* 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 ozone; triethylamine In dichloromethane; dimethyl sulfoxide at -40℃; for 0.5 h; Inert atmosphere
In a 50ml three-necked flask with magnetic stirring,Add 20ml of dichloromethane and 4,6-dichloro-5-allylpyrimidine(5.0 g, 0.026 mol), followed by the addition of dimethyl sulfoxide (8 g, 0.104 mol) and triethylamine (5.5 mL, 0.040 mol).Cool to -40 ° C, pass O3 until the reaction solution turns blue,Stop using O3 and switch to N2 for 30 minutes.Exclude O3 in the system.Add thiourea (2.0 g, 0.026 mol) and naturally raise to room temperature.Starch potassium iodide test paper detection (unchanged blue),Ensure that no peroxide is present in the reaction system. Add 60ml of water,The mixture was extracted twice with methylene chloride.The yield was 88percent.
83.01%
Stage #1: With potassium osmate(VI) dihydrate In water; acetone for 0.0833333 h; Stage #2: With sodium periodate In water; acetone at 20 - 40℃; for 2 h;
Step 3 - Synthesis of compound ID; Compound 1C (9.73 g, 51.47 mmol) was dissolved in an acetone: water (1:1, 290 mL) mixture and to the resulting solution was added potassium osmate dihydrate (0.64 g, 1.75 mmol). The resulting reaction was allowed to stir for about 5 minutes, then solid sodium periodate (44 g, 205,37 mmol) was added in 4 portions over 1 hour, ensuring that the reaction temperature did not exceed 40 0C. The resulting suspension was stirred for 1 hour as the reaction was allowed to gradually cool to room temperature. The reaction mixture was filtered and the filtrate was concentrated to remove acetone. The resulting aqueous solution was extracted with dichloromethane (2x) and the combined organic layers were washed with 10percent sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide compound ID (8.16 g, 83.01percent).
83.01%
Stage #1: With potassium osmate(VI) dihydrate; water In acetone for 0.0833333 h; Stage #2: With sodium periodate In water at 40℃; for 2 h;
Step 3 - Synthesis of Compound ID; Compound 1C (9.73 g, 51.47 mmol) was dissolved in a mixture of acetone: water (1 :1, 290 mL) and to the resulting solution was added potassium osmate dihydrate (0.64 g, 1.75 mmol). The resulting mixture was allowed to stir for about 5 minutes, then sodium periodate (44 g, 205.37 mmol) was added in 4 portions over a 1 hour period, during which time the temperature of the reaction did not exceed 40 0C. The resulting suspension was stirred for 1 hour as the reaction cooled to room temperature. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to remove acetone. The resulting aqueous solution was extracted with dichloromethane (2x) and the combined organic layers were washed with 10percent sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide compound ID (8.16 g, 83.01percent).
83.01%
Stage #1: With potassium osmate(VI) dihydrate In water; acetone Stage #2: With sodium periodate In water; acetone at 20 - 40℃; for 2 h;
Step 3 - Synthesis of Compound ID; Compound 1C (9.73 g, 51.47 mmol) was dissolved in a mixture of acetone: water (1:1,290 mL) and to the resulting solution was added potassium osmate dihydrate (0.64 g, 1.75 mmol). The resulting solution was allowed so stir for 5 minutes, then solid sodium periodate (44 g, 205.37 mmol) was added in 4 portions over a 1 hour period. The temperature of the reaction didn't exceed 400C during this addition. The resulting suspension was allowed to stir for 1 hour as the reaction cooled to room temperature on its own. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to remove acetone. The resulting aqueous solution was extracted 2 times with dichloromethane and the combined organic layers were washed with 10percent sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide compound ID (8.16 g, 83.01percent).
83.01%
Stage #1: With potassium sulfate dihydrate In water; acetone for 0.0833333 h; Stage #2: With sodium periodate In water; acetone at 40℃; for 4 h;
Compound 1B (9.73 g, 51.47 mmol) was dissolved in an acetone: water (1 :1 , 290 mL) mixture and to the resulting solution was added potassium osmate dihydrate (0.64 g, 1.75 mmol). The reaction was allowed to stir for 5 minutes, then solid sodium periodate (4 4g, 205.37 mmol) was added in 4 portions over a 1 hour period, during which time, th reaction temperature did not exceed 40 °C. The resulting suspension was was allowed to stir at room temperature for x hours for 1 hour, during which time the reaction mixture was permitted to cool to room temperature on its own. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous layer was extracted with dichloromethane (2 x 200 mL) and the combined organic layers were washed with 10percent sodium thiosulfate solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide Compound 1C (8.16 g, 83.01percent), which was used without further purification.
76%
With ozone In methanol; dichloromethane at -40℃; for 2 h;
A solution of compound 4 (100 g, 0.53 mol) in MeOH (400 ml) and CH2Cl2 (150 ml) was cooled to –40°C, and ozone was bubbled through the mixture for 2 h. Then the reaction mixture was purged with nitrogen for 20 min to remove the excessive ozone. Thiocarbamide (40 g, 0.53 mol) was added to the mixture and stirred for 1 h until the starch-KI paper did not turn blue. The solvent was distilled off, the residue was extracted with CH2Cl2 (300 ml) and washed with water (2×100 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the residue that was triturated with petroleum ether (200 ml). Yield 76.8 g (76percent), white solid, mp 88–90°C (mp 89–91°C19). 1H NMR spectrum (DMSO-d6), δ, ppm: 9.75 (1H, s, CHO); 8.89 (1H, s, H-2); 4.24 (2H, s, CH2).13C NMR spectrum (DMSO-d6), δ, ppm: 196.9; 161.8;157.0; 126.4; 44.5. Mass spectrum, m/z (Irel, percent): 192[M(35Cl,37Cl)]+(12), 190 [M(35Cl)]+ (20), 162 (100).
74%
With potassium osmate(VI); sodium periodate; water In acetone at 20 - 40℃; for 2 h;
Step 1 : (4,6-Dichloro-5-pyrimidinyl)acetaldehyde (209)To a stirred solution of 4,6-dichloro-5-(2-propen-1-yl)pyrimidine (2, 274 g, 1.45 mol) in 1 :1 acetone-H2O (7.6 L) was added K2OsO4"2H2O (18 g, 0.0493 mol). Solid NaIO4 (1.24 kg, 5.8 mol) was added portionwise during 1 h; the reaction temperature did not exceed 40 0C. The resulting suspension was stirred for 1 h as the reaction cooled to RT. The mixture was filtered and the filtrate was concentrated to remove the acetone. The aqueous layer was extracted with CH2CI2 (5 x 1 L). The combined extracts were washed with 10percent Na2S2O3 solution (2 x 3.5 L), with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 204 g (74percent) of the product 209 as a shiny amber solid. 1H NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1 H), 8.86 (s, 1 H), 4.21 (s, 2 H).
1.7 g
Stage #1: With osmium(VIII) oxide; 4-methylmorpholine N-oxide In 1,4-dioxane; water at 20℃; for 2 h; Stage #2: With sodium periodate In 1,4-dioxane; water at 20℃; for 3 h;
Step 4:To a stirred solution of 5-allyl-4,6-dichloropyrimidine (2.5 g) in dry dioxane (25 mL), N-methyl morpholine N-oxide (2.3 g) and osmium tetroxide (0.85 mL, 25percent solution in water) were added. The reaction mixture was stirred at room temperature for 2 hours before being quenched by solid sodium bisulphate. The reaction mixture was filtered through celite bed. The celite bed was washed with dioxane (10 mL). The combined filtrate was taken into a 100 mL three necked round bottom flask and sodium metaperiodate (6 g, in 5mL water) was added. The reaction mixture was stirred at room temperature for about 3 hours, then diluted with water (30 mL). Aqueous layer was extracted with dichloromethane (2 x 25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2S04. Evaporation of solvents under reduced pressure gave crude product, which was treated with hexane to offer a solid. The solid obtained was filtered, washed with cold hexane (50 mL) and dried under vacuum to get 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.7g) as white solid. XH NMR (DMSO- d6): δ 4.21 (s, 2H), 8.86 (s, IH), 9.7 (s, IH).
2.00 g
With sodium periodate; osmium(VIII) oxide In tetrahydrofuran at 20 - 22℃; for 0.566667 h;
[0108] 5-Allyl-4r6-dichloropyrimidine (see Montgomery, J.A. and Hewson, K., J. Med. C em. 1967, 10, 665-667) (2.00 g, 10.6 mmol) was dissolved in THF (16 mL). Osmium tetraoxide (30 mg, 0.10 mmol) was added and after a few min, the reaction mixture turned very dark. Sodium metaperiodate (4.75 g, 22.2 mmol) was then added in portions over 34 min and the reaction mixture temperature was maintained at 20-22 °C. The solids were removed by filtration and were washed well with THF (2x5 mL). Saturated brine was added to the filtrate and the phases were separated. The aqueous phase was saturated with solid sodium chloride and the phases separated. The aqueous phase was extracted with additional EtOAc (2 x10 mL). The organic extracts were combined and concentrated under reduced pressure. The crude residue was dried in vacuo and the title compound was isolated as a gray solid (2.00 g, 99percent yield). 1H N R (300 MHz, CDCI3) δ 9.80 (s, 1 H), 8.74 (s, 1 H) and 4.14 (s, 2H).
Reference：
[1] Patent: CN108409745, 2018, A, . Location in patent: Paragraph 0038; 0040; 0043; 0046; 0048; 0049; 0052
[2] Patent: WO2010/9195, 2010, A1, . Location in patent: Page/Page column 76-77
[3] Patent: WO2010/9207, 2010, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2010/9208, 2010, A1, . Location in patent: Page/Page column 73-74
[5] Patent: WO2011/62885, 2011, A1, . Location in patent: Page/Page column 34
[6] Chemistry of Heterocyclic Compounds, 2018, vol. 54, # 6, p. 638 - 642[7] Khim. Geterotsikl. Soedin., 2018, vol. 54, # 6, p. 638 - 642,5
[8] Journal of Organic Chemistry, 2009, vol. 74, # 9, p. 3587 - 3590
[9] Patent: WO2008/8895, 2008, A1, . Location in patent: Page/Page column 171
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 40, p. 11754 - 11759[11] Angew. Chem., 2015, vol. 54, p. 11754 - 11759,5
[12] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10972 - 10994
[13] Tetrahedron, 1997, vol. 53, # 10, p. 3831 - 3842
[14] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 12, p. 1929 - 1937
[15] Patent: WO2013/138436, 2013, A1, . Location in patent: Page/Page column 61-62
[16] Patent: WO2014/22744, 2014, A1, . Location in patent: Paragraph 0108
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 80℃; for 3 h; Inert atmosphere
To a solution of compound 3 (290 g, 1.91 mol) in MeCN (600 ml), N,N-dimethylaniline (60 ml) was added, then the mixture was warmed to 80°C and POCl3 (822 g, 5.36 mol) was added dropwise. The reaction mixture was refluxed for 3 h under nitrogen atmosphere. Then it was quenched with ice-water (500 ml) and concentrated to dryness under reduced pressure. The residue was extracted with 1,2-dichloroethane (500 ml), washed with water (3×100 ml) and aqueous Na2CO3 (200 ml). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude, that was purified by vacuum distillation (94–96°C, 8 mmHg). Yield 306 g (85percent), light yellow oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz):8.64 (1H, s, H-2); 5.89–5.82 (1H, m, =CH); 5.17–5.09 (2H,m, =CH2); 3.64 (2H, d, J = 6.2, CH2). 13C NMR spectrum(CDCl3), δ, ppm: 162.0; 155.8; 131.0; 130.6; 118.2; 34.0. Mass spectrum, m/z (Irel, percent): 191 [M(35Cl,37Cl)+H]+ (61),189 [M(35Cl)+H]+ (100),
57.95%
With N-benzyl-N,N,N-triethylammonium chloride; N,N-diethylaniline; trichlorophosphate In acetonitrile for 15 h; Reflux
Step 2 - Synthesis of compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (-260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was cooled to room temperature, poured over crushed ice, washed sequentially with sodium bicarbonate, brine and water, then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified using flash column chromatography on silica gel (100percent CH2Cl2) to provide compound 1C (9.73 g, 57.95percent).
57.95%
With N-benzyl-N,N,N-triethylammonium chloride; N,N-diethylaniline; trichlorophosphate In acetonitrile for 15 h; Reflux
Step 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylamide (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed with sodium bicarbonate, brine and water respectively and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to provide a crude residue which was purified using flash column chromatography on silica gel (100percent DCM) to provide compound 1C (9.73 g, 57.95percent).
57.95%
With N-benzyl-N,N,N-triethylammonium chloride; N,N-diethylaniline; trichlorophosphate In acetonitrile for 15 h; Reflux
Step 2 - Synthesis of Compound 1C; Compound IB (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, . 77.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) were taken up in acetonitrile (about 260 mL) and the resulting reaction was heated to reflux and allowed to stir at this temperature for 15 hours. The reaction mixture was cooled, poured over crushed ice and washed sequentially with saturated aqueous sodium bicarbonate, brine and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (CH2CI2) and the product 1C was isolated (9.73 g, 57.95percent).
57.95%
With N-benzyl-N,N,N-triethylammonium chloride; N,N-diethylaniline; trichlorophosphate In acetonitrile for 15 h; Reflux
A solution of Compound 1A (13.5 g, 88.73 mmol), diethylaniline (15.9 g, 106.48 mmol), benzyltriethyl ammonium chloride (40.42 g, 177.46 mmol) and phosphorous oxychloride (74.0 g, 482.68 mmol) in acetonitrile (-260 mL) was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature, poured over crushed ice, washed sequentially with saturated aqueous sodium bicarbonate solution, brine and water, then extracted with ethy. acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (100percent Ch^C^) to provide Compound 1 B (9.73g, 57.95percent).
2.7 g
Stage #1: at 80℃; for 3 h; Inert atmosphere Stage #2: With sodium hydrogencarbonate In water
Step 3:A 100ml three necked round bottom flask was charged with 5-allylpyrimidine- 4,6-diol (4 g) and phosphorusoxychloride (25 mL) under nitrogen atmosphere. The reaction mixture was heated to 80°C for 3 hours. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The resulting oil was neutralized with saturated NaHCC solution and pH was adjusted to 8-9. The aqueous layer was diluted with dichloromethane (100 mL) and was extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2S04. Evaporation of solvents under reduced pressure gave crude compound, which was purified by column chromatography using MeOH/CHCls (0.4:9.6) as eluent to afford 5-allyl-4,6-dichloropyrimidine (2.7 g). XH NMR (DMSO-d6): δ 3.59-3.61 (d, 2H), 5.00-5.05 (dd, IH), 5.13-5.16 (dd, IH), 5.85-5.94 (m, IH), 8.8 (s, IH).
Reference：
[1] Chemistry of Heterocyclic Compounds, 2018, vol. 54, # 6, p. 638 - 642[2] Khim. Geterotsikl. Soedin., 2018, vol. 54, # 6, p. 638 - 642,5
[3] Journal of Organic Chemistry, 2009, vol. 74, # 9, p. 3587 - 3590
[4] Patent: WO2010/9195, 2010, A1, . Location in patent: Page/Page column 76-77
[5] Patent: WO2010/9207, 2010, A1, . Location in patent: Page/Page column 45
[6] Patent: WO2010/9208, 2010, A1, . Location in patent: Page/Page column 73-74
[7] Patent: WO2011/62885, 2011, A1, . Location in patent: Page/Page column 34
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3639 - 3648
[9] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 12, p. 1929 - 1937
[10] Patent: US2010/144758, 2010, A1, . Location in patent: Page/Page column 65-66
[11] Patent: WO2013/138436, 2013, A1, . Location in patent: Page/Page column 61-62
4
[ 1193-21-1 ]
[ 106-95-6 ]
[ 16019-31-1 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With 2,2,6,6-tetramethylpiperidine zinc chloride lithium chloride complex In tetrahydrofuran at 25℃; for 0.75 h; Stage #2: With copper(I) cyanide di(lithium chloride) In tetrahydrofuran at -20℃; Stage #3: at -60 - 0℃; for 4 h;
Synthesis of 5-allyl-4,6-dichloropyrimidlne (8c): 4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1 M in THE; 0.05 mL, 5 mol percent) was then slowly added at -20° C. Allyl bromide (242 mg, 2.0 mmol) was then slowly added at -60° C. The resulting mixture was then allowed to warm up slowly to 0° C. for 4 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (5.x.30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:2) furnished 8c as a colourless solid (215 mg, 89percent). 1H NMR (300 MHz, CDCl3) δ: 8.64 (s, 1 H), 5.80-5.90 (m, 1 H), 5.09-5.18 (m, 2 H), 3.64 (dt, 3J=6.4 Hz, 4J=1.4 Hz, 2 H).13C NMR (75 MHz, CDCl3) δ: 162.0, 155.8, 130.9, 130.6, 118.2, 34.0.MS (70 eV, El) m/z (percent): 188 (70) [M+], 125 (22), 117 (44), 90 (59), 64 (35), 49 (43), 41 (100).IR (ATR) {tilde over (v)} (cm-1): 2969, 2360, 1739, 1639, 1539, 1513, 1435, 1406, 1375, 1348, 1313, 1290, 1200, 1162, 1129, 1090, 989, 929, 906, 839, 777, 687, 668, 627, 621, 616.HRMS (El) for C7H6Cl2N2 (187.9908): 187.9913.
75%
Stage #1: With 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex In tetrahydrofuran at -78℃; for 1 h; Stage #2: With copper(I) bromide In tetrahydrofuran for 0.5 h;
The alkylation step by conducted using a modified procedure: TMPMgCl·LiCl (0.8M, 11.0 mL, 8.8 mmol) was added to a solution of 2,4,6-trichloropyrimidine (1.47 g, 8.0 mmol) in anhydrous THF (20 mL) at -78 oC. After stirring for 1 hour, CuBr (230 mg, 1.6 mmol) was added and stirring was continued for 30 min before allyl bromide (0.73 mL, 8.4 mmol) was added. The reaction was allowed to warm to room temperature, then quenched by addition of sat. NH4Cl solution. EtOAc was added and the layers were separated. The organic phase was dried and Na2SO4 and concentrated. The residue was purified by silica gel chromatography [heptane/EtOAc, 95:5 – 3:1] to give the alkylated product as a white solid (1.31 g, 73 percent). This was transformed to the final product by the same procedure as for 2 using allylamine followed by standard N-Boc protection to give the productas a colourless oil (1.51 g, 75percent).
Step 2: 4,6-Dichloro-5-(2-propen-1 -yl)pyrimidine (2)A round-bottomed flask was charged, under N2, with 6-hydroxy-5-(2-propen-1-yl)-4(1 H)- pyrimidinone (1) (19.0 g, 125.0 mmol) and phosphorous oxychloride (200 ml_). The mixture was refluxed for 4 h and then cooled to RT. The reaction mixture was poured very slowly into ice cold (5 0C) water (2000 ml.) with vigorous stirring. The product was extracted with CH2CI2 (4 x 250 ml_). The combined organic layer was washed with sat. NaHCO3 (1 x 100 ml_), brine (1 x 50 ml_), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 22.70 g (96percent) of the title compound 2 as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1 H), 5.90 - 5.80 (m, 1 H), 5.17 - 5.09 (app. m, 2 H), 3.65 (app. d, J = 6.4 Hz, 2 H) ); LCMS (ESI): m/z 190 (M + H)+.
Reference：
[1] Patent: WO2008/8895, 2008, A1, . Location in patent: Page/Page column 63
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10972 - 10994
6
[ 16019-30-0 ]
[ 16019-31-1 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 40, p. 11754 - 11759[2] Angew. Chem., 2015, vol. 54, p. 11754 - 11759,5
[3] Patent: WO2003/105770, 2003, A2, . Location in patent: Page 47
Step 2: 4,6-Dichloro-5-(2-propen-1 -yl)pyrimidine (2)A round-bottomed flask was charged, under N2, with 6-hydroxy-5-(2-propen-1-yl)-4(1 H)- pyrimidinone (1) (19.0 g, 125.0 mmol) and phosphorous oxychloride (200 ml_). The mixture was refluxed for 4 h and then cooled to RT. The reaction mixture was poured very slowly into ice cold (5 0C) water (2000 ml.) with vigorous stirring. The product was extracted with CH2CI2 (4 x 250 ml_). The combined organic layer was washed with sat. NaHCO3 (1 x 100 ml_), brine (1 x 50 ml_), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 22.70 g (96%) of the title compound 2 as a light yellow oil. 1H NMR (400 MHz, DMSO-d6): delta 8.08 (s, 1 H), 5.90 - 5.80 (m, 1 H), 5.17 - 5.09 (app. m, 2 H), 3.65 (app. d, J = 6.4 Hz, 2 H) ); LCMS (ESI): m/z 190 (M + H)+.
(S)-2-[(1R,4S)-4-(4-Amino-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopent-2-enylmethoxy]-phenoxy-phosphorylamino}-3-phenyl-propionic acid methyl ester[ No CAS ]
(S)-2-[(1S,4R)-4-(4-Amino-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopent-2-enylmethoxy]-phenoxy-phosphorylamino}-3-phenyl-propionic acid methyl ester[ No CAS ]
With N-benzyl-N,N,N-triethylammonium chloride; N,N-diethylaniline; trichlorophosphate; In acetonitrile; at 110℃;
A mixture of 5-allyl-4, 6-dihydroxypyrimidine [(5-1)] [prepared following the procedure described in J. Med. Chem. , 10: 665 (1967) ] (6.0 g, 39.4 mmol), diethylaniline (7.5 mL, 46 [MMOL),] benzyltriethylammonium chloride (18 g, 79 mmol) and [POC13] (20 mL) in acetonitrile (100 [ML)] was heated at [110 C] with stirring overnight. The reaction mixture was cooled and poured onto crushed ice, and extracted with ethyl acetate. The organic layer was washed with water (20 mL) dried over anhdydrous [NA2SO4] and concentrated to an oil which was passed through a short band of silica gel using [CH2C12] as eluent; yield 3.3 g. 1H NMR [(CDC13)] : [8] 3.67 (m, 2H, [CH2),] 5.14 (m, 2H, CH2), 5.89 (m, 1H, CH), 8.66 (s, [1H,] H-2).
With trichlorophosphate; at 90℃; for 4h;Inert atmosphere;
5-allyl-6-hydroxy-3H-pyrimidin-4-one (1.0 equiv) was then treated with phosphorus oxychloride (4.1 equiv, neat) under an argon atmosphere. The mixture was heated at reflux (4 hours, 90 C) and then cooled to room temperature. Ice-cold DI water was added drop-wise to the reaction mixture with vigorous stirring until all phosphorus oxychloride was quenched. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford 5-allyl-4,6-dichloropyrimidine as a light yellow oil in 70.0% yield. NMR matched literature. NMR (400 MHz, DMSO-^) delta 8.81 (s, 1H), 6.04 - 5.72 (m, 1H), 5.28 - 4.87 (m, 2H), 3.72 - 3.49 (m, 2H).
With osmium(VIII) oxide; 4-methylmorpholine N-oxide; In 1,4-dioxane; water; for 1h;
This compound was prepared by modification of the procedure described in J. Med. Chem. [10] : 665 (1967). A solution of 5-2 (3.0 g, 15.7 mmol) in dioxane (20 mL) was stirred with 4-methylmorpholine-N-oxide (2.8 g, 24 mmol) and osmium tetroxide [(4%] solution in water, 6.2 [ML)] for one h. Sodium bisulfite (2.6 g) was added to the mixture and the precipitated solid was removed by filtration through celite and the filtrate was concentrated in vacuo to a solid which was dissolved in [CH2C12] (50 mL). Sodium periodate on silica gel [(10%] by weight, 50 g) was added to the solution. The reaction mixture was stirred at room temperature for 10 min. Silica gel was removed by filtration and the filtrate was washed with [5%] aqueous sodium thiosulphate solution, dried over anhydrous [NA2SO4] and concentrated in vacuo. The residue was dissolved in [CH2C12] and passed through a short column of silica gel using 0.5% [METHANOL/CH2CL2] as eluent; yield 2.5 g. 1H NMR (CDC13): 8 4.14 (s, [1H,] CH2), 8.73 (s, [1H,] H-2), 9.80 (s, 1H, CHO).
Step 4: 6-Chloro-lambda/-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(2-propen-1 -yl)-4- pyrimidinamine (4)To a mixture of NaH (7.94 g, 60% dispersion in mineral oil, washed with anhydrous toluene) and anhydrous THF (50 ml.) was added, at RT under N2, 2-fluoro-4- (methylsulfonyl)aniline (3) (12.51 g, 66.12 mmol) in THF (150 ml_). The mixture was stirred at RT for 1 h and then compound 2 (12.50 g, 66.12 mmol) in THF (50 ml.) was added. The resulting reaction mixture was refluxed for 3 h. The mixture was allowed to cool to room temperature and then poured slowly into H2O (600 ml.) and the mixture was extracted with EtOAc (4 x 300 ml_). The combined organic layer was washed with brine (1 x 50 ml_), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude product was crystallized from EtOAc to give 10.3 g of solid material. The mother liquor was concentrated and purified by SiO2 flash column chromatography to give an additional 9.35 g of product. A total yield of 19.65 g (87%) of the title compound 4 was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-Ok): delta 9.10 (s, 1 H), 8.29 (s, 1 H), 7.84 - 7.82 (dd, Ji = 9.2 Hz, J2 = 1.6 Hz, 1 H), 7.78 - 7.72 (m, 2 H), 5.96 - 5.86 (m, 1 H), 5.1 1 and 5.09 (dd, Jlambda = 10.4 Hz, J2 = 1.2 Hz, 1 H), 5.07 <n="66"/>and 5.03 (dd, J1 = 16.0 Hz, J2 = 1.6 Hz, 1 H), 3.58 (d, J = 5.6 Hz, 2 H), 3.27 (s, 3 H); LCMS (ESI): m/z 342 (M + H)+.
Synthesis of 5-allyl-4,6-dichloropyrimidlne (8c): 4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25 C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1 M in THE; 0.05 mL, 5 mol %) was then slowly added at -20 C. Allyl bromide (242 mg, 2.0 mmol) was then slowly added at -60 C. The resulting mixture was then allowed to warm up slowly to 0 C. for 4 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (5×30 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane 1:2) furnished 8c as a colourless solid (215 mg, 89%). 1H NMR (300 MHz, CDCl3) delta: 8.64 (s, 1 H), 5.80-5.90 (m, 1 H), 5.09-5.18 (m, 2 H), 3.64 (dt, 3J=6.4 Hz, 4J=1.4 Hz, 2 H).13C NMR (75 MHz, CDCl3) delta: 162.0, 155.8, 130.9, 130.6, 118.2, 34.0.MS (70 eV, El) m/z (%): 188 (70) [M+], 125 (22), 117 (44), 90 (59), 64 (35), 49 (43), 41 (100).IR (ATR) v (cm-1): 2969, 2360, 1739, 1639, 1539, 1513, 1435, 1406, 1375, 1348, 1313, 1290, 1200, 1162, 1129, 1090, 989, 929, 906, 839, 777, 687, 668, 627, 621, 616.HRMS (El) for C7H6Cl2N2 (187.9908): 187.9913.
75%
The alkylation step by conducted using a modified procedure: TMPMgCl·LiCl (0.8M, 11.0 mL, 8.8 mmol) was added to a solution of 2,4,6-trichloropyrimidine (1.47 g, 8.0 mmol) in anhydrous THF (20 mL) at -78 oC. After stirring for 1 hour, CuBr (230 mg, 1.6 mmol) was added and stirring was continued for 30 min before allyl bromide (0.73 mL, 8.4 mmol) was added. The reaction was allowed to warm to room temperature, then quenched by addition of sat. NH4Cl solution. EtOAc was added and the layers were separated. The organic phase was dried and Na2SO4 and concentrated. The residue was purified by silica gel chromatography [heptane/EtOAc, 95:5 - 3:1] to give the alkylated product as a white solid (1.31 g, 73 %). This was transformed to the final product by the same procedure as for 2 using allylamine followed by standard N-Boc protection to give the productas a colourless oil (1.51 g, 75%).
In 1-ethoxyethanol; at 150℃; for 2h;Microwave irradiation;
Example 15 Preparation of (5-Allyl-6-chloro-pyrimidin-4-yl)-m-tolyl-amine The mixture of <strong>[16019-31-1]5-allyl-4,6-dichloro-pyrimidine</strong> (1.7 g, 8.98 mmol), m-tolylamine (0.96 mL, 8.98 mmol) in ethoxyethanol (10 mL) was microwaved at 150 C. for 2 h. The solvent was removed and the residue obtained was purified by silica gel chromatography to afford 1.7 g of (5-allyl-6-chloro -pyrimidin-4-yl)-m-tolyl-amine. MS (ESI) 259.4 (M+H)+
Step 1 : 4-[6-Chloro-5-(2-propen-1 -yl)-4-pyrimidinyl]amino}-2,5-difluorobenzonitrile(51) NaH (60% dispersion in oil, 967 mg, 24.2 mmol) was added to a 100 mL round bottom flask along with 5 mL anhydrous toluene. The suspension was stirred for 10 min and the toluene was decanted off. 4-Amino-2,5-difluorobenzonitrile (1.9 g, 12.2 mmol) in 40 mL anhydrous THF was then added to the NaH slurry dropwise over several minutes. The resulting mixture was stirred at ambient temperature for 15 min at which time compound 2 (2.4 g, 12.7 mmol) in 10 mL anhydrous THF was added slowly over several minutes. The mixture was then heated to reflux for 2 h. The reaction was then cooled to room temperature and diluted with 100 mL water and a white precipitate (1.62 g) formed which was removed via filtration and dried under reduced pressure. The filtrate was then transferred to a separatory funnel and was extracted with methylene chloride (3 x 100 mL). The combined organic extracts were then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The crude residue was then recrystallized from MeOH to give an additional 0.57 g of the desired product 51. as a white solid; 2.19 g total (51 %). 1H NMR (400 MHz, CDCI3): delta 3.67 (d, J = 6.0 Hz, 2 H), 5.21 - 5.50 (m, 2 H), 5.77 - 6.02 (m, 1 H), 7.29 - 7.41 (m, 1 H), 7.41 - 7.53 (s, 1 H), 8.50 (s, 1 H), 8.67 - 8.85 (m, 1 H).
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