give methyl 3-(bromomethyl)benzoate (10, 67 g, Yield: 94%) as a yellowish oil. The obtained oil was then dissolved in triethyl phosphate (130 g, 0.71 mol), heated to 160 °C and kept at this temperature for an additional 10 h. The mixture was concentrated on a rotary evaporator and then purified by flash chromatography(PE:EA = 5:1~PE:EA = 1:3) to give 11 as a yellow oil, which was used without any further purification.
94%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 80℃; for 16h;
14
To a solution of methyl 3-methylbenzoate (4.0 g, 26.60 mmol) in CCU (150 mL) was added BS (5.69 g, 31.96 mmol), and the suspension was heated at 80 °C for 5 min and AIBN (2.18 g, 13.30 mmol) was added. The suspension continued to stir at 80 °C for 16 h. The mixture was cooled to RT and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography eluting with EA/petroleum ether from 0% to 3% to give methyl 3-(bromomethyl)benzoate (5.7 g, 94%) as a white oil
92%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 70℃;
1.2 (2) Preparation of methyl meta-bromomethyl benzoate
Use 30ml CCl4 to dissolve 7.6g methyl meta-methyl benzoate in a dry 100ml three-necked flask, add 0.23g AIBN (azobisisobutyronitrile), 9.36g NBS (bromosuccinimide) 3 times The reaction system is added (the interval between the two additions is about 2h), and the temperature is increased to 70°C. During the reaction, the system turns from yellow to orange and finally turns white. TLC tracking (developing solvent: ethyl acetate: petroleum ether = 1:5) When the reaction is almost complete, the succinimide and unreacted bromosuccinimide are removed by filtration, and the filtrate obtained is rotary evaporated to obtain a yellow oily product 10.2g, yield 92%.
91%
With N-Bromosuccinimide In Carbon tetrachloride at 50℃; for 5h; Heating / reflux;
IV; 2.2
To a mixture of methyl-m-toluate (180 g, 1.2 mol) and N-bromosuccimide (235 g, 1.32 mol) in CCl4 (2 L) was added in portion benzoyl peroxide (18 g, 0.1 times) at 50° C. The mixture was refluxed for 5 h. Then the mixture was allowed to cool down to 40° C. and the solid was filtered off. The filtrate was concentrated to give methyl 3-(bromomethyl)benzoate (252 g, 91%) as light yellow liquid.
87%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride at 70℃; for 4h;
To a solution of Intermediate BL (5.0g, 33.29 mmol) and benzoyl peroxide (0.4 g, 1.66 mmol) in CC14 (60.0 mL) was added NBS (5.75 g, 33.29 mmol). The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 1% ethyl acetate in petroleum ether as the eluent to afford Intermediate BM (6.8 g, 87%) as pale yellow oil. NMR (CDC13): δ 8.07 (s, 1H), 8.00-7.96 (m, 1H), 7.60-7.58 (m, 1H), 7.43 (t, J= 7.67 Hz, 1H), 4.52 (s, 2H), 3.93 (s, 3H).
85%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 4h; Heating;
85%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride Reflux; Inert atmosphere;
1.2 2) Preparation of methyl 3-(bromomethyl)benzoate (3)
In a two-neck round bottom flask, NBS (6.2 g, 34.9 mmol) and AIBN (0.3 g, 1.7 mmol) were added and protected with argon.The above product 2 (5.2 g, 34.9 mmol) was dissolved in carbon tetrachloride and added to the flask.The reaction was refluxed overnight. The reaction was monitored by TLC, the solvent was evaporated, and washed with water.Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and evaporated.A pale yellow solid 3 was obtained in a yield of 85%.
84%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride Inert atmosphere; Reflux;
75%
With N-Bromosuccinimide; Perbenzoic acid In Carbon tetrachloride Heating;
71%
With sulfuric acid; dihydrogen peroxide; potassium bromide In chloroform; water monomer for 3h; Inert atmosphere; Schlenk technique; Reflux; Irradiation;
70%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride at 76℃; for 6h; Inert atmosphere;
70%
With N-Bromosuccinimide; benzoic acid anhydride In Carbon tetrachloride for 6h; Inert atmosphere; Reflux;
66%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 2h; Reflux;
56%
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 5h; Heating;
53%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene Inert atmosphere; Heating;
10%
With N-Bromosuccinimide In cyclohexane for 16h; Reflux;
11
Synthesis Example 11; Synthesis of Compound 22; Methyl-3-methyl benzoate (1.5 g, 10 mmol) and N-bromosuccinimide (5.34 g, 30 mmol) was suspended in cyclohexane (50 ml). To the suspension, a catalytic amount of hydrogen peroxide was added, and the reaction mixture was heated to reflux for 16 h. The reaction mixture was then filtered, and evaporated to yield 0.231 g (10%) as a yellow oil. Compound 21 was then formed by coupling methyl 3-bromomethylbenzoate to thionicotinamide intermediate IIa in the manner of Method A to yield 180 mg (45%) of compound 22 as a crystalline material. ESI-MS m/z=397.1 [M+H]+.
10%
With N-Bromosuccinimide; dihydrogen peroxide In cyclohexane for 16h; Reflux;
11
Methyl-3-methyl benzoate (1.5 g, 10 mmol) and N-bromosuccinimide (5.34 g, 30 mmol) was suspended incyclohexane (50 ml). To the suspension, a catalytic amount of hydrogen peroxide was added, and the reaction mixturewas heated to reflux for 16 h. The reaction mixture was then filtered, and evaporated to yield 0.231 g (10%) as a yellowoil. Compound 21 was then formed by coupling methyl 3-bromomethylbenzoate to thionicotinamide intermediate IIa inthe manner of Method A to yield 180 mg (45%) of compound 22 as a crystalline material. ESI-MS m/z = 397.1 [M+H]+.
With Carbon tetrachloride; bromine Irradiation.Gluehlampenlicht;
With bromine In Carbon tetrachloride Heating; Irradiation;
With N-Bromosuccinimide; Perbenzoic acid In Carbon tetrachloride for 3h; Heating;
With hydrogen bromide; bromine In Carbon tetrachloride Heating;
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride for 2h; Heating;
With N-Bromosuccinimide In Carbon tetrachloride
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 2h; Heating;
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 5h; Heating / reflux;
5.1 Example 5 PREPARATION OF [ {(7-[(6, 7-DIFLUOROQUINOLIN-2-YL) METHOXY] -5, 11-DIHYDRO[1]BENZOXEPINO[3, 4-B] PYRINDIN-5-YL) THIO} METHYL] BENZOIC ACID. Step 1 : Methyl 3-(bromomethyl) benzoate
Example 5 PREPARATION OF [ {(7-[(6, 7-DIFLUOROQUINOLIN-2-YL) METHOXY] -5, 11-DIHYDRO LBENZOXEPINO [3, 4-B] PYRINDIN-5-YL) THIO} METHYL] BENZOIC ACID. Step 1 : Methyl 3-(bromomethyl) benzoate. A mixture of 5.5 g (36 MMOL) of methyl 3-methylbenzoate, 7.1 g (39.5 MMOL) of N- Bromosuccinimide and 0.44 g (1.8 MMOL) of benzoyl peroxide in 75 ml of C14C is REFLEXED for 5 h. The solid is filtered and washed with CI4C. The mother liquors are concentrated and a yellow solid is obtained which is, ESSENTIALLY, MONOBROMATED product. This is used in the next step without further purification.
With N-Bromosuccinimide In acetonitrile Irradiation;
With N-Bromosuccinimide In Carbon tetrachloride for 1h; Heating / reflux; Mercury lamp exposure;
142
Methyl 3-methylbenzoate (1.00 g) was dissolved in carbon tetrachloride (10 ml). N-Bromosuccinic imide (1.22 g) and 2,2-azobisisobutyronitrile (catalytic amount) were added to the resulting solution. The resulting mixture was heated under reflux for 1 hour under exposure to a mercury lamp. After the insoluble matter was filtered off, a residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate = 20:1) on a silica gel column, whereby a colorless oil (1.34 g) was obtained. The colorless oil thus obtained (0.62 g) was dissolved in N,N-dimethylformamide (10 ml). Sodium azide (0.38 g) was added and the resulting mixture was stirred at room temperature for 20 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (15 ml). Triphenylphosphine (0.75 g) was added to the resulting solution, followed by stirring for 5 hours at an external temperature of about 50°C. About 28% aqueous ammonia (7 ml) was added and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, followed by extraction with ether. The extract was acidified with dilute hydrochloric acid. To the aqueous layer thus separated, a dilute aqueous solution of sodium hydroxide was added to make it alkaline, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in dichloromethane (7 ml). Under ice cooling, di-tert-butyl dicarbonate (0.45 g) was added and the resulting mixture was stirred at room temperature for 3 days. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate = 5:1) on a silica gel column, whereby the title compound (0.29 g, 35%) was obtained.1H-NMR(CDCl3) δ: 1.46(9H,s), 3.91(3H,s), 4.36(2H,d,J=5.9Hz), 4.97(1H, br), 7.40(1H, t, J=7.8Hz), 7.49(1H, d, J=7.8Hz), 7.90-8.00(2H, m). MS (FAB)m/z: 266(M+H)+.
With N-Bromosuccinimide In acetonitrile Irradiation;
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 3h; Reflux; Irradiation; Inert atmosphere;
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 3h; Inert atmosphere; Reflux; Irradiation;
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 70℃; for 11h;
With N-Bromosuccinimide In Carbon tetrachloride
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform for 4h; Inert atmosphere; Reflux;
With N-Bromosuccinimide; dibenzoyl peroxide In Carbon tetrachloride for 6h; Reflux;
4.2.6 General preparation of compound 8b-c
To a solution of methyl 4-methylbenzoate or methyl 3-methylbenzoate (69mmol) in CCl4 (70mL) was added NBS (76mmol) and benzoyl peroxide (2.3mmol) and the resulting solution was refluxed for 6h under lamp. After cooling to room temperature, the precipitate was filtered. The filtrate was washed with sat. NaHCO3, dried with Na2SO4 and concentrated to give yellow oil. This material was added to DMF (60mL) and potassium phthalimide (124mmol) was added. The reaction mixture was stirred at 90°C for 10h and poured into H2O (600mL). The precipitate was filtered and dried to give a light yellow solid. This intermediate was added into C2H5OH (200mL) and 80% hydrazine hydrate (207mmol) was added. The mixture was refluxed for 9h. After cooling to room temperature, the precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/CH3OH (100/1, v/v). 4.2.6.1 Methyl 4-(aminomethyl)benzoate (8b) (0033) Compound 8b was synthesized from compound 10a. Light yellow solid (6.9g, 61%); m.p. 104-106°C; IR (KBr): ν 3367, 1723, 1568, 1475cm-1; 1HNMR (400MHz, DMSO-d6): δ 8.02 (d, J=8.3Hz, 2H, Ar-H), 7.40 (d, J=8.4Hz, 2H, Ar-H), 3.95 (s, 2H, CH2N), 3.93 (s, 3H, CH3O), 1.67 (brs, 2H, NH2); 13CNMR (100MHz, DMSO-d6): δ 167.0 (C=O), 148.3 (C), 129.9 (CH), 128.7 (C), 126.9 (CH), 52.0 (CH2), 46.1 (CH3); ES-MS 166.1 (M+H)+; HRMS calcd for C9H12NO2+ 166.0868, found 166.0870.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 70℃; for 6h;
4.1.12 General procedure for the synthesis of intermediates 9a-9g. Methyl 4-(bromomethyl)benzoate (9a)
General procedure: Compound 8a (4.505g, 30.00mmol), NBS (5.339g, 30.00mmol) and AIBN (492.6mg, 3.00mmol) were dissolved in CCl4 (60mL). Then the mixture was stirred at 70°C. After completion, the mixture was concentrated under vacuum and purified by flash chromatography with ethyl acetate and petroleum ether (PE:EA=8:1) to give 4.582g of compound 9a in 67% yield as a white solid. 1H NMR (500MHz, Chloroform-d) δ 8.02 (d, J=1.7Hz, 1H), 8.00 (d, J=2.0Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.45 (d, J=1.9Hz, 1H), 4.50 (s, 2H), 3.92 (s, 3H). MS(ESI)m/e[M+H]+: 228.9. Synthesis of intermediates 9b-9g. The required compounds 8b-8g were reacted using a procedure similar to the synthesis of 9a to afford 9b-9g (58-72% yield).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 12h; Reflux; Glovebox; Inert atmosphere;
3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
71 Preparation of 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester
EXAMPLE 71 Preparation of 3-[(4-Acetyl-3-hydroxy-2-propylphenoxy) methyl]benzoic acid methyl ester 1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with methyl 3-bromomethylbenzoate according to the procedure of Example 69 and the product was purified by recrystallization from methylene chloride-ether to give 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester, the title compound, mp 141°-143°, in 89% yield. Analysis Calculated for C20 H22 O5: C, 70.16; H, 6.48. Found: C, 69.99; H, 6.41.
With 18-crown-6 ether; In acetonitrile; for 24h;Heating / reflux;
To methyl 3-bromomethyl-benzoate (25.28 g, 0.11 mol) in acetonitrile (230 ml) is added potassiumcyanide (14.3 g, 0.22 mmol) and 18-crown-6 (1.00 g, 2.6 mmol) and the mixture is heated to reflux for24 h. After filtration, the crude product is transferred to the next step without any further purification.Yield: 18.5 g (96 %)
68%
In ethanol; at 60℃;
a) methyl 3-(cyanomethyl)benzoateA slurry of methyl 3-(bromomethyl)benzoate (4.0 g, 17.5 mmol) and potassium cyanide (1.2 g, 18.4 mmol) in ethanol (40 ml) was heated at 60 C over night, filtrated and evaporated. The residue was purified using column chromatography on SiO2 affording 2.1 g (68%) of the title compound.1H NMR (399.988 MHz, CDC13) delta 8.06 - 7.98 (m, 2H), 7.56 (d, J= 8.0 Hz, IH), 7.51 - 7.46 (m, IH), 3.94 (s, 3H), 3.82 (s, 2H)
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) arid sodium cyanide (4.33 g, 88.4 mmol) in DMf (25 ml) and water (1 ml) was stirred at 75 C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined orgaiiics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of colourless oil. NMR: 7.90 (s, I H), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 1; 3-Cgammaanomethyl-benzoic acid methyl esterA suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g5 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of colourless oil. NMR: 7.90 (s5 IH), 7.86 (d, IH), 7.60 (d, IH)5 7.50 (m5 IH)5 4.10 (s, 2H)5 3.80 (s, 3H); m/z 175.
70%
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 chi 100 ml). The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane- EtOAc) to give7.2 g (70%) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100 ml x 3). The combined organics were dried with Na2SC>4(s) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give7.2 g (70%) of colourless oil. NMR (400 MHz): 7.90 (s, 1H), 7.86 (d, 1H), 7.60 (d, 1H), 7.50 (m, 1H), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 15; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 hours. The reaction mixture was quenched with water (50 ml), extracted with EtOAc (3 x 100 <n="52"/>ml) and the combined organics were dried and concentrated under reduced pressure. The residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of a colourless oil.1HNMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z: 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 9; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of niethyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 2 3-Cyanomethyl-benzoic acid methyl ester A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C. for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organics were dried with NaCl(sat) and then Na2SO4(s). The solvents were removed under reduced pressure. The resulting residue was purified by column chromatography utilizing an 20 ISCO system (hexane-EtOAc) to give 7.2 g (70%/o) of colourless oil. NMR: 7.90 (s, 1H); 7.86 (d, 1H); 7.60 (d, 1H); 7.50 (m, 1H); 4.10 (s, 2H); 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 50; 3-Cyanomethylbenzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodiumcyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (100ml x 3). The combined organics were dried with Na2SO4(s) and concentrated under reducedpressure. The resulting residue was purified by column chromatography utilizing an ISCOsystem (hexane-EtOAc) to give7.2 g (70%) of colourless.oil. NMR (400 MHz): 7.90 (s, 1 H),7.86 (d, 1 H), 7.60 (d, 1 H), 7.50 (m, 1 H)3 4.10 (s, 2 H), 3.80 (s, 3 H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 12; 3-Cvanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 0C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc. The combined organics were dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of colourless oil. NMR: 7.90 (s, 1Eta), 7.86 (d, 1Eta), 7.60 (d, 1Eta), 7.50 (m, 1Eta), 4.10 (s, 2Eta), 3.80 (s, 3H); m/z 175.
70%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;
Method 6; 3-Cyanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 0C for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined <n="28"/>organics were dried with NaCl(sat) and then Na2S O4(s). The solvents were removed under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of colourless oil. NMR: 7.90 (s, IH), 7.86 (d, IH), 7.60 (d, IH), 7.50 (m, IH), 4.10 (s, 2H), 3.80 (s, 3H); m/z 175.
70%
In DMF (N,N-dimethyl-formamide); water; at 75℃; for 5h;
Method 4; 3-Cyanomethyl-benzoic acid methyl ester; A suspension of methyl-3-(bromomethyl)benzoate (13.5 g, 58.9 mmol) and sodium cyanide (4.33 g, 88.4 mmol) in DMF (25 ml) and water (1 ml) was stirred at 75 C for 5 hours. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organics were dried with Na2S04(s) and concentrated under reduced pressure. The resulting residue was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 7.2 g (70%) of a colourless oil.
In water; N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of methyl 3-(bromomethyl)benzoate <n="48"/>(1.0 g, 4.37 mmol) in 9 niL of DMF was added a solution of sodium cyanide (0.26 g, 1.2 equiv.) in 1 niL of water at room temperature. The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and water (20 mL). The organic layer was washed with water (20 mL x 3 times) and saturated lithium chloride solution (20 mL), and then dried over MgSO4 and concentrated under reduced pressure to give a sticky oil. The crude material was dissolved in 20 mL of CH2Cl2 and 20 mL of MeOH and then 10% Pd/C (0.5 g) and 1.5 mL of cone. HCl were added at room temperature. The mixture was placed under 50 psi of hydrogen on the Parr hydrogenation apparatus for 1O h and then filtered through a pad of Celite and the pad was washed with 20% MeOH in CH2Cl2. The pale yellow solution was concentrated under reduced pressure to give a crude material which was suspended in MeOH (5 mL) and then diluted with diethyl ether (100 mL) to give a white precipitate. The precipitate was filtered on sintered glass filter and washed with 30 mL of diethyl ether and dried with suction for 1 h to give the title compound (0.74 g, 78%).
(2R,3S)-3-(meta-carboxybenzyl)malic acid trimethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
Stage #1: (R)-dimethyl malate With lithium diisopropyl amide In tetrahydrofuran at -20℃; for 0.5h;
Stage #2: 3-methoxycarbonylbenzyl bromide In tetrahydrofuran at -78 - -20℃;
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) In dichloromethane at 20℃; for 10h; Heating / reflux;
2
Example 2: Preparation of Methyl 3-bromomethylbenzoate; To a solution of Methyl 3-methylbenzoate (150 g, I mol) and l,3-Dibromo-5,5-dimethyl hydantoin (DDH) (15O g, 0.52 mol) in dichloromethane (500 ml) was added AIBN (0.1 g, 0.0006 mol) at room temperature and heated under reflux for 1O h. AIBN in 0.1 g lots were added intermittently during reflux to complete the reaction. After completion of the reaction (monitored by TLC), the reaction mixture was poured into cold water (600 ml) and the organic layer was separated. The aqueous layer was extracted again with dichloromethane (200 ml). The combined organic layer was washed with water and dried over anhydrous sodium sulphate and the solvent was removed by distillation. Colorless liquid, 220 g (96 % yield)Note: The product contains some dibromo derivative also. Benzoyl peroxide could be used as a radical initiator.
With phosphorus tribromide; In diethyl ether; for 2h;
To the solution of compound B4 (28 g, 0.168 mol) in 700 mL of Et2O was added PBr3 (17.4 mL, 0.185 mol) dropwise. The solution was stirred for 2 h, and then the reaction was poured into 500 mL of ice-water. The aqueous layer was extracted with Et2O. The combined organic layers were washed with sat. NaHCO3, water, and brine consecutively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give 34 g of compound B5 as an oil (yield: 70%).
70%
With phosphorus tribromide; In diethyl ether;
Synthesis of Compound B5: [Show Image] To the solution of compound B4 (28 g, 0.168 mol) in 700 mL of Et2O was added PBr3 (17.4 mL, 0.185 mol) dropwise. The solution was stirred for 2 h, and then the reaction was poured into 500 mL of ice-water. The aqueous layer was extracted with Et2O. The combined organic layers were washed with sat. NaHCO3, water, and brine consecutively. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give 34 g of compound B5 as an oil (yield: 70%).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 1h;
4.00 g of <strong>[67853-03-6]methyl 3-(hydroxymethyl)benzoate</strong> was dissolved in 80 ML of methylene chloride, to which 9.47 g of triphenylphosphine was added in small portions in an ice bath followed by addition of 12.00 g of carbon tetrabromide in small portions, and this solution was stirred for one hour at room temperature.. The reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to yield 5.02 g of methyl 3-(bromomethyl)benzoate as colorless oil. NMR(90MHz,CDCl3) delta value: 3.93(3H,s), 4.52(2H,s), 7.42-8.07(4H,m)
With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
To a cooled (0 C) solution of 3 (4.6 g, 27.5 mmol) in anhydrous DCM (75 ml) was slowly added PBr3 solution (11.2 g, 41.3 mmol) under nitrogen atmosphere. The reaction mixture was allowed to gradually reached room temperature and stirred for 2 hours. The reaction vessel was cooled in ice bath and the contents were quenched by slowly adding saturated NaHCO3 solution till slightly basic pH (7 - 8). The organic layer was washed with brine, water, dried with sodium sulphate and evaporated to yield 4 as white crystals (4.4 g, 69%). The product was used in the next step without further purification.
With phosphorus tribromide; In diethyl ether; at 0 - 20℃; for 2h;
Tribromophosphane (1.7 g, 6.6 mmol) was added to a solution of 3-hydroxymethyl- benzoic acid methyl ester (1 g, 6.0 mmol) in diethyl ether (20 mL) at 0C. The reaction mixture was allowed to warm to RT and stirred for 2 h. It was then treated with water. The aqueous phase was basified with saturated NaHCO3 solution (15 mL) and extracted with dichioromethane. Combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give 3-bromomethyl-benzoic acid methyl ester which was dissolved in NMP. 6-pyridin-3-yI-2H-pyridazin-3-one (1.1 g, 6.5 mmol) and cesium carbonate (2.1 g, 6.5 mmol) were then added to this solution and the reaction mixture was stirred at RT for 12 h. It was treated with water, the aqueous phase was extracted with ethyl acetate (3 x 15 mL) and combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica afforded the title product as a yellow solid (0.8 g, 57%). LC/MS: (Method A) 322.2 (M+ H), RT. 2.51mm, 66.4% (Max).
Reference Example 30 Production of methyl 3-(cyanomethyl)benzoate To a solution of methyl 3-(bromomethyl)benzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95?30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil. 1H-NMR (DMSO-d6, 300 MHz) delta 3.88 (3H, s), 4.17 (2H, s), 7.57 (1H, t, J=7.6 Hz), 7.61-7.69 (1H, m), 7.88-7.95 (1H, m), 7.97 (1H, br s).
In dimethyl sulfoxide;
EXAMPLE 235A methyl 3-(cyanomethyl)benzoate A solution of methyl 3-(bromomethyl)benzoate (2.29 g, 0.01 mol) and potassium cyanide (3.26 g, 0.05 mol) in DMSO (20 mL) was heated to 100 C. for 1 h. The reaction mixture was cooled, partitioned between ether and water, washed with brine, dried (Na2SO4) and concentrated to give the title compound. MS(ESI) m/e 193 (M+NH4)+.
In N,N-dimethyl-formamide;
91a Methyl 3-(cyanomethyl)benzoate Methyl 3-(bromomethyl) benzoate (8.5 g, 37 mmol) and sodium cyanide (1,8 g, 37 mmol) were stirred at room temperature in DMF (40 mL) overnight. The mixture was diluted with EtOAc and extracted several times with water containing a small amount of brine, then brine, dried (MgSO4), and solvent removed in vacuo. The crude product (6.8 g, yellow oil) was sufficiently pure to be used in the next step without purification. IR(neat): cm-1 2249, 1722. 1 H-NMR(300 MHz, CDCl3): 8.03-8.01 (m, 2H), 7.57-7.46 (m, 2H), 3.94 (s, 3H), 3.82 (s, 2H).
With sodium cyanide; In dimethyl sulfoxide; at 0 - 20℃; for 2h;
0.924 g of sodium cyanide was dissolved in 15 ML of dimethylsulfoxide, to which a solution of 4.00 g of methyl 3-(bromomethyl)benzoate in 5 ML of dimethylsulfoxide was added in an ice bath, and this solution was stirred for 2 hours at room temperature.. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 3.00 g of methyl 3-(cyanomethyl)benzoate as orange oil. NMR(90MHz,CDCl3) delta value: 3.81(2H,s), 3.94(3H,s), 7.46-7.54(2H,m), 7.99-8.06(2H,m)
In water; ethyl acetate; N,N-dimethyl-formamide;
Step A 3-Cyanomethyl-benzoic acid methyl ester. A mixture of 3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45 C. for 45 minutes and was stirred at room temperature for 18 h. The reaction was heated at 40 C. for 24 h, was cooled to room temperature, and additional potassium cyanide (1.02 g, 15.71 mmol) was added. The reaction was heated at 40 C. for 18 h and was cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3*25 mL). The combined organic layers were washed with 1N LiC1followed by brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M+18).
In water; ethyl acetate; N,N-dimethyl-formamide;
Step A 3-Cyanomethyl-benzoic acid methyl ester A mixture of 3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45 C. for 45 minutes and was stirred at room temperature for 18 h. The reaction was heated at 40 C. for 24 h, was cooled to room temperature, and additional potassium cyanide (1.02 g, 15.71 mmol) was added. The reaction was heated at 40 C. for 18 h and was cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3*25 mL). The combined organic layers were washed with 1N LiCl followed by brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M+18).
With potassium carbonate In acetone at 25℃; for 14h;
1.a
(a) To a suspension of methyl 3-(bromomethyl) benzoate (2) (1.0 g, 7.2 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone (1OmI) was added salicylamide (1) (1.0 g, 7.2 mmol) and the reaction was stirred at 25° C. for 14 hours. The solution was concentrated in vacuo and the resulting residue was treated with water (50 ml) and extracted into dichloromethane (2*50 ml). The combined organic layers was dried with MgSO4, filtered and concentrated in vacuo to yield a white solid which was purified by column chromatography (50 g silica, hexane: ethyl acetate) to yield 3-(2-carbamoyl-phenoxymethyl)-benzoic acid methyl ester (3) as white solid (2.0 g, 97.60%); m/z [M+1]+ 285
methyl 3-(4-ethoxy-2-formyl-phenoxymethyl)-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.1 47.1
47.1 Analogously to Example 52.1, from 5-ethoxy-2-hydroxybenzaldehyde and methyl 3-bromomethylbenzoate there was prepared methyl 3-(4-ethoxy-2-formyl-phenoxymethyl)-benzoate; m.p. 67-69° C., MS: 314 (M)+.
With sodium hydroxide; In methanol; dichloromethane;
EXAMPLE 14 3-Morpholin-4-yl-methyl-benzoic Acid Commercially available methyl 3-bromomethyl benzoate (5 g, 22 mmole) was dissolved in dichloromethane (20 mL) and morpholine (3.93 mL, 45 mmol) was added. The solution was allowed to stir for 12 h, and filtered. The solvent of the filtrate was removed under reduced pressure. The resulting crude ester was dissolved in methanol, and sodium hydroxide (4.6 mL of 5N solution) was added. The solution was stirred overnight at 40 C. for 12 h. The solvent was partially removed under reduced pressure. The crude was acidified, dichloromethane was added and the solution was cooled in ice. After one hour, it was filtered, to provide the title product (2.3 g, 41%) as the white solid hydrochloride salt: 1H-NMR (DMSO-d6) delta13.1 (bs, 1H), 11.8 (bs, 1H), 8.14 (s, 1H), 7.92 (m, 2H), 7.65 (t, J=4 Hz, 1H), 4.39 (bs, 2H), 3.91(m, 4H), 3.12 (m, 4H). MS (EI-NEG):[M+]221; Anal.RP-HPLC: 99% purity.
With NaH In ethanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide
5.A 2-(3-methoxycarbonylphenyl)methyl-dihydro-4,5-diphenyl-1H-imidazol-2-one
A. To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50 mL DMF was added to a suspension of NaH (0.8 g, 20 mmol) in 25 mL DMF. The suspension was stirred at ambient temperatures for 30 minutes, then heated to 50° C. for 30 minutes. A solution of methyl 3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then added and the reaction stirred for 10 min at 50° C. The mixture was poured into 1N HCl, filtered, washed with water and dried. Chromatography on silica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded 1.2 g of 3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as a whim solid.
With sodium hydroxide; sodium iodide; In methanol; water; ethyl acetate; acetone;
EXAMPLE 4 Preparation of 3-cyanomethyl-benzoic acid 10 g (43.66 millimoles) of methyl-3-bromomethyl-benzoate are dissolved in 50 ml of anhydrous acetone, whereupon 3.2 g (65.5 millimoles) of sodium cyanide (dried at 105° C.) and 0.327 g (2.18 millimoles) of sodium iodide are added. The reaction mixture is refluxed for 10 hours, cooled and carefully filtered. The acetone is distilled off in vacuo. The crude residue is suspended in 120 ml of ethyl acetate and the suspension is washed twice with 20 ml of water each. The organic solvent is distilled off in vacuo, the residue is dissolved in 20 ml of methanol and a solution of 5.24 g of sodium hydroxide and 20 ml of water is added. The reaction mixture is stirred at room temperature overnight. The methanol is distilled off in vacuo, the residue is diluted with 20 ml water and 20 ml of a saturated sodium chloride solution and the mixture is acidified with a 2N aqueous sodium hydrogen sulfate solution to pH=1-2. The mixture is extracted three times with 60 ml of ethyl acetate each. The organic extract is dried, filtered and the solvent is evaporated in vacuo. The residual crude product is used for the halogenation reaction according to Example 5. (Yield: 5.62 g/80percent, crude product) Analytical data: TLC: Rf =0.3 (1:1 mixture of benzene and ethyl acetate).
methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; potassium carbonate In methanol
18.A (A)
(A) Methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate 2-Hydroxy-6-methoxybenzaldehyde (4.56 g, 0.03 M), methyl 3-bromomethylbenzoate (6.87 g, 0.03 M), anhydrous potassium carbonate (4.455 g), sodium iodide (0.18 g) and methanol (50 ml) were refluxed with stirring for 18 hr. The cooled reaction mixture was filtered and the solid washed well with methanol. The filtrate was evaporated to dryness and the residue triturated with 1 N sodium hydroxide solution. The solid was filtered off and washed with water to give methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate, 3.27 g, 36%, m.p. 96°-97° C. from ethyl acetate/petrol.
47.1 (1)
(1) Methyl 3-[β-(3-pyridyl)phenethyl]benzoate 3-Benzylpyridine (1.00 g, 5.91 mmol) and methyl 3-bromomethylbenzoate (1.54 g, 6.50 mmol) were reacted in the same way as in Example 7 (2) to obtain methyl 3-[β-(3-pyridyl)phenethyl]benzoate (0.47 g).
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In thiophene; methanol; hexane; dichloromethane
22 Methyl 3-(3-tetradecyloxiranyl)benzoate
EXAMPLE 22 Methyl 3-(3-tetradecyloxiranyl)benzoate Methyl 3-(bromomethyl)benzoate (0.92 g, 4.0 mmol) was dissolved in 5.0 ml of 7% aqueous methanol. Tetrahydrothiophene (0.70 ml, 8.0 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was removed, the residue was washed with hexane, and the crude salt was dried under vacuum. The crude salt was suspended in 25 ml of methylene chloride with benzyltriethylammonium chloride (0.10 g) and 1-pentadecanal (0.85 g, 3.75 mmol) at 0°C. To the suspension was added 8.0 ml of 10 N sodium hydroxide at 0°C. The reaction mixture was stirred at 0°C for 5 min. and at room temperature for 20 min. then poured into ether/water. The ether layer was washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated. The crude white solid was flash chromatographed on silica gel using 100:1 then 50:1 hexane/ethyl acetate as eluent to give 0.73 g of product which was mostly trans and 0.33 g of a mixture. The trans product (0.73 g) was dissolved in 5 ml of warm hexane. Cooling at 0°C gave the product as a precipitate of white powder, m.p. 44-45°C. The lithium salt of the product was prepared as described in Example 1.
3-(2-bromo-6-ethoxy-4-formyl-phenoxymethyl)-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 70℃; for 1h;
a) 3-(2-Bromo-6-ethoxy-4-formylphenoxymethyl)-benzoic acid methyl ester; 3-Bromomethylbenzoic acid methyl ester (0.77 g), K2CO3 (1.0 g) and a catalytic amount of n-Bu4NI were added to a solution of 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0.75 g) in 10 mL DMF and the reaction mixture was stirred at 70 C. for 1 h. A solution of 3% citric acid in water was added and the reaction mixture was extracted with ethyl acetate. The organic phases were washed with water and brine, dried over MgSO4 and concentrated. The title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (1/4, v/v), Rf=0.25).Yield: 1.08 g. 1H NMR (CDCl3): delta=9.84 (s, 1H), 8.20 (bs, 1H), 8.02 (bd, 1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.47 (t, 1H), 7.39 (d, 1H), 5.21 (s, 2H), 4.17 (q, 2H), 3.94 (s, 3H), 1.51 (t, 3H).
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 70℃; for 1h;
3-Bromomethylbenzoic acid methyl ester (0.77 g), K2CO3 (1.0 g) and a catalytic amount of W-Bu4NI were added to a solution of 5-bromo-3-ethoxy-4- hydroxybenzaldehyde (0.75 g) in 10 mL DMF and the reaction mixture was stirred at 700C for l h. A solution of 3% citric acid in water was added and the reaction mixture was extracted with ethyl acetate. The organic phases were washed with water and brine, dried over MgSO4 and concentrated. The title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (1/4, v/v), Rf= 0.25).Yield: 1.08 g. 1HNMR (CDCl3): delta = 9.84 (s, IH), 8.20 (bs, IH), 8.02 (bd, IH), 7.77 (d, IH)3 7.65 (d, IH), 7.47 (t, IH), 7.39 (d, IH), 5.21 (s, 2H), 4.17 (q, 2H), 3.94 (s, 3H)3 1.51 (t, 3H).
Stage #1: 5-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; oil at 20℃; for 2.16667h;
Stage #2: 3-methoxycarbonylbenzyl bromide In N,N-dimethyl-formamide; oil at 20 - 28℃;
59.a
To a 3 -neck round bottom flask equipped with a magnetic stirring bar and two nitrogen inlets was added sodium hydride (60% dispersion in oil) (5.1 g, 0.128 mol). The sodium hydride was washed with hexanes and the flask was equipped with an addition funnel. The addition funnel was charged with λ/,λ/-dimethylformamide (175 mL) and the solvent was added to the sodium hydride. The flask was equipped with a thermometer and the addition funnel was charged with a solution of 5- benzyloxyindole (25.3 g, 0.113 mol) in λ/,λ/-dimethylformamide (350 mL). The 5- benzyloxyindole solution was slowly added dropwise to the stirred sodium hydride suspension at room temperature under a nitrogen atmosphere over a period of 2 h. Gas evolution was observed during the addition of the 5-benzyloxyindole solution. The dark brown reaction mixture was stirred for 10 minutes. To the reaction mixture was added dropwise a solution of methyl-3-bromomethyl benzoate (28.5 g, 0.124 mol) in λ/,N-dimethylformamide (200 mL) at room temperature under a nitrogen atmosphere over a period of 1 h. The reaction mixture warmed slightly to 28 0C upon addition of the methyl-3-bromomethyl benzoate solution. The reaction mixture was stirred overnight. Water (50 mL) was added to the stirred reaction mixture very slowly dropwise before adding another 50 mL of water more rapidly. No discernible gas evolution was evident upon addition of water, however, the reaction mixture warmed slightly to 28 0C. The quenched reaction mixture was transferred to a separatory funnel which contained ethyl acetate (1200 mL) and water (1100 mL). The mixture was stirred with the aid of a spatula. The aqueous phase was separated and the organic phase was washed with water (2 x 500 mL) followed by brine (500 mL). The organic phase was dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 45.3 g of the crude product as an oil. Approximately one- half of the crude product was purified by flash chromatography over silica with a hexanes:ethyl acetate gradient (100:0 to 70:30) to give 6.9 g of methyl 3-({5- [(phenylmethyl)oxy]-lH-indol-l-yl}methyl)benzoate as a yellow oil. The remaining crude product was purified by flash chromatography over silica with a hexanes: ethyl acetate gradient (100:0 to 70:30) to give another 5.4 g of methyl 3-({5- [(phenylmethyl)oxy]-lH-indol-l-yl}methyl)benzoate as a yellow oil for a total yield of 12.3 g (29%). 1H NMR (400 MHz; CDCl3): δ 7.93 (d, J = 8 Hz, IH), 7.91 (s, IH), 7.47 (d, J = 7 Hz, 2H), 7.36 (m, 4H), 7.20 (m, 2H), 7.13 (m, 2H), 6.91 (dd, J = 9, 2 Hz, IH), 6.48 (d, J = 3 Hz, IH), 5.32 (s, 2H), 5.09 (s, 2H), 3.90 (s, 3H). ES-LCMS m/z 372(M + H)+.
29%
Stage #1: 5-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;
Stage #2: 3-methoxycarbonylbenzyl bromide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With caesium carbonate In N,N-dimethyl-formamide at 65℃;
3-[4-(3-Aminomethyl-phenyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester: A mixture of 3-fluoro benzonitrile and piperazine (2.5 equiv) was heated at 145° C. creating a melt. The mixture was stirred for 1.5 h after which time TLC indicated complete conversion. The reaction mixture was cooled to room temperature and the resultant solid was triturated with acetone, collected via filtration, acidified and then diluted with heptanes to again provide a precipitate. The solid was collected via filtration and dried. The derived piperazine adduct was dissolved in DMF (0.5 M) and 3-bromomethyl-benzoic acid methyl ester (1.5 equiv) and Cs2CO3 (1.5 equiv) were added followed by heating at 65° C. overnight. The mixture was diluted with ethyl acetate, washed with H2O and saturated NaCl solution, dried (Na2SO4) and concentrated. The crude product was dissolved in a mixture of MeOH and concentrated HCl (3 equiv) and 10% Pd/C (0.15 g) were added. The mixture was placed under H2 gas (1 atm) for 20 h. Catalyst was removed by filtration through Celite; the pad was washed with MeOH, and the pale yellow solution was concentrated under reduced pressure to give a tan solid that was used without additional purification.
Step 1: synthesis of methyl 3-(cyanomethyl)benzoate (1)To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2 x 500mL). The combined organic layers were washed with water, brine, dried (Na2S04), filtered and evaporated under reduced pressure to yield methyl 3- (cyanomethyl)benzoate 1 (17g, 89%). 1H-NMR (400 MHz, CDC13) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
89%
In N,N-dimethyl-formamide; at 20℃;
Step 1: synthesis of methyl 3-(cyanomethyl)benzoate (1) To a solution of 3-(bromomethyl)benzoic acid methyl ester (25 g, 109 mmol) in DMF (250 mL) was added NaCN (5.4 g, 109 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into water (1.5 L), followed by the extraction with TBME (2*500 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield methyl 3-(cyanomethyl)benzoate 1 (17 g, 89%). 1H-NMR (400 MHz, CDCl3) 3.82 (s, 2H), 3.94 (s, 3H), 7.48 (m, 1H), 7.57 (m, 1H), 8.03 (m, 2H).
85%
In water; N,N-dimethyl-formamide; at 75℃; for 5h;Inert atmosphere;
A suspension of methyl-3-(bromomethyl)benzoate (0.5 g, 2.18 mmol) and sodium cyanide (0.16 g, 3.27 mmol) in DMF (0.93 mL) and H2O (0.04 mL) was stirred at 75 C for 5 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with H2O (3×), dried (Na2SO4) and the solvents were evaporated. The residue was purified by column chromatography (silica gel, from 80:20 hexane/EtOAc to 70:30 hexane/EtOAc) to afford 0.324 g (85%) of a colourless oil identified as methyl 3-(cyanomethyl)benzoate 29b. 1H NMR (400.13 MHz, CDCl3): delta 8.02-8.00 (m, 2H, ArH), 7.56-7.53 (m, 1H, ArH), 7.50-7.46 (m, 1H, ArH), 3.93 (s, 3H, CH3), 3.81 (s, 2H, CH2) ppm. 13C NMR (100.62 MHz, CDCl3): delta 166.3 (s), 132.3 (d), 131.0 (s), 130.5 (s), 129.3 (d), 129.2 (d), 129.1 (d), 117.5 (s), 52.3 (q), 23.4 (t) ppm. HMRS (ESI+): Calcd for C10H10NO2 ([M+H]+), 176.0706; found, 176.0703. IR (NaCl): nu 3003 (w, C-H), 2954 (w, C-H), 2252 (w, CN), 1722 (s, CO), 1439 (m), 1287 (m) cm-1. UV (MeOH): lambdamax 283, 229 nm.
81%
In ethanol; water; at 65℃; for 2h;
Methyl 3-(cyanomethyl)benzoate 15. To a stirring aqueous solution (60 mL) of potassium cyanide (3.62 g, 55.7 mmol) at 65C was added dropwise methyl 3-(bromomethyl)benzoate 14 (10.2 g, 44.5 mmol) in absolute ethanol (50 mL) over a period of 0.5 h. After addition, the reaction was stirred for 1.5 h at 65C. The solution was then diluted with absolute ethanol (500 mL), cooled on ice bath, filtered, and concentrated with a rotary evaporator. The crude was treated with chloroform (350 mL), dried over MgS04, filtered, concentrated, and used without further purification. Yield 6.3 g (81%). ¾-NMR (CDC13): 3.81 br s (2H, CH2), 3.93 s (3H, CH3); 7.45-7.51 m (1H, CH), 7.53-7.58 m (1H, CH), 7.99-8.04 m (2H, CH).
51%
In dimethyl sulfoxide; at 0 - 10℃; for 3.25h;
To a cold solution of Intermediate BM (7.2 g, 31.44 mmol) in DMSO (35.0 mL) at 0 C was added a sodium cyanide (3.0 g, 62.88 mmol) portionwise over 15 minutes. After the addition was complete, the reaction mixture was allowed to stir at 10 C for 3 hours. Ice cold water was added to the reaction mixture (50 mL), and the reaction was extracted with ethyl acetate (3 chi 50 mL), washed with water (2 chi 25 mL) and brine (25 mL), dried over anhydrous Na2S04, and the solvent was removed to afford the crude product. This material was purified by column chromatography (silica gel 100-200 mesh) using 10% ethyl acetate in petroleum ether as the eluent to afford Intermediate BN (2.8 g, 51%) as a pale brown liquid. NMR (CDC13): delta 9.44-9.42 (m, 2H), 8.90-8.78 (m, 2H), 4.63 (s, 3H), 4.49 (s, 2H). Mass (M-H): 174.1.
In water; N,N-dimethyl-formamide; at 20℃; for 2h;
3-(2-Aminoethyl)benzoic acid methyl ester hydrochloride: To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.37 mmol) in DMF (9 mL) was added a solution of NaCN (0.26 g, 1.2 equiv.) in H2O (1 mL) at room temperature. The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (30 mL) and H2O (20 mL). The organic layer was washed with H2O (3×20 mL) and saturated LiCl solution (20 mL), and then dried over MgSO4 and concentrated under reduced pressure to give sticky oil. The crude material was dissolved in CH2Cl2 (20 mL) and MeOH (20 mL) and 10% Pd/C (0.5 g) and conc. HCl (1.5 mL) were added at room temperature. The mixture was placed under hydrogen gas (50 psi) on a Parr hydrogenation apparatus for 10 h, filtered through a pad of Celite and the pad was washed with 20% MeOH in CH2Cl2. The pale yellow solution was concentrated under reduced pressure to give a crude product that was suspended in MeOH (5 mL) and diluted with diethyl ether (100 mL) to give a white precipitate. The precipitate was collected by filtration on sintered glass, washed with 30 mL of Et2O and dried under suction for 1 h to give the title compound (0.74 g, 78%).
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;
267.A
To a solution of phenylethyl mercaptan (0.66 g, 4.80 mmol) and methyl 3- (bromomethyl)benzoate (1.0 g, 4.37 mmol) in DMF (10 mL) was added Cs2CO3 (2.84 g, 8.73 mmol). The suspension was stirred at rt for 3 h. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with brine three times, dried over MgSO^ The filtrate was concentrated in vacuo to give a light yellow oil. The crude product was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane to give the desired product (1.2 g, 96%) as a colorless oil. 1H NMR (CDCl3) 6 8.00 (s, 1H), 7.96- 7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.42 (t,J= 8.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.25- 7.17 (m, 3H), 3.95 (s, 3H), 3.76 (s, 2H), 2.89-2.85 (m, 2H), 2.69-2.65 (m, 2H). MS (ESI): 287.1 (M + H)+.
With 18-crown-6 ether; In acetonitrile; at 20℃; for 72h;
(i) Production of methyl 3-(cyanomethyl)benzoate; To a solution of methyl 3-bromobenzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95?30/70), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil. 1H-NMR (DMSO-d6, 300 MHz) delta 3.88 (3H, s), 4.17 (2H, s), 7.57 (1H, t, J = 7.6 Hz), 7.61 - 7.69 (1H, m), 7.88 - 7.95 (1H, m), 7.97 (1H, br s).
In methanol; for 16h;Reflux;
2d: Methyl 3-(2-(methyIamino)ethyl)benzoate; To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22 ºC and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3- (cyanomethyl)benzoate.
In methanol; for 16h;Reflux;
To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.1 1 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22 C and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3-(cyanomethyl)benzoate. To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in 31 mL of THF stirred at -10 C was slowly added 710 mg ( 18.7 mmol) of sodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroacetic acid. The mixture was warmed to 22 C and stirred for about 16 h. About 100 mL of water was carefully added to the mixture (gas evolution). The mixture was extracted with ethyl acetate (5 x 50 mL). The organic phase was washed with brine, dried ( a2S04), filtered and evaporated to give methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification. Method B To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC20. The mixture was stirred for about 16 h at 22 C and 100 mL of water was added. The mixture was extracted with ethyl acetate (2 x 100 m L) and the organic phase was washed with brine, dried (Na2S04) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(terl- butoxycarbonylam ino)ethyl)benzoate which was further converted to III by Method C (described below).
With potassium carbonate In tetrahydrofuran; water at 80℃; for 4h; Inert atmosphere;
I-1
Indole-6-boronic acid, 386 mg (2.4 mmol) and methyl-3-(bromomethyl)benzoate, 460 mg (2.0 mmol), were added into a 100 ml round-bottomed flask containing 15 ml THF, and then 230 mg of Pd(PPh3)4 was added, followed by 3 ml of 2M aqueous K2CO3. The mixture was stirred and heated to 80° C. under N2 for over 4 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, 10 ml H2O was added and the product extracted with ethyl acetate (10 ml×3). The organic solvent was combined and dried with anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified by chromatographic column using hexane:ethyl acetate (7:1) as eluent. The ester, 360 mg, was obtained as a pale yellow solid, yield 67%. A portion of the ester, 20 mg, was dissolved in 4 ml THF:methanol (4:1), and 1 ml 25% aqueous NaOH was added. The mixture was stirred for 3 hours at room temperature, then adjusted to pH 3.0 using 2M HCl. The solution was extracted with CH2Cl2, 3×15 ml. The organic solvent was combined and dried with Na2SO4, then evaporated to dryness. The final product was purified by HPLC using acetonitrile/H2O as eluent. The acetonitrile was removed from the eluent, the eluent frozen and lyophilized. After lyophilization, 11 mg target compound was obtained as a grey powder.Analysis: Mass calculated for C16H13NO2: 251; LCMS: 252.6 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (1H, s), 7.75 (1H, d, J=7.3 Hz), 7.51 (1H, d, J=7.9 Hz), 7.41 (2H, m), 7.26 (1H, t, J=3.0 Hz), 7.21 (1H, s), 6.87 (1H, dd, J=7.9 Hz, J=1.2 Hz), 6.35 (1H, s), 4.08 (2H, s).
67%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 4h; Reflux; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran at 80℃; for 4h; Inert atmosphere;
Stage #1: methyl 3-(methoxycarbonylmethyl)-1H-indole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at -15℃; for 0.25h;
Stage #2: 3-methoxycarbonylbenzyl bromide In N,N-dimethyl-formamide at -15 - 20℃;
To a solution of 3-Bromomethyl-benzoic acid methyl ester (25.6 g, 111.7 mmol) in DMF was added potassium phthalimide at rt and the reaction mixture stirred 85 C over a period of 12h. The resulting mixture was diluted with ethyl acetate (1.5 Lit), washed with water (5X300 mL), brine (300 mL) and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-(l,3-Dioxo-l,3-dihydro-isoindol-2-ylmethyl)-benzoic acid methyl ester colourless solid (30.0 g, 95.5 %)
95.5%
In N,N-dimethyl-formamide; at 85.0℃; for 12.0h;
To a solution of 3-Bromomethyl-benzoic acid methyl ester (25.6 g, 111.7 mmol) in DMF was added potassium phthalimide at rt and the reaction mixture stirred 85 C. over a period of 12 h. The resulting mixture was diluted with ethyl acetate (1.5 Lit), washed with water (5*300 mL), brine (300 mL) and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid methyl ester colourless solid (30.0 g, 95.5%)
In N,N-dimethyl-formamide; at 90.0℃; for 10.0h;
General procedure: To a solution of methyl 4-methylbenzoate or methyl 3-methylbenzoate (69mmol) in CCl4 (70mL) was added NBS (76mmol) and benzoyl peroxide (2.3mmol) and the resulting solution was refluxed for 6h under lamp. After cooling to room temperature, the precipitate was filtered. The filtrate was washed with sat. NaHCO3, dried with Na2SO4 and concentrated to give yellow oil. This material was added to DMF (60mL) and potassium phthalimide (124mmol) was added. The reaction mixture was stirred at 90C for 10h and poured into H2O (600mL). The precipitate was filtered and dried to give a light yellow solid. This intermediate was added into C2H5OH (200mL) and 80% hydrazine hydrate (207mmol) was added. The mixture was refluxed for 9h. After cooling to room temperature, the precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/CH3OH (100/1, v/v). 4.2.6.1 Methyl 4-(aminomethyl)benzoate (8b) (0033) Compound 8b was synthesized from compound 10a.
Stage #1: 4,5-dichloroimidazole With potassium carbonate In N,N-dimethyl-formamide
Stage #2: 3-methoxycarbonylbenzyl bromide In N,N-dimethyl-formamide at 120℃; for 18h;
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0 %)
94%
With thionyl chloride; at 25℃; for 1h;Reflux;
To a solution of 3-Bromomethyl-benzoic acid (1 g, 4.6 mmol) in methanol (20 mL) was added thionyl chloride (1.1 g, 9.3 mmol) drop wise at 25 C. The reaction mixture was refluxed over a period of 1 h and methanol was removed under reduced pressure to obtain crude sticky mass. The crude mass was diluted with ethyl acetate and washed with water and dried over sodium sulphate. Ethyl acetate was evaporated under reduced pressure to obtain 3-Bromomethyl-benzoic acid methyl ester as light yellow oil (1.0 g, 94.0%)
3-(4-Bromo-3-fluoro-phenoxymethyl)-benzoic acid methyl ester A mixture of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (18.34 g, 96 mmol), 3-bromomethylbenzoic acid methyl ester (20 g, 87.3 mmol), potassium carbonate (13.3 g, 96 mmol), and acetone (300 mL) was heated to reflux overnight, followed by cooling to room temperature and filtered. The filtrate was evaporated. The solid was washed with water and cold MeOH to give 3-(4-bromo-3-fluoro-phenoxymethyl)-benzoic acid methyl ester, 28 g (72%). LC-MS (ES) calculated for C15H12BrFO3, 338; obsd 339 [M+H]+.
In water; N,N-dimethyl-formamide; at 20℃; for 18h;
Step 1: methyl 3-[(methylsulfonyl)methyl]benzoate A mixture of methyl 3-(bromomethyl)benzoate (2.29 g, 10.0 mmol) and sodium methylsulfonate (1.25 g, 85% purity, 10.0 mmol based on 85%) in dimethylformamide (10 mL) and water (5 mL) was stirred at 20 C. for 18 h. The reaction was diluted with water (30 mL) and the resulting solid suction filtered, with water washes, and dried under vacuum to afford the title compound as a white solid (2.06 g). MS (ESI) m/z 246.1; HRMS: calcd for C10H12O4S+ Na+, 251.03485. Found (ESI, [M+Na]+), 251.0350
With potassium carbonate; In acetone; at 20℃; for 1h;
Compound 5 (300 mg, 1 . 56mmol), potassium carbonate (372 mg, 2 . 34mmol) and 3-bromo methyl benzoic acid methyl ester (229 mg, 1 . 56mmol) dissolved in acetone (10 ml), the reaction at room temperature 1 hour, reducing pressure and evaporating the solvent after filtering, separation and purification to obtain the chromatographic column 212 mg compound 3, the yield is 40% ; melting point is 121-123C. 1 HNMR (CDCl 3) delta 2.40 (3H, s, 4-CH 3), 3.92 (3H, s, -OCH 3), 4.25 (2H, s, 7-SCH 2-), 6.22 (1H, s, 3-H), 7.14-7.18 (2H, m, J1 = 8.1Hz, J2 = 2.1Hz, 6-H & 8-H), 7.38,7 . 57,7.94 (3H, d, J = 7.5Hz, Hofaromatic), 7.45 (1H, d, J = 8.1Hz, 5-H), 8.06 (1H, s, Hofaromatic) .ESIMSm/z339 (M +-H).
12%
With potassium carbonate; In acetone; at 20℃;
General procedure: A mixture of 44 (300 mg, 1.56 mmol), K2CO3 (372 mg, 2.34 mmol), and halogenated compound (1 equiv) in acetone (10 mL) was stirred for 0.5-3.5 h at rt. After filtering the mixture and removing the solvent in vacuo, the residue was purified by column chromatography (eluent: hexane/EtOAc 85:15) to obtain the target compounds (11-23) as white solids.
a) 3-(Methoxymethyl)benzoic acid; To a solution of methyl 3-(bromomethyl)benzoate (1129-28-8, 1.05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74 g, 13.8 mmol). The suspension was stirred at 50 C. for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50 C. for 1.5 hr.After cooling to rt aqueous HCl was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as a colorless oil (749 mg, 96%). LCMS RtB=2.47 min; [M+H]+=167.0]
96%
Building Block B3.1: 4-Bromomethyl-5-(3-methoxymethyl-phenyl)-oxazole a) 3-(Methoxymethyl)benzoic acid To a solution of methyl 3-(bromomethyl)benzoate, 1.05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74 g, 13.8 mmol). The suspension was stirred at 50 C. for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50 C. for 1.5 hr.After cooling to rt aqueous HCl was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as colorless oil (749 mg, 96%). LCMS RtB=2.47 min; [M+H]+=167.0]
96%
To a solution of methyl 3-(bromomethyl)benzoate, 1 .05 g, 4.6 mmol) in dry MeOH (30 ml) under argon at rt was added sodium methanolate (0.74g, 13.8 mmol). The suspension was stirred at 50 C for 2 hr and then aqueous KOH (5M) was added and the mixture again stirred at 50 C for 1 .5 hr.After cooling to rt aqueous HCI was added to adjust the pH to 2-3. The aqueous phase was extracted with ethyl acetate, the organic phase dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as colorless oil (749 mg, 96%). LCMS RtB = 2.47 min; [M+H]+ = 167.0]
8
Example 8: Synthesis of 3-[4-(4-Cyano-phenyl)-pyrazol-l-ylmethyl]-N-((S)-6- dimethylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide (Compound 5) Add sodium carbonate (5.80 g, 41.7 mmol) to a solution of 4-bromopyrazole (3.10 g, 20.9 mmol) and methyl 3-bromomethylbenzoate (4.8 g, 20.9 mmol) in 40 mL of dimethylacetamide. Stir the mixture at 60 °C overnight. Cool the reaction to room temperature and pour into 300 mL of ice water. Collect the resulting solid by filtration and dry to afford 6.0 g, 98% yield of 3-(4-bromo- pyrazol-l-ylmethyl)-benzoic acid methyl ester.
79%
Stage #1: 4-bromo-1H-pyrazole With sodium hexamethyldisilazane In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 0.7h;
Stage #2: 3-methoxycarbonylbenzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;
9.H
Step H. Methyl 3-((4-bromo-lH-pyrazol-l-yl)methyl)benzoater[00155] To a solution of 4-bromo- lH-pyrazole (l .OOg, 6.80 mmol) in DMF (1 1.7 mL) at 0 °C was added 1 M solution of NaHMDS in THF (7.48 mL, 7.48 mmol) slowly over 2 min. The reaction mixture was stirred for 10 min and then the cooling bath was removed. After 30 min a solution of methyl 3-(bromomethyl)benzoate (1.71 g, 7.48 mmol) in DMF (1.9 mL) was added slowly, and the resulting mixture was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was quenched with saturated aq. ammonium chloride (~1 mL), and partitioned between diethyl ether and water. The resulting mixture was stirred vigorously for 15 min. After this time, the organic layer was separated, dried over anhydrous Na2S04, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-60% ethylacetate:hexanes) to afford the title compound (1.59 g, 79%). LCMS, [M+H]+ = 295.0. XH NMR (400 MHz, CDC13) δ 8.00 (d, J= 7.1 Hz, 1H), 7.94 (s, 1H), 7.50 (s, 1H), 7.47 - 7.36 (m, 3H), 5.31 (s, 2H), 3.92 (s, 3H).
With N,N,N′,N′-tetramethyl-N″-tert-butylguanidine In acetonitrile at 20℃;
93.A; 96.A
Step A: Preparation of methyl 3-((3-iodo-4-nitro-lH-indazol-l- yOmethyObenzoate : To a slurry of 3-iodo-4-nitro-lH-indazole (1.0 g, 3.46 mmol) and methyl 3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH3CN (12 mL) was added 2-tert- butyl-l ,l,3,3-tetramethylguanidine (0.697 mL, 3.46 mmol) dropwise, and the mixture was allowed to stir overnight at ambient temperature. The mixture was then concentrated and diluted with saturated aqueous NH4CI (40 mL) and EtOAc (70 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organic extracts were washed with brine, then dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography (50% EtOAc/hexane) to provide 1.04 g (68%>) of the product as a yellow/orange solid.
With potassium carbonate In N,N-dimethyl-formamide
228.a
Example 2283 -(3 -(4-(Pyrimidin-2-yl)piperazine- 1 -carbonyl)benzyl)quinazoline-2,4( 1H, 3H)-dione a) 3-(3-Methoxycarbonylbenzyl)quinazoline-2,4(lH,3H)-dione: A suspension of quinazoline- 2,4(lH,3H)-dione (2.5 g, 15.4 mmol), methyl 3-(bromomethyl)benzoate (3.56 g, 15.4 mmol) and K2C03 (4.26 g, 30.8 mmol) in DMF (30 mL) was stirred at room temperature overnight. To the mixture was added 150 mL water and the precipitates were collected. The crude product was purified by chromatography on silica (CH2Cl2:MeOH=200: l) to give the title compound (0.87 g, 18.2% yield) as white solid. 1H NMR (DMSO-d6): 11.51 (s, 1H), 8.00- 7.90 (m, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.75-7.55 (m, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.30- 7.15 (m, 2H), 5.14 (s, 2H), 3.83 (s, 3H). MS: m/z 311.2 [M+H]+.
18.2%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
228.a a) 3-(3-Methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione
A suspension of quinazoline-2,4(1H,3H)-dione (2.5 g, 15.4 mmol), methyl 3-(bromomethyl)benzoate (3.56 g, 15.4 mmol) and K2CO3 (4.26 g, 30.8 mmol) in DMF (30 mL) was stirred at room temperature overnight. To the mixture was added 150 mL water and the precipitates were collected. The crude product was purified by chromatography on silica (CH2Cl2:MeOH=200:1) to give the title compound (0.87 g, 18.2% yield) as white solid. 1H NMR (DMSO-d6): 11.51 (s, 1H), 8.00-7.90 (m, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.75-7.55 (m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.30-7.15 (m, 2H), 5.14 (s, 2H), 3.83 (s, 3H). MS: m/z 311.2 [M+H]+.
0.3 g
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;
1.4 (4) 3- [benzoate 3-methylene] -2,4 (1H) - quinazoline-dione (I18)
Weigh 2.0g 2,4- (1H, 3H) - quinazolinedione (V) was dissolved in 25mL of dry DMF, under reaction system was stirred at normal temperature conditions, was slowly added 4.0g of anhydrous K2CO3(End plus 20min), was added 1g 3- 0.5H bromomethyl benzoate (added in three portions were added 3.2g), stirred at room temperature 24h.100mL water was added to the reaction system, with (3 × 50mL) and extracted with ethyl acetate, the combined organic phase was concentrated by rotary evaporation, the crude product was dried to give a white solid.Separation by column chromatography (eluent: ethyl acetate: cyclohexane = 1/2) to give product 3- [3-methylene benzoate] -2,4- (1H) - quinazoline I dione180.3g, white solid
Step 1 : Synthesis of methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate[00109] To a stirred solution of methyl-3-(bromomethyl)benzoate (0.5 g, 2 mmol) in THF (10 mL) was added potassium ditertiary butyl phosphate (0.5 g, 2 mmol). The reaction flask was heated to 70 °C for 2 h. After the flask was cooled to rt, EtOAc (50 mL) was added to the mixture. The organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to yield methyl 3-((di-tert- butoxyphosphoryloxy)methyl)benzoate (0.35 g, 0.9 mmol). 3/4 NMR (400MHz, CHC13- d): delta 1.47 (s, 18H), 3.91 (s, 3H), 5.03 (d, 2H, J=7.6 Hz), 7.44 (t, J= 7.6 1H), 7.60 (dd, J = 1.2 and 7.2), 7.98 (ddd, J= 1.2, 2.8 and 7.6, 1H), 8.05 (t, J= 0.4, 1H).
methyl 3-[4-(8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-ylmethyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;
The compound (120 mg, 0.39 mmol) obtained in Production Example 92 was dissolved in N,N-dimethylformamide, and methyl 3-bromomethylbenzoate (99 mg, 0.43 mmol) and potassium carbonate (59 mg, 0.43 mmol) were added thereto. The mixture was stirred at 70 C. overnight. After the solvent was distilled off, ethyl acetate was added to the residue. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate 5:1) to give the title compound (170 mg, 95.0%) as an oily substance. 1H-NMR (CDCl3, delta): 2.1-2.5 (6H,m), 2.7-2.9 (4H,m), 3.3-3.5 (2H,m), 3.54 (2H,s), 3.91 (3H,s), 7.1-7.2 (4H,m), 7.3-7.4 (2H,m) 7.5-7.6 (1H,m), 7.9-8.0 (2H,m), 8.39 (1H,dd,J=1.9 Hz, 4.9 Hz)
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃;
A solution of 3-bromomethyl-benzoic acid methyl ester (9.6, 41.9 mmol), 6-chloro-2H- pyridazin-3-one (5.4 g, 41.9 mmol) and cesium carbonate (13.6 g, 41.9 mmol) in NMP (10 mL) was stirred at RT overnight. The reaction mixture was then treated with ice cold water and the solid formed was filtered. Purification by flash chromatography on silica of this crude afforded the title compound as an off-white solid (9.8 g, 94%). 1H NMR (400 MHz, DMSO-de): delta 7.90-7.88 (m, 2H), 7.58 (dd, J = 5.88, 5.64 Hz, 2H), 7.53-7.49 (m, 1 H), 7.11 (d, J = 9.72 Hz, 1 H), 5.27 (s, 2H), 3.84 (s, 3H). LC/MS: (Method A) 279.0 (M+H), RT. 3.7 min, 93.8% (Max), 93.9% (254 nm).
91%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
Example 2 Synthesis of compound 2a: 3-(3-Chloro-6-oxo-6H-pyridazin-1-ylmethyl)-benzoic acid methyl ester The reaction mixture of <strong>[19064-67-6]6-chloro-2H-pyridazin-3-one</strong> (6850.0 mg; 51.43 mmol; 1.0 eq.), 3-bromomethyl-benzoic acid methyl ester (12145.0 mg; 51.43 mmol; 1.0 eq.) and DIEA (12.8 ml; 77.14 mmol; 1.5 eq.) in MeCN (40 ml) was stirred at rt overnight. The precipitate was filtered and washed with ACN to yield the title compound as an off-white solid (13000.0 mg; yield: 91%). LC-MS (M+H)+: 279.
With potassium carbonate; In acetonitrile; at 20℃; for 2h;
a- Synthesis of Int. 266: 7 (2.00g, 9.09mmol) was dissolved in ACN (20mL). K2C03 (1.51g, 10.9mmol) and methyl 3-(bromomethyl)benzoate (2.19g, 9.54mmol) were added. The r.m. was stirred for 2h at r.t. An extra amount of methyl 3-(bromomethyl)benzoate (0.208g, 0.909mmol) was then added, as well as DMF (lmL). The r.m. was stirred at r.t. for 17 h. The crude mixture was diluted in EtOAc, washed with water and brine (3 times). The organic layer was separated, dried over MgS04 and evaporated in vacuo to afford 3.82g of Int. 266, pale pink oil (Quant.).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
DMF (125 mL) was added to 4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenol (8.46 g, 38 mmol), methyl 3-(bromomethyl)benzoate (8.8 g, 38 mmol), and potassium carbonate (10.6 g, 77 mmol), and stirred at room temperature overnight. The resultant was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, methanol (150 mL), water (30 mL), and lithium hydroxide (4.8 g, 114 mmol) were added, and stirred at room temperature overnight. After the solvent was distilled away under reduced pressure, the resultant was diluted with ethyl acetate, then washed with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. To the resulting residue, dichloromethane (150 mL), 1-ethyl-3-(3-dimethylaminopropyl) -carbodiimide hydrochloride (hereinafter, WSC) (7.34 g, 38.2 mmol), tert-butyl L-prolinate (7.95 g, 38.2 mmol), and triethylamine (9.65 mL), 69.4 mmol) were added, and stirred at room temperature overnight. The resultant was washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate). To the resulting compound, TFA (150 mL) was added, and stirred at room temperature for 3 hours. The solvent was distilled away under reduced pressure to thus obtain the title compound. Yield: 15.1 g (33.5 mmol), percentage yield: 88% MS (ESI, m/z) 452 [M+H]+
dimethyl 3,3'-oxybis(methylene)dibenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
To a mixture of <strong>[67853-03-6]methyl 3-(hydroxymethyl)benzoate</strong> (500 mg, 3.01 mmol) in DMF (5 mL) cooled to 0 C. was added a 60% sodium hydride dispersion in mineral oil (180 mg). The mixture was stirred for 0.5 h at 0 C., then methyl 3-(bromomethyl)benzoate (690 mg, 3.01 mmol) was added and the mixture stirred an additional 4 h at room temperature, then diluted with EtOAc. The solution was washed with aqueous HCl, saturated aqueous NaHCO3, H2O, and brine, then dried over Na2CO3 and the solvent removed. The resulting residue was purified by silica gel chromatography to give 450 mg (48%) of the product 185a.
3-(3-(methoxycarbonyl)benzylthio)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In N,N-dimethyl-formamide; for 16h;
A mixture of <strong>[4869-59-4]3-mercaptobenzoic acid</strong> (154 mg, 1.00 mmol), methyl 3-(bromomethyl)benzoate (229 mg, 1.00 mmol) and K2CO3 (414 mg, 3.00 mmol) in DMF (1 mL) was stirred for 16 h, then solvent removed. The resulting residue was purified by silica gel chromatography to give 300 mg (90%) of the product.
methyl 3-(((5-carbamoylpyridin-3-yl)oxy)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With caesium carbonate at 20℃; for 20h;
4 Methyl 3-(((5-Carbamoylpyridin-3-yl)oxy)methyl)benzoate (ID3)
Methyl 3-(((5-Carbamoylpyridin-3-yl)oxy)methyl)benzoate (ID3) A mixture of methyl 3-(bromomethyl)benzoate (ID1, 1.14 g, 4.98 mmol), 5-hydroxynicotinamide (ID2, 760 mg, 5.50 mmol) and Cs2CO3 (3.27 g, 10.0 mmol) was allowed to stir at rt for 20 h and then poured into ice-water (300 mL). The resulting mixture was extracted with EtOAc (300 mL) and the organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by the flash column chromatography (0-10% MeOH/CH2Cl2) to give compound ID3 as a pale solid (335 mg, 23%). 1H NMR (DMSO-d6, 600 MHz) δ 8.66 (d, J=1.8 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.13 (brs, 1H), 8.08 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.87 (dd, J=2.1, 2.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.61 (brs, 1H), 7.58 (dd, J=7.8, 7.8 Hz, 1H), 5.33 (s, 2H), 3.87 (s, 3H). HRMS (ESI+) calcd for C15H15N2O4 (M+H)+ 287.1026, found 287.1023.
methyl 3-(((1H-indol-6-yl)oxy)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
General procedure: A mixture of appropriate hydroxyindole (0.5 mmol, 1 eq.), cesium carbonate (1 mmol, 2 eq.) and acetontrile (30 mL) was stirred at room temperature for 10 min, and then ethyl bromoacetate/ ethyl 4-bromobutanoate/ methyl bromomethylbenzoate (0.55 mmol, 1.1 eq) was added. Stirred at room temperature for 1-3 h and then 50 mL of water was added. The mixture was extracted with ethyl acetate (2*30 mL). The combined organic layer was washed with water (3*30 mL), followed by brine (2*30 mL), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel, eluting with PE/EA (5:1 to 3:1) or CH2Cl2/MeOH (20:1 to 15:1) to give title product.
methyl 3-((2,6-diaminopyridin-4-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.9%
Zinc powder (0.696 g, 10.6 mmol) in THF (11 mL) was treated with 1,2- dibromoethane (0.014 mL, 0.16 mmol) and TMS-Cl (0.020 mL, 0.16 mmol) under argon. After 30 mm, the solution was treated with methyl 3-(bromomethyl)benzoate (1.22 g, 5.32 mmol) dissolved in minimal amount of THF. After 30 mm, the solution was treatedwith <strong>[329974-09-6]4-bromopyridine-2,6-diamine</strong> (0.200 g, 1.06 mmol), tri(tertbutylphosphonium)tetrafluoroborate (0.03 1 g, 0.11 mmol) and Pd2(dba)3 (0.049 g, 0.053 mmol) and allowed to stir overnight. The solution was extracted from water with EtOAc. The organic layer was concentrated, and the residue purified by silica gel chromatography to furnish the title compound (7a, 0.175 g, 0.680 mmol, 63.9% yield).MS(ESI) m/z 258.0 (M+H).
methyl 3-formyl-1-(3-(methoxycarbonyl)benzyl)-1H-indole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
General procedure: To a solution of 2a (500 mg, 2.46 mmol) in dry DMSO (8 ml) was added NaH(60%, 108 mg, 2.71 mmol) and stirred at room temperature for 1 h.4-Chlorobenzyl bromide (557 mg, 2.71 mmol) was added and stirred at room temperature for 10 h. The reaction solution was quenched with saturated NH4Cl and extracted with CH2Cl2 (150 ml× 3), and the combined organic layers dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 as elunt to give 3a as a white solid
methyl 3-formyl-1-(3-(methoxycarbonyl)benzyl)-1H-indole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
General procedure: To a solution of 2a (500 mg, 2.46 mmol) in dry DMSO (8 ml) was added NaH(60%, 108 mg, 2.71 mmol) and stirred at room temperature for 1 h.4-Chlorobenzyl bromide (557 mg, 2.71 mmol) was added and stirred at room temperature for 10 h. The reaction solution was quenched with saturated NH4Cl and extracted with CH2Cl2 (150 ml× 3), and the combined organic layers dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 as elunt to give 3a as a white solid
To a solution of tert-butyl-N-methylcarbamate (3.00 g, 22.9 mmol) in THF (50 mL) was added NaH (1 .37 g, 34.3 mmol) in portions at 0 C. The reaction mixture was stirred at 15 C for an hour. Then 81 (5.24 g, 22.9 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 15 C for 13 h. The reaction was quenched by ice water (10 mL) slowly and then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified via silica gel columnchromatography (petroleum ether/ethyl acetate = 4:1) to give 82 (2.9 g, 45%) as a colorless oil.1H N R (400 MHz, CDCI3) 7.95-7.91 (m, 2H), 7.42-7.38 (m, 2H), 4.45 (s, 2H), 3.91 (s, 3H), 2.85 (s, 3H), 1 .48 (s, 9H). To a solution of 82 (2.8 g , 10 mmol) in THF (20 mL) was added LiAIH4(456 mg , 12.0 mmol) in portions at 0 C. The mixture was stirred at 15 C for 2 hours. The mixture was cooled to 0 C and quenched by saturated solution of potassium sodium tartrate (0.5 mL), the mixture was concentrated in vacuum (40C) to give 83 (1 .8 g, 71 %) as a colorless oil.1H NMR (400 MHz, CDCI3) 7.32-7.29 (m, 2H), 7.27-7.23 (m, 1 H), 7.15-7.14 (m, 1 H), 4.68 (s, 2H), 4.42 (s, 2H), 2.82 (s, 3H), 1 .48 (s, 9H). To a solution of 83 (1 .5 g, 6.0 mmol) in DCM (20 mL) was added A/-Fmoc-(S)-valine (2.23 g, 6.57 mmol), DCC (1 .6 g, 7.8 mmol) and DMAP (73 mg, 0.60 mmol). The mixture was stirred at 15 C for 12 h. Then DCM (10 mL) was added and the organic layer was washed with brine (10 mL x 3), dried over Na2S04and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4: 1) to give 84 (1 .8 g, 53%) as a colorless oil.1H NMR (400 MHz, CDCI3) 7.70-7.80 (m, 2H), 7.54-7.62 (m, 2H), 7.35-7.42 (m, 2H), 7.23-7.33 (m, 4H), 7.19 (br s, 2H), 5.34-5.32 (m, 1 H), 5.29-5.14 (m, 2H), 4.43-4.41 (m, 4H), 4.40-4.14 (m, 4H), 2.83 (s, 3H), 2.12-2.23 (m, 1 H), 1 .47 (s, 9H), 0.86 (dd, J - 6.84, 2.87 Hz, 6H). To a solution of 84 (1 .00 g, 1 .75 mmol) in THF (6 mL) was added piperidine (298 mg, 3.50 mmol). The mixture was stirred at 15 C for 12 h . The mixture was concentrated in reduced pressure at 40 C. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1 :4) to give 85 (400 mg, 65%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) 7.37-7.35 (m, 1 H), 7.34-7.29 (m, 1 H), 7.27-7.22 (m, 1 H), 7.18-7.17 (m, 1 H), 5.16-5.06 (m, 2H), 4.37 (s, 2H), 3.15 (d, J - 4.0 Hz, 1 H), 2.74 (s, 3H), 1 .99-1 .84 (m, 1 H), 1 .42-1 .39 (m, 9H), 0.85 (d , J = 6.8 Hz, 3H), 0.79 (s, J = 6.4 Hz, 3H). To a solution of Acid-04 (164 mg, 0.856 mmol) in DMF (3 mL) was added HATU (390 mg, 1 .03 mmol) and TEA (260 mg, 2.57 mmol). The mixture was stirred at 20 C for 1 h. Then 85 (300 mg, 0.856 mmol) was added in one portion. The mixture was stirred at 20 C for 1 1 h. The reaction was quenched by water (10 mL) slowly at 0 C and then extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL x 1), dried over anhydrous Na2S04, filtered and then HCI/EtOAc (4 M, 4 mL) was added. The mixture was stirred at 20 C for 12 h. The mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Luna C18 100 x 30 mm; liquid phase: 0.1 %TFA-ACN; B%: 10%-40%, 12 min). After prep. HPLC, 3N HCI (2 mL) was added before freeze drying. 6-122 (137 mg, 33%) was obtained as an off white solid.1H N R (400 MHz, DMSO-cfe) 9.21 (br s, 2H), 9.03 (s, 1 H), 8.59 (d, J - 8.0 Hz, 1 H), 7.55-7.51 (m, 2H), 7.46-7.45 (m, 2H), 7.35 (d, J - 8.0 Hz, 1 H), 7.24 (d, J - 8.0 Hz, 1 H), 5.19 (s, 2H), 4.97 (s, 2H), 4.37 (t, J - 8.0 Hz 1 H), 4.10 (s, 2H), 2.39 (s, 3H), 2.21 -2.16 (m, 1 H), 0.96 (d, J = 6.0 Hz, 6H); ESI-MS m/z 425 [M+H]+; HPLC purity: 94.93% (220 nm), 87.86% (254 nm).
methyl 3-[(6-bromoindolin-1-yl)methyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
General procedure: 458 mg (2.0 mmol) of methyl 3-(bromomethyl) benzoate (6a) and 382 mg (2.0 mmol) 6-bromoindole (5a) were added into a 50 mL flask, then 5.0 mL anhydrous DMF and 1.38 g (10.0mmol) potassium carbonate were added. The mixture was stirred at room temperature overnight.TLC indicated no starting material remained and the reaction was quenched by adding 25 mLwater. The solution was extracted with ethyl acetate (30 mL ×3) or dichloromethane (30 mL ×3).The organic solvent was combined and evaporated, the product was purified by flash column chromatography using hexane : ethyl acetate (7:1) as eluent. 655.2 mg target compound obtainedas pale yellow oil, yield 95percent.
6-bromo-1-[(3-methoxyphenyl)methyl]indoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
General procedure: 458 mg (2.0 mmol) of methyl 3-(bromomethyl) benzoate (6a) and 382 mg (2.0 mmol) 6-bromoindole (5a) were added into a 50 mL flask, then 5.0 mL anhydrous DMF and 1.38 g (10.0mmol) potassium carbonate were added. The mixture was stirred at room temperature overnight.TLC indicated no starting material remained and the reaction was quenched by adding 25 mLwater. The solution was extracted with ethyl acetate (30 mL ×3) or dichloromethane (30 mL ×3).The organic solvent was combined and evaporated, the product was purified by flash column chromatography using hexane : ethyl acetate (7:1) as eluent. 655.2 mg target compound obtainedas pale yellow oil, yield 95percent.
methyl 3-[(6-bromo-5-fluoroindol-1-yl)methyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
General procedure: 458 mg (2.0 mmol) of methyl 3-(bromomethyl) benzoate (6a) and 382 mg (2.0 mmol) 6-bromoindole (5a) were added into a 50 mL flask, then 5.0 mL anhydrous DMF and 1.38 g (10.0mmol) potassium carbonate were added. The mixture was stirred at room temperature overnight.TLC indicated no starting material remained and the reaction was quenched by adding 25 mLwater. The solution was extracted with ethyl acetate (30 mL ×3) or dichloromethane (30 mL ×3).The organic solvent was combined and evaporated, the product was purified by flash column chromatography using hexane : ethyl acetate (7:1) as eluent. 655.2 mg target compound obtainedas pale yellow oil, yield 95%.
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 8h;
3.2 2. Preparation of Intermediate 4b
Take 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (250mg, 0.82mmol), methyl 3-(bromomethyl)benzoate (224mg , 0.98mmol), K2CO3 (170mg, 1.23mmol), KI (13mg, 0.08mmol) was added to a 50ml reaction bottle, 15ml DMF was added to dissolve and stir, the reaction was carried out at room temperature for 8 hours, and the reaction was detected by TLC. The reaction solution was poured into 100 ml of ice water, stirred, and a white solid was precipitated. 30 ml of ethyl acetate was added, and the extractor was extracted three times. The organic phases were combined, washed with saturated brine, and the organic phase was distilled off under reduced pressure. Silica gel column chromatography (dichloromethane Methane: methanol = 200:1) to obtain 302 mg of white solid with a yield of 81.6%.
methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate In acetonitrile at 60℃; for 3h;
15.15-1 Step 15-1 Synthesis of methyl 3-(((2.4-dichlorophenyl )thio)methyl ibenzoate (INT 15-A)
To a stirring solution of 2,4-dichlorobenzenethiol (750 mg, 4.19 mmol) in MeCN (20 mL) were added methyl 3-(bromomethyl)benzoate (959 mg, 4.19 mmol) and potassium carbonate (753 mg, 5.45 mmol). The reaction mixture was heated at 60 °C for 3h, cooled to room temperature, diluted with H2O (20 mL) and extracted with Et20 (2 X 20 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated to afford 1.3g (94 %) of methyl 3-(((2,4-dichlorophenyl)thio)methyl)benzoate (INT 15-A) as a yellow oil that solidified upon standing. LCMS-ESI (m/z) calculated for C15H12CI2O2S: 325.9; found 327.1 [M+H]+, tR = 12.5 min. (Method 3).
methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.5%
With potassium carbonate In acetonitrile at 60℃; for 16h;
34.34-1 Step 34-1 Synthesis of methyl 3-((2-bromo-4-(trifluoromethvnphenoxy)methvnbenzoate
Step 34-1 Synthesis of methyl 3-((2-bromo-4-(trifluoromethvnphenoxy)methvnbenzoate A vial containing a stirring solution of 2-bromo-4-(trifluoromethyl)phenol (316 mg, 1.31 mmol) in MeCN (5 mL) was charged with methyl 3-(bromomethyl)benzoate(300 mg, 1.31 mmol) and K2CO3 (235 mg, 1.70 mmol). The resulting yellow suspension was stirred at 60°C for 16 hours, cooled to room temperature, diluted with H2O and extracted 3x with Et20. The organic layers were combined, washed with brine, concentrated under reduced pressure, and purified by S1O2 chromatography (EA/hexanes) to yield 451 mg (88.5 %) of methyl 3-((2-bromo-4-(trifluoromethyl)phenoxy)methyl)benzoate (INT 34-A) as a white solid. LCMS-ESI (m/z) calculated for C^ElnBrFsCb: 389.2; found 391.0 (M+H)+, tR = 6.7 min. (Method 1).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
