* 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 ammonia In water; butan-1-ol at 85℃; for 8 h; Sealed tube
A mixture of 4,6-dichloro-5-methoxypyrimidine (5.0g, 28.1mmol), 30percent 10 aqueous ammonia (45mL), and n-butanol (15mL) was heated at 85°C in a sealed tube for 8h. The reaction mixture was then concentrated under reduced pressure and suspended in brine (150mL). The white precipitate was filtered off and the fliter cake was recrystallized from EtOH to give the title compound as an off-white solid. Yield (4.1g, 90percent). 1H NMR (400MHz, DMSO-d6) δ 7.97 (s, 1H), 7.29 (s, 2H), 3.71 (s, 3H). MS (ESI, positive ion) m/z: 159.91 [M+ H]+.
90%
With ammonium hydroxide In butan-1-ol at 85℃; for 8 h; Sealed tube
Starting material 1 (4,6-dichloro-5-methoxypyrimidine 5.0 g, 28.1 mmol), 30percent aqueous ammonia solution (45 mL), 15 mLThe n-butanol was added to the sealed tube and reacted at 85 ° C for 8 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to give a white solid.The color solid was dissolved in a suspension with 150 mL of an aqueous solution of sodium chloride and stirred at room temperature for 0.5 hour, followed by suction filtration.The alcohol and diethyl ether were washed to obtain Intermediate 1. The yield was 90percent.
40%
With ammonia In water; butan-1-ol at 90℃; for 2.5 h;
Description 16; 4-Amino-6-chloro-5-methoxypyrimidine; A mixture of 4, 6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol), 33percent aqueous ammonia (30 ml) and 1'butanol (15 ml) was heated at 90°C in a sealed tube for 2.5 hours. The mixture was allowed to cool and the precipitate removed by filtration, and dried to give the title compound as a white solid (1. 8 g, 40percent). 1H NMR (400 MHz, DMSO-d6) 3.71 (3 H, s), 7.30 (2 H, br s), 7.96 (1 H, s).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1148 - 1164
[2] Patent: CN108164548, 2018, A, . Location in patent: Paragraph 0209; 0210; 0211
[3] Organic Process Research and Development, 2015, vol. 19, # 6, p. 639 - 645
[4] Patent: WO2005/47279, 2005, A1, . Location in patent: Page/Page column 33
2
[ 5193-84-0 ]
[ 5018-38-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
With triethylamine; trichlorophosphate In toluene at 100 - 105℃; for 1.5 h; Reflux
Example 3.2 Preparation of 4,6-Dichloro-5-methoxypyrimidine A suspension of 5-methoxypyrimidine-4,6-diol (96.0 g, 676 mmol) and triethylamine (95.0 mL, 680 mmol) in anhydrous toluene (1.2 L) was heated to 100-105° C., and a solution of POCl3 (140 mL, 1.5 mol) in anhydrous toluene (200 mL) was added over 30 min. The mixture was refluxed for 1 h and cooled to ambient temperature. The toluene layer was decanted and ice was added. The dark, heavier layer was separated, more ice was added, and the mixture was extracted with toluene (2*200 mL). The toluene extracts were combined, and the aqueous layer was discarded. The organic extract was then washed with saturated NaHCO3 (2*300 mL), brine (400 mL), dried over MgSO4, and concentrated to give the title compound (103.4 g, 86percent yield) as a white solid. 1H NMR (CDCl3) δ 4.00 (s, 3H), 8.55 (s, 1H).
75.6%
With N,N-diethylaniline; trichlorophosphate In heptane-ethyl acetate
Example 3 4,6-dichloro-5-methoxypyrimidine A modified form of the process described by Bretschneider, Richter and Kloetze, Monatsh. Chem. 96 (6), 1661-76 (1965) was used. A mixture of 4,6-dihydroxy-5-methoxypyrimidine (113.6 g 0.8 mol), POCl3 (600 ml) and N,N-diethylaniline (50 ml) was heated to reflux for 3 hours. The excess phosphorous oxychloride was removed by distillation in vacuo . The residue was poured over ice-water. The white solid formed was filtered. It was dissolved in heptane-ethyl acetate 7/3 (400 ml) and chromatographed on silica gel, eluding with Hep/AcOEt 7/3, thereby yielding 108.2 g of a white solid (75.6percent).
40%
Stage #1: for 1 h; Heating / reflux Stage #2: at 20℃; Heating / reflux
HPLC/MS: (rt=0.5 min) Synthesis of 4,6-dichloro-5-methoxy-pyrimidine: A mixture of 5 g (35.2 mmoles) of 5-methoxy-4,6-dihydroxy-pyrimidine and 40 ml of phosphorus oxychloride, is taken to reflux for one hour. After returning to ambient temperature, a mixture of 4.8 ml of N,N-diethylaniline and 18 ml of phosphorus oxychloride is added dropwise. The mixture is again taken to reflux for 4 hours 30 minutes. After cooling down, the reaction mixture is poured slowly into a mixture of ice and water then neutralized by a saturated solution of sodium bicarbonate. This aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue obtained is purified on silica eluding with a mixture of cyclohexane and acetate (95-5). 2.5 g (Yield=40percent) of expected product is obtained in the form of a white powder. TLC: Rf=0.48 [Silicagel, eluent: cyclohexane-ethyl acetate (80-20)] 1H-NMR (MeOD): δ 4.00 (s, CH3-O); 8.55 (s, 1H, N=-N) HPLC/MS: rt=1.3 min
Reference：
[1] Patent: US2009/286816, 2009, A1, . Location in patent: Page/Page column 12
[2] Patent: EP714896, 1996, A1,
[3] Patent: US2006/52398, 2006, A1, . Location in patent: Page/Page column 39
[4] Patent: US5300506, 1994, A,
[5] Patent: US5077293, 1991, A,
[6] Patent: US2009/281114, 2009, A1,
[7] Patent: US5434154, 1995, A,
3
[ 124-41-4 ]
[ 5018-38-2 ]
[ 5193-88-4 ]
Yield
Reaction Conditions
Operation in experiment
57%
at 0 - 20℃; for 19 h;
Preparation of Compound 4-Chloro-5,6-dimethoxypyrimidine 4,6-Dichloro-5-methoxypyrimidine (300 mg, 1.68 mmol) was added to MeOH (lOmL). Then the reaction mixture was cooled to 0 °C. It was treated with NaOMe (99 mg, 1.85 mmol) and allowed to warm to room temperature. The reaction mixture was then stirred for 19 hours at room temperature. After the reaction was completed, it was put under the vacuum to remove MeOH. The resulting residue was diluted with EtOAc, which was then washed with sat. NH4CI followed by brine. The organic layer was dried over Na2S04 and then concentrated. The residue was flash chromatographed on silica gel eluting with 0 to 10percent EtOAc/Hexane to provide 4- chloro-5,6-dimethoxypyrimidine as a white solid (168 mg, 57percent); m.p.53-55 °C; NMR (400 MHz, CDCI3) δ 8.27 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDC13) δ 163.6, 151.6, 151.3, 138.2, 60.7, 54.8.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8086 - 8098
6
[ 5018-38-2 ]
[ 425394-89-4 ]
Yield
Reaction Conditions
Operation in experiment
91.11%
With aluminum (III) chloride In dichloromethane at 0 - 50℃; for 6 h;
To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (50 g, 0.27 mol) in dichloroethane (800 mL) at 00 C, anhydrous aluminum chloride (50.48 g, 0.4 11 mol) was added in a single portion. The reaction mixture was stirred vigorously at 50° C for 6 h. After completion, the mixture was cooled to 0°C and aqueous HC1 solution (1 M, 400 mL) was added slowly followed by addition of MeOH (100 mL). The mixture was stirred vigorously at room temperature for 10 mm, diluted with water and extracted with EtOAc. The combined organic layers were washed with satd. NaC1, dried over Na2504, filtered and concentrated to afford 4, 6- dichloropyrimidin-5-ol (41 g, 91.11percent). UPLC = Calculated for C4H2C12N20 is 164.97, Observed = 165.9.
1 g
With aluminum (III) chloride In 1,2-dichloro-ethaneReflux
A suspension of 4,6-dichloro-5-methoxypyrimidine (2.0 g, 11.2 mmol) and aluminum chloride (2.0 g, 15.0 mmol) in DCE (10 mL) was heated to reflux for 3-4 h. The mixture wasconcentrated under reduced pressure, cooled to 0 °C and quenched with ice-water. The mixture was diluted with 1M HC1 (10 mL). The precipitated solid was filtered and dried well to yield 1.0 g of the desired compound. ‘H NMR (400 MHz, DMSO-d6) ö 8.39 (s, 1H), 11.67 (brs, 1H).
With ammonia; In water; butan-1-ol; at 85℃; for 8h;Sealed tube;
A mixture of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.0g, 28.1mmol), 30% 10 aqueous ammonia (45mL), and n-butanol (15mL) was heated at 85C in a sealed tube for 8h. The reaction mixture was then concentrated under reduced pressure and suspended in brine (150mL). The white precipitate was filtered off and the fliter cake was recrystallized from EtOH to give the title compound as an off-white solid. Yield (4.1g, 90%). 1H NMR (400MHz, DMSO-d6) delta 7.97 (s, 1H), 7.29 (s, 2H), 3.71 (s, 3H). MS (ESI, positive ion) m/z: 159.91 [M+ H]+.
90%
With ammonium hydroxide; In butan-1-ol; at 85℃; for 8h;Sealed tube;
Starting material 1 (<strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> 5.0 g, 28.1 mmol), 30% aqueous ammonia solution (45 mL), 15 mLThe n-butanol was added to the sealed tube and reacted at 85 C for 8 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to give a white solid.The color solid was dissolved in a suspension with 150 mL of an aqueous solution of sodium chloride and stirred at room temperature for 0.5 hour, followed by suction filtration.The alcohol and diethyl ether were washed to obtain Intermediate 1. The yield was 90%.
40%
With ammonia; In water; butan-1-ol; at 90℃; for 2.5h;
Description 16; 4-Amino-6-chloro-5-methoxypyrimidine; A mixture of 4, 6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol), 33% aqueous ammonia (30 ml) and 1'butanol (15 ml) was heated at 90C in a sealed tube for 2.5 hours. The mixture was allowed to cool and the precipitate removed by filtration, and dried to give the title compound as a white solid (1. 8 g, 40%). 1H NMR (400 MHz, DMSO-d6) 3.71 (3 H, s), 7.30 (2 H, br s), 7.96 (1 H, s).
6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methoxy-4-chloro-pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 130℃; for 2h;
HPLC/MS: rt=1.3 min Synthesis of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-5-methoxy-4-chloro-pyrimidine: 2.2 g (12.3 mmoles) of <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> solubilized in 25 ml of dimethylacetamide and 3640 mul of diisopropylethylamine are added into a single-necked flask containing 800 mg (3.68 mmoles) of 4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidine released from its salt. This mixture is heated at 130 C. for 2 hours then concentrated to dryness under vacuum. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chromatographed on alumina eluding with a mixture of cyclohexane and acetate (80-20). 900 mg (Yield=68%) of expected product is obtained in the form of a yellow powder. Preparation of the naphthyridine in free amine form: 2.4 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic amberlyst A21 resin (resin of R-NMe2 type) in a CH2Cl2/MeOH/AcOEt mixture 1/1/1 under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 800 mg (3.68 mmoles) of free naphthyridine is obtained. (Yield=88%). TLC: Rf0.4 [alumina, eluent: ethyl acetate cyclohexane (30-70)]1H-NMR (MeOD): ? 1.75 to 1.95 (m, 6H, NH-CH2-CH2-CH2, N-CH2-CH2-CH-CH2); 2.70 (t, 1H, CH2-CH-CH2); 2.8 (m, 2H, NH-CH2-CH2-CH2); 3.15 and 3.75 (2m, 4H, CH2-CH2-N-CH2-CH2); 3.75 (s, CH3-O); 6.4 and 7.15 (2d, 2H, CH?CH naphthyridine); 8.1 (s, 1H, N?CH-N).HPLC/MS: (rt=0.53 min and 2.56 min): 359(M); 360(MH+); 361 (M+2H++).
With triethylamine; trichlorophosphate; In toluene; at 100 - 105℃; for 1.5h;Reflux;
Example 3.2 Preparation of 4,6-Dichloro-5-methoxypyrimidine A suspension of 5-methoxypyrimidine-4,6-diol (96.0 g, 676 mmol) and triethylamine (95.0 mL, 680 mmol) in anhydrous toluene (1.2 L) was heated to 100-105 C., and a solution of POCl3 (140 mL, 1.5 mol) in anhydrous toluene (200 mL) was added over 30 min. The mixture was refluxed for 1 h and cooled to ambient temperature. The toluene layer was decanted and ice was added. The dark, heavier layer was separated, more ice was added, and the mixture was extracted with toluene (2*200 mL). The toluene extracts were combined, and the aqueous layer was discarded. The organic extract was then washed with saturated NaHCO3 (2*300 mL), brine (400 mL), dried over MgSO4, and concentrated to give the title compound (103.4 g, 86% yield) as a white solid. 1H NMR (CDCl3) delta 4.00 (s, 3H), 8.55 (s, 1H).
75.6%
With N,N-diethylaniline; trichlorophosphate; In heptane-ethyl acetate;
Example 3 4,6-dichloro-5-methoxypyrimidine A modified form of the process described by Bretschneider, Richter and Kloetze, Monatsh. Chem. 96 (6), 1661-76 (1965) was used. A mixture of 4,6-dihydroxy-5-methoxypyrimidine (113.6 g 0.8 mol), POCl3 (600 ml) and N,N-diethylaniline (50 ml) was heated to reflux for 3 hours. The excess phosphorous oxychloride was removed by distillation in vacuo . The residue was poured over ice-water. The white solid formed was filtered. It was dissolved in heptane-ethyl acetate 7/3 (400 ml) and chromatographed on silica gel, eluding with Hep/AcOEt 7/3, thereby yielding 108.2 g of a white solid (75.6%).
40%
HPLC/MS: (rt=0.5 min) Synthesis of 4,6-dichloro-5-methoxy-pyrimidine: A mixture of 5 g (35.2 mmoles) of 5-methoxy-4,6-dihydroxy-pyrimidine and 40 ml of phosphorus oxychloride, is taken to reflux for one hour. After returning to ambient temperature, a mixture of 4.8 ml of N,N-diethylaniline and 18 ml of phosphorus oxychloride is added dropwise. The mixture is again taken to reflux for 4 hours 30 minutes. After cooling down, the reaction mixture is poured slowly into a mixture of ice and water then neutralized by a saturated solution of sodium bicarbonate. This aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue obtained is purified on silica eluding with a mixture of cyclohexane and acetate (95-5). 2.5 g (Yield=40%) of expected product is obtained in the form of a white powder. TLC: Rf=0.48 [Silicagel, eluent: cyclohexane-ethyl acetate (80-20)] 1H-NMR (MeOD): delta 4.00 (s, CH3-O); 8.55 (s, 1H, N=-N) HPLC/MS: rt=1.3 min
With N,N-diethylaniline; trichlorophosphate; In hexane;
4,6-Dichloro-5-methoxypyrimidine A modified procedure of Bretschneider, Richter, and Klotze, Monatsh. Chem. 96(6), 1661-76 (1965), was used. A mixture of 4,6-dihydroxy-5-methoxy-pyrimidine (125.84 g, 0.887 mole), POCl3 (700 mL), and N,N-diethylaniline (50 mL) was refluxed for 3 hours to give a brown solution. The solution was cooled and then the excess POCl3 was removed in vacuo. Hexane (about 300 mL) was added to the residue and the mixture was refluxed with stirring. The hot hexane layer was decanted into a beaker, and residue treated two more times with hot hexane. The hexane extracts (total volume about 1 L) were concentrated in vacuo to give the crude product as a white solid (116.5 g, 73.3%). This material was recrystallized from pet ether to give colorless needles (92.0 g +16.51 g second crop, 93.1% total recovery).
With N,N-diethylaniline; trichlorophosphate; In hexane;
B. 4,6-Dichloro-5-methoxypyrimidine A modified procedure of Bretschneider, Richter, and Klotzer, Monatsh. Chem. 96(6), 1661-76 (1965), was used. A mixture of 4,6-Dihydroxy-5-methoxy-pyrimidine (125.84 g, 0.887 mole), POCl3 (700 mL), and N,N-diethylaniline (50 mL) was refluxed for 3 hours to give a brown solution. The solution was cooled and then the excess POCl3 was removed in vacuo. Hexane (about 300 mL) was added to the residue and the mixture was refluxed with stirring. The hot hexane layer was decanted into a beaker, and residue treated two more times with hot hexane. The hexane extracts (total volume about 1 l) were concentrated in vacuo to give the crude product as a white solid (116.5 g, 73.3%). This material was recrystallized from pet ether to give colorless needles (92.0 g+16.51 g second crop, 93.1% total recovery).
With N,N-diethylaniline; trichlorophosphate; In hexane;
4,6-Dichloro-5-methoxypyrimidine A modified procedure of Bretschneider, Richter, and Klotze, Monatsh. Chem. 96(6), 1661-76 (1965), was used. A mixture of 4,6-dihydroxy-5-methoxy-pyrimidine (125.84 g, 0.887 mole), POCl3 (700 mL), and N,N-diethylaniline (50 mL) was refluxed for 3 hours to give a brown solution. The solution was cooled and then the excess POCl3 was removed in vacuo. Hexane (about 300 mL) was added to the residue and the mixture was refluxed with stirring. The hot hexane layer was decanted into a beaker, and residue treated two more times with hot hexane. The hexane extracts (total volume about 1 L) were concentrated in vacuo to give the crude product as a white solid (116.5 g, 73.3%). This material was recrystallized from pet ether to give colorless needles (92.0 g+16.51 g second crop, 93.1% total recovery).
With N,N-diethylaniline; trichlorophosphate; In hexane;
4,6-Dichloro-5-methoxypyrimidine A modified procedure of Bretschneider, Richter, and Klotze, Monatsh. Chem. 96(6), 1661-76 (1965), was used. A mixture of 4,6-dihydroxy-5-methoxy-pyrimidine (125.84 g, 0.887 mole), POCl3 (700 mL), and N,N-diethylaniline (50 mL) was refluxed for 3 hours to give a brown solution. The solution was cooled and then the excess POCl3 was removed in vacuo. Hexane (about 300 mL) was added to the residue and the mixture was refluxed with stirring. The hot hexane layer was decanted into a beaker, and residue treated two more times with hot hexane. The hexane extracts (total volume about 1 L) were concentrated in vacuo to give the crude product as a white solid (116.5 g, 73.3%). This material was recrystallized from pet ether to give colorless needles (92.0 g+16.51 g second crop, 93.1% total recovery).
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 1h;
A solution of <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (5.62 g, 27.9 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.02 g, 27.9 mmol) in 200 mL THF was chilled to 0 C. A 1.0 M solution of potassium t-butoxide (30.7 mL, 30.7 mmol) was added drop-wise with stirring and the resulting mixture then was allowed to stir at 0 C. for one hour. Saturated ammonium chloride (100 mL) was added and the solution extracted with ethyl acetate. The organic phase was washed with brine and dried with magnesium sulfate, solvent removed to yield 9.10 g (94.8% yield). 1HNMR (CDCl3, 400 MHz) delta 1.48 (s, 2H), 1.79-1.83 (m, 2H), 1.99-2.04 (m, 2H), 3.33-3.39 (m, 2H), 3.72-3.77 (m, 2H), 3.91 (s, 3H), 5.30-5.38 (m, 1H), 8.26 (s, 1H). Exact mass calculated for C15H22ClN3O4: 343.13, found: 344.3 (MH+).
With potassium tert-butylate; In tetrahydrofuran; at 5 - 10℃; for 2h;Inert atmosphere;
Example 3.4 Preparation of 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic Acid Isopropyl Ester A solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (71.0 g, 380 mmol) and <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (71.6 g, 400 mmol) in anhydrous THF (1 L) was cooled to 5 C. under N2. A solution of potassium t-butoxide (1.0 M in THF, 380 mL, 380 mmol) was added dropwise over 1 h. The reaction temperature was kept under 10 C. during addition. The reaction mixture was stirred at 5-10 C. for 1 h, quenched with saturated NH4Cl (200 mL), and diluted with ether (1 L) and water (1 L). The aqueous phase was separated and discarded. The organic extract was washed with brine (800 mL), dried over MgSO4, and then concentrated. The residue was dissolved in hexane (400 mL) and filtered over Celite to remove a small amount of brown solid. The solvent was removed from the filtrate to afford a pale amber oil which gradually crystallized to give the title compound (130 g, 98.6% yield) as a pale amber solid. Exact Mass calculated for C14H20ClN3O4: 329.1. Found: LCMS m/z=330.2 (M+H+); 1H NMR (400 MHz, CDCl3) delta 1.25 (d, J=6.2 Hz, 6H), 1.82 (m, 2H), 2.02 (m, 2H), 3.40 (m, 2H), 3.80 (m, 2H), 3.91 (s, 3H), 4.95 (m, 1H), 5.39 (m, 1H), 8.27 (s, 1H).
85%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.75h;
To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (3.15 g, 17 mmol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (3.00 mg, 17 mmol) in 15 ml of THF, 1M potassium-t-butoxide in THF (18.4 ml, 18.4 mmol) was added dropwise at 0 C. After 45 min, the crude mixture was extracted with CH2Cl2 and brine. Organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3:1?1:1 v/v) to provide 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (4.7 g, 85%). 1HNMR (CDCl3, 400 MHz) delta 1.24-1.28 (d, 6H), 1.80-1.84 (m, 2H), 2.00-2.05 (m, 2H), 3.37-3.44 (m, 2H), 3.77-3.81 (m, 2H), 3.91 (s, 3H), 4.92-4.95 (m, 1H), 5.38-5.40 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C14H20ClN3O4329.11, found 330.1 (MH+).
65%
To a solution of 2a (3.18 g, 17 mmol) in 18 mL of THF at room temperature, was added potassium tert-butoxide (2.06 g, 1.2 eq). The resulting mixture was stirred at room temperature for 30 minutes then 4,6-dichloro-5,methoxy-pyrimidine (3 g, 17 mmol) was added. The reaction mixture was stirred at room temperature for 8h then the solvent was evaporated. The residue was taken up with DCM and purified on silica gel (elution with 25% ethyl acetate in hexanes) to give 3.64 g of 8a (65% yield).
59%
With sodium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; at 100℃; for 10h;Inert atmosphere;
To a solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (240 mg, 1.34 mmol) and isopropyl 4-hydroxypiperidine-1-carboxylate (326 mg, 1.74 mmol) in anhydrous 1 ,4- dioxane (3 ml.) at 100 0C, was added a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.34 ml_, 1.34 mmol, 1.0 M). The reaction mixture was heated for 10 hours and then allowed to cool to room temperature. The reaction was then quenched with water (3 ml.) and diluted with ethyl acetate (20 ml_). The solution was then washed with sequentially with saturated aqueous sodium bicarbonate solution (10 ml.) and brine (10 ml.) followed by drying over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (0 - 100% ethyl acetate in heptane) to give isopropyl 4-[(6- chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate as oil (260 mg, 59 %). 1H NMR (400 MHz, deuterochloroform) delta 8.25 (1 H, s) 5.29 - 5.44 (1 H, m) 4.84 - 5.01 (1 H, m) 3.90 (3 H, s) 3.72 - 3.82 (2 H, m) 3.31 - 3.47 (2 H, m) 1.93 - 2.10 (2 H, m) 1.72 - 1.89 (2 H, m) 1.25 (6 H, d, J=6.24 Hz); LCMS (ES+): 329.0 (M+1 ).
With sodium hydride; In N,N-dimethyl-formamide; at -5 - 20℃; for 18h;Inert atmosphere;Product distribution / selectivity;
A 500 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet was purged with N2 and charged with NaH (4.4 g; 0.1 1 mol) and N,N-dimethylformamide (50 ml). In a separate flask were dissolved 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (18.7 g; 0.1 mol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (17.9 g; 0.1 mol) in DMF (50 ml; 0.5 L/mol). The prepared solution was then added dropwise to the above- mentioned NaH/DMF suspension while maintaining the temperature between - 10 and -5C. The resulting mixture is then stirred for one hour, then allowed to warm up to room temperature and stirred for 17 hours. Water (300 ml; 3 L/mol) was added dropwise while maintaining the temperature between 15-300C by cooling with tap water. Heptane (125 ml; 1.25 L/mol) was added and the resulting mixture was heated up to 55C. The aqueous layer was discarded; the organic layer was cooled down to 200C and stirred for another 3-2Oh. The resulting precipitate was filtered and dried in vacuum (at) 500C for 2Oh to yield the title compound as a residue.
With sodium hydride; In N,N-dimethyl-formamide; at -10 - 20℃; for 18h;Inert atmosphere;Product distribution / selectivity;
Example 1 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester A 500 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet was purged with N2 and charged with NaH (4.4 g; 0.1 1 mol) and N,N-dimethylformamide (50 ml). In a separate flask were dissolved 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (18.7 g; 0.1 mol) and <strong>[5018-38-2]4,6-dichloro-5-methoxy-pyrimidine</strong> (17.9 g; 0.1 mol) in DMF (50 ml; 0.5 L/mol). The prepared solution was then added dropwise to the above- mentioned NaH/DMF suspension while maintaining the temperature between - 10 and -5C. The resulting mixture is then stirred for one hour, then allowed to warm up to room temperature and stirred for 17 hours. Water (300 ml; 3 L/mol) was added dropwise while maintaining the temperature between 15-300C by cooling with tap water. Heptane (125 ml; 1.25 L/mol) was added and the resulting mixture was heated up to 55C. The aqueous layer was discarded; the organic layer was cooled down to 200C and stirred for another 3-2Oh. The resulting precipitate was filtered and dried in vacuum at 500C for 2Oh to yield the title compound.
4-[2-(4-chlorophenyl)ethoxy]-5-methoxy-6-chloropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; n-heptane; ethyl acetate;
EXAMPLE C STR22 2.40 g (15.2 mmol) of 2-(4-chlorophenyl)ethanol were added dropwise at 40 C. to a suspension of 680 mg (22.7 mmol) of sodium hydride (80% suspension in oil) in 40 ml of dry tetrahydrofuran, and the mixture was stirred until the evolution of hydrogen had ceased. The mixture was then allowed to cool to room temperature, whereupon 2.7 g (15.2 mmol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (Monatshefte Chem. 96, 1661 (1965) were added in portions. The mixture was stirred for 1 hour at room temperature and for 4 hours at 40 C. For work-up, the reaction mixture was poured into saturated ammonium chloride solution and extracted with diethyl ether. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using n-heptane/ethyl acetate (4:1). 4.0 g (88% of theory) of 4-[2-(4-chlorophenyl)ethoxy]-5-methoxy-6-chloropyrimidine was obtained in the form of a viscous oil which crystallized slowly upon drying (melting point 70-71 C.).
Method 2 4-(5-Methoxy-4-pyrimidinyl)-2-methylpiperazine A solution of 2-methylpiperazine (20 g) in water (100 mL) was reacted with solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmole) in a procedure similar to that given for Method 2 of Example 14. After hydrogenation and filtration of the catalyst, the product was extracted from the filtrate with CH2 Cl2. The extracts were concentrated in vacuo, and the residue was Kegelrohr distilled to give a clear oil (5.46 g, 99.8%). The oil was dissolved in acetonitrile and concentrated HCl added to form the salt which was recrystallized from i-PrOH and dried in vacuo to give the product as a White powder (4.02 g, m.p. 185-188 C.).
With hydrogenchloride; In water; acetonitrile;
Method 2 4-(5-Methoxy-4-pyrimidinyl)-2-methylpiperazine A solution of 2-methylpiperazine (20 g) in water (100 mL) was reacted with solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmole) in a procedure similar to that given for Method 2 of Example 14. After hydrogenation and filtration of the catalyst, the product was extracted from the filtrate with CH2Cl2. The extracts were concentrated in vacuo, and the residue was Kegelrohr distilled to give a clear oil (5.46 g, 99.8%). The oil was dissolved in acetonitrile and concentrated HCl added to form the salt which was recrystallized from i-PrOH and dried in vacuo to give the product as a White powder (4.02 g, m.p. 185-188 C.).
With hydrogenchloride; In water; acetonitrile;
Method 2 4-(5-Methoxy-4-pyrimidinyl)-2-methyl-piperazine A solution of 2-methylpiperazine (20 g) in water (100 mL) was reacted with solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmol) in a procedure similar to that given for Method 2 of Example 21. After hydrogenation and filtration of the catalyst, the product was extracted from the filtrate with CH2Cl2. The extracts were concentrated in vacuo, and the residue was Kugelrohr distilled to give a clear oil (5.46 g, 99.8%). The oil was dissolved in acetonitrile and concentrated HCl added to form the salt which was recrystallized from i-PrOH and dried in vacuo to give the product as a white powder (4.02 g, m.p. 1.85-188 C.
With hydrogenchloride; In water; acetonitrile;
4-(5-Methoxy-4-pyrimidinyl)-2-methylpiperazine Method 2 A solution of 2-methylpiperazine (20 g) in water (100 mL) was reacted with solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmole) in a procedure similar to that given for Method 2 of Example 14. After hydrogenation and filtration of the catalyst, the product was extracted from the filtrate with CH2 Cl2. The extracts were concentrated in vacuo, and the residue was Kugelrohr distilled to give a clear oil (5.46 g, 99.8%). The oil was dissolved in acetonitrile and concentrated HCl added to form the salt which was recrystallized from i-PrOH and dried in vacuo to give the product as a white powder (4.02 g, m.p. 185-188 C.).
4-Chloro-5-methoxy-4-(1-piperazinyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; acetonitrile;
4-Chloro-5-methoxy-4-(1-piperazinyl)pyrimidine Piperazine (30 g) was dissolved in water (150 mL) and then solid 4,6-Dichloro-5-methoxypyrimidine (10.00 g, 55.8 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The product was extracted from the aqueous reaction mixture with methylene chloride (yield 12.67 g, 99.2%). A sample (5 g) of the crude product was chromatographed on silica gel using a gradient of 20-40% methanol/ethyl acetate as the eluent. The product was then dissolved in acetonitrile and concentrated HCl added to give the salt as a white powder which was dried in vacuo to give the analytical sample (4.0 g, m.p.: 169-173 C. bubbles). Anal. Calcd for C9 H13 N4 OCl.1.5 HCl.0.2 H2 O, C, 37.67; H, 5.24; N, 19.53 H2 O; 1.26. Found: C, 37.63; H, 4.99; N, 1946 H2 O; 1.47.
With hydrogenchloride; In water; acetonitrile;
4-Chloro-5-methoxy-4-(1-piperazinyl)pyrimidine Piperazine (30 g) was dissolved in water (150 mL) and then solid 4,6-Dichloro-5-methoxypyrimidine (10.00 g, 55.8 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The product was extracted from the aqueous reaction mixture with methylene chloride (yield 12.67 g, 99.2%). A sample (5 g) of the crude product was chromatographed on silica gel using a gradient of 20-40% methanol/ethyl acetate as the eluent. The product was then dissolved in acetonitrile and concentrated HCl added to give the salt as a white powder which was dried in vacuo to give the analytical sample (4.0 g, m.p.: 169-173 C. bubbles). Anal. Calcd for C9H13N4OCl1.5HCl.0.2H2O,
1-(5-Methoxy-4-pyrimidinyl)piperazine Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.00 g, 27.9 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2 Cl2. The CH2 Cl2 extracts were dried over Na2 SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl was added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219-221.5 C.).
With hydrogenchloride; In water; acetonitrile;
D. 1-(5-Methoxy-4-pyrimidinyl)piperazine Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.00 g, 27.9 mmol) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2 Cl2. The CH2 Cl2 extracts were dried over Na2 SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219-221.5 C.).
With hydrogenchloride; In water; acetonitrile;
1-(5-Methoxy-4-pyrimidinyl)piperazine Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.00 g, 27.9 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2Cl2. The CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl was added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 2190-221.5 C.).
With hydrogenchloride; In water; acetonitrile;
1-(5-Methoxy-4-pyrimidinyl)piperazine Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.00 g, 27.9 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2 Cl2. The CH2 Cl2 extracts were dried over Na2 SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl was added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219-221.5 C.).
4-chloro-5-methoxy-6-piperazin-1-yl-pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; acetonitrile;
C. 6-Chloro-5-methoxy-4-(1-piperazinyl)pyrimidine Piperazine (30 g) was dissolved in water (150 mL) and then solid 4,6-Dichloro-5-methoxypyrimidine (10.00 g, 55.8 mmol) was added. The mixture was vigorously stirred for 2 hr at room temperature during which the 4,6-Dichloro-5-methoxypyrimidine dissolved. The product was extracted from the aqueous reaction mixture with methylene chloride (yield 12.67 g, 99.2%). A sample (5 g) of the crude product was chromatographed on silica gel using a gradient of 20-40% methanol/ethyl acetate as the eluent. The product was then dissolved in acetonitrile and concentrated HCl added to give the salt as a white powder which was dried in vacuo to give the analytical sample (4.0 g, m.p.: 169-173 C. bubbles). Anal. Calcd for C9 H13 N4 OCl*1.5 HCl*0.2 H2 O; C, 37.67; H, 5.24; N, 19.53 H2 O; 1.26; Found: C, 37.63; H, 4.99; N, 19.46 H2 O; 1.47.
19.2 g (83.9%)
With sodium hydroxide; In ethanol; dichloromethane; water;
Example 9 4-chloro-5-methoxy-6-piperazin-1-yl-pyrimidine A modification of the process used by Smith et al. in EP 0464604 was used. To a solution of 21.5 g (0.25 mol) of piperazine in 150 ml of EtOH and 50 ml of water stirred vigorously at 25C were added 17.9 g (0.1 mol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong>. The reaction was held for 3 hours, with the temperature held to between 25-30C. At the end of this time, the reaction mixture was concentrated to dryness and to the residue was added 100 ml of a solution 1N NaOH followed by extraction with 3 x 100 ml of dichloromethane. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel, eluding with CH2Cl2/EtOH/NH4OH 70/25/5 thus to yield 19.2 g (83.9%) of a colourless oil which rapidly solidifies.
In water; at 20℃; for 2h;
4. Preparation of 4-chloro-5-methoxy-6-(piperazin-1-yl)pyrimidine Piperazine (6.00 g, 70 mmol, 6.25 eq) is dissolved in water (30 ml), and to this solution is added <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (2.00 g, 11.2 mmol, 1.0 eq). The mixture is stirred vigorously at room temperature for 2.0 h, during which <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> is gradually dissolved. The aqueous phase is extracted with CH2Cl2 (25 ml*2). The extracted liquids are combined, dried over anhydrous sodium sulfate and filtered by vacuum filtration, and concentrated to give a light yellow oily crude product (2.66 g). ESI-MS [M+H]+: m/z 229.08
With hydrogenchloride; In water; acetonitrile;
6-Chloro-5-methoxy-4-(1-piperazinyl)pyrimidine Piperazine (30 g) was dissolved in water (150 mL) and then solid 4,6-Dichloro-5-methoxypyrimidine (10.00 g, 55.8 mmole) was added. The mixture was vigorously stirred for 2 h at room temperature during which the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> dissolved. The product was extracted from the aqueous reaction mixture with methylene chloride (yield 12.67 g, 99.2%). A sample (5 g) of the crude product was chromatographed on silica gel using a gradient of 20-40% methanol/ethyl acetate as the eluent. The product was then dissolved in acetonitrile and concentrated HCl added to give the salt as a white powder which was dried in vacuo to give the analytical sample (4.0 g, m.p.: 169-173 C. bubbles). Anal. Calcd for C9 H13 N4 OC1*1.5 HCl*0.2 H2 O C, 37.67; H, 5.24; N, 19.53 H2 O; 1.26 Found: C, 37.63; H, 4.99; N, 19.46 H2 O; 1.47
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 15h;
3-(S)-(6-Chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester. To a solution of (S)-3 -Amino- l-(tert-butyloxycarbonylpiperidine (2.30 g, 11.5 mmol) in isopropanol (30 mL), 4,6-dichloro-5-methoxypyrimidine (2.06 g, 1 1.5 mmol), described in the literature by Anderson et al., Org. Proc. Res. Dev. 1997, 1, 310, was added followed by DIPEA (4 mL, 23.0 mmol). The resulting solution was heated at 800C for 15 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (20:80 to 100:0). The title compound was obtained as a colourless oil (2.91 g, 74percent). MS (ES+) m/e = 343, (ES-) m/e 341. 1H NMR (400 MHz, DMSO-d6) deltaH 1.45 (9H, s), 1.61 (IH, m), 1.70-1.79 (2H, m), 1.88-1.96 (IH, m), 3.33-3.39 (IH, m), 3.47-3.52 (2H, m), 3.61-3.66 (IH, m), 3.87 (3H, s), 4.12 (IH, br s), 5.49 (IH, br s), 8.16 (IH, s). [alpha]D23°C +20 (c = 0.1 in MeOH).
4-(6-chloro-5-methoxy-pyrimidin-4-yl)-piperazin-1-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dichloromethane; water; acetonitrile;
Example 14 4-(6-chloro-5-methoxy-pyrimidin-4-yl)-piperazin-1-carbaldehyde 17.9 g (0.1 mol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong>, 11.4 g (0.1 mol) of 1-piperazinylcarboxaldehyde and 13.8 g (0.1 mol) of potassium carbonate in 150 ml of acetonitrile were stirred at 20C for 48 hours. The reaction mixture was concentrated to dryness, 100 ml of distilled water were added, followed by extraction with con 3 x 100 ml of CH2Cl2. The extracts were dried and concentrated. 24.3 g (94.7%) of a white solid were yielded. 1H-NMR: (CDCl3, ppm): 8.22 (s, 1H); 8.12 (s, 1H) 3.95-3.82 (s.c., 4H); 3.79 (s, 3H); 3.65 (s.c, 2H); 3.50 (s.c., 2H)
N1-(6-chloro-5-methoxy-pyrimidin-4-yl)-N1-methyl-ethane-1,2-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 11 N1-(6-chloro-5-methoxy-pyrimidin-4-yl)-N1-methyl-ethane-1,2-diamine Following the process described in Example 9 and starting out from 17.9 g (0.1 mol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> and 11.1 g (0.15 mol) of N-methylethylenediamine, 13.6 g (62.8%) of an oil were yielded. 1H-NMR: (DMSO-d6, ppm): 8.1 (s, 1H); 368 (s, 3H) 3.62 (t, 2H); 3.21 (s, 3H); 2.75 (t, 2H); 1.5 (s.a, 2H)
(6-chloro-5-methoxy-pyrimidin-4-yl)-methylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13.4 g (92%)
With sodium hydroxide; methylamine; In ethanol;
Example 7 (6-chloro-5-methoxy-pyrimidin-4-yl)-methylamine To 17.9 g (0.1 mol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> in 100 ml of absolute ethanol were added 31.25 ml (0.25 mol) of an 8M solution of methylamine in ethanol. The reaction was maintained with stirring, the temperature being controlled so as not to rise above 30C. At the end of 1 hour, 100 ml of a solution of 1N NaOH were added. The reaction mixture was concentrated to dryness. The residue was treated with 100 ml of distilled water and extracted with 3 x 100 ml of CH2Cl2. The extracts were dried and concentrated to yield 13.4 g (92%) of a white solid. 1H-NMR: (DMSO-d6, ppm): 8.12 (s, 1H), 7.67 (s.a.), 3.80 (s, 3H), 2.95 (d, 3H)
Example 8 4-chloro-5,6-dimethoxypyrimidine Following a modified form of the process described by Bretschneider et al., Monatsh Chem. 96 , 1661-1669 (1965), to 6 g (0.11 mol) of sodium methoxide in 150 ml of methanol were added at 0C 17.9 g (0.1 mol) of 4,6-dichloro-5-methoxypyrimidine. The mixture was held at 0C with stirring for 1 hour. It was allowed to rise to room temperature (25C), the salts formed were filtered. The filter liquors were concentrated to dryness. The residue was treated with 100 ml of distilled water and extracted with 3 x 100 ml of CH2Cl2. The extracts were dried and concentrated, thereby yielding 16.1 g of a completely pure white solid. (92.2%). 1H-NMR: (DMSO-d6, ppm): 8.41 (s, 1H); 4.03 (s, 3H) 3.88 (s, 3H)
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 8h;
A mixture of (8-chloro-2-phenylquinolin-3-yl)methanamine (0.035 g, 0.13 mmol) in n-butanol (3 mL) was treated with DIEA (0.046 mL, 0.26 mmol, 2.0 eq) followed with <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (0.025 g, 0.14 mmol, 1 eq) at 100 0C for 8 h . The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep column using 0 to 100% gradient of CH2Cl2MeOHrNH4OH (89:9:1) in CH2Cl2 as eluent to provide 6-chloro-N-((8- chloro-2-phenylquinolin-3-yl)methyl)-5-methoxypyrimidin-4-amine as a white solid. 1H-NMR (DMSO-d6) delta ppm 8.33 (s, IH), 8.20 (t, 1 H), 8.02-8.04 (m, 1 H), 7.99 (s, 1 H), 7.93-7.95 (m, 1 H), 7.70 (d, J=6.60, 1 H), 7.46 - 7.61 (m, 1 H), 4.73 (d, J=5.71, 2 H), 2.51 (s, 3 H), Mass Spectrum (ESI) m/e = 412 (M + 1).
With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h;
Example 3A. tert-Butyl 4-(6-chloro-5-methoxypyrimidin-4-ylamino)piperidine- 1-carboxylate[00147] To a mixture of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (5.34 g, 30 mmol) and 4-amino-l-BOC-piperidine (6.30 g, 31.5 mmol) in THF (150 mL) was added K2CO3 (6.22 g, 45 mmol). Upon completion of addition, the reaction mixture was allowed to stir at ambient temperature for about 16 h. After this time, the reaction mixture was filtered through a pad of SiO2 gel and concentrated to afford 9.83 g (96%) of Example 3 A as an off-white solid. 1H NMR (400 MHz, CDCl3): delta 1.40 (m, 2H), 1.47 (s, 9H), 2.04 (m, 2H), 2.92 (broad s, 2H), 3.86 (s, 3H), 4.12 (m, 3H), 5.33 (d,lH, J = 1.7 Hz), 8.13 (s, IH). LRMS (ESI): 343.1 [M + H]+.
With caesium carbonate; In dimethyl sulfoxide; at 60℃;Product distribution / selectivity;
Example 1(6-Chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine A 100-mL Schlenk flask with a magnetic stir bar was charged with 4,6-dichloro-5-methoxypyrimidine (4.66 g, 0.026 mol), <strong>[897732-75-1]6-methanesulfonyl-2-methyl-3-pyridinamine</strong> (3.72 g, 0.020 mol), and DMSO (20 mL). After the mixture was stirred to dissolve the components, Cs2CO3 (8.48 g, 0.026 mol) was added, and the resulting mixture heated to 60 C. After 4.5 h and additional portion of Cs2CO3 (2.00 g, 0.0061 mol) was added and heating continued overnight. The reaction was quenched by addition of the reaction mixture to well stirred, saturated NH4Cl (200 mL); resulting in the formation of a tan precipitate. The precipitate was filtered, air dried and stirred with MTBE, and the resulting mixture filtered again. The resulting solid was purified by column chromatography on silica gel (200 g) using CH2Cl2 followed by 1% IPA-CH2Cl2 after 2-L of CH2Cl2 had eluted to yield the title compound as a white to light yellow solid.1H NMR (300 MHz, CDCl3) delta: 8.99 (d, 1H, J=8.6 Hz), 8.37 (s, 1H), 8.00 (d, 1H, J=8.6 Hz), 7.49 (br s, 1H), 4.08 (s, 3H), 3.21 (s, 3H), 2.69 (s, 3H).HRMS: [MH]+ m/z=329.0465.NOTE: (6-Chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-methyl-amine was also isolated as a by-product from the above reaction mixture.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; toluene; at 100℃; for 16h;Inert atmosphere;
To 2.5 g of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> in 20 ml. of toluene, 5 ml_ of water and 5 ml_ of DME was added 1.9 g of 4-tolyl boronic acid, 5.8 g of potassium carbonate and 810 mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 100 0C for 16 hours in an oil bath. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography yielding 2.17 g of P15.
P16 10 To a solution of 4-fluorophbetanol (630 mg, 5.61 mmol) in 20 ml THF at rt was added 1BuOK (815 mg, 7.26 mmol, 1.3 eq.) and mixture for about 10 min. and cooled to 0 0C. To this was added <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (1.0 g, 5.59 mmol) in one portion and the mixture was stirred overnight while allowing to warm to rt. It was quenched with aq. NH4CI, extracted 3x with ethyl acetate, the combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and the residue purified by flash chromatography using 10% ethyl acetate in hexanes to provide 950 mg of P16 and 14 mg of 10.LCMS for 10: 331.2 (MH+)
To a solution of 4-cynaophenol (400 mg, 3.36 mmol) in 10 ml THF at rt was added potassium-tert-butoxide (380 mg, 3.39 mmol, 1.2 eq) and stirred for 20 minutes. To this was added <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (500 mg, 2.79 mmol) and stirred for 3 days at rt. It was quenched by the addition of aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography using 20% ethyl acetate in hexanes to provide 175 mg of P28.
To 1g of 4-aminobenzonitrile in 5OmL of dry THF at O0C was added 1.34g of 60% sodium hydride in mineral oil and the mixture stirred under nitrogen for 10 minutes. 1.5 g of the <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (commercially available) was then added and the mixture allowed warming to room temperature while stirring. After about 16 hours the reaction mixture was quenched with water then the mixture extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness yielding 2.73g of a tan solid. The solid was triturated with diethyl ether and filtered yielding 1.73g of the desired product.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; toluene; at 140℃;Inert atmosphere; in a pressure tube; microwave reactor;
To 1.44g of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> in 5mL of toluene, 3 mL of water and 3 mL of DME was added 1 g of 5-cyanoindole-2-boronic acid, 2.23 g of potassium carbonate and 311 mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 140 0C in a pressure tube using a microwave reactor. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The solid residue was triturated in ethyl acetate and filtered. The filtrate then evaporated to dryness and purified by flash chromatography yielding 240mg of P12.
With potassium carbonate; In 1,4-dioxane; at 125℃;Inert atmosphere;
Example 10H. 2-[(6-Chloro-5-methoxy-4-pyrimidinyl)amino]-ethanolTo a solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (1.00 g, 5.59 mmol) in dioxane (15 mL) was added 2- aminoethanol (348 mg, 5.70 mmol) and potassium carbonate (926 mg, 6.70 mmol). The reaction was refluxed at 125 C. On completion, the reaction mixture was cooled to room temperature, the resulting suspension was filtered and the filtrate concentrated in vacuo. Both the filtered solid and the solid obtained from concentration of the filtrate were identified as the title compound and combined to afford 1.2g (5.89mmol, quantitative yield) of the title compound. [M + H]+ = 203.9
With potassium carbonate; In 1,4-dioxane; at 140℃; for 1h;Microwave irradiation;
To a solution of 4,6-dichloro-5-methoxypynmidine (1.50 g, 8.4 mmol) in dioxane (15 mL) was added 2-aminoethanol (0.52 g, 8.5 mmol) and K2C03 (1.39 g, 10.1 mmol). The reaction was heated in a microwave apparatus at 140 C for 1 hour, then cooled to room temperature. The resulting suspension was filtered and the filtrate was concentrated in vacuo to provide compound 13A as a white solid, which was used without further purification
10.5 g
With potassium carbonate; In 1,4-dioxane; at 125℃; for 8h;
To a stirred solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (10 g, 55.8 mmol) in 1,4-dioxane(100 mL) were added ethanolamine (3.42 mL, 56.9 mmol) and potassium carbonate (9.26 g,67.0 mmol) and the mixture was refluxed at 125 C for 8 h. The mixture was cooled to RTand partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 10.5 g of the desired product. ?H NMR (400 MHz, DMSO-d6) oe 3.44 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 4.80-4.85 (br s, 1H), 7.55 (s, 1H), 8.04 (s, 1H); ESI-MS (m/z) 204 (M+H)t
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 18h;
A solution of intermediate 4c (1.0 g, 5.3 mmol) in 5 ml THF was added to a solution of commercially available <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (945 mg, 5.3 mmol) and N,N- diisopropylethylamine (1.45 ml, 7.9 mmol) in 20 ml THF. The reaction mixture was stirred at 50C for 18h. Then, water was added and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by reversed phase HPLC to give the desired product 1.05 g (3.2 mmol).
7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride[ No CAS ]
[ 5018-38-2 ]
[ 1349197-72-3 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 0.5h;Microwave irradiation;
Intermediate 16a; N,N-diisopropylethylamine (486 mu, 2.6 mmol) was added to a mixture of commercially available 7-trifluoromethyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (250 mg, 1.1 mmol) and commercially available <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (188 mg, 1.1 mmol) in 2 ml NMP. The reaction mixture was heated in the microwave at 120C for 30 min. Then, dichloromethane was added and the mixture was washed with water (2x). The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was purified by reversed phase HPLC to give the desired product (231 mg, 672 muiotaetaomicron).
Intermediate 4; Commercially available 3-trifluoromethyl-aniline (322 mu, 2.6 mmol) and commercially available <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (358 mg, 2.0 mmol) were added to a mixture of 0.2 ml 32% aqeuous hydrochloric acid and 2 ml water. The reaction mixture was refluxed over night. The resulting precipitate was filtered, washed with water and dried at 50C to give the desired product (501 mg, 1.47 mmol).
Example 3: Preparation of 6-chloro-N-[2-[2-fluoro-4-[[4-(trifluoromethyl)-2-pyridyl] oxy]phenyl]ethyl]-5-methoxy-pyrimidin-4-amine (V-14) To a solution of 2-[2-fluoro-4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]ethanamine hydrochloride (344 mg, 0.9 mmol) in NMP (5 ml.) was added diisopropylethylamine (0.36 mL, 2.1 mmol). The solution was stirred for 5 min at room temperature at which time <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (150 mg, 0.8 mmol) was added. The reaction mixture was stirred at 80C overnight then allowed to cool to room temperature. Water was added and was extracted with MTBE (3x). The combined organic layers were washed with water, dried over Na2S04, and concentrated in vacuo. The residue was purified by flash silica column chromatography to provide 288 mg (0.65 mmol, 78%) of the light yellow oily product.
2-[2-fluoro-4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]ethanamine hydrochloride[ No CAS ]
[ 5018-38-2 ]
[ 1448663-73-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
Example 3: Preparation of methyl 6-[2-[2-fluoro-4-[[4-(trifluoromethyl)-2- pyridyl]oxy]phenyl]ethylamino]-5-methoxy-pyrimidine-4-carboxylate (V-4) To a solution of 2-[2-fluoro-4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]ethanamine hydrochloride (344 mg) in NMP (5 ml.) was added diisopropylethylamine (0.36 ml_, 2.1 mmol). The solution was stirred for 5 min at r.t., at which time <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (150 mg, 0.8 mmol) was added. The reaction mixture was stirred at 80C overnight and was then allowed to cool to r.t.. Water was added and the mixture was extracted with MTBE (3x). The combined organic layers were washed with water, dried over Na2S04, and concentrated in vacuo. The residue was purified by flash silica column chromatography to provide 288 mg (0.65 mmol, 78%) of the light yellow oily 6-chloro-N-[2-[2-fluoro-4-[[4-(trifluoromethyl)-2- pyridyl]oxy]phenyl]ethyl]-5-methoxy-pyrimidin-4-amine.
78%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃;
To a solution of 2-[2-fluoro-4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]ethanamine hydrochloride (344 mg, 0.9 mmol) in N-methyl-2-pyrrolidone (5 mL) was added diisopropylethylamine (0.36 mL, 2.1 mmol). The solution was stirred for 5 min at room temperature at which time <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (150 mg, 0.8 mmol) was added. The reaction mixture was stirred at 80 C overnight then allowed to cool to room temperature. Water was added and was extracted with methyl feri-butylether (3x). The combined organic layers were washed with water, dried over Na2S04, and concentrated in vacuo. The residue was purified by flash silica column chromatography to provide 288 mg (0.65 mmol, 78%) of the light yellow solid product.
To a solution of 4-hydroxyphenylethylamine hydrochloride (300 mg) in Nu,Nu-dimethyl formamide (DMF, 5 mL) was added diisopropylethylamine (355 mg, 2 equiv.). The solution was stirred for 5 min before the addition of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (249 mg, 1 equiv.). The reaction mixture was then stirred for 16 h at room temperature before it was concentrated in vacuo. The residue was dissolved in DMF (10 mL) and was stirred with sodium hydride (66 mg, 2.2 equiv.) for 20 min at room temperature. Another portion of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (269 mg, 1 .2 equiv.) was introduced into the reaction mixture, which was then left to stir at room temperature for 48 h. The DMF was then removed in vacuo and the product was purified by flash silica column chromatography to afford 178 mg (31 % yield) of the product as a white solid.
31%
With sodium hydride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 64h;
To a solution of 4-hydroxyphenylethylamine hydrochloride (300 mg) in dimethyl formamide (DMF, 5 mL) was added diisopropylethylamine (355 mg, 2 equiv.). The solution was stirred for 5 min before the addition of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (249 mg, 1 equiv.). The reaction mixture was then stirred for 16 h at room temperature before it was concentrated in vacuo. The residue was dissolved in DMF (10 mL) and was stirred with sodium hydride (66 mg, 2.2 equiv.) for 20 min at room temperature. Another portion of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (269 mg, 1 .2 equiv.) was introduced into the reaction mixture, which was then left to stir at room temperature for 48 h. The DMF was then removed in vacuo and the product was purified by flash silica column chromatography to afford 178 mg (31 %) of the product as a white solid.
1-[4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenoxy]propan-2-amine hydrochloride[ No CAS ]
[ 5018-38-2 ]
6-chloro-5-methoxy-N-[1-methyl-2-[4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenoxy]ethyl]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
General procedure: To a solution of amine (320 mg, 0.8 mmol) in N-methyl-2-pyrrolidone (6 mL) was added diisopropylethylamine (270 mg, 2 mmol). The solution was stirred for 5 mm at room temperature at which time <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (150 mg, 0.8 mmol) was added. The reaction mixture was stirred at 80C overnight then allowed to cool to room temperature. Water was added and the resulting mixture was extracted with methyl tert-butylether (3x). The combinedorganic layers were washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by HPLC to provide 139mg (0.3 mmol, 37%) of the light yellow oily product.
With potassium carbonate; In 1,4-dioxane; at 20℃; for 1h;
A mixture of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (1.0 g, 5.59 mmol), 4-phenylpiperidine (0.937 g, 5.81 mmol), and potassium carbonate (1.62 1 g, 11.73 mmol) in dioxane (50 ml) was stirred at room temperature for 1 hr and then heated to reflux for 1 h. The mixture was cooled and 35% hydrazine (10.12 ml, 112 mmol) was added. The mixture washeated to reflux for 16 h. The mixture was cooled, diluted with water to give an oil. The oil was suctioned out to give 4-hydrazinyl-5-methoxy-6-(4-phenylpiperidin-1- yl)pyrimidine (1.1 g, 65.8%). LCMS: Rt = 2.265 mm, 65%, (M+H) = 300.
With potassium carbonate; In 1,4-dioxane; at 20℃; for 2h;Reflux;
mixture of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (0.50 g, 2.79 mmol), 4-(4- fluorophenyl)piperidine (0.52 1 g, 2.90 mmol), and potassium carbonate (0.8 11 g, 5.87 mmol) in dioxane (10 ml) was stirred at room temperature for 1 hr and then heated to reflux for 1 h. The mixture was cooled and 35% hydrazine (5.06 ml, 55.9mmol) was added. The mixture was heated to reflux for 16 hr overnight. The reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried with magnesium sulfate, and concentrated to give a yellow oil (0.88g, 100%). LCMS: Rt = 0.79 mm, 50%, (M+H) = 318. The material was used without purification.
Preparation of Compound 4-Chloro-5,6-dimethoxypyrimidine 4,6-Dichloro-5-methoxypyrimidine (300 mg, 1.68 mmol) was added to MeOH (lOmL). Then the reaction mixture was cooled to 0 C. It was treated with NaOMe (99 mg, 1.85 mmol) and allowed to warm to room temperature. The reaction mixture was then stirred for 19 hours at room temperature. After the reaction was completed, it was put under the vacuum to remove MeOH. The resulting residue was diluted with EtOAc, which was then washed with sat. NH4CI followed by brine. The organic layer was dried over Na2S04 and then concentrated. The residue was flash chromatographed on silica gel eluting with 0 to 10% EtOAc/Hexane to provide 4- chloro-5,6-dimethoxypyrimidine as a white solid (168 mg, 57%); m.p.53-55 C; NMR (400 MHz, CDCI3) delta 8.27 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDC13) delta 163.6, 151.6, 151.3, 138.2, 60.7, 54.8.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 1.0h;
Potassium 2-niethylpropan-2-olate (17.3 niL, 17.3 mmol) was added to a solution of 1- (4-(irifiuoromethyl)pyrimidin-2--yl)piperidin-4-ol (3.89 g, 15.7 mmoi) and 4,6-dichioro--5- methoxypyrimidinc (2.82 g, 15.7 mmol) in THF (58 mL) at 0 C. The reaction was warmed toroom temperature and stirred fOr I Iv The reaction was concentrated to a yellow solid and triturated with EtOAc and hexanes to afford 6.07 g of the tide compound. Exact mass calculated for C,1H,5CIF,N501?. 38909, found: LCMS rn/a = 390.4 [M+H]?; ?H NMR (400 MHz, CDCI3) S ppm I .86-1.96 (m, 2H), 2,08-2,17 (in, 21-1), 3.75-3.84 (in. 2Fl), 3.92 (s, 3H), 4.21-4.29 (m. 21-1), 5.50 (septet, J= 3.8 Fiz, 11-1). 6.77 (d, .J= 4,8 1-lz, lFl). 8.29 (s, 11-1), 8,50 (d,,J= 4.8 Flz, 1H).
4-chloro-6-cyclopropylmethoxy-5-fluoro-pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: 0.55 mL (5.99 mmol) cyclopropane methanol in 15 mL THF are charged with 0.31 g (7.19 mmol) NaH and the reaction mixture is stirred at r.t. for 10 min. Then 1.00 g (5.99 mmol) 4,6-dichloro-5-fluoro-pyrimidine are added and stirred at r.t. for 1 h. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The organic layers are combined, washed with water (2×), dried over MgSO4, filtered and the solvent is removed in vacuo.For example XIII.2 KOtBu is used as base and added portionwise at 0 C. to the alcohol. The mixture is added at 0 C. to the corresponding pyrimidine in THF.
(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol[ No CAS ]
[ 5018-38-2 ]
4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.05 g
With sodium hydride; In tetrahydrofuran; mineral oil; at 50℃; for 2h;
A) 4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidine To a solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (450 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (760 mg) in THF (8.0 mL) was added 60% sodium hydride (200 mg) at 0C, and the mixture was stirred at 50C for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g) as a white solid. MS (ESI+) : [M+H]+445.9
(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol[ No CAS ]
[ 5018-38-2 ]
4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 g
With sodium hydride; In tetrahydrofuran; mineral oil; at 50℃; for 2h;
A) 4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidine To a solution of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (420 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (760 mg) in THF (10 mL) was added 60% sodium hydride (200 mg) at 0C, and the mixture was stirred at 50C for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a white solid. MS (ESI+) : [M+H]+433.8
N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-6-chloro-5-methoxy-N-methylpyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;Inert atmosphere;
4,6-dichloro-5-methoxy-pyrimidine (0.66g, 3.68mmol) and (3R, 4R) -1- benzyl -N, 4- dimethyl-piperidin-3-amine (0.80g, 3.68 mmol) was dissolved in DMF (5mL), was added potassium carbonate (1.02g, 7.36mmol), 70 reaction was stirred overnight under nitrogen.Water was added (100 mL) to quench the reaction, extracted with ethyl acetate (80mL × 3), the organic phase was washed with water (50 mL) washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, subjected to column chromatography (eluent: PE / EtOAc (v / v) = 1/1), to give the product 1.13g, yield: 85.0%.
4-(6-chloro-5-methoxypyrimidin-4-yl)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;
2-Nitro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)anilmne (5.18 g), 4,6-dichloro-5-methoxypyrimidine (3.86 g), tetrakis(triphenylphosphane)palladiurn(0) (1.13 g) and aqueous sodium carbonate solution (29 ml, 2.0 M) were dissolved in 160 mL dioxane. The reaction mixture was stirred at 80D for 3h. Undissolved corn pouds were filtered off and washed withdichloromethane. The filtrate was concentrated under reduced pressure, treated with ethyl acetate and the undissolved precipitate was filtered off. The filtrate was concentrated under reduced pressure and purified by flash chromatography. The precipitate and the purified compound were combined.Yield: 1.92 g of 100% pure title compound.LC-MS (Method 2): Rt = 1.08 mm; MS (ESipos): m/z = 281 [M+H]1H-NMR (400 MHz, DMSO-d6) O [ppm] = 3.70 - 3.83 (m, 3H), 7.15 (d, 1H), 7.94 (s, 2H), 8.20 (dd, 1H), 8.79 (s, 1H), 8.95 (d, 1H).
(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-5-methoxypyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 24h;
A solution of 4,6-dichloro-5-methoxypyrimidine (500 mg, 2.79 mmol) and <strong>[66399-30-2](S)-1-(4-fluorophenyl)ethan-1-amine</strong> (389 mg, 2.79 mmol) in THF (5 mL) was added DIPEA (1.46 mL, 8.38 mmol). The solution was stirred for 24 h at 50 C. H2O (50 mL) was added to the cooled solution and extracted with 10% IPA/DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to afford (S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-5-methoxypyrimidin-4-amine compound 4 (770 mg, 98%) as thick orange liquid. The compound was used for the next step without further purification. MS (ESI): Calcd. for C13H13ClFN3O: 281, found 282 (MH+).
4-((6-chloro-5-methoxypyrimidin-4-yl)amino)-3-fluorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃;
Add 100mL two-necked flasks in sequence4,6-dichloro-5-methoxypyrimidine (1 g, 5.7 mmol),<strong>[63069-50-1]2-fluoro-4-cyanoaniline</strong> (0.6 g, 4.4 mmol),Potassium carbonate (2.4 g, 17 mmol) and 20 mL DMF. The reaction warmed to 65 C,The reaction was stirred overnight. The reaction solution was poured into ice water and extracted twice with ethyl acetate.It was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product.Purified by silica gel column chromatography (petroleum ether (PE): ethyl acetate (EA) = 3: 1) to obtain 0.68 g of a brownish yellow solid with a yield of 55%.
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