* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 35 - 38
[2] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 2, p. 509 - 513
3
[ 59938-06-6 ]
[ 113-00-8 ]
[ 16075-42-6 ]
Yield
Reaction Conditions
Operation in experiment
20.6 g
Stage #1: With sodium hydroxide In ethanol at 20℃; for 16 h; Stage #2: at 20℃; for 4 h;
Step2: To a solution of compound [63] (22.8 g, 2.4 mmol, I eq.), absolute ethanol ( lOOmL) was added and mixture was stirred at RT for 1 hrs. NaOH pellets (9.55g, 238 mmol, 1 eq.) were added and mixture was stirred at ambient temperature for 1 6 hrs. A solution of compound [84] was added by mean of dropping funnel over a period of 2 hrs. The mixture was further stirred for 2 hrs. The solvent was evaporated and residue was taken in water (500 ml) and stirred vigorously for 2 hrs and allowed to stand at RT overnight. The precipitates formed were filtered, dried under vaccum to obtain compound [85] as light yellow solid (20.6 g, 53percent)
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 4, p. 398 - 406[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 4, p. 502 - 511
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 4, p. 398 - 406[2] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 4, p. 502 - 511
8
[ 16075-42-6 ]
[ 375857-65-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 35 - 38
9
[ 16075-42-6 ]
[ 935534-47-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
With N-Bromosuccinimide In acetonitrile at 20℃; for 4.5 h; Darkness
To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel. The aqueous layer was separated and extracted with EtOAc. The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2. The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2*20 mL of hexane to give the title product as a beige solid (31.2 g, 85percent). tR: 0.82 min (LC-MS 1).
85%
With N-Bromosuccinimide In acetonitrile for 7 h; Darkness
To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (600 mL) was added in the dark a solution of N-bromosuccinimide (34.8 g, 195 mmol) in acetonitrile (200 mL) over a period of 2.5 h. The reaction mixture was stirred for 4.5 h at RT and then concentrated. The residue was dissolved in EtOAc and H2O, the organic solvents were separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 10percent to 40percent to provide the title compound as a beige solid (31.2 g, 85percent). LC-MS: Rt 0.82 min; (LCMS method 2).
82%
With N-Bromosuccinimide In chloroform for 20 h;
Method 9; Synthesis of 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine; [0249] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g,22.5 mmol) was added. After stirring for an additional 4 hours the solution was added toCH2Cl2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine:LCMS (m/z): 242/244 (MH+); 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H).
82%
Stage #1: With N-Bromosuccinimide In chloroform for 20 h; Stage #2: With sodium hydroxide In dichloromethane; chloroform; water
[0250] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2CI2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and <n="97"/>the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS (m/z): 242/244 (MH+). 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H).
82%
Stage #1: With N-Bromosuccinimide In chloroform for 20 h; Darkness Stage #2: With sodium hydroxide In dichloromethane; chloroform
[0092] Synthesis -bromo-4-(trifluoromethyl)pyrimidin-2-amine[0093] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2C12 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2S04, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS im/z): 242/244 (MH ). 3/4 NMR (CDC13): δ 8.52 (s, 1H), 5.38 (bs, 2H).
75%
With N-Bromosuccinimide In chloroform at 20 - 50℃; for 20 h;
4-(Trifluoromethyl)pyrimidin-2-ylamine (2 g, 12.3 mmol) was suspended in chloroform (70 ml) followed by the addition of N-bromosuccinimide (3.3 g, 18.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours and then at room temperature for 15 hours. A mixture of methylene chloride (50 ml) and 1 M sodium hydroxide (50 ml) was added, the resulting mixture was stirred, and then the organic layer was fractionated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 75percent) as a pale orange solid.1H-NMR (CDCl3) δ: 5.37 (2H, brs), 8.52 (1H, s).
73%
With N-Bromosuccinimide In dichloromethane at 25℃; for 48 h; Darkness
To a solution of compound 31(500mg, 3.06 mmol) in DCM (60 mL) was added NBS (1.66g, 9.32 mmol). The solution was stirred in the dark for 2d at rt. Then the reaction was quenched with iN NaOH (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound 32 as a white solid (530 mg, 73percent yield), which was used directly in the next step without further purification. ‘H NIVIR (CDC13): 8.52(s, 1H), 5.29(bs, 2H).
resin bound 3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-diazopropanoic acid[ No CAS ]
[ 16075-42-6 ]
3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-trifluoromethylpyrimidin-2-ylamino)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 138 3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-trifluoromethylpyrimidin-2-ylamino)propanoic acid 2-Amino-4-trifluoromethylpyrimidine gave the title compound (1.2 mg) HPLC-MS Retention time 2.62 min; MH+ 500.
6-(trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine bishydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In isopropyl alcohol; at 40℃; under 3040.2 Torr;
1.1 6-(Trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) To a solution of 10g (45.11 mmol) of <strong>[16075-42-6]4-trifluoromethyl-pyrimidin-2-ylamine</strong> and 0.065g of palladium 10 wt. % on activated carbon in 5 ml of isopropanol was added 45 ml of a solution of hydrochloric acid in isopropanol (5-6 N).. The mixture was shaken at 40C under hydrogen pressure of 4 atmospheres until hydrogen uptake ceased. The catalyst was removed by filtration and washed with isopropanol.. The filtrate was evaporated to dryness to afford 12.14g of pure product as a white solid.. Mp: 138-140C.
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 4.5h;Darkness;
To a solution of <strong>[16075-42-6]2-amino-4-trifluoromethylpyrimidine</strong> (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel. The aqueous layer was separated and extracted with EtOAc. The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2. The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2*20 mL of hexane to give the title product as a beige solid (31.2 g, 85%). tR: 0.82 min (LC-MS 1).
85%
With N-Bromosuccinimide; In acetonitrile; for 7h;Darkness;
To a solution of <strong>[16075-42-6]2-amino-4-trifluoromethylpyrimidine</strong> (25 g, 0.15 mol) in CH3CN (600 mL) was added in the dark a solution of N-bromosuccinimide (34.8 g, 195 mmol) in acetonitrile (200 mL) over a period of 2.5 h. The reaction mixture was stirred for 4.5 h at RT and then concentrated. The residue was dissolved in EtOAc and H2O, the organic solvents were separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 10% to 40% to provide the title compound as a beige solid (31.2 g, 85%). LC-MS: Rt 0.82 min; (LCMS method 2).
82%
With N-Bromosuccinimide; In chloroform; for 20h;
Method 9; Synthesis of 5-bromo-<strong>[16075-42-6]4-(trifluoromethyl)pyrimidin-2-amine</strong>; [0249] To a solution of <strong>[16075-42-6]2-amino-4-trifluoromethylpyrimidine</strong> (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g,22.5 mmol) was added. After stirring for an additional 4 hours the solution was added toCH2Cl2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82%) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine:LCMS (m/z): 242/244 (MH+); 1H NMR (CDCl3): delta 8.52 (s, IH), 5.38 (bs, 2H).
82%
[0250] To a solution of <strong>[16075-42-6]2-amino-4-trifluoromethylpyrimidine</strong> (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2CI2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and <n="97"/>the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82%) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS (m/z): 242/244 (MH+). 1H NMR (CDCl3): delta 8.52 (s, IH), 5.38 (bs, 2H).
82%
[0092] Synthesis -bromo-<strong>[16075-42-6]4-(trifluoromethyl)pyrimidin-2-amine</strong>[0093] To a solution of <strong>[16075-42-6]2-amino-4-trifluoromethylpyrimidine</strong> (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2C12 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2S04, filtered and concentrated, yielding 10.9 g (82%) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS im/z): 242/244 (MH ). ¾ NMR (CDC13): delta 8.52 (s, 1H), 5.38 (bs, 2H).
75%
With N-Bromosuccinimide; In chloroform; at 20 - 50℃; for 20h;
4-(Trifluoromethyl)pyrimidin-2-ylamine (2 g, 12.3 mmol) was suspended in chloroform (70 ml) followed by the addition of N-bromosuccinimide (3.3 g, 18.4 mmol) and the resulting mixture was stirred at 50 C. for 5 hours and then at room temperature for 15 hours. A mixture of methylene chloride (50 ml) and 1 M sodium hydroxide (50 ml) was added, the resulting mixture was stirred, and then the organic layer was fractionated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 75%) as a pale orange solid.1H-NMR (CDCl3) delta: 5.37 (2H, brs), 8.52 (1H, s).
73%
With N-Bromosuccinimide; In dichloromethane; at 25℃; for 48h;Darkness;
To a solution of compound 31(500mg, 3.06 mmol) in DCM (60 mL) was added NBS (1.66g, 9.32 mmol). The solution was stirred in the dark for 2d at rt. Then the reaction was quenched with iN NaOH (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound 32 as a white solid (530 mg, 73% yield), which was used directly in the next step without further purification. ?H NIVIR (CDC13): 8.52(s, 1H), 5.29(bs, 2H).
(3aRS,6RS,6aRS)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5']-bipyrimidin-6-yl)-6-((tert-butyldimethylsilyl)oxy)hexahydro-2H-cyclopenta[d]oxazol-2-one[ No CAS ]
(4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5']-bipyrimidin-6-yl)-5-2-(((tert-butyldiphenylsilyl)oxy)propyl)-4-methyloxazolidin-2-one[ No CAS ]
(45,5S)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5']-bipyrimidin-6-yl)-5-2-(((tert-butyldiphenylsilyl)oxy)propyl)-4-methyloxazolidin-2-one[ No CAS ]
(4R,4S)-4-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27 g
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In methanol; water; at 22℃; under 2250.23 Torr; for 24h;Autoclave;
In an autoclave, under 3 bars at 22 C., for 24 hours, a mixture of 1.1 g of 10% Pd/C, of 22 g of <strong>[16075-42-6]2-amino-4-(trifluoromethyl)pyrimidine</strong> dissolved in 200 mL of water, 50 mL of methanol and 50 mL of 12N HCl is hydrogenated. The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure. The obtained residue is dried in an oven, in the presence of P2O5, in order to obtain 27 g of (4R,4S)-4-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride, as a grey solid including the following characteristics: Mass spectrum (method A), ES+/-: [M+H]+: m/z 168; Rt (min)=0.17
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In methanol; water; at 22℃; under 2250.23 Torr; for 24h;
(4R,4S)-4-(Trifluoromethyl)-1 ,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride can be prepared in the following way. A mixture of 1 .1 g of 10% Pd/C, 22 g of 2-amino-4- (trifluoromethyl)pyrimidine dissolved in 200 ml of water, 50 ml of methanol and 50 ml of 12N HCI is hydrogenated at 3 bar, at 22C, for 24 hours in an autoclave. The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure. The residue obtained is oven-dried, in the presence of P2O5, so as to give 27 g of (4R,4S)-4-(trifluoromethyl)-1 ,4,5,6- tetrahydropyrimidin-2-ylamine hydrochloride, in the form of a grey solid, the characteristics of which are the following: Mass spectrum (method A), ES+/-: [M+H]+: m/z 168; Tr (min) = 0.17
(8S)-9-[2-(6-dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-9-(1-hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
tert-butyl {4-(2-((S)-8-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-oxo-2-(trifluoromethyl)-2,3,4,6-tetrahydro-1H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl)phenyl}carbamate[ No CAS ]
(8S)-9-[2-(4-aminophenyl)ethyl]-2-(1S,45)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-9-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-9-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
(8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
1-ethyl-3-{4-[2-((S)-8-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}urea[ No CAS ]
methyl 3-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate[ No CAS ]
(8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one[ No CAS ]
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