* 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.
Stage #2: With sodium hydroxide In ethanol; water at 105℃; for 5 h;
General procedure: A mixture of NaOH (0.04 mol, 1.60 g), deionized water (20 mL) and ethanol (20 mL) were poured into a 150 mL three-necked flask, then phenol (0.04 mol, 3.76 g) was slowly added under stirring. Twenty minutes later, the above sodium chloroacetate was added dropwise. The reaction solution was heated to 105 °C and refluxed for 5 h. After cooling down, the pH value of the mixture was acidified to 1-2 with diluted hydrochloric acid. The precipitate was collected by filtration and washed with diluted hydrochloric acid many times. Recrystallized and dried under a vacuum, resulting in a white solid product of the phenoxyacetic acid (4a).
77%
Stage #1: With sodium hydroxide In waterCooling with ice Stage #2: for 0.333333 h; Stage #3: at 105℃; for 5 h;
General procedure: Compounds B1−7 were prepared by similar procedures. In atypical synthesis of B1, monochloroacetic acid (0.04 mol,3.78 g) was dissolved in deionized water (15 mL) under thecondition of stirring and an ice bath. Then NaOH (25 percent) wasadded dropwise until the pH value was adjusted to 9−10, thena solution of sodium chloroacetate was obtained. To a solutionof NaOH (0.03 mol, 1.20 g), deionized water (15 mL) andethanol (5 mL), phenol (0.04 mol, 3.76 g) was slowly addedunder stirring. After addition, the mixture was stirred for20 min, then the above sodium chloroacetate was addeddropwise, and heated to 105 °C and refluxed for 5 h. Thereaction mixture was cooled to room temperature. The pHvalue of the mixture was acidified to 1−2 with diluted hydrochloricacid. The precipitate was filtered, washed with dilutedhydrochloric acid many times, and recrystallized and dried invacuum, resulting in a white solid product of thephenoxyacetic acid (B1)
Reference：
[1] Luminescence, 2018, vol. 33, # 5, p. 855 - 862
[2] Synthetic Communications, 2004, vol. 34, # 3, p. 377 - 382
[3] Journal of Molecular Structure, 2014, vol. 1074, p. 487 - 495
[4] Journal of Fluorescence, 2015, vol. 25, # 4, p. 849 - 859
[5] Luminescence, 2015, vol. 30, # 5, p. 677 - 685
[6] Journal of the American Chemical Society, 1931, vol. 53, p. 304
[7] Journal of the American Chemical Society, 1943, vol. 65, p. 1555
[8] Journal of the Indian Chemical Society, 1991, vol. 68, # 6, p. 358 - 359
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4597 - 4601
[10] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4726 - 4733
[11] Patent: WO2010/10186, 2010, A1, . Location in patent: Page/Page column 76
[12] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 9, p. 4801 - 4813
[13] Indian Journal of Heterocyclic Chemistry, 2012, vol. 21, # 3, p. 269 - 272
[14] Research on Chemical Intermediates, 2016, vol. 42, # 6, p. 5269 - 5280
[15] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 199 - 218
[16] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3180 - 3186
[17] Bioorganic Chemistry, 2015, vol. 59, p. 151 - 167
[18] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5951 - 5955
2
[ 6964-29-0 ]
[ 1878-91-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 0 - 20℃; for 4 h;
To a stirred solution of CX (7 g, 27.02 mmol) in THF:H20 (1 : 1, 50 mL) under inert atmosphere was added lithium hydroxide monohydrate (11.3 g, 41.90 mmol) at 0 °C. The reaction was warmed to RT for 4 h. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The residue was diluted with water (40 mL) and acidified with HC1 to pH~2 and filtered. The obtained solid was triturated with toluene (2x30 mL) to afford CY (4.5 g, 73percent) as a white solid. *H NMR (400 MHz, DMSO-i: δ 13.03 (br s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 4.66 (s, 2H). MS (ESI): m/z 231 [M+l]+
Reference：
[1] Patent: WO2014/117090, 2014, A1, . Location in patent: Page/Page column 141-142
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1979, vol. 18, p. 69 - 70
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1675 - 1684
[4] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7401 - 7406
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 806 - 810
[6] European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2197 - 2204
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2526 - 2530
3
[ 106-41-2 ]
[ 3926-62-3 ]
[ 1878-91-7 ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: With sodium hydroxide In ethanol; water at 20℃; for 0.333333 h; Stage #2: at 102℃; for 5 h;
General procedure: 55mmol monochloroacetic acid was dissolved in 15mL deionized water under the condition of ice water bath, then 30percent NaOH solution was used to adjust pH 8–9, sodium chloroacetate solution was obtained. 45mmol NaOH was dissolved in mixed solvent of 15mL deionized water and 5mL ethanol at room temperature with constant stirring, 45mmol phenol was subsequent slowly added. After stirring for another 20min, sodium chloroacetate solution was added. Subsequently, the mixture was refluxed at 102°C for 5h. After the mixture was cooled to room temperature, pH was adjusted to 1–2 with 2.0mol·L−1 HCl, amounts of white precipitations were gained. The precipitations were filtered and washed 3 times with dilute hydrochloric acid, dried at 60°C. White crude product was dispersed in 100mL heated deionized water, pH was adjusted to 8.0 using saturated potassium carbonate solution, then mixture solution was filtered, and filtrate was collected. White precipitated was obtained by adjusting pH of filtrate to 1–2 with 2.0mol·L−1 HCl. After cooled down to room temperature naturally, the mixture was filtered, washed with dilute hydrochloric acid, dried overnight in vacuum, then target product (b1) was obtained. The synthetic procedures of phenoxyacetic acid derivative (b2−7) were similar to that of phenoxyacetic acid (b1).
Reference：
[1] Luminescence, 2014, vol. 29, # 8, p. 1113 - 1122
[2] Dyes and Pigments, 2018, vol. 158, p. 28 - 35
4
[ 10265-68-6 ]
[ 1878-91-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603
5
[ 4841-23-0 ]
[ 1878-91-7 ]
Reference：
[1] Monatshefte fur Chemie, 2004, vol. 135, # 1, p. 83 - 87
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 2, p. 154 - 156
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3732 - 3735
6
[ 106-41-2 ]
[ 1878-91-7 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1979, vol. 18, p. 69 - 70
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 806 - 810
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3732 - 3735
[4] Patent: WO2014/117090, 2014, A1,
[5] European Journal of Organic Chemistry, 2015, vol. 2015, # 10, p. 2197 - 2204
[6] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5601 - 5603
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2526 - 2530
7
[ 122-59-8 ]
[ 1878-91-7 ]
Reference：
[1] Chemische Berichte, 1982, vol. 115, # 7, p. 2592 - 2605
[2] Journal of Organic Chemistry, 1947, vol. 12, p. 435[3] Journal of Organic Chemistry, 1948, vol. 13, p. 937
8
[ 106-41-2 ]
[ 79-08-3 ]
[ 1878-91-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 967 - 978
[2] International Journal of Chemical Kinetics, 2001, vol. 33, # 10, p. 612 - 616
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 0 - 20℃; for 4h;
To a stirred solution of CX (7 g, 27.02 mmol) in THF:H20 (1 : 1, 50 mL) under inert atmosphere was added lithium hydroxide monohydrate (11.3 g, 41.90 mmol) at 0 C. The reaction was warmed to RT for 4 h. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The residue was diluted with water (40 mL) and acidified with HC1 to pH~2 and filtered. The obtained solid was triturated with toluene (2x30 mL) to afford CY (4.5 g, 73%) as a white solid. *H NMR (400 MHz, DMSO-i: delta 13.03 (br s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 4.66 (s, 2H). MS (ESI): m/z 231 [M+l]+
Lithium hydroxide monohydrate (2.0 eq.) was added to a solution of (4-bromo-phenoxy)-acetic acid ethyl ester 1 (1.0 eq.) in THF/H2O (1:1), and the mixture was stirred overnight at RT. The reaction mixture was neutralized with 37% HCl, diluted with AcOEt, sequentially washed with water and brine, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to produce the desired pure compound 2, with a global yield of 83% for steps (a) and (b), that is an average yield of 91% for each step. NMR 1H (CDCl3, 300 MHz), delta (ppm): 4.30 (s, 2H, -OCH2-), 6.70-7.30 (m, 4H, ArH), and 9.50 (s, 1H, COOH). Data consistent with the literature 2.
With water; sodium hydroxide; In ethanol; at 20℃; for 4h;
General procedure: A solution of corresponding substituted ethylaryloxyacetate (3a-f, 25 mmol) in ethanol (100 mL) was treated with 10% aqueous sodium hydroxide (9 mmol). After 4 h at room temperature and evaporation under reduced pressure of ethanol, the aqueous phases were acidified at pH 4 with HCl (2 N). Removal of precipitate by filtration yielded the crude acids, which were recrystallized in ethanol to afford substituted aryloxyacetic acid 4a-f, yield 66-90%.
With lithium hydroxide monohydrate; In methanol; water; for 2h;Reflux;
General procedure: To a stirred solution of methyl ester (2a-i, 1 mmol) in MeOH-H2O (3 : 1, 4 mL) was added LiOH?H2O (2 mmol), and the resulting mixture was refluxed for 2 h. After cooling, the solvent was removed under reduced pressure, the residue was acidified with 10% HCl aq. The aqueous mixture was extracted with EtOAc (5 mL x 6), and the organic extracts were combined, dried over Na2SO4, and evaporated to give the carboxylic acid. To a stirred solution of amide (3a-n, 3' and 3'', 1 mmol) in CH2Cl2 (5 mL) was added TFA (8 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO2 aq., and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (5 mL x 10), and the organic layer and extracts were combined, dried over K2CO3, and evaporated to give the amine. To a stirred solution of the carboxylic acid prepared above in CH2Cl2 (5 mL) was added CDI (1 mmol), and the reaction mixture was stirred at room temperature for 1 h. To the mixture was added a solution of the amine prepared above in CH2Cl2 (2 mL), and the resulting solution was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (15 g, hexane : acetone = 5 : 1 ~ 3 : 1) to give substituted acetamide.
Equimolar (5-7 mmol) NaOH and substituted phenol was dissolved in 15 mL water followed by the addition of equimolar (5-7 mmol) NaOH and bromoacetic acid in 15 mL water. The solution was refluxed for 4-8 h, allowed to cool to RT, acidified with concentrated H2SO4 and extracted with ethyl acetate (3×15 mL). The organic layer was extracted with saturated NaHCO3 (3×20 mL). The aqueous layer was acidified with con. HCl followed by extraction with ethyl acetate (3×15 mL), dried over anhydrous MgSO4 and solvent removed under vacuum resulting in the substituted phenoxyacetic acid (e.g., compound 1d of Scheme 1, above). A solution of the phenoxyacetic acid in 20 mL SOCl2 and a drop of dimethyl formamide was refluxed for 3-6 h then excess SOCl2 removed by distillation to give the crude acyl chloride (e.g., compound 1e of Scheme 1, above). A solution of acyl chloride in 15 mL anhydrous acetone was added to a solution of sodium isothiocyanate in ice cold anhydrous acetone and stirred at RT for 3 h to give the acyl isothiocyanate followed by the addition of 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide. After stirring overnight, the solution was poured onto ice and recrystallized in dichloromethane and methanol to give the thiourea product. 4-Bromophenol (1 g, 5.8 mmol) to afford 10 (4-bromophenoxy)acetic acid (1.27, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.41 (d, J=11.1 Hz, 2H), 6.81 (d, J=9.1 Hz, 2H), 4.67 (s, 2H). 10 (4-bromophenoxy)acetic acid (1.5 g, 6.5 mmol) to afford the title thiourea (0.06 g, 2%) as a white 12 solid. 1H NMR (400 MHz, DMSO-d6) delta 12.30 (s, 1H), 11.76 (s, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.04 Hz, 2H), 7.00 (d, J=9.08 Hz, 2H), 6.81 (s, 1H), 4.95 (s, 2H), 2.31 (1, 6H). 13C NMR (DMSO-d6) delta 178.3, 169.6, 157.0, 132.2, 128.6, 123.5, 116.8, 112.7, 66.1.
To a solution of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-Carbonyldiimidazole (0.84 g, 5.2 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0 0C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as a white solid. LCMS calculated for (M+H): 245.0; found: 244.9, 246.9.
3-[2-(4-bromo-phenoxy)acetyl-amino]-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21.52%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
<Example 26> 3-[2-(4-bromo-phenoxy)aceryl-amino]-benzamide <n="36"/>To a mixture of (4-bromo-phenoxy)-acetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg,3.0 mmol), N<3-dimethylaminopropyl)-N'-etiiyl carbodiimideHCl (EDC) (517.6 mg, 2.7 mmol) and 1- hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N, N-dsopropylefhyamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization fi"om the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo- phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield).1HNMR (DMSO-dg) 10.21 (IH, s, NH), 8.09 (IH, s, aromatic-H), 7.94 (IH, s, MH2), 7.79 (IH, d, J =8.1 Hz5 aromatic-H), 7.35 - 7.59 (5H, m, aromatic-H, NH2), 6.99 (2H, d, J = 9.3 Hz, aromatic-H), 4.72 (2H, s, CH2).
21.52%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
To a mixture of (4-bromo-phenoxyacetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg, 3.0 mmol), N-(3-ethylaminopropyl)-N'-ethyl carbodiimide HCl (EDC) (517.6 mg, 2.7 mmol) and 1-hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo-phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield). 1H-NMR (DMSO-d6) 10.21 (1H, s, NH), 8.09 (1H, s, aromatic-H), 7.94 (1H, s, NH2), 7.79 (1H, d, J=8.1 Hz, aromatic-H), 7.35-7.59 (5H, m, aromatic-H, NH2), 6.99 (2H, d, J=9.3 Hz aromatic-H), 4.72 (2H, s, CH2).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
<Example 15> 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid methyl esterTo a solution of the <strong>[1878-91-7]4-bromophenoxy acetic acid</strong> (139 mg, 0.6 mmol) and amine (76 mg, 0.5 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH = 12 : 3: 1) gave 3-[2-(4-bromo-phenoxy)- acerylamino]-benzoic acid methyl ester as a white solid (138 mg, 76% yield). :. . 1H-NMR (CDCl3,.300Hz). . 8.32 (IH5 S5MI)5 8.06 (IH5 m, aromatic)5-7.99 (IH5 m5 aromatic), 7.84.(IH5 m, aromatic), 7.42-7.47 (3H5 m, aromatic), 6.89 (2H, m, aromatic), 4.59 (2H, s, OCH2CO), 3.92 (3H, s, OCH3).
76%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of the <strong>[1878-91-7]4-bromophenoxy acetic acid</strong> (139 mg, 0.6 mmol) and amine (76 mg, 0.5 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=12:3:1) gave 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (138 mg, 76% yield). 1H-NMR (CDCl3, 300 Hz) 8.32 (1H, s, NH), 8.06 (1H, m, aromatic), 7.99 (1H, m, aromatic), 7.84 (1H, m, aromatic), 7.42-7.47 (3H, m, aromatic), 6.89 (2H, m, aromatic), 4.59 (2H, s, OCH2CO), 3.92 (3H, s, OCH3).
56%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere;
EDCI (1.5 eq.) and HOBt (1.5 eq.) were added to a solution of (4-bromo-phenoxy)-acetic acid 2 (1.0 eq.), 3-amino-benzoic acid methyl ester (1.5 eq.), and DIPEA (1.5 eq.) in DMF, and the reaction mixture was stirred for 48 h at RT. After evaporation of the DMF under reduced pressure, the reaction mixture was diluted with AcOEt and sequentially washed with 0.1 M HCl solution, aqueous sodium bicarbonate, and brine and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to produce a crude solid, which was washed several times with diethyl ether to give the pure desired compound 3 (56% yield). Rf = 0.73 (n-hexane:AcOEt:MeOH = 6:3:1); NMR 1H (CDCl3, 300 MHz), delta (ppm): 3.92 (s, 3H, -OCH3), 4.59 (s, 2H, -OCH2CO-), 6.89 (m, 2H, ArH), 7.42-7.47 (m, 3H, ArH), 7.84 (m, 1H, ArH), 7.99 (m, 1H, ArH), 8.06 (1H, m, ArH), and 8.32 (1H, s, -NH-). Data consistent with the literature 3.
4-bromophenoxy acetic acid t-butyl ester[ No CAS ]
[ 1878-91-7 ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h;
To a solution of 4-bromophenoxyacetic acid t-butyl ester (4 g) in dichloromethane (10 ml) was added trifluoroacetic acid (30 ml) at room temperature. After being stirred at the same temperature for 3 hours, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give 4-bromophenoxy acetic acid (2.1 g) as a power. NMR (DMSO-d6, delta): 4.67 (2H, s), 6.89 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz) MS (ESI-): 230 (M-H)
podophyllotoxin-4-O-4-bromophenoxyacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;
Example 2 A. Podophyllotoxin-4-O-ester of 4-bromophenoxyacetic acid (000320) ; The mixture of podophyllotoxin (20 mg, 0.048 mmol), 4-bromophenoxyacetic acid (22 mg, 0.1 mmol), EDCI (25 mg, 0.13 mmol), DMAP (2 mg, 0.02 mmol) and dichloromethane (3 ml) were stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting liquid was separated by column chromatography (eluent: ethyl acetate and petroleum ether) to afford 21 mg podophyllotoxin-4-O-4-bromophenoxyacetate, mp. [0158] The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz); delta 7.42 (t, 2H, Ar-H), 6.81 (d, 2H, Ar-H), 6.62 (s, 1H, Ar-H), 6.54 (s, 1H, Ar-H), 6.37 (s, 2H, Ar-H), 5.99 (d, 3H, OCH2O), 4.74 (q, 2H, COCH2O, 4.60 (d, 1H, H4), 4.37 (t, 1H, H11), 4.21 (t, 1H, H11), 3.81 (s, 3H, OCH3), 3.74 (s, 6H, OCH3), 2.95 (d, 1H, H2), 2.85 (m, 1H, H3).
N-deacetyl-N-(4-bromophenoxyacetyl)thiocolchicine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 23h;
The reaction mixture of N-deacetylthiocolchicine (24 mg, 0.053 mmol), 4-bromophenoxyacetic acid (34.6 mg, 0.15 mmol), EDCI (29 mg), DMAP (3 mg) and dichloromethane (3 ml) was stirred at room temperature for 23 h. Then dichloromethane (20 ml) was added. Organic layer was washed with H2O, 5% Na2CO3 and brine, and then dried over MgSO4. After the solvent was removed under vaccum, the residue was separated by column chromatography (eluent: ethyl acetate and petroleum ether) to afford 30 mg N-Deacetyl-N-(4-bromophenoxyacetyl)thiocolchicine, mp 108-l 10 C. [0555] The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz).
EXAMPLE 128 (5R)-3-(4-Bromophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one Following the procedure described for Example 117, the title compound was prepared from 4-bromophenoxyacetic acid and (2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one. 1 H NMR(CD3 COCD3) delta 0.93(3H, t), 1.78(3H, s), 2.12(2H, q), 3.15(3H, s), 7.05(2H, d), 7.50(2H, d), 7.94(2H, d), 8.05(2H, d).
Intermediate 69. 2-(4-bromophenoxy)-N-methoxy-N-methylacetamide; To a solution of 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (8 g, 34.6 mmol) in tetrahydrofuran (120 ml.) was added 4-methylmorpholine (11.4 g, 103.8 mmol) and 2-Chloro-4,6-dimethoxy- 1 ,3,5-triazine (7.3 g, 41.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. N,O-dimethylhydroxylamine (3.38 g, 34.6 mmol) was slowly added into the reaction mixture and stirred at room temperature overnight. The precipitate was filtered and the solution was used as a title compound in the next reaction without further purification.
Intermediate 44. 1-(4-Bromophenoxy)-3-phenylacetone; To a solution of 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (8.0 g, 34.6 mmol) in anhydrous tetrahydrofuran (120 mL) was added 4-methylmorpholine (11.4 ml_, 0.104 mol) and 2- chloro-4,6-dimethoxy-1 ,3,5-triazine (7.3 g , 41.6 mmol). The mixture was stirred at room temperature for 1 hour and then, N,O-dimethylhydroxylamine hydrochloride (3.38 g, 34.6 mmol) was slowly added. The reaction was stirred at room temperature overnight. The precipitated solid was filtered and the resulting solution was cooled to -4O0C. Then, a 2M solution of benzylmagnesium chloride in anhydrous tetrahydrofuran (17.6 mL, 35.3 mmol) was slowly added under nitrogen. The mixture was warmed to room temperature for 2 hours and a saturated solution of ammonium chloride (200 mL) was added. The solvent was removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (2 x 75 mL). The organic layer was washed with 1 N hydrochloric acid (2 x 50 mL), water (-2 x 50 mL), and brine (50 mL), dried (Na2SO4) and the solvent was removed under reduced pressure. The title compound was obtained (3.7 g, 35%) as an oil.
Oxalyl chloride (0.5 mL, 5.9 mmol) was added to a suspension of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (0.462 g, 2.0 mmol) in methylene chloride (10 mL) and 2 drops of N,N-dimethylformamide. The mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure. The residue was diluted with methylene chloride (10 mL), cooled with ice-water bath, and IM of sodium hydroxide aqueous solution (3.0 mL) was added. To the mixture was added pyrrolidine (167 muL, 2.0 mmol). The mixture was stirred and allowed to warm to RT. The organic layer was separated, washed with water and brine, dried over Na2SOzI, filtered, and concentrated. The residue was directly used in next step without further purification (550 mg, 96.7%). LCMS: (M+H) = 286.0/284.0
With triethylamine hydrochloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Reflux;
2 (1 eq), acetamide oxime HCLNEt3 (2eq), EDCLHCl (2 eq), DIPEA (4 eq), in THF (1 OO mL) was heated at reflux for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give (3) as shown in the scheme above.
(1R)-1-{5-[(2,2,2-trifluoroethyl)oxy]pyridin-2-yl}ethylamine dihydrochloride[ No CAS ]
[ 1257111-31-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h;
Example 28(Rs)-2-(4-bromophenoxys)-N-(l-(5-(2.2.2-trifluoroethoxys)pyridin-2-yls)ethyls)acetamid e[0374] To a suspension of (R)-l-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2 HCl salt (173 mg, 0.79 mmol) and 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (200 mg, 0.87 mmol) in dichloromethane (5 mL) were added triethylamine (400 mg, 3.9 mmol), EDC (180 mg, 0.94 mmol) and HOBT (60 mg, 0.39 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. Sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ ethylacetate = 2/1 (v/v) to furnish 276 mg (81% yield) of the title as a colorless oil.; 1H-NMR (300 MHz, CDCI3) delta 8.30 (1 H, m), 7.66 (1 H, brd, J = 8.1 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.26-7.24 (2H, m), 6.84 (2H, d, J = 8.8 Hz), 5.22 (1 H, m), 4.48 (2H, qAB, J = 14.6 Hz), 4.40 (2H1 qAB, J= 8.1 Hz), 1.49 (3H, d, J= 7.3 Hz), LCMS (Method A) m/r. M+1 434.8; tR = 3.15 min.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and a 2-aryloxyacetic acid derivative (0.23 mmol) in DMF (2 ml) was added TBTU (0.23 mmol) followed by diisopropylethylamine (0.23 mmol, 37 muL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below.The following compounds were synthesized according to this procedure:Example 128 Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl)-thiazolo[5,4-d]pyrimidineThis compound was obtained from 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (43 mg);MS m/z (%): 543 ([M+H]+, 100).
43 mg
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
Examples 128-129 Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-(2-aryloxyacetyl)-piperazin-1-yl)-thiazolo[5,4-d]pyrimidine analogues General Procedure [0849] To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and a 2-aryloxyacetic acid derivative (0.23 mmol) in DMF (2 ml) was added TBTU (0.23 mmol) followed by diisopropylethylamine (0.23 mmol, 37 muL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below. [0850] The following compounds were synthesized according to this procedure: Example 128 Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl)-thiazolo[5,4-d]pyrimidine This compound was obtained from 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (43 mg); MS m/z (%): 543 ([M+H]+, 100).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and a 2-aryloxyacetic acid derivative (0.23 mmol) in DMF (2 ml) was added TBTU (0.23 mmol) followed by diisopropylethylamine (0.23 mmol, 37 muL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below. [0865] The following compounds were synthesized according to this procedure: Example 128 Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl)-thiazolo[5,4-d]pyrimidine [0866] This compound was obtained from 2-<strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (43 mg); [0867] MS m/z (%): 543 ([M+H]+, 100).
General procedure: The syntheses of 3a-j were accomplished using the literature procedure.22 1,3-Dimethyl-5,6-diaminouracil23 (4 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC; 5.36 mmol) were dissolved in 42 mL dioxane/H2O (1:1) and the appropriate phenoxyacetic acid (4 mmol) was added. A thick suspension was obtained and the pH was adjusted to 5-6 with 4 N aqueous HCl. The reaction was stirred for 2 h at room temperature and neutralized with aqueous NaOH (1 N). The precipitate was collected by filtration and subsequently dissolved in 40 mL dioxane/H2O (1:1). The reaction was heated under reflux for 2 h, cooled to 0 C and acidified to a pH of 4 with 4 N aqueous HCl. The resulting precipitate, the corresponding 1,3-dimethyl-8-substituted-7H-xanthinyl analogue, was collected by filtration, washed with 50 mL H2O and dried at 50 C. The 7H-xanthinyl analogue was used in the subsequent reaction without further purification. The corresponding 1,3-dimethyl-8-substituted-7H-xanthinyl analogue (2 mmol) was dissolved in a minimum amount of DMF (approximately 20 mL) at 90 C. K2CO3 (5 mmol), followed by iodomethane (4 mmol), and the reaction mixture was stirred at 90 C for 1 h. The reaction progress was followed with TLC employing neutral alumina sheets and ethyl acetate/dichloromethane (1:1) as mobile phase. The insoluble materials were removed by filtration. H2O (350 ml) was added to the filtrate and the mixture was cooled on ice for 3 h. The precipitate that formed was collected by filtration and dried overnight at room temperature. The products were recrystallized from methanol/ethyl acetate (7:5).
General procedure: Each substituted benzoic acid or aroyloxy acetic acid (7a-s) 0.088 mol was refluxed for 2-12 h in 2.4 mol of HCl gas saturated anhydrous ethanol. Then a hot solution was poured into 300 mL of water (no hydrochloride separates) to which solid Na2CO3 was added until the solution turns neutral. Precipitated ester was filtered by suction, dried and recrystallized from ethanol or methanol. In case of liquid esters, the neutralized solution was extracted with chloroform (25 mL x 3), the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear liquid.
With acetyl chloride; for 24h;Cooling with ice; Reflux;
General procedure: Compounds D1-7 were prepared by similar procedures. In atypical synthesis of D1, a mixture of phenoxyacetate(10 mmol, 1.80 g), hydrazine hydrate (80 %, 5 mL) and absoluteethanol (30 mL) was added to a 150 mL three-neckflask, then the reaction mixture was refluxed for 5 h. Themixture was cooled to room temperature. The crude productwas collected by filtration and washed several times with ethanol.After drying, white needle crystal was recrystallizedfrom ethanol and dried in vacuum
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
To a solution of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (500 mg, 2.00 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was added 2 M oxalyl chloride in methylene chloride (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. Ammonium hydroxide (15 mL) was added dropwise via additional funnel. After addition, the mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried and concentrated in vacuo to give 2-(4-bromophenoxy)acetamide (350 mg, 70% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 7.37-7.35 (m, 2H), 6.81-6.79 (m, 2H), 4.59 (s, 2H).
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (500 mg, 2.10 mmol) in N,N-dimethylformamide (15 mL) was added methylamine hydrochloride (320 mg, 5.10 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (570 mg, 3.00 mmol), 1-hydroxybenzotriazole (400 mg, 3.00 mmol) and N-methyl-morpholine (600 mg, 6.00 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics was dried and concentrated to give the title compound (580 mg, 90% yield) that was used without further purification. 1H NMR (400 MHz, CDCl3) delta 7.45 (d, 2H), 6.79 (d, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.91 (d, 3H).
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