* 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 water; iron; ammonium chloride In ethanol for 2 h; Reflux
Step 1 5-Amino-2-chloro-phenol To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96percent) as a white solid.
96%
With water; iron; ammonium chloride In ethanol for 2 h; Reflux
Step 1 5-Amino-2-chloro-phenol To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96percent) as a white solid.
96%
With iron; ammonium chloride In ethanol; water for 2 h; Reflux
To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96percent) as a white solid.
96%
With iron; ammonium chloride In ethanol; water for 2 h; Reflux
Step 1 5-Amino-2-chloro-phenolTo a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96percent) as a white solid.
70%
With tin(II)chloride dihydrate In ethanol at 60℃; for 3 h;
Compound 3 (1.0 g, 5.7 mmol, 1 equiv) was dissolved in 5 mlethanol, followed by addition of SnCl22H2O (14 g, 63.5 mmol,11 equiv). The reaction mixture stirred at 60 C for 3 h. After coolingto room temperature, the reaction mixture was neutralizedwith 2percent aqueous NaOH solution and adjusted to pH 7. The resultingprecipitate was filtered and dried under vacuum at 40 C. Further, this dried solid was stirred in EtOAc for 4 h, and then evaporatedthe solvent under reduced pressure to give compound 4 asan off white powder (0.58 g) with the yield of 70percent. Mp: 166–168 C, 1H NMR (400 DMSO-d6) d ppm: 5.12 (br s, 2H, NH2), 6.02(dd, 1H, J = 2.5 Hz, 2.4 Hz, Ph-H), 6.20 (d, 1H, J = 2.5 Hz, Ph-H),6.86 (d, 1H, J = 8.5 Hz, Ph-H), 9.51 (s, 1H, Ph-OH); ESI-MS: 142.1[MH]. C6H6ClNO [143.57].
Reference：
[1] Patent: US2003/100580, 2003, A1,
[2] Patent: US2010/160388, 2010, A1, . Location in patent: Page/Page column 58
[3] Patent: US2010/160389, 2010, A1, . Location in patent: Page/Page column 49
[4] Patent: US2011/28502, 2011, A1, . Location in patent: Page/Page column 44-45
[5] Patent: US2011/71143, 2011, A1, . Location in patent: Page/Page column 36
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8413 - 8426
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 3, p. 668 - 671
[8] Environmental Toxicology and Chemistry, 2001, vol. 20, # 7, p. 1381 - 1389
[9] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7398 - 7405
[10] Patent: WO2007/38387, 2007, A2, . Location in patent: Page/Page column 24; 25
[11] Przemysl Chemiczny, 1951, vol. 30, p. 647[12] Chem.Abstr., 1952, p. 11141
[13] Biochemical Journal, 1956, vol. 64, p. 38,39
[14] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 110-111
2
[ 13726-14-2 ]
[ 6358-06-1 ]
Reference：
[1] Patent: US3948596, 1976, A,
3
[ 1009-36-5 ]
[ 6358-06-1 ]
Reference：
[1] Environmental Toxicology and Chemistry, 2001, vol. 20, # 7, p. 1381 - 1389
4
[ 97-52-9 ]
[ 6358-06-1 ]
Reference：
[1] Environmental Toxicology and Chemistry, 2001, vol. 20, # 7, p. 1381 - 1389
5
[ 121-88-0 ]
[ 6358-06-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 3, p. 668 - 671
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7398 - 7405
2-Bromothiazole 1 (2 equiv), 5-amino-2-R-phenol 2 (1 equiv) and 37percent HCl solution (2 equiv) in 10percent aqueous EtOH solution was stirred at 900C for 24h. The reaction mixture was diluted with ethyl acetate and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2- bromothiazole (0.25 mL, 2.78 mmol), <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (200 mg, 1.39 mmol) and 37percent HCl solution (0.24 mL, 2.78 mmol) in 10percent aqueous EtOH solution (5 mL) was stirred at 900C for 24h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69 percent yield (217 mg).1H NMR (400 MHz, CD3OD) .pound. 7.34 (d, J= 2.5 Hz, IH), 7.21 (d, J= 3.7 Hz, IH), 7.18 (d, J= 8.6 Hz, IH), 6.88 (dd, J= 8.6, 2.5 Hz, IH), 6.76 (d, J= 3.7 Hz, IH); 13C NMR (125 MHz5CD3OD) .pound. 167.1, 155.0, 142.8, 139.8, 131.4, 114.7, 111.4, 109.7, 107.3.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
The preparation of the analogues 4a-h involved the reaction between 2-bromotbiazole 1 with the corresponding 5-amino-2-R-phenol 2, followed by reaction with 4-bromo-2-methyl-2- butene in presence Of Cs2CO3 as a base (Scheme 1; see Table 1 for antiviral activities (EC50) and cytotoxicities (IC50) of these compounds, as determined using human MT-2 cells infected with IHB strain of HIV-I). EPO <DP n="25"/>Scheme 1. General synthesis for analogues 4a-h.
2-Bromopyridine or 2-chloropyrimidine (2equiv.), 5-amino-2-substitutedphenol (lequiv) and 37percent HCl solution (2equiv) in 10percent aqueous EtOH solution (0.2M) was stirred at 9O0C for 24h. The reaction mixture was diluted with AcOEt and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2- bromopyridine (0.13 mL, 1.4 mmol) and <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (100 mg, 0.7 mmol) in 10percent aqueous EtOH (2 mL) was heated at 90 0C for 18h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 24 percent yield (36 mg). EPO <DP n="71"/>1H NMR (500 MHz, CD3OD) 58.11 (dd, J= 5.1, 1.1 Hz5 IH), 7.55 (ddd, J= 8.7, 7.1, 1.9 Hz, IH)5 7.37 (d, J= 2.5 Hz5 IH)5 7.15 (d, J= 8.7 Hz, IH), 6.88 (dd5 J= 8.7, 2.5 Hz5 IH)5 6.82 (d, J= 8.7 Hz5 IH)5 6.75 (dd, J= 7.15 5.1 Hz, IH); 13C NMR (125 MHz5 CD3OD) "5157.8, 154.7, 148.6, 143.O5 139.3, 131.1, 116.2, 114.2, 113.0, 112.3, 108.6.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
Typical syntheses of these derivatives was performed by reaction of 2-broniopyridine, 2-chloiOpyrimidine, 4-amino-2-chloropyrimidine15, 2-chloro-4-methylpyrimidine165 2-chloro- 4-metlioxypyrimidine17 and 2-amino-4-chloropyrimidine1 with the corresponding 5-arnino-2- substitutedphenols in the presence of HCl, followed by reaction with 4-bromo-2~methyl-2- butene in presence of Cs2CO3 as a base. Compounds 46 and 47 were synthesized by reaction of 2-chloro-5-(pyrimidin-2-ylamino)phenol 35d with 4-methylpent-3-en-2-ol18 and (2- methylcyclopent-l-yl)methanol19, respectively, using Mitsunobu conditions20.
2-Chloropyrimidine (1.5 g, 13.3 mmol), <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (318mg, 2.2mmol) and 37percent HCl solution (LImL5 13.3mmol) in 10percent aqueous EtOH solution (1OmL) was stirred at 9O0C for 24h. Afterwards, 2-chloropyrimidine (1.5g, 13.3) was added and after 24 h, the reaction mixture was diluted with AcOEt and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product (179mg, 36percent yield) was used for the next step without additional purification. 1H NMR (500 MHz, CD3OD) .pound.8.43 (d, J= 4.9 Hz, 2H), 7.58 (d, J= 2.4 Hz, IH), 7.17 (d, J = 8.7 Hz, IH), 7.03 (dd, J= 8.3, 2.5 Hz, IH), 6.79 (t, J= 4.8 Hz5 IH); 13C NMR (125 MHz5 CD3OD) .pound. 161.9, 159.5, 154.6, 141.7, 130.9, 115.0, 114.0, 113.3, 109.2.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
Typical syntheses of these derivatives was performed by reaction of 2-broniopyridine, 2-chloiOpyrimidine, 4-amino-2-chloropyrimidine15, 2-chloro-4-methylpyrimidine165 2-chloro- 4-metlioxypyrimidine17 and 2-amino-4-chloropyrimidine1 with the corresponding 5-arnino-2- substitutedphenols in the presence of HCl, followed by reaction with 4-bromo-2~methyl-2- butene in presence of Cs2CO3 as a base. Compounds 46 and 47 were synthesized by reaction of 2-chloro-5-(pyrimidin-2-ylamino)phenol 35d with 4-methylpent-3-en-2-ol18 and (2- methylcyclopent-l-yl)methanol19, respectively, using Mitsunobu conditions20.
Using a high pressure tube, propyne (excess) was condensed in a mixture of 2,4- dichloro-pyrimidine, CuI (10 molpercent), Pd(PPh3)2Cl2 (5 molpercent), and Et3N (solvent) at -78 0C. The mixture was slowly warmed up and stirred at room temperature for 12 h. After this period, the mixture was quenched with aqueous NH4Cl. The aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed with brine, dried over EPO <DP n="39"/>anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 9.The compound 9 and CuBr (1.0 equiv) in DMA-Et3N (7:1 mixture, 0.02M) was heated at 130 0C for 12 h. The reaction was protected from the light by covering the flash with aluminum foil. After this period, the mixture was quenched with aqueous NH4Cl. The aqueous phase was thoroughly extracted with hexanes. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 10.Compound 10, <strong>[6358-06-1]5-amino-2-chlorophenol</strong> 2a (1.0 equiv) and 37percent HCl solution (1.0 equiv) in 10percent aqueous EtOH solution was stirred at 9O0C for 12h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated. The crude product was purified by flash chromatography on silica gel to give 11.A mixture of 11 and Cs2CO3 (1.1 equiv) in acetone (0.1 M) was treated with 3,3- dimethylallyl bromide (1.0 equiv) at room temperature. After 2-4h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4CI solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 59.Scheme 6c. Synthesis for Pyrrolopyrimidine (Azaindolizine) 59. EPO <DP n="40"/>Synthesis of Isoquinoline Derivatives 62.
2-chloro-5-(furo[2,3-<i>c</i>]pyridin-7-ylamino)-phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
7-Chloro-furo[2,3-c]pyridine I21, 5-amino-2-R-phenol 2 (1.0 equiv) and 37percent HCl solution (1.0 equiv) in 10percent aqueous EtOH solution were stirred at 9O0C for 12h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated. The crude product was purified by flash chromatography on silica gel to give 3.A mixture of 3 and Cs2CO3 (1.1 equiv) in acetone (0.1 M) was treated with 3,3-dimethylallyl bromide (1.0 equiv) at room temperature. After 2-4h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 4.
2-chloro-5-(furo[3,2-c]pyridine-4-ylamino)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
4-Chloro-furo[3,2-c]pyridine, 5-amino-2-R-phenol 2 (1.0 equiv) and 37percent HCl solution (1.0 equiv) in 10percent aqueous EtOH solution were stirred at 9O0C for 12h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated. The crude product was purified by flash chromatography on silica gel to give 56.A mixture of 6 and Cs2CO3 (1.1 equiv) in acetone (0.1 M) was treated with 3,3-dimethylallyl bromide (1.0 equiv) at room temperature. After 2-4h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4CI solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 7.Scheme 5c. Synthesis for Furopyridines 55.
Step-1: tert-butyl(3-((tert-butyldimethylsilyl)oxy)-4-chlorophenyl)carbamate A solution of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (10.00 g, 69.7 mmol) in THF (350 mL) was treated with di-tert-butyl dicarbonate (20 mL, 86 mmol) and stirred at reflux overnight. The solvent was evaporated under reduced pressure to provide a brown oil. The oil was then dissolved in EtOAc (300 mL), washed with water, saturated aqueous NaHCO3, and brine (300 mL each), dried (Na2SO4), filtered, and evaporated under reduced pressure to provide 21.01 g of impure tert-butyl(4-chloro-3-hydroxyphenyl)carbamate as a brown oil (LCMS: m/z 244 [M+H]+). This material was dissolved in DMF (130 mL) and cooled on an ice bath. Imidazole (11.74 g, 172 mmol) was then added slowly (over ?10 minutes). A solution of TBDMS-Cl (14.98 g, 99 mmol) in DMF (45 mL) was added (over ?2 minutes). The ice bath was removed and the solution was stirred at room temperature overnight. Once LCMS indicated the reaction had gone to completion, the solution was diluted with EtOAc (1 L) and washed with water (2*600 mL), half-saturated aqueous NaHCO3 (600 mL), half-saturated aqueous NH4Cl (600 mL), saturated NaHCO3 (600 mL), and brine (600 mL). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure to provide 28.00 g of a brown solid. The sample was dissolved in EtOAc, silica gel (33 g) was added, and the solvent was evaporated under reduced pressure. The material was divided into two batches, each of which was purified by column chromatography on a Biotage® MPLC chromatography system using a 330 g silica gel column eluted with 0 to 5percent EtOAc in hexanes and with isocratic elution at 4.5percent or 5percent EtOAc when the product eluted. The product fractions were collected and provided 21.76 g of tert-butyl(3-((tert-butyldimethylsilyl)oxy)-4-chlorophenyl)carbamate (21.76 g, 60.8 mmol, 88percent yield) as a peach-colored solid. 1H NMR (300 MHz, DMSO-d6): delta ppm 9.43 (s, 1H), 7.23-7.28 (m, 1H), 7.22 (d, J=2.35 Hz, 1H), 7.09-7.16 (m, 1H), 1.46 (s, 9H), 0.99 (s, 9H), 0.21 (s, 6H). LCMS (Method 1): m/z 358 [M+H]+.
In tetrahydrofuran;Reflux;
A solution of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (iO.00 g,69.7 mmol) in THF (350 mE) was treated with di-tert-butyl dicarbonate (20 mE, 86 mmol) and stirred at reflux overnight. The solvent was evaporated under reduced pressure to provide a brown oil. The oil was then dissolved in EtOAc (300 mE), washed with water, saturated aqueous NaHCO3, and brine (300 mE each), dried (Na2504), filtered, and evaporated under reduced pressure to provide 2i .Oi g of impure tert-butyl (4-chloro-3-hydroxyphenyl)carbamate as a brown oil (ECMS: mlz 244 [M+H]). This material was dissolved in DMF (i30 mE) and cooled on an ice bath. Imidazole (ii .74 g, i 72 mmol) was then added slowly (over .10 minutes). A solution of TI3DMS-Cl (i4.98 g, 99 mmol) in DMF (45 mE) was added (over 2 minutes). The ice bath was removed and the solution was stirred at room temperature overnight. Once ECMS indicated the reaction had gone to completion, the solution was diluted with EtOAc (i E) and washed with water (2x600 mE), half-saturated aqueous NaHCO3 (600 mE), half-saturated aqueous NH4C1 (600 mE), saturated NaHCO3 (600 mE), and brine (600 mE). The organic layer was dried (Mg504), filtered, and evaporated under reduced pressure to provide 28.00 g of a brown solid. The sample was dissolved in EtOAc, silica gel (33 g) was added, and the solvent was evaporated under reduced pressure. The material was divided into two batches, each of which was purified by column chromatography on a Biotage® MPEC chromatography system using a 330 gsilica gel column eluted with 0 to 5percent EtOAc in hexanes and with isocratic elution at 4.5percent or 5percent EtOAc when the product eluted. The product fractions were collected and provided 2i.76 g of tert-butyl (3-((tert-butyldimethylsilyl) oxy)-4-chlorophenyl)carbamate (2i.76 g, 60.8 mmol, 88percent yield) as a peach-colored solid. ?H NMR (300 MHz, DMSO-d5): oe ppm 9.43 (s, iH), 7.23-7.28 (m, iH), 7.22 (d, J=2.35 Hz, iH), 7.09-7.i6 (m, iH), i.46 (s, 9H), 0.99 (s, 9H), 0.2i (s, 6H). ECMS (Method i): m/z 358 [M+H]
33 g (97%)
In tetrahydrofuran;
c). 4-Chloro-3-hydroxyphenylcarbamic acid tert-butyl ester To a solution of <strong>[6358-06-1]2-chloro-5-aminophenol</strong> (20 g, 0.14 mol) in THF (150 mL) was added a solution of di-tert-butyl dicarbonate (33 g, 0.15 mol) in THF (150 mL). The reaction was heated at reflux for 6 h, at which time it was allowed to cool to room temperature. The solvent was removed in vacuo and the residue diluted with ether (500 mL) and washed with 1 M citric acid (2*300 mL). The aqueous washings were extracted with ether (300 mL) and the combined organics washed with brine (300 mL), dried (MgSO4). and concentrated. The resultant brown solid was triturated with hexanes and dried in vacuo to give 33 g (97percent) of the title compound: mp 103-106° C.
c). N-[3-(2-Dimethylamino-ethoxy)-4-iodo-phenyl]-3,4-dimethoxy-benzenesulfonamide To a solution of the compound of Example 1(b) (0.25 g, 0.81 mmol) in N,N-dimethylformamide (4 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (1 eq, 0.81 mmol, 0.19 g). The pale orange solution was allowed to stir at room temperature for 23 hours. The crude product was purified via Gilson HPLC purification (10-90percent acetonitrile/water over 5 minutes) and lyophilized overnight. The resulting hydochloride salt was azeotroped 1* methanol and 1* methylene chloride to furnish the product (0.16 g, 35percent) as a fluffy white solid. MS (ES+) m/e 507 (M+H)+.
Stage 1: N-(4-chloro-3-hydroxy)phenyl-2',2',2'-trifluoroacetamide STR6 6.0 g (42 mmoles) of 5-amino-2-chloro phenol are dissolved in 75 ml of diethyl ether and, at room temperature, the solution is mixed dropwise with 10.2 ml (15.4 g, 73 mmoles) of trifluoro-acetic acid anhydride. When the exothermic reaction is completed the diethyl ether is distilled off. The crude product obtained (15.5 g) is recrystallized from 20 ml of an ethanol-water mixture (2:1). 3.0 g (91percent of the theoretical yield) of a white powder having a melting point of 145° to 147° C. are obtained.
EXAMPLE 2 A mixture of 15.2 g. of 3,4,5,6-tetrahydrophthalic anhydride, 14.4 g. of <strong>[6358-06-1]3-hydroxy-4-chloroaniline</strong> and 50 ml. of glacial acetic acid was refluxed with stirring for 2 hours and then, the reaction mixture was cooled to a room temperature and water was added to precipitate a crystal and the crystal was separated by a filtration and recrystallized from isopropanol to obtain N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 236.5°-238° C.; yellow crystal) (yield: 87.5percent).
In acetic acid;
Step A N-(3-Hydroxy-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide Employed 47.5 g of <strong>[6358-06-1]3-hydroxy-4-chloroaniline</strong> (0.33 mol); 38.2 of 3,4,5,6-tetrahydrophthalic anhydride (0.25 mol) and 350 ml of glacial acetic acid.
EXAMPLE 21 Following the procedure of Example 20, each of the phosphinates under column III is reacted with <strong>[6358-06-1]2-chloro-5-aminophenol</strong>, followed by reaction with 3,4,5,6-tetrahydrophthalic anhydride to give the corresponding tetrahydrophthalimide in Table A.
Preparation of 2-chloro-5-acetaminophenol 0.05 Mole (7.17 grams) of <strong>[6358-06-1]2-chloro-5-aminophenol</strong> is dissolved in 21 cc of dioxane at 75°C. There is then added, with agitation, 0.05 mole (5.1 grams) of acetic anhydride. At the end of this addition, the reaction medium is maintained for 10 minutes at 70°C and then cooled. The raw product which has crystallized in then filtered and recrystallized in a hydroalcoholic medium. It exhibits a melting point of 212°C. 2-fluoro-5-acetamino phenol is prepared in a similar manner.
With hydrogen bromide; acetic acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Preparation of 2-chloro-5-aminophenol 4.35 Moles (688 grams) of 2-chloro-5-amino anisole are introduced into 3.44 liters of hydrobromic acid (d = 1.49) to which has been added 1.38 liters of acetic acid. The resulting mixture is heated for 3 hours at reflux at which time it is cooled to 0°C. The 2-chloro-5-aminophenol hydrobromide that has precipitated is then filtered, introduced into 3 liters of ice water and neutralized with concentrated ammonia so as to precipitate 2-chloro-5-aminophenol. The desired product which is then filtered to provide a yield of 495 g exhibits, after drying, a melting point of 160°C.
4-chloro-6,7-dimethoxylquinazoline hydrochloride[ No CAS ]
[ 6358-06-1 ]
4-(4-chloro-3-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In isopropyl alcohol;
EXAMPLE 3 A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (500 mg, 1.916 mmol), (prepared as described for the starting material in Example 2), and <strong>[6358-06-1]4-chloro-3-hydroxyaniline</strong> (300 mg, 2.09 mmol), (as described in UK patent 1427658), in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-3-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (605 mg, 86percent). m.p. >250° C. 1H NMR Spectrum: (DMSOd6) 4.02(s, 3H); 4.04(s, 3H); 7.15(dd, 1H); 7.34-7.44(m, 3H); 8.28(s, 1H); 8.82(s, 1H); 10.52(s, 1H); 11.24(s, 1H) MS: 332 [MH]+
2-Bromopyridine or 2-chloropyrimidine (2equiv.), 5-amino-2-substitutedphenol (lequiv) and 37percent HCl solution (2equiv) in 10percent aqueous EtOH solution (0.2M) was stirred at 9O0C for 24h. The reaction mixture was diluted with AcOEt and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 4- amino-2-chloropyrimidine (70 mg, 0.5 lnmol) and <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (78 mg, 0.5 mmol) in 10percent aqueous EtOH (2 niL) was heated at 90 0C for 18h. The title compound was obtained in 47 percent yield a (60 mg) and used for the next step without addittional purification. 1H NMR (500 MHz, CD3OD) .pound. 7.78 (d, J= 6.1 Hz, IH)5 7.45 (s, IH), 7.19 (d, J = 8.7 Hz, IH), 7.04 (dd, J= 8.7, 2.5 Hz, IH), 6.07 (d, J= 6.1 Hz, IH); 13C NMR (125 MHz, CD3OD) .pound. 164.5, 163.4, 156.5, 154.7, 141.4, 131.0, 114.2, 111.6, 110.3, 98.8.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
Typical syntheses of these derivatives was performed by reaction of 2-broniopyridine, 2-chloiOpyrimidine, 4-amino-2-chloropyrimidine15, 2-chloro-4-methylpyrimidine165 2-chloro- 4-metlioxypyrimidine17 and 2-amino-4-chloropyrimidine1 with the corresponding 5-arnino-2- substitutedphenols in the presence of HCl, followed by reaction with 4-bromo-2~methyl-2- butene in presence of Cs2CO3 as a base. Compounds 46 and 47 were synthesized by reaction of 2-chloro-5-(pyrimidin-2-ylamino)phenol 35d with 4-methylpent-3-en-2-ol18 and (2- methylcyclopent-l-yl)methanol19, respectively, using Mitsunobu conditions20.
With triethylamine; In isopropyl alcohol; for 1h;Heating / reflux;
4-Hydroxyquinazoline 21 (0.8 g, 5.5 mmol) and N,N-diisopropylethylamine (0.5 ml) were refluxed in phosphorus oxychloride (11.0 ml) for 15 h. Phosphorus oxychloride was distilled under reduced pressure, the resulting oil was diluted with ethyl acetate washed with K2CO3 solution, dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 6 (0.48 g, 58percent)A solution of 5-amino-2-Chloro-phenol 18a and 4-chloroquinazoline 22 (1.1 equiv), triethylamine (2.0 equiv) in isopropanol was refluxed with stirring for 1 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography on silica gel to give 23a. EPO <DP n="41"/>A solution of 23a (0.115 g, 0.42 mmol) and Cs2CO3 (0.163 g, 0.5 mmol) in acetone (5.0 ml) was treated with 3,3-dimethylallyl bromide (0.059 ml, 0.5 mmol) at room temperature. After 9 h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 63a (0.09 g, 63percent).Scheme 8c. Synthesis for Quinazoline 63b.
To a solution of 5-amino-2-R-phenol 14, 1-Cliloroisoquinoline 13 (1.3 equiv) in 10percent aqueous EtOH 37percent HCl (1.0 equiv) was added, the solution was stirred at 9O0C for 6h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated. The crude product was purified by flash chromatography on silica gel to give 15.Solution of 15 and Cs2CO3 (1.2 equiv) in acetone (0.1 M) was treated with 3,3-dimethylallyl bromide (1.2 equiv) at room temperature. After 2-4 h, the reaction mixture was diluted with EtOAc and washed with aqueous NH4Cl solution and brine. The organic phase was dried over anhydrous Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel to give 16.Scheme 7q. Synthesis for Isoquinolines 62.
2-Bromopyridine or 2-chloropyrimidine (2equiv.), 5-amino-2-substitutedphenol (lequiv) and 37percent HCl solution (2equiv) in 10percent aqueous EtOH solution (0.2M) was stirred at 9O0C for 24h. The reaction mixture was diluted with AcOEt and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 4- amino-2-chloropyrimidine (70 mg, 0.5 mmol) and 5-ammo-2-chlorophenol (78 mg, 0.5 mmol) in 10percent aqueous EtOH (2 mL) was heated at 90 0C for 18h. The title compound was obtained in 47 percent yield a (60 mg) and used for the next step without addittional purification.1H NMR (500 MHz, CD3OD) .pound.7.81 (d, J= 5.9 Hz, IH), 7.44 (d, J= 2.5 Hz, IH), 7.14 (d, J= 8.7 Hz, IH), 7.00 (dd, J= 8.7, 2.5 Hz, IH), 5.99 (d, J= 5.9 Hz, 2H); 13C NMR (125 MHz,CD3OD) .pound. 166.3, 161.6, 156.8, 154.5, 142.1, 130.8, 114.7, 113.5, 109.4, 98.6.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
Typical syntheses of these derivatives was performed by reaction of 2-broniopyridine, 2-chloiOpyrimidine, 4-amino-2-chloropyrimidine15, 2-chloro-4-methylpyrimidine165 2-chloro- 4-metlioxypyrimidine17 and 2-amino-4-chloropyrimidine1 with the corresponding 5-arnino-2- substitutedphenols in the presence of HCl, followed by reaction with 4-bromo-2~methyl-2- butene in presence of Cs2CO3 as a base. Compounds 46 and 47 were synthesized by reaction of 2-chloro-5-(pyrimidin-2-ylamino)phenol 35d with 4-methylpent-3-en-2-ol18 and (2- methylcyclopent-l-yl)methanol19, respectively, using Mitsunobu conditions20.
With potassium carbonate; In N,N-dimethyl-formamide;
Example 92 Production of N-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (422 mg, 2.93 mmol), potassium carbonate (843 mg, 6.1 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (226 mg, 27percent) was obtained as a brown solid. 1H-NMR (DMSO-d6, 300 MHz) delta 0.73-0.86 (4H, m), 1.85-1.98 (1H, m), 5.47 (2H, s), 6.47-6.51 (1H, m), 6.51 (1H, s), 7.04 (1H, d, J=9.5 Hz), 7.17 (1H, d, J=9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J=9.5 Hz), 11.06 (1H, s).
Example 10; Preparation of 1 -(5-tert-butylisoxazol-3-yiy3-(4-chloro-3-(6J-dimethoxyquinazolin-4-yloxy)phenvl)urea; [00687] Example 1 OA: A mixture of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (1.Og, 6.97 mmol) and 5-tert-butyl-3isocyanatoisoxazole (1.16 g, 6.97 mmol) in toluene (40 mL) was heated at 70 °C overnight. It was purified by silica gel chromatography with 0- 25percent EtOAc/hexane as eluants to afford l-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3- hydroxyphenyl)urea as solid.
With tetra-N-butylammonium tribromide; In methanol; dichloromethane; at 20℃; for 0.333333h;
Step 2 5-amino-4-bromo-2-chloro-phenol To a solution of <strong>[6358-06-1]5-amino-2-chloro-phenol</strong> (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18percent) as a white solid.
18%
With tetra-N-butylammonium tribromide; In methanol; dichloromethane; at 20℃; for 0.333333h;
Step 2 5-Amino-4-bromo-2-chloro-phenol To a solution of <strong>[6358-06-1]5-amino-2-chloro-phenol</strong> (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18percent) as a white solid.
18%
With tetra-N-butylammonium tribromide; In methanol; dichloromethane; at 20℃; for 0.333333h;
To a solution of <strong>[6358-06-1]5-amino-2-chloro-phenol</strong> (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18percent) as a white solid.
18%
With tetra-N-butylammonium tribromide; In methanol; dichloromethane; at 20℃; for 0.333333h;
Step 2 5-Amino-4-bromo-2-chloro-phenolTo a solution of <strong>[6358-06-1]5-amino-2-chloro-phenol</strong> (15.85 g, 110.4 mmol) in dichloromethane (300 ml) and MeOH (150 ml) was added tetrabutylammonium tribromide (58.6 g, 121.4 mmol). The mixture was stirred at room temperature for 20 minutes, and then was partitioned between saturated aqueous Na2SO3 and Et2O. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 5-amino-4-bromo-2-chloro-phenol (4.38 g, 18percent) as a white solid.
Acetic anhydride (3.0 mL, 42.0 mmol) was added to a solution of 4-chloro-3-hydroxy aniline (4.0 g, 28 mmol) in acetic acid (20 mL), and the reaction was refluxed for 5 mins. The reaction mixture was cooled to room temperature and the product was solidified. It was filtered off and washed with water (10 mL) and dried to obtain the product 17a in 93percent yield (4.8 g) as a creamy white solid. There was no need for further purification. [0160] 1H NMR (400 MHz, Acetone) delta 9.26 (br s, 1H), 9.01 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 2.09 (s, 3H). [0161] 13C NMR (101 MHz, Acetone) delta 169.66, 154.05, 140.20, 130.49, 115.18, 112.16, 108.56, 24.35. HRMS (ESI) calculated for C8H8ClNO2 [M+Na]+: 208.0136. Found: 208.0144.
+). EXAMPLE 713-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-chloro-7-(ethyloxy)-/\\/-(1 -phenylcvclopropyl)-2-[3- (trifluorometh l)phenyll-4-quinolinecarboxamide6-chloro-7-hvdroxy-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarbox acidTo a solution of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (5.74 g, 40 mmol) in ethanol (100 mL) was added 3-(trifluoromethyl)benzaldehyde (6.96 g, 40.0 mmol) dropwise. The mixture was stirred at reflux for 1 h. 2-Oxobutanoic acid (4.08 g, 40.0 mmol) was added portionwise. The reaction mixture was stirred at reflux for additional 3 h, cooled to room temperature and stirred overnight. The mixture was filtered, and the filter cake was washed with ethanol and air dried to give 6-chloro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (1 1 .2 g, 73percent yield). MS (m/z) 382.0 (M+H+).
INTERMEDIATE PREPARATION 114-chloro- -[(1-methylethyl)oxy]anilineA mixture of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (2.87 g, 20 mmol), 2-bromopropane (4.92 g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) in acetonitrile (50.00 mL) was heated to reflux over the weekend. The reaction mixture was filtered, and the solids were washed with ethyl acetate. The filtrate concentrated in vacuo and the residue was purified via column chromatography (ISCO, 0-40percent ethyl acetate/hexanes) to afford 4-chloro-3-[(1- methylethyl)oxy]aniline (3.7 g, 100percent yield).
87%
With potassium carbonate; In acetonitrile; at 20℃; for 24h;Reflux;
] A mixture of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (20 g, 139mmol) and 2-bromopropane (26 mE, 278 mmol) and K2C03(38.4 g, 278 mmol) in CH3CN (300 mE) was refluxed for 24h. The reaction mixture was cooled to room temperature, filtered and the solid was washed with ethyl acetate (150 mE). The filtrate was concentrated and the residue was purified by ISCO (Si02: Flex/EtOAc 0 to 40percent) to give the title compound (22.6 g, 87percent)
58%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2.5h;
To a mixture of <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (148 mg, 1.03 mmol) and K2CO3 (296 mg, 2.14 mmol) in DMF (2.0 mL) was added EtI (100 muL, 1.25 mmol). The whole was stirred at 60°C for 2.5 h and then diluted with AcOEt. The organic layer was washed with water and brine, dried and concentrated. Column chromatography (n-hexane : AcOEt=3 : 1) of the residue gave the title compound (88.5 mg, 0.515 mmol, 50percent) as a pale yellow paste.
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