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Structure of 74733-27-0 * 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 bromine In tetrachloromethane for 1.75 h; Heating / reflux; Irradiation
To a refluxing mixture of methyl 2-methoxy-4-methyl-benzoate (21.625 g, 120 mmol) in CC14 (240 mL) was addeddropwise a solution of bromine (6.19 mL, 120 mmol) in CC14(75 mL) over 1.5 h. During the bromine addition thereaction was irradiated with a 250 W tungsten lamp. Afterthe addition, the reaction was refluxed for 15 min andconcentrated, and vacuum pumped to give methyl 2-methoxy-4-(bromomethyl)benzoate as an oil (29.864 g, 96percent)..NMR (400MHz, CDC13): 5 partial 2.40 (s, 3H), 3.87 (s, 3H),3.91 (s, 3H), 4.44 (s, 2H).FIA-MS, m/e: 259 (m+1).
91%
With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide In water at 120℃; Microwave irradiation
General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0–200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 °C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc–hexane gradient
48%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethaneReflux; Darkness
Stage 1: methyl 4-bromomethyl-2-methoxy-benzoate To 5.38 g of methyl 2-methoxy-4-methyl benzoate in 20 mL of carbon tetrachloride, are added 5.3 g of N-bromosuccinimide (1 equivalent) and 490 mg of AIBN (0.1 equivalent) away from direct light. The whole is refluxed by heating overnight. The reaction medium is evaporated under reduced pressure and then purified on silica gel (petroleum ether/ethyl acetate: 90/10) leading to 3.73 g of the desired product. Yield: 48percent 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.76 (d, 1H), 6.99 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H)
27%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2 h; Inert atmosphere
Compound 15 (27 mg, 0.1497 mmol) was diluted with 5 mL of CCl 4, and NBS (N-bromosuccinimide, 27 mg, 1.497 mmol) and an AIBN catalytic amount were added to a round bottom flask with two rounds replaced with argon gas, And stirred for 2 hours. After confirming the completion of the reaction, gradually cool to room temperature, and filter using Celite. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 16 as a transparent liquid. (0.009 g, 27percent).
10 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 18 h; Reflux
To a solution of methyl 2-methoxy-4-methylbenzoate (10.00 g, 55 mmol) in CCl4 (150 mL) were added NBS (1 1.8 g, 66 mmol) and AIBN (0.100 g). The reaction mixture was refluxed for 18 h. The reaction mass was diluted with diethyl ether and washed with 25percent NaOH solution. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (m, 6H), 4.68 (s, 2H), 7.06 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 7.61 (d, / = 7.8 Hz, 1H); MS (m/z): 259.13 (M)+.
144 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 70℃; for 15 h; Inert atmosphere
3C. Methyl 4-(bromomethyl)-2-methoxy-benzoatestirred solution of methyl 2-methoxy-4-methyl-benzoate (100 g, 555 mmol) and Nbromosuccinimide (108.6 g, 610 mmol) in carbon tetrachloride (1300 mL) wasdegassed with nitrogen for 15 minutes. CL,CL’-Azoisobutyronitrile (18.2 g, 111 mmol) was added in one portion and the resulting mixture heated to 70°C for 15 hours then allowed to cool to room temperature. The mixture was poured into water (600 mL) and then the separated aqueous phase extracted with DCM (2 x 800 mL). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to givethe title compound (144 g) which was used without further purification.
Reference：
[1] Patent: WO2004/108677, 2004, A1, . Location in patent: Page 199
[2] Synlett, 2014, vol. 25, # 17, p. 2485 - 2487
[3] Patent: US2009/209586, 2009, A1, . Location in patent: Page/Page column 13
[4] Patent: KR2016/20674, 2016, A, . Location in patent: Paragraph 0053; 0115; 0116
[5] Bulletin de la Societe Chimique de France, 1962, p. 2255 - 2261
[6] Patent: EP2133353, 2009, A1, . Location in patent: Page/Page column 54-55
[7] Patent: US6359134, 2002, B1, . Location in patent: Referential example 28
[8] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 22, p. 6768 - 6778
[9] Patent: WO2013/186692, 2013, A1, . Location in patent: Page/Page column 107; 108
[10] Patent: US2014/163066, 2014, A1, . Location in patent: Paragraph 0313-0314
[11] Patent: WO2015/120390, 2015, A1, . Location in patent: Page/Page column 92; 138; 139
[12] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 2, p. 185 - 190
[13] Patent: US5880147, 1999, A,
[14] Patent: EP2272835, 2011, A1, . Location in patent: Page/Page column 19-20
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 40℃; for 2h;
Step ASodium hydride (60 % in mineral oil, 30 mg, 0.75 mmol) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl- phenyl}-methyl-amine (0.31 g, 0.75 mmol) and <strong>[74733-27-0]4-bromomethyl-2-methoxy-benzoic acid methyl ester</strong> (0.320 g, 1.23 mmol) in DMF (3 mL) at room temperature. The reaction is heated to 40 0C for 2 h. The mixture is diluted with water and is extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude residue is purified via radial chromatography (2 mm plate, 20 to 40 THF -heptane) to afford 4-[( {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3- <n="131"/>ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid methyl ester (303 mg, 68%). ES/MS m/e 596.0 (M + 1).
methyl 4-[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 50 - 60℃; for 0.5h;
1.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}propanoate, 0.809 g of methyl 4-(bromomethyl)-2-methoxy benzoate, and 0.539 g of potassium carbonate were suspended in 10 ML of N,N-dimethylformamide, and this suspension was stirred for 30 minutes at temperatures of 50 to 60C. The reaction mixture was cooled to room temperature, which was then added to a mixture of ethyl acetate and water, and this mixture was adjusted to PH 2 with 6M hydrochloric acid for the separation of the organic phase 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 the solvent was distilled out thereof under reduced pressure.. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to yield 1.08 g of methyl 4-[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}-2-methoxybenzoate as yellow oil. NMR(400MHz,CDCl3) delta value: 1.59-1.66(2H,m), 1.76-1.98(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.66(3H,s), 3.90(3H,s), 3.94(3H,s), 4.80-4.83(1H,m), 5.20(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.03(1H,d,J=8.0Hz), 7.09(1H,s), 7.50(1H,d,J=8.8Hz), 7.52-7.55(2H,m), 7.84(1H,d,J=8.0Hz), 12.68(1H,s)
To a mixture of methyl 2-methoxy-4-(bromomethyl)-benzoate (10.36 g, 40 mmol) and DMF (80 mL) was added solidsodium methylthiolate (4.21 g, 60 mmol), and the mixture wasstirred for 18 h. The reaction was poured into EtOAc(300 mL) and water (400 mL), and partitioned. The aqueouslayer was extracted with EtOAc (2 X 200 mL). The combinedorganic layer was washed with water (3 X 100 mL), dried(MgSC>4) and concentrated. The resulting residue waschromatographed (400 g SiC>2, hexanes to 10% EtOAc/hexanes)to give the title compound as colorless oil (3.8 g, 36%).1-NMR (400 MHz, CDCls): 5 2.00 (s, 3H) , 3.68 (s, 2H) , 3.88(s, 3H) , 3.92 (s, 3h), 6.90 (d, J = 7.7 Hz, 1H), 6.95 (s,1H), 7.75 (d, J = 7.7 Hz, 1H) .FIA-MS, m/e: 226.9 (m+1).Analysis for C^H^C^S:Calcd: C, 58.38; H, 6.24;Found: C, 56.57; H, 5.98.
EXAMPLE 228 2-Methoxy-4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester Made by the procedure of Example 217 with methyl 4-bromomethyl-2-methoxybenzoate; mp 201-203 C.
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 240 2-Methoxy-4-[6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl]-benzoic acid methyl ester Made by the procedure of Example 217 with 4-bromomethyl-2-methoxy-benzoic acid methyl ester; mp 200-203 C.
47
[ 74733-27-0 ]
[ 189094-76-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; sodium hydrogencarbonate; In N-methyl-acetamide; hexane; water; ethyl acetate;
The whole of this crude product was dissolved in 100 ml of dimethylformamide, and 13.48 g (164 mmol) of sodium acetate were added to the solution. The resulting mixture was then stirred at 60 C. for 2.5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure and the concentrate was mixed with water. It was then extracted with a mixture of ethyl acetate and hexane. The extract was washed with 2N aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to obtain 10.49 g of crude methyl 4-acetoxymethyl-2-methoxybenzoate.
With N-Bromosuccinimide; In tetrachloromethane; ethyl acetate;
Methyl 4-bromomethyl-2-methoxybenzoate: A solution of methyl 2-methoxy-4-methyl benzoate (99.0 g, 0.55 mole), N-bromosuccinimide (109.0 g, 0.61 mole) and bisazoisobutyronitrile (50 mg) in carbon tetrachloride (1000 mL) was refluxed under an argon atmosphere while a sun lamp was directed on the flask. After 75 min., the heat lamp was removed and the reaction mixture was allowed to cool. During the reaction, the color of the solution had changed from light orange to dark orange to light yellow. After cooling, the reaction mixture was washed three times with 10% sodium bicarbonate, dried (MgSO4) and solvent removed to yield the crude product as an amber oil. After chromatography on silica gel using 20% ethyl acetate/hexane as the eluent, there was obtained 104 g (70%) of the titled product as a crystalline solid, m. pt, 55-56. NMR (CDCl3, 300 MHz, ppm): 3.88 (s, 3H); 3.92 (s, 3H); 4.45 (s, 2H); 7.0 (s, 1 h); 7.01 (d, J=7.5 Hz, 1H); 7.78 (d, J=7.5 Hz, 1 h).
4-Hydroxymethyl-2-methoxybenzoic acid: A mixture of <strong>[74733-27-0]methyl 4-bromomethyl-2-methoxybenzoate</strong> (25.0 g, 96.5 mmol), potassium hydroxide (10.83 g, 193 mmol) and water (400 mL) was refluxed with stirring for 2 hr. The reaction mixture was cooled, further basified to pH 14, and extracted three times with ethyl ether. The reaction solution was then acidified to pH 1 and extracted several times with ethyl acetate. The ethyl acetate layers were combined, dried (Na2 SO4) and evaporated to yield 16.3 g (93%) of the title compound as an off white solid, m. pt 106-111, whose purity was suitable for use without further purification. Additional purification is effected by recrystallization from ethyl acetate and hexane, m. pt, 112-115. NMR (CDCl3 /d6-DMSO, 300 MHz, ppm): 4.00 (s, 3H); 4.70 (s, 2H); 7.00 (d, J=7.5 Hz, 1 h); 7.I3 (s, 1H); 7.95 (d, J=7.5 Hz, 1H).
4-Carbomethoxy-3-methoxybenzyl bromide N-Bromosuccinimide (45.3 g) was added to methyl 2-methoxy-4-methylbenzoate (45.8 g) in carbon tetrachloride (~11) containing a trace of dibenzoyl peroxide. The suspension was heated under reflux until no orange colour persisted, then cooled, filtered and the filtrate evaporated to give the title compound, bp 136-144/7 mm. tau(CDCl3) 6.17 (3H, s), 6.13 (3H, s), 5.59 (2H, s), 2.9-3.15 (2H, m), 2.3 (1H, d, J=8 Hz).
4-Carbomethoxy-3-methoxybenzaldehyde 2-Nitropropane (1.0 g) was added to sodium methoxide (from 0.24 g sodium) in methanol (30 ml) and the solution refluxed for 1/2 hour. 4-Carbomethoxy-3-methoxybenzyl bromide (2.67 g) in methanol was added and the solution refluxed for 1 hour. The methanol was evaporated, the residue partitioned between 2N sodium hydroxide and chloroform. The chloroform layer was shaken with further sodium hydroxide until no more yellow colour was extracted, dried and evaporated to yield the title compound (1.66 g). tau(CDCl3) 6.1 (3H, s), 6.05 (3H, s), 2.4-2.6 (2H, m), 2.07 (1H, d, J=8 Hz), -0.05 (1H, s).
EXAMPLE 199 2-Methoxy-4-[5'-(8-phenyl-octylcarbamoyl)-3,3"-bis-trifluoromethyl-[1,1':3'1"]terphenyl]-2'yloxymethyl]-benzoic acid step 1 To a solution of 2'-hydroxy-3,3"-bis-trifluoromethyl-[1,1':3'1"]terphenyl-5'-carboxylic acid (8-phenyl-octyl)-amide (0.755 g, 1.23 mmol, 1 eq) in acetone (12 mL) was added K2CO3 (0.857 g, 6.2 mmol, 5.0 eq) and <strong>[74733-27-0]4-bromomethyl-2-methoxy benzoic acid methyl ester</strong> (Julia, M.; Chastrette, F.; BSCFAS; Bull.Soc.Chim.Fr.; FR; 1962; 2255-2261). (0.325 g, 1.25 mmol, 1.0 eq). The reaction was heated at reflux overnight. Additional <strong>[74733-27-0]4-bromomethyl-2-methoxy benzoic acid methyl ester</strong> (0.072 g, 0.28 mmol, 0.2 eq) was added and reflux was continued for 1 h. The reaction was cooled to rt and concentrated in vacuo. The residue was partitioned between EtOAc and brine, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane) to afford 2-methoxy-4-[5'-(8-phenyl-octylcarbamoyl)-3,3"-bis-trifluoromethyl-[1,1':3'1"]terphenyl-2'yloxymethyl]-benzoic acid methyl ester. (0.847, 87%) as a colorless oil. 1H NMR (CDCl3) delta7.88-7.42 (m, 10H); 7.25-7.10 (m, 5H); 6.24-6.10 (m, 3H); 4.18 (s, 2H); 3.85 (s, 3H); 3.65 (s, 3H); 3.46 (dd, 2H); 2.58 (t, 2H); 1.60 (m, 4H); 1.34 (m, 8H).
With N-Bromosuccinimide; CH3I; potassium carbonate;azobisisobutyronitrile; In tetrachloromethane; diethyl ether; acetone;
C. Methyl 4-Bromomethyl-2-methoxybenzoate. A mixture of 4-methylsalicylic acid (20 g, 131.5 mmol), CH3I (74.7 g, 526.3 mmol), and K2CO3 (36.2 g, 262 mmol) in 250 mL of acetone was maintained at reflux for 4 days. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue taken up in Et2O and washed with 2 N NaOH. The organic extract was concentrated under reduced pressure. From this crude material, 10 g (55.6 mmol) was taken up in 100 mL of CCl4; and N-bromo-succinimide (10.8 g, 61.1 mmol) and a catalytic amount of AIBN were added. The mixture was heated at reflux for 4 h and then diluted 10 fold with Et2O. The organics were washed with 25% NaOH (aq.) and concentrated under reduced pressure. Crude product was recrystallized from EtOAc-hexanes, giving 14.2 g (99%) of the desired bromide. 1H NMR (CDCl3) delta 7.77 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.99 (s, 1H), 4.47 (s, 2H), 3.94 (s, 3H), 3.91(s, 3H).
With water; calcium carbonate; In 1,4-dioxane; at 100℃; for 16h;
Stage 2: methyl 4-Hydroxymethyl-2-methoxy-benzoate To 1.5 g of the product obtained in the previous stage in 25 mL of dioxane is added a suspension of 2.55 g (4.4 equivalents) of calcium carbonate in 25 mL of water. The whole is heated for 6 hours at 100 C. After evaporation of the reaction medium, the crude product is taken up in dichloromethane, acidified with a 1 N hydrochloric acid solution. The reaction medium is extracted several times with dichloromethane, the collected organic phases are then dried on magnesium sulfate, filtered and evaporated under reduced pressure, leading to 1.10 g of the desired product. Yield: 96% 1H NMR (CDCl3, 300 MHz) delta (ppm): 7.78 (d, 1H), 7.01 (m, 1H), 6.93 (d, 1H), 4.73 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H)
2-ethoxy-8-methoxyadenine trifluoroacetate[ No CAS ]
[ 74733-27-0 ]
[ 1059071-97-4 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Example 62 6-Amino-2-ethoxy-9-(3-methoxy-4-morpholin-4-ylmethylbenzyl)-7,9-dihydropurin-8-one 2-Hydroxy-4-methylbenzoic acid (600 mg, 4 mmol), methyl iodide (1.4 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) were added to DMF (10 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and to the residue were added ethyl acetate and water. The mixture was separated, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and to the residue were added NBS (700 mg, 5 mmol), benzoyl peroxide (100 mg) and carbon tetrachloride (6 mL), and the mixture was stirred at 80C for 5 hours. The insoluble materials were separated by filtration, and the filtrate was washed with sodium thiosulfate and water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was added to 2-ethoxy-8-methoxyadenine TFA salt (250 mg, 0.8 mmol), potassium carbonate (420 mg, 3 mmol) and DMF (5 mL), and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation, and water and chloroform were added to the residue, and the mixture was separated. The organic phase was dried over magnesium sulfate, and purified by silica gel column chromatography (CHCl3/MeOH=50/1) to give a white solid (310 mg). This solid and lithium aluminum hydride (74 mg, 2 mmol) were added to THF (10 mL), and the mixture was stirred under ice-cooling for 2 hours. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added thionyl chloride (0.3 mL) and dichloromethane (5 mL), and the mixture was stirred at 40C for 2 hours. The solvent was removed by evaporation, and to the residue were added morpholine (0.2 mL), diisorpopylethylamine (0.5 mL) and DMF (5mL), and the mixture was heated at 80C with stirring for 2 hours. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (CHCl3/MeOH/28 % NH3=100/3/2) to give the title compound (46 mg). 1H NMR (DMSO-d6) delta 9.95 (1H, s), 7.22 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 1.2 Hz), 6.78 (1H, dd, J = 1.4, 8.0 Hz), 6.46 (2H, s), 4.83 (2H, s), 4.20 (2H, q, J = 7.0 Hz), 3.74 (3H, s), 3.54 (4H, t, J = 4.6 Hz), 3.40 (3H, s), 2.34 (4H, m), 1.25 (3H, t, J = 7.0 Hz).
1.61 mL of cyclopentanecarboxylic acid was dissolved in 5 mL of tetrahydrofuran, and this mixture was added dropwise to 50 mL of solution of lithium diisopropylamide in tetrahydrofuran prepared from 20.9 mL of n-butyllithium in n-hexane (1.56 M) and 4.58 mL of diisopropylamine at -30C, and then this mixture was stirred for one hour at 5C and for another one hour at room temperature. After the reaction mixture was cooled to -30C, a solution of 5.00 g of <strong>[74733-27-0]methyl 4-(bromomethyl)-2-methoxybenzoate</strong> in 5 mL of tetrahydrofuran was added dropwise to this mixture, which was then stirred for 1.5 hours at -10C and for another 1.5 hours at room temperature. A saturated aqueous solution of ammonium chloride and diethyl ether were successively added to the reaction mixture, and the organic phase was separated therefrom. A saturated aqueous solution of sodium hydrogen carbonate was added to the resultant organic phase, from which an aqueous phase was separated, followed by adjustment to pH 2 with 6M hydrochloric acid, and then the organic layer was separated therefrom by adding chloroform thereto. 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 the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:2] to yield 0.718 g of 1-[3-methoxy-4-(methoxycarbonyl)benzyl]-cyclopentanecarboxylic acid as colorless oil. NMR(400MHz,CDCl3) delta value: 1.62-1.72(6H,m), 2.05-2.12(2H,m), 3.00(2H,s), 3.84(3H,s), 3.87(3H,s), 6.78-6.80(3H,m), 7.71(1H,d,J=8.0Hz)
With triethylamine; In dichloromethane; at 0 - 20℃;
Reference Example 16; Methyl 2-methoxy-4-(morpholin-4-ylmethyl)benzoate; [Show Image] To methyl 2-methoxy-4-methylbenzoate (4.71 g) obtained in Reference Example 15 were added N-bromosuccinimide (5.58 g) and 2,2'-azobis(2-methylpropionitrile) (0.43 g), and the mixture was stirred under nitrogen at 70C for 7 hours. Thereto was added ether (70 ml). The insoluble was filtered off, and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in methylene chloride (45 ml), and thereto were added morpholine (2.27 g) and triethylamine (5.28 g) at 0C. Then, the mixture was stirred at room temperature for 5 hours. Thereto was added water (20 ml), and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [0.5% methanol-chloroform] to give the titled compound (1.28 g) as a colorless oil. 1H-NMR(CDCl3): delta 2.45(4H, m), 3.51(2H, s), 3.72(4H, m), 3.88(3H, s), 3.92(3H, s),6.94(1H, d, J=7.9), 7.00(1H, s), 7.75(1H, d, J=7.9)
A solution of 17 (3000 mg, 18.1 mmol) in DMF (5.0 mL) was added to a suspension of 60% NaH in oil (1019 mg, 25.5 mmol) in DMF (10 mL) with cooling in an ice-bath and the mixture was stirred for 30 min, then MeI (3.5 mL, 56.2 mmol) was added to it. Stirring was continued at room temperature for 18 h, then the mixture was acidified with 2 N HCl and extracted with AcOEt. The organic layer was washed with brine, and dried over MgSO4. Filtration, evaporation of the solvent in vacuo and purification of the residue by flash column chromatography (AcOEt/n-hexane = 1/4) gave 3252 mg (100%) of methyl 2-methoxy-4-methylbenzoate as a colorless oil; 1H NMR (CDCl3, 500 MHz, delta; ppm): 7.72 (1H, d, J = 8.5 Hz), 6.79 (1H, d, J = 6.7 Hz), 6.78 (1H, s), 3.90 (3H, s), 3.87 (3H, s), 2.37 (3H, s); MS (FAB) m/z: 181 (MH+). AIBN (578 mg, 3.52 mmol) was added to a solution of methyl 2-methoxy-4-methylbenzoate (3172 mg, 17.6 mmol) and NBS (3446 mg, 19.4 mmol) in CCl4 (40 mL) and the resulting mixture was heated at 70 C for 8 h. After cooling, the reaction mixture was concentrated and purified by flash column chromatography (AcOEt/n-hexane = 1/6 to 1/3) to give a crude bromine compound that was used in the next reaction without further purification. AcOK (9062 mg, 92.3 mmol) was added to a solution of the crude bromine compound in DMF (10 mL) and the resulting mixture was stirred at room temperature for 15 h, then poured into water and extracted with AcOEt. The organic layer was washed with brine, and dried over MgSO4. Filtration, evaporation of the solvent in vacuo and purification of the residue by flash column chromatography (AcOEt/n-hexane = 1/4 to 1/1) gave 2395 mg (57%; 2 steps) of 18 as a colorless solid; 1H NMR (CDCl3, 500 MHz, delta; ppm): 7.80 (1H, d, J = 7.9 Hz), 6. 69 (1H, d, J = 7.9 Hz), 6.95 (1H, s), 5.12 (2H, s), 3.92 (3H, s), 3.89 (3H, s), 2.13 (3H, s); MS (FAB) m/z: 239 (MH+).
63.0 g
In N,N-dimethyl-formamide; at 80℃; for 1h;
1 3D. Methyl 4-(acetoxymethyl)-2-methoxy-benzoateA stirred mixture of methyl 4-(bromomethyl)-2-methoxy-benzoate (144 g, 558 mmol) and potassium acetate (285 g, 2.9 mol) in dry DMF (1440 mL) was heated to 80C for one hour then the cooled mixture was poured into ice-water (5000 mL). The mixturewas extracted with DCM (2 x 1000 mL) and the combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 15%EtOAc/hexanes as the eluent to give the title compound (63.0 g, 48% over two steps).
2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In ethanol; dichloromethane; water;
Example 4-1 Synthesis of 2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzoic acid methyl ester To 100 mL of ethanol were added 10.0 g of 1-methylpiperazine and 20.2 g of triethylamine. To the mixture cooled with ice, 25 mL of a solution of 24.6 g of <strong>[74733-27-0]4-(bromomethyl)-2-methoxy-benzoic acid methyl ester</strong> in ethanol was added dropwise. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated. To the residue, 75 mL of water and 250 mL of methylene chloride were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated. The residue was purified by amino-silica gel column chromatography (heptane/AcOEt system) to give 22.4 g of the title compound (85% yield).
tert-butyl (3R)-3-[(3-methoxy-4-methoxycarbonylphenyl)methoxy]pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
1 40A. tert-Butyl (3R)-3-[(3-methoxy-4-methoxycarbonyl-henyl)methoxy]yrrolid me-i - carboxylateA solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.9 g, 15.5 mmoL) in DMF (8 mL) was added to a stirred slurry of sodium hydride (60% in mineral oil, 1 .86 g, 4.65 mmol) in DMF (10 mL) at 0C under a nitrogen atmosphere and the resultingmixture stirred for 10 minutes. A solution of methyl 4-(bromomethyl)-2-methoxy- benzoate (4.0 g, 15.5 mmol) in DMF (7 mL) was added dropwise over 20 minutes maintaining the temperature at 0C. The resulting mixture was allowed to warm to room temperature and stirring continued for 30 minutes before cooling back to 0C. Methyl iodide (2.9 mL, 4.65 mmol) was added and the solution was allowed to warm toroom temperature and stirring continued for one hour then the mixture was poured into ice cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2504) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 20%EtOAc/hexane as the eluent to give thetitle compound (4.3 g, 76%).
methyl 4-(diethoxyphosphorylmethyl)-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
at 100℃; for 12h;Sealed tube;
1 43A. Methyl 4-(diethoxyhowhorylmethyl)-2-methoxy-benzoateA solution of methyl 4-(bromomethyl)-2-methoxy-benzoate (6.0 g, 23.3 mmol) in triethyl phosphite (12 mL) was heated to 100C in a sealed tube for 12 hours. The solution was allowed to cool to room temperature and evaporated under reduced pressure to leave the title compound (7.2 g, 98%) as a yellow solid which was used without further purification.
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