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Structure of 66399-30-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With ammonium formate In methanol at 70℃; for 2.5 h; Inert atmosphere Stage #2: With amine transaminase-117; sodium pyruvate In methanol at 20℃; for 24 h; Darkness; Inert atmosphere; Enzymatic reaction
A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd°-nanocatalyst (Pd°-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wtpercent, 1 molpercent) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70°C for the time shown in table 4. Next, the vial was put on ice and methanol (0.367 mL) was added, followed by 6 mL of an aqueous buffer solution (50 mM HEPES, pH 8.2) containing amine transaminase (ATA) and 2-5 equivalents sodium pyruvate (1 equiv. = 0.2 mmol, 22 mg). The tubes were put in darkness and room temperature for 24 hours with gentle mixing on an orbital shaker. Enantiomeric excess (ee) was determined by HPLC analysis (triplicate samples).
Reference：
[1] Patent: WO2016/96905, 2016, A1, . Location in patent: Page/Page column 25
[2] Chemistry Letters, 2004, vol. 33, # 11, p. 1424 - 1425
[3] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5314 - 5327
[4] Organic Process Research and Development, 2014, vol. 18, # 6, p. 788 - 792
[5] ACS Catalysis, 2016, vol. 6, # 6, p. 3932 - 3940
2
[ 444643-11-2 ]
[ 444643-12-3 ]
[ 66399-30-2 ]
Yield
Reaction Conditions
Operation in experiment
86 % ee
With hydrogen In methanol at 60 - 100℃; for 21 h; Heating
367 mg (1.51 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 18.0 mg (0.123 wt percent as Pd) of 5percent palladium/active carbon (water content: 50 wt percent) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.5 MPa and stirring for 21 hours at 60° C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00031] [00159] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 73percent, a:b=1:99 and 86percent ee, respectively. [00160] 1H-NMR (TMS, CDCl3): 1.39 (d, 6.6 Hz, 3H), 2.10 (br, 2H), 4.11 (q 6.6 Hz, 1H), 7.12-7.38 (Ar-H, 4H).Example 25Step 3: Hydrogenolysis (Corresponding to Table 1, Run 5) [00161] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 7.3 mg (0.05 wt percent as Pd) of 5percent palladium/active carbon (water content: 50 wt percent) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.5 MPa and stirring for 21 hours at 100° C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00032] [00162] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 84percent, a:b=1:99 and 86percent ee, respectively.Example 26Step 3: Hydrogenolysis (Corresponding to Table 1, Run 6) [00163] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 11.0 mg (0.075 wt percent as Pd) of 5percent palladium/active carbon (water content: 50 wt percent) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.8 MPa and stirring for 21 hours at 60° C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl )ethylamine (5) represented by the following formula: [C00033] [00164] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral CC and found to be 72percent, a:b=1:99 and 86percent ee, respectively.
86 % ee
With hydrogen; acetic acid In methanol at 25℃; for 21 h; Heating
365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 300.0 mg (2 wt percent as Pd) of 5percent palladium/active carbon (water content: 50 wt percent) were added to 112.5 ml of methanol and 37.5 ml of acetic acid, followed by setting the hydrogen pressure to 7 MPa and stirring for 21 hours at 25° C. (internal pressure at completion of the reaction: 3 MPa). Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00034] [00166] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 43percent, a:b=1:99 and 86percent ee, respectively.Reference Example 2Step 3: Hydrogenolysis (Corresponding to Table 16 Run 3) [00167] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 300.0 mg (2 wt percent as Pd) of 5percent palladium/active carbon (water content; 50 wt percent) were added to 112.5 ml of methanol and 37.5 ml of acetic acid, followed by setting the hydrogen pressure to 7 MPa and stirring for 21 hours at 25° C. (internal pressure at completion of the reaction: 5.5 MPa). Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00035] [00168] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 72percent, a:b=1:99 and 86percent ee, respectively.
With pyridoxal 5'-phosphate In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 24 h; Resolution of racemate; Enzymatic reaction
General procedure: All experiments were carried out keeping the protein content constant (8 mg mL−1) if not otherwise stated. One of the substrates rac-1a–d (50 mM), sodium pyruvate (50 mM) and pyridoxal-5′-phosphate monohydrate (0.2 mg mL−1) in phosphate buffer (1 mL, 0.1 M, pH 7.5) containing IPA or DMSO as a possible cosolvent (10, v/v-percent) was added to a 2 mL Eppendorf tube, containing the ω-transaminase sol–gel catalyst (25 or 50 mg). The reaction was shaken (170 rpm) at 30 °C. After 24 h the reaction was stopped by centrifuging the mixture and removing the solution by pipette. The solid catalyst was reused while conversion was monitored by taking a sample (5 μL) from the solution and diluting it with the HPLC eluent (500 μL). The sample was filtered and analyzed for conversion by HPLC. A sample (400 μL) for ee(S)−1 analysis was taken, and aqueous NaOH (2 M, 50 μL) was added followed by the extraction of the amine into ethyl acetate (400 μL). The organic phase (300 μL) was dried with Na2SO4, and after filtration the amine in the sample (200 μL) was derivatized with acetic anhydride (10 μL) to determine the enantiomeric excess of (S)-1 by GC.#10;
Reference：
[1] Process Biochemistry, 2013, vol. 48, # 10, p. 1488 - 1494
7
[ 17640-21-0 ]
[ 403-40-7 ]
[ 1373832-85-9 ]
[ 66399-30-2 ]
Yield
Reaction Conditions
Operation in experiment
37%
at 23℃; for 3 h; Molecular sieve; Enzymatic reaction
General procedure: One of the amines rac-1a-i (2 mmol) and isopropyl methoxyacetate (2 mmol) were added into a reaction vessel containing Novozym 435 (25 mg) and molecular sieves (4 Å, 50 mg). The reaction mixture was shaken (170 rpm) at room temperature (23 °C) if not otherwise stated. The reaction was stopped by filtering off the enzyme at (50 +/- 0.5)percent conversion. Isolation of the products was performed by silica gel chromatography using a mixture of hexane and ethylacetate and/or mixture of dichloromethane and methanol as eluent.
With amine transaminase; sodium pyruvate In methanol at 20℃; for 24h; Cooling with ice; Darkness; Enzymatic reaction; enantioselective reaction;
> 99 % ee
Stage #1: 1-(4-fluorophenyl)ethylamine With (R)-amine dehydrogenase In dimethyl sulfoxide at 37℃; Resolution of racemate; Microbiological reaction; Enzymatic reaction;
Stage #2: With (S)-ω-transaminase In dimethyl sulfoxide at 37℃; for 24h; Resolution of racemate; Microbiological reaction; Enzymatic reaction; enantioselective reaction;
> 99.2 % ee
With NAD‐depended oxidase from Strepto coccusmutans; variant of NADHdependent ε‐deaminating L‐lysine dehydrogenase from Geobacillus stearothermophilus; nicotinamide adenine dinucleotide In aq. buffer at 30℃; for 48h; stereoselective reaction;
Stage #1: 1-(4-fluorophenyl)ethylamine With (SP)-O-ethylphenylphosphonothioic acid In diethyl ether at 20℃; for 6h;
Stage #2: With potassium hydroxide
With chiral stationary phase including isopropyl-functionalized CF6 In methanol; acetic acid; triethylamine; acetonitrile at 0℃;
35.22
In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 μL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode.
61 % ee
With pyridoxal 5'-phosphate; ω-transaminase from Thermomicrobium roseum; piruvate In aq. buffer at 37℃; for 18h; Resolution of racemate; Enzymatic reaction; enantioselective reaction;
With N-ethyl-N,N-diisopropylamine; at 125℃; for 18h;
(a) (S)-1-(1-(4-Fluorophenyl)ethyl)-4-tosylpiperazine. A mixture of <strong>[42137-88-2]N,N-bis(2-chloroethyl)-p-toluenesulfonamide</strong> (32 g, 110 mmol, Lancaster), (S)-4-(fluorophenyl)ethylamine (14 g, 98 mmol, Synquest) and N,N-diisopropyl-ethylamine (35 mL, Aldrich) was heated at 125 C. with stirring for 18 h. The reaction mixture was allowed to cool to 95 C., a 1:1 EtOH/water mixture (85 mL) was added dropwise, and the stirring was continued for 75 min. The reaction mixture was left to reach room temperature and the precipitated solids were filtered. The filter cake was washed with a 40:60 EtOH/water mixture (2*25 mL) and suspended in a 40:60 EtOH/water mixture (100 mL). The suspension was stirred for 75 min at room temperature and was filtered. The filter cake was washed with a 50:50 EtOH/water mixture (2*25 mL) and hexane (50 mL), and dried under vacuo at 55 C. for 18 h to give the title product as a brown solid. M.p.: 124-126 C. MS (ESI, pos. ion) m/z: 363 [M+1].
A vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), HCO2NH4 (37.8 mg, 2 mmol, 10.0 equiv.) and Pd-nanocatalyst (Pd-AmP-MFC, 2.68 mg, 0.002 mmol, 8 wt%, 1 mol%) in MeOH (0.3 mL) under N2 atmosphere was stirred at 70C for the time shown in table 4. Next, the vial was put on ice and methanol (0.367 mL) was added, followed by 6 mL of an aqueous buffer solution (50 mM HEPES, pH 8.2) containing amine transaminase (ATA) and 2-5 equivalents sodium pyruvate (1 equiv. = 0.2 mmol, 22 mg). The tubes were put in darkness and room temperature for 24 hours with gentle mixing on an orbital shaker. Enantiomeric excess (ee) was determined by HPLC analysis (triplicate samples).
With hydrogen;5%-palladium/activated carbon; In methanol; at 60 - 100℃; under 3750.38 - 6000.6 Torr; for 21h;Heating;
367 mg (1.51 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 18.0 mg (0.123 wt % as Pd) of 5% palladium/active carbon (water content: 50 wt %) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.5 MPa and stirring for 21 hours at 60 C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00031] [00159] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 73%, a:b=1:99 and 86% ee, respectively. [00160] 1H-NMR (TMS, CDCl3): 1.39 (d, 6.6 Hz, 3H), 2.10 (br, 2H), 4.11 (q 6.6 Hz, 1H), 7.12-7.38 (Ar-H, 4H).Example 25Step 3: Hydrogenolysis (Corresponding to Table 1, Run 5) [00161] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 7.3 mg (0.05 wt % as Pd) of 5% palladium/active carbon (water content: 50 wt %) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.5 MPa and stirring for 21 hours at 100 C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00032] [00162] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 84%, a:b=1:99 and 86% ee, respectively.Example 26Step 3: Hydrogenolysis (Corresponding to Table 1, Run 6) [00163] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 11.0 mg (0.075 wt % as Pd) of 5% palladium/active carbon (water content: 50 wt %) were added to 1.5 ml of methanol, followed by setting the hydrogen pressure to 0.8 MPa and stirring for 21 hours at 60 C. Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl )ethylamine (5) represented by the following formula: [C00033] [00164] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral CC and found to be 72%, a:b=1:99 and 86% ee, respectively.
With hydrogen; acetic acid;5%-palladium/activated carbon; In methanol; at 25℃; under 22502.3 - 52505.3 Torr; for 21h;Heating;
365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 300.0 mg (2 wt % as Pd) of 5% palladium/active carbon (water content: 50 wt %) were added to 112.5 ml of methanol and 37.5 ml of acetic acid, followed by setting the hydrogen pressure to 7 MPa and stirring for 21 hours at 25 C. (internal pressure at completion of the reaction: 3 MPa). Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00034] [00166] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 43%, a:b=1:99 and 86% ee, respectively.Reference Example 2Step 3: Hydrogenolysis (Corresponding to Table 16 Run 3) [00167] 365 mg (1.50 mmol) of the crude product of the optically active secondary amine (4f) produced in Example 23 and 300.0 mg (2 wt % as Pd) of 5% palladium/active carbon (water content; 50 wt %) were added to 112.5 ml of methanol and 37.5 ml of acetic acid, followed by setting the hydrogen pressure to 7 MPa and stirring for 21 hours at 25 C. (internal pressure at completion of the reaction: 5.5 MPa). Following completion of the reaction, the reaction liquid was filtered with Celite, concentrated and vacuum dried to obtain a crude product of the optically active 1-(4-fluorophenyl)ethylamine (5f) represented by the following formula: [C00035] [00168] Conversion, selectivity at the cleavage position (the previously mentioned a:b) and optical purity of the crude product were determined by chiral GC and found to be 72%, a:b=1:99 and 86% ee, respectively.
N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
Example 17: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (44 mg, yield 98%). 1H-NMR (CDCl3): 1.52 (3H, d, J = 6.83 Hz), 3.73 (3H, s), 4.03 (3H, s), 4.04 (3H, s), 4.96 (1H, m), 5.15 (1H, d, J = 6.59 Hz), 6.44 (1H, d, J = 5.12 Hz), 6.66 (1H, d, J = 2.68 Hz), 6.77 (1H, dd, J = 8.78, 2.68 Hz), 6.87 (1H, s), 7.04 (2H, dd, J = 8.78, 8.78 Hz), 7.36 (2H, dd, J = 8.72, 5.37 Hz), 7.41 (1H, s), 7.55 (1H, s), 8.16 (1H, d, J = 8.78 Hz), 8.46 (1H, d, J = 5.12 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Example 2: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (33 mg, yield 71%). 1H-NMR (CDCl3): delta 1.49 (3H, d, J = 6.83 Hz), 4.04 (3H, s), 4.04 (3H, s), 4.94 - 4.99 (1H, m), 6.42 (1H, d, J = 5.34 Hz), 7.04 (2H, dd, J = 8.78, 8.78 Hz), 7.09 (2H, d, J = 8.54 Hz), 7.33 (2H, dd, J = 8.54, 5.37 Hz), 7.37 (1H, s), 7.46 (2H, d, J = 8.78 Hz), 7.57 (1H, s), 8.42 (1H, d, J = 5.10 Hz)
N-{3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
Example 11: N-{3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (26 mg, yield 58%). 1H-NMR (CDCl3): 1.48 (3H, d, J = 6.83 Hz), 4.01 (3H, s), 4.05 (3H, s), 4.94 - 4.99 (1H, m), 5.43 (1H, d, J = 6.83 Hz), 6.28 (1H, d, J = 5.37 Hz), 7.02 (2H, dd, J = 8.78, 8.78 Hz), 7.11 (1H, d, J = 8.78 Hz), 7.18 (s, 1H), 7.24 (1H, dd, J = 8.78, 2.68 Hz), 7.28 (1H, dd, J = 5.37, 8.78 Hz), 7.39 (1H, s), 7.59 (1H, s), 7.60 (1H, d, J = 2.44 Hz), 8.43 (1H, d, J = 5.12 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Example 14: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (36 mg, yield 77%). 1H-NMR (CDCl3): 1.49 (3H, d, J = 6.83 Hz), 2.17 (3H, s), 4.03 (3H, s), 4.05 (3H, s), 4.87 (1H, d, J = 6.83 Hz), 4.94 - 4.99 (1H, m), 5.97 (1H, s), 6.47 (1H, d, J = 5.12 Hz), 7.01 - 7.07 (4H, m), 7.33 (2H, dd, J = 8.54, 5.12 Hz), 7.42 (1H, s), 7.52 (1H, s), 7.58 (1H, d, J = 8.29 Hz), 8.48 (1H, d, J = 5.37 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Example 26: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. A solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (34 mg, yield 76%). 1H-NMR (CDCl3): 1.48 (3H, d, J = 6.83 Hz), 2.11 (3H, s), 2.16 (3H, s), 4.06 (6H, s), 4.78 (1H, d, J = 5.86 Hz), 5.00 (1H, m), 5.97 (1H, s), 6.26 (1H, d, J = 5.37 Hz), 6.90 - 7.25 (5H, overlapped), 7.30 (2H, m), 7.46 (1H, s), 7.59 (1H, s), 8.44 (1H, d, J = 5.37 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Example 29: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluorophenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 76%). 1H-NMR (CDCl3): 1.50 (3H, d, J = 6.83 Hz), 4.03 (6H, s), 4.97 (1H, m), 5.55 (1H, d, J = 6.59 Hz), 6.46 (1H, d, J = 5.37 Hz), 6.87 - 6.96 (3H, overlapped), 7.01 (1H, dd, J = 8.78, 8.78 Hz), 7.33 (2H, dd, J = 8.54, 5.37 Hz), 7.42 (1H, s), 7.50 (1H, s), 8.17 (1H, dd, J = 9.03, 9.03 Hz), 8.48 (1H, d, J = 5.37 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Example 32: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (27 mg, yield 59%). 1H-NMR (CDCl3): 1.48 (3H, d, J = 6.83 Hz), 4.00 (3H, s), 4.05 (3H, s), 4.98 (1H, m), 5.55 (1H, d, J = 7.08 Hz), 6.37 (1H, d, J = 5.37 Hz), 7.00 (2H, dd, J = 8.54, 8.54 Hz), 7.00 (1H, overlapped), 7.10 (1H, dd, J = 8.78, 8.78 Hz), 7.28 (2H, dd, J = 8.54, 5.37 Hz), 7.33 (1H, s), 7.38 (1H, s), 7.46 (1H, dd, J = 12.18, 2.44 Hz), 7.58 (1H, s), 8.44 (1H, d, J = 5.37 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Example 8: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 77%). 1H-NMR (CDCl3): 1.49 (3H, d, J = 6.34 Hz), 2.09 (3H, s), 2.13 (3H, s), 4.05 (3H, s), 4.05 (3H, s), 4.95 - 5.00 (2H, m), 6.28 (1H, d, J = 5.37 Hz), 6.92 (1H, s), 7.04 (2H, dd, J = 8.78, 8.78 Hz), 7.33 (2H, dd, J = 8.54, 5.12 Hz), 7.42 (1H, s), 7.51 (1H, s), 7.57 (1H, s), 8.44 (1H, d, J = 5.12 Hz)
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Example 23: N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyphenyl}-N'-[(1S)-1-(4-fluorophenyl)ethyl]urea 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (45 mg, yield 100%). 1H-NMR (CDCl3): 1.48 (3H, d, J = 6.83 Hz), 3.71 (3H, s), 4.00 (3H, s), 4.04 (3H, s), 5.00 (1H, m), 5.48 (1H, d, J = 7.32 Hz), 6.29 (1H, d, J = 5.37 Hz), 6.62 (1H, dd, J = 8.54, 2.44 Hz), 6.99 (3H, overlapped), 7.19 (1H, s), 7.29 (1H, dd, J = 8.54, 5.12 Hz), 7.38 (1H, s), 7.47 (1H, d, J = 2.44 Hz), 7.61 (1H, s), 8.41 (1H, d, J = 5.37 Hz)
With N-ethyl-N,N-diisopropylamine; In 1-ethoxyethanol; at 135℃;
EXAMPLE 1 6-Chloro-N-[(1S)-1-(4-fluorophenyl)ethyl]pyrazin-2-amine A solution of S-(-)-1-(4-fluorophenyl)-ethylamine (5.0 g, 35. 9 mmol), 2, 6-dichloropyrazine (5. 90 g, 39. 6 nunol), diisopropylethylamine (12.5 mL, 71. 8 mmol) in ethoxyethanol (25 mL) was heated at 135C undef N : overnight. The sulvent was removed in vacuo and the residue washed with I I20 (2 x 30 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue triturated with hexancs (2 x 10 mL) to give a light brown solid. The washings were combined, concentrated and the residue obtained chromatographed using ethyl acetate-hexane (1: 4-1: 2) to'sep. =ate solid product which, combined with the original solids, gave the total product (7. 07 g, 78%). 1H-n. m. r. (CDCl3) No.1,56 (d, 3H, J = 6. 8 Hz, CH3), 4.81-4. 94 (m, 1H, CH), 5. 05 (m, 1, NH), 6.98-7.07 (m,2H,ArH),7.29-7.36 (m, 2H, ArH), 7.60 (s, 1H, pyraz-H), 7.80 (s, 1H, pyraz-H).
4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-methanesulfonyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid benzyl ester[ No CAS ]
[ 66399-30-2 ]
4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[(S)-1-(4-fluorophenyl)ethylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; for 48h;
A solution of 4- (5-cyclopropyl-lH-pyrazol-3-ylamino)-2-methanesulfonyl-7, 8- dihydro-5H-pyrido [4, 3-d] pyrimidine-6-carboxylic acid benzyl ester (Method 144; 0.10 g, 0.21 mmol), (S)-l- (4-fluoro-phenyl)-ethylamine (0.30 g, 2.1 mmol), and DIPEA (0.27 g, 2.1 mmol) inn-BuOH (3 ml) was heated to110 C in a sealed tube for 48 hours. The reaction was cooled to25 C, concentrated under reduced pressure, acidified with 0.5 N HCl (50 ml), and extracted with DCM (3 x 50 ml). The combined organic layer was dried overMgSO4, concentrated, and purified by column chromatography (DCM:MeOH = 80: 1) to give the title compound (0.6 g, 54%). MS: Calcd.: 527; Found: [M+H] + 528.
4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-methanesulfonyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester[ No CAS ]
[ 66399-30-2 ]
4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[(S)-1-(4-fluorophenyl)ethylamino]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; for 48h;
A mixture of4- (5-cyclopropyl-lH-pyrazol-3-ylamino)-2-methanesulfonyl-5, 8- dihydro-6H-pyrido [3,4-d] pyrimidine-7-carboxylic acid benzyl ester (Method 149; 2.0 g, 4.3 mmol), <strong>[66399-30-2](S)-1-(4-fluoro-phenyl)-ethylamine</strong> (0.30 g, 2.1 mmol), and DIEA (5.5 g, 42.6 mmol)n-BuOH (15 ml) was heated to110 C in a sealed tube for48 hours, cooled to25 C, concentrated, acidified with 0.5 N HCl (100 ml), and extracted with DCM (3 x 150 ml). The combined organic layer was dried overMgS04, concentrated, and purified by column chromatography (DCM:MeOH =80 : 1) to give the title compound (0.7 g,31%). MS: Calcd. : 527; Found: [M+H]+ 528.
(S)-(6-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-[1-(4-fluoro-phenyl)-ethyl]-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With triethylamine;tetra-(n-butyl)ammonium iodide; In toluene; at 20℃; for 17h;Heating / reflux;
0.300 g (3.0 MMOL) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.514 g (3.7 MMOL) of (S)-1- (4-fluorophenyl)-ethylamine were added successively to a solution of 0.500 g (2.5 mmol) of 5-METHYL-6, 7-DICHLORO- [1, 2,4] triazolo [1, 5-a] pyrimidine in 10 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and DICHLOROMETHANE was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and with water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.520 g (1,7 mmol, 68% of theory) of the title compound having a melting point of 103-104C. H-NMR (CDC13) 8 : 8.25 (s, 1 H), 7.30 (dd, 2H), 7.00 (t, 2H), 6.25 (m, 1 H), 6.05 (bd, 1 H), 2.60 (s, 3H), 1.75 (d, 3H).
With potassium carbonate; In acetonitrile; at 0 - 25℃; for 17h;
To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH3CN (20 ml), was added (5)-l-(4-fluoro- phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at 0 0C. The reaction mixture was stirred at 25 C for 17 hrs. The solid was removed by filtration and the resulted cake was washed with EtOAc (20 ml). The combined filtrate was concentrated and purified by column chromatography (hexane - EtOAc = 10 : 1) to give the title compound as a yellow solid (1.74 g, 82%). 1H NMR (400 MHz) delta 8.65 (d, J= 7.6 Hz, IH), 8.43 (d, J= 8.4 Hz, IH), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J= 8.8 Hz, IH), 5.37 (m, IH), 1.59 (d, J= 6.8 Hz, 3H)
82%
With potassium carbonate; In acetonitrile; at 0 - 25℃; for 17h;
To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH3CN (20 ml), was added (S)-l-(4-fluoro- phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at 0 C. The reaction mixture was stirred at EPO <DP n="45"/>25 0C for 17 hours. The solid was removed by filtration and the resulted cake was washed with EtOAc (20 ml). The combined filtrate was concentrated and purified by column chromatography (hexane : EtOAc = 10 : 1) to give the title compound as a yellow solid (1.74 g, 82%). NMR (400 MHz) 8.65 (d, J= 7.6 Hz, IH), 8.43 (d, J= 8.4 Hz, IH), 7.51 (m, 2H), 7.16 (m, 2H)5 6.81 (d, J= 8.8 Hz, IH), 5.37 (m, IH), 1.59 (d, J= 6.8 Hz, 3H).
(S)-5,6-dichloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In acetonitrile; at 0 - 25℃; for 17h;
To a mixture of 2,3,6-trichloro-5-nitropyridine (1.00 g, 4.40 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in anhydrous acetonitrile (10 ml) was added (^-l-^-fluoro- phenyl)-ethylamine (0.64 g, 4.62 mmol) dropwise at 0 C. After addition, the reaction mixture was stirred at 25 0C for 17 hours. The solid was removed by filtration and washed with EtOAc (20 ml). After evaporation of the solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 10 : 1) to give the title compound as a yellow solid (0.61 g, 79% pure, 33%). NMR (400 MHz, CDCl3) 8.46.(br s, 2H), 7.36 (m, 2H), 7.03 (m, 2H), 5.40 (m, IH), 1.63 (d, J= 6.8 Hz, 3H).
33%
With potassium carbonate; In acetonitrile; at 0 - 25℃; for 17h;
To a mixture of 2,3,6-trichloro-5-nitropyridine (1.00 g, 4.40 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in anhydrous acetonitrile (10 ml) was added (£)-l-(4-fluoro- phenyl)-ethylamine (0.64 g, 4.62 mmol) dropwise at 0 0C. After addition, the reaction mixture was stirred at 25 C for 17 hours. The solid was removed by filtration and washed with EtOAc (20 ml). After evaporation of the solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 10 : 1) to give the title compound as a yellow solid (0.61 g, 79% pure, 33%). NMR (400 MHz, CDCl3) 8.46.(br s, 2H), 7.36 (m, 2H), 7.03 (m, 2H), 5.40 (m, IH), 1.63 (d, J= 6.8 Hz, 3H).
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(1S)-1-(4-fluoro-phenyl)-ethyl]-5-nitro-pyrimidine-2,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 25℃; for 1h;
A mixture of 2-chloro-iV~(5-cyclopropyl- lH-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 76; 1.0 g, 3.6 mmol), (iS)-l-(4-fluorophenyl)ethanamine (0.5 g, 3.6 mmol), and DIEA (0.6 g, 4.6 mmol) in ra-BuOH (15 ml) was stirred at 25 0C for 1 hour and then concentrated. The resulting oil was purified by column chromatography (DCM : MeOH = 50 : 1) to give the title compound (0.8 g, 60%). MS: Calcd.: 383; Found: [M+H]+ 384.
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; for 18h;
A suspension of 2,5-difluoro-6-(5-methyl-lH-pyrazol-3-ylamino)nicotinomtrile (Method 41, 0.20 g, 0.85 mmol), DIEA (0.14 g, 1.1 mmol), and (5)-l-(4-fluorophenyl) ethanamine (0.23 g, 1.7 mmol) in n-BuOH (2 ml) was heated to 130 0C for 18 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2 x 50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH = 100 : 1) to give the title compound (0.27 g, 91%). 1H NMR (400 MHz, CD3OD) delta 7.38-7.32 (m, 3H), 7.03-6.99 (m, 2H)5 5.99 (br s, IH), 5.15-5.14 (m, IH), 2.24 (s, 3H), 1.53 (d, J= 6.8 Hz, 3H). MS: Calcd.: 354; Found: [M+H]+ 355.
A solution of 2,3,6-trifluoro-5-nitropyridine (Method 24, 2.Og, 11.2 mmol) in THF (50ml) was cooled to 0 0C. (5)-l-(4-Fluorophenyl)ethanamine (1.56g, 11.2mmol) was added and the reaction was stirred at 0 0C for 30 minutes. The reaction was quenched with water (50 EPO <DP n="102"/>ml) and then extracted with DCM (2 x 75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexane-DCM = 1 : 1) to give the title compound (2.3 g, 70%).
70%
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 2,3,6-trifluoro-5-nitropyridine (Method 56, 2.0 g, 11.2 mmol) in THF (50 ml) was cooled to 0 0C, to which was added (S)-l-(4-fluorophenyl)ethanamine (1.56 g, 11.2 mmol). The reaction was stirred at 0 0C for 30 min., then quenched with water (50 ml) and extracted with DCM (2 x 75 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexanes-DCM = 1 : 1) to give the title compound (2.3 g, 70%).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 135℃; for 48h;In sealed tube;
2-Chloro-5-fluoro-6-(5-isopropoxy-lH'-pyrazol-3-ylaniino)nicotinonitrile (Method 2;5 1.4g, 5.0 mmol) and (S)-l-(4-fluorophenyl)ethanamine (1.Og, 9.0 mmol) were added to a solution of «-BuOEta (8 ml) and DIEA (0.8g, 6.0 mmol) in a sealed tube. The reaction was heated to 135 C for 48 hrs, cooled to 25 0C, and concentrated. The resulting residue was purified by column chromatography (DCM - MeOH = 80 : 1) to give the title compound (0.9Og, 48%). 1H NMR (400 MHz, CD3OD) delta 7.43 (d, J= 10.5 Hz5 IH), 7.39-7.35 (m, 2H),LO 7.04-6.99 (m, 2H), 5.47 (s, IH)3 5.12-5.11 (m, IH), 4.60-4.51 (m, IH), 1.56 (d, J= 7.0 Hz, 3H), 1.33-1.30 (m, 6H). MS: Calcd.: 398; Found: [M+H]+ 399
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 48h;In sealed tube;
A portion of 2-chloro-6-(5-cyclopropyl-lH"-pyrazol-3-ylamino)-5-fluoronicotinonitrile 0 (Method 1; 0.8g, 2.8 mmol) and (S)-l-(4-fluorophenyl)ethanamine (0.8g, 5.6 mmol) were added to a solution of rc-BuOH (4 ml) and DIEA (0.5g, 3.7 mmol) in a sealed tube. The reaction was heated to 140 C for 48 hrs, then cooled to 25 C and concentrated. The resulting residue was purified by column chromatography (DCM - MeOH = 50 : 1) to give the title compound (0.55g, 50%). 1H NMR (400 MHz, CDCl3) delta 8.44 (br s, IH), 7.37-7.33 (m, 2H), 5 7.27 (d, J= 9.6 Hz, IH), 7.07-7.03 (m, 2H), 6.11 (s, IH), 5.24-5.20 (m, 2H), 1.87-1.83 (m, IH), 1.60 (d, J- 6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380; Found: [M+H]+ 381.
50%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 48h;
mixture of 2-chloro-6-(5-cyclopropyl-lH-pyrazol-3-ylamino)-5- fluoronicotinonitrile (Method 43; 0.8 g, 2.8 mmol), (S)-l-(4-fluorophenyl)ethanamine (0.8 g,5.6 mmol), and DIEA (0.5 g, 3.7 mmol) in «-BuOH (4 ml) was heated in a sealed tube at 140C for 48 hrs. The reaction mixture was concentrated and purified by column chromatography(DCM : MeOH = 50 : 1) to give the title compound (0.55 g, 50%). MS: Calcd.: 380; Found:[M+H]+ 381.
With sodium t-butanolate;palladium diacetate; (biphenyl-2-ylmethylene)bis(dimethylphosphine); In toluene; at 85℃;
To a 25 ml round bottom flask was added Pd(OAc)2 (45 mg, 0.2 mmol), (biphenyl-2- ylmethylene)bis(dimethylphosphine) (120 mg, 0.4 mmol) and sodium tert-butoxide (480 mg, 5.0 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 2,6-dichloropyridine (300 mg, 2.0 mmol) and [(15)-l-(4-fluorophenyl)ethyl]amine (306 mg, 2.2 mmol) in toluene (4 ml). The reaction mixture was heated at 85 C overnight. The solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (10-40% EtOAc in hexanes) gave the title compound (339 mg, 68%). 1H NMR (CDCl3) delta 1.55 (m, 3H), 4.66 (m, IH), 5.07 (br s, IH), 6.01 (m, IH), 6.54 (m, IH), 7.00 (m, 2H), 7.25 (m, 3H).
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 2h;Inert atmosphere;
Step 1 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine 300 mg of 2,6-dichloropyridine, 296 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 119 mg of 2-(di-t-butylphosphino)biphenyl, 487 mg of sodium t-butoxide and 45 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85 C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the objective compound as pale yellow oil.
With palladium diacetate; sodium t-butanolate; In toluene; at 85℃; for 2h;Inert atmosphere;
step 1 (S) -6- chloro -N- [1- (4- fluorophenyl) ethyl] pyridin-2-aminein deaerated toluene 6 ml, 2, 6 - dichloropyridine 300mg, (S) - (- ) - 1- (4-fluorophenyl) ethylamine 296 mg, 2-addition (di -t- butyl phosphino) biphenyl 119 mg, sodium t- butoxide 487mg and palladium acetate 45mg sequentially and, under an argon atmosphere, and stirred for 2 hours at 85 C..The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 210mg as a pale yellow oil.
A solution of commercially available N-Boc-trans-4-hydroxyl-L-proline ester (2.93 g) in CH2Cl2 (20 ml) was cooled to -30 C and treated with DIEA (4.8 ml). After the addition of triflic anhydride (2.2 ml), the mixture was stirred at -30 0C for 60 min and then treated with a solution of the commercially available amine in CH2Cl2 (20 ml). The mixture was allowed to warm to rt overnight. The mixture was diluted with CH2Cl2 (20 ml), washed with 0.5 M Na2CO3 (2 x 50 ml) and brine (50 ml). The organic phase was dried over MgSO4 and concentrated to leave a residue, which was purified by chromatography on silica (CH2Cl2/acetone, 4:1) to afford the title compound (2.22 g, 75 %, MH+ = 367).
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 0 - 20℃; for 96.4667h;Product distribution / selectivity;
Example 5 Synthesis of 1-[1-(4-fluorophenyl)ethyl]piperidin-2-one A solution of 5-bromovaleryl chloride (1.0 ml) in toluene (2 ml) was added dropwise to a two-layer mixed solution of a vigorously stirred solution of 1.0 g of (S)-1-(4-fluorophenyl)ethylamine (7.19 mmol) in 5 ml of toluene and a 50% sodium hydroxide solution (7 ml) under ice-cooling over 13 minutes. After stirring the reaction mixture at the same temperature for 15 minutes, benzyltriethylammonium chloride (164 mg) was added to the reaction solution. The reaction mixture was stirred at room temperature for four days. To the reaction solution was added 30 ml of ice water and the layers were separated. Then, the aqueous layer is reextracted with toluene (7 ml). The combined organic layers were sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure to provide 1.38 g of the title compound as a colorless oil (yield: 87%). 1H-NMR (600 MHz, CDCl3) delta (ppm): 1.49 (d, J = 7 Hz, 3H), 1.60 (m, 1H), 1.74 (overlapped, 1H), 1.76 (overlapped, 2H), 2.48 (m, 2H), 2.77 (m, 1H), 3.10 (m, 1H), 6.13 (q, J = 7 Hz, 1H), 7.01 (dd, J = 9, 9 Hz, 2H), 7.26 (dd, J = 9, 6 Hz, 2H).
87%
With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 20℃; for 96h;
PRODUCTION EXAMPLE 1 Preparation of 1-[1-(4-fluorophenyl)ethyl]piperidin-2-one A solution of 5-bromovaleryl chloride (1.0 ml) in toluene (2 ml) was added dropwise to a bilayer mixture of a vigorously-stirred solution of 1.0 g of (S)-1-(4-fluorophenyl)ethylamine (7.19 mmol) in 5 ml of toluene and an aqueous 50% sodium hydroxide solution (7 ml) under ice-cooling over 13 minutes. The reaction mixture was stirred at the same temperature for 15 minutes, and then benzyltriethylammonium chloride (164 mg) was added thereto. The reaction mixture was further stirred at room temperature for 4 days. To the reaction solution was added 30 ml of ice water, and the solution was separated. The aqueous layer was then reextracted with toluene (7 ml). The combined organic layers were washed sequentially with water, 1 N hydrochloride, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 1.38 g (yield: 87%) of the title compound as a colorless oily substance. 1H-NMR (600 MHz, CDCl3) delta (ppm): 1.49 (d, J=7 Hz, 3H), 1.60 (m, 1H), 1.74 (overlapped, 1H), 1.76 (overlapped, 2H), 2.48 (m, 2H), 2.77 (m, 1H), 3.10 (m, 1H), 6.13 (q, J=7 Hz, 1H), 7.01 (dd, J=9, 9 Hz, 2H), 7.26 (dd, J=9, 6 Hz, 2H).
Synthesis of 1-[(S)-1-(4-fluorophenyl)ethyl]piperidin-2-one A solution of 5-bromovaleryl chloride (1.0 mL) [CAS #4509-90-4] in toluene (2 mL) was added dropwise to a two-layer mixture of a vigorously stirred solution of (S)-1-(4-fluorophenyl)ethylamine (1.0 g) [CAS #66399-30-2] in toluene (5 mL) and a 50% sodium hydroxide solution (7 mL) under ice-cooling over 13 minutes. The reaction solution was stirred at the same temperature for 15 minutes. Benzyltriethylammonium chloride (164 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for four days. Ice water was added to the reaction solution and the organic layer was separated. Then, the aqueous layer is reextracted with toluene. The combined organic layers were sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.38 g of a crude product of the title compound. The property values of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 1.48 (d, J = 7.2 Hz, 3H), 1.55-1.80 (m, 4H), 2.47 (m, 2H), 2.76 (m, 1H), 3.09 (m, 1H), 6.12 (q, J = 7.2 Hz, 1H), 7.01 (dd, J = 8.4, 8.4 Hz, 2H), 7.26 (m, 2H).
tert-butyl {2-[{4-[(2,4-difluorobenzyl)oxy]-3-methoxybenzyl}([(1S)-1-(4-fluorophenyl)ethyl]amino}carbonyl)amino]ethyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
620 mg (4.46 mmol) (15)-l-(4-fluorophenyl)ethylamine and 0.93 ml (5.37 mmol) diisopropyl- ethylamine are dissolved in 10 ml dichloromethane and cooled to 00C. 943 mg (4.68 mmol) 4- nitrophenylchloroformate is added and after 5 min the cooling bath is removed. Stirring is continued for 1.5 h until 750 mg (1.78 mmol) ter/-butyl [2-({4-[(2,4-difluorobenzyl)oxy]-3- methoxybenzyl}amino)ethyl]carbamate and 0.79 ml (4.44. mmol) diisopropylethylamine dissolved in 2.5 ml dichloromethane are added to the suspension. The mixture is stirred at rt before poured on IN hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The product is isolated from the crude mixture by chromatography on silica gel (gradient dichloromethane to dichloromethane/methanol 100: 1) to yield 904 mg (87% of th.) of the title compound.LC-MS (method 1 ): R1 = 2.78 min, m/z = 588 (M+H)+1H-NMR (400 MHz, DMSO-d6): delta = 7.60 (q, IH), 7.38-7.28 (m, 3H), 7.17-7.07 (m, 3H), 7.00 (d, IH), 6.89 (t, IH), 6.80 (s, IH), 6.76 (d, IH), 6.70 (d, IH), 5.05 (s, 2H), 4.90 (m, IH), 4.48 (s, 2H), 3.65 (s, 3H), 3.22-3.15 (m, 2H), 3.02-2.95 (m, 2H), 1.37 (s, 12H).
Example 3A solution of (S)-I -(4-fluorophenyl)ethanamine (214 muL, 1.63 mmol) in THF (1.0 mL) was added to a solution of cyanuric chloride (300 mg, 1.63 mmol) in THF (10.0 mL) at OC. The mixture was stirred at 0 C for 15 min and then DIPEA (284 muL, 1.63 mmol) was added. The mixture was stirred at 0 C for further 15 min. 5-Isopropylthiazol-2- amine (compound 1) (255 mg, 1.79 mmol) and DIPEA (312 muL, 1.79 mmol) were added and the mixture was subjected to microwave irradiation at 15OC for 10 min. 1-Methylpiperazine (362 muL, 3.26 mmol) and DIPEA (568 muL, 3.26 mmol) were added and the mixture was subjected to microwave irradiation at 6OC for 20 min. EtOAc was added and the mixture was washed with saturated NaHCO3 solution and brine, respectively. The organic phase was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel(DCM/MeOH 99:1 to 96:4 and then EtOAc/DCM/MEOH 80:15:5) to yield the compound 3 (75 mg, 10% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6, 8OC): delta 10.31 (s, 1H), 7.43 (m, 2H), 7.34 (d, J= 8.0 Hz, 1H), 7.08 (m, 2H), 7.02 (m, 1H), 5.23 (s, 1H), 3.74 (m, 4H), 3.10 (m, 1H), 2.34 (m, 4H), 2.22 (s, 3H), 1.47 (d, J= 6.8 Hz, 3H), 1.28 (d, J = 6.8 Hz, 6H). MS (ESI): Calcd. for C22H30FN8S: 457, found 457(M+H)+
Stage #1: (S)-1-(4-Fluoro-phenyl)-ethylamine; methyl 6-fluoro-3-formylbenzoate With potassium carbonate In dimethyl sulfoxide at 70℃;
Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 70℃; for 2h;
Stage #3: With sulfuric acid; dihydrogen peroxide In methanol; water at 2℃; for 6h;
75A.1.i+ii
i) To (S)-1-(4-fluorophenyl)ethylamine (170 mg, 1.2 mmol) is added K2C03 (50 mg, 0.36 mmol) and a solution of fluoroarene 15a3 (55 mg, 0.30 mmol) in DMSO (0.5 mL). The reaction is agitated on an orbital shaker at 70 °C overnight. Water (1 mL) and HCI 12M (0.7 mL) are added and this reaction mixture is stirred for 2 h at 70 °C. The resulting solution is diluted with EtOAc (4 mL), washed with brine (2x) andconcentrated under vacuum.ii) To the resulting residue is added MeOH (3 mL) and the reaction mixture is cooled to 2 °C and H202 30% (45 μL, 0.40 mmol) and H2S04 16% (25 μL, 0.04 mmol) are added. The reaction is stirred for 6 h at 2 °C. To the resulting solution is added brine (2 mL) and the desired product is extracted (2x) with EtOAc (4 mL). The combined organic phases are washed (2x) with brine, dried over MgS04, filtered andconcentrated under vacuum.
With sodium carbonate; In ethanol; for 5h;Heating; Reflux;
Example 6. (S)-8-[l-(4-Fluorophenyl)ethyl]-5-methyl-7,8-dihydro-6H-pyrrolo[3,2e][l,2,4] triazolo[l,5-a]pyrimidine [Compound 7]A mixture of intermediate 7-chloro-6-(2-chloroethyl)-5-methyl[l,2,4]triazolo[l,5- fl]pyrimidine (390 mg, 1.7 mmol), (S)-4-fluoro- -methylbenzylamine (378 mg, 2.7 mmol, ee 99%) and sodium carbonate (324 mg, 3.0 mmol) in ethanol (5 mL) was heated under reflux for 5 h. The mixture was cooled to room temperature, filtered, and the solvent removed from the filtrate. The crude product was triturated with di- isOpropylether to afford 8-[(S)-l-(4-fluorophenyl)ethyl]-5-methyl-7,8-dihydro-6H- pyrrolo[3,2e][l,2,4] triazolo[l,5-a]pyrimidine as a yellow solid (430 mg, 85 %).1H NMR (CDCI3) delta 1.71 (3 Eta, d), 2.39 (3 Eta, s), 3.06 (2 Eta, m), 3.44 (1 Eta, m), 3.84 (1 Eta, m), 6.85 (1 Eta, q), 7.03 (2 Eta, m), 7.34 (2 Eta, m) and 8.30 (1 Eta, s).LCMS (ES+): 298 (MH+, 100%).
85%
With sodium carbonate; In ethanol; for 5h;Heating; Reflux;
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃; for 3h;Inert atmosphere;
Step 1 (S)-1-{2-Chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl}ethanone 535 mg of 1-(2,6-dichloropyridin-4-yl)ethanone (Steps 1 and 2 of Example 29), 391 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 262 mg of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1.28 g of cesium carbonate and 63 mg of palladium acetate were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100 C. for 3 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 132 mg of the objective compound as pale yellow powder. MS (ESI) m/z 293 (M+H)
With palladium diacetate; caesium carbonate; In toluene; at 89℃; for 3h;Inert atmosphere;
step 1 (S) -1- {2- chloro-6- [1- (4-fluorophenyl) ethylamino] pyridin-4-yl} ethanonein deaerated toluene 10 ml, 1- (2 , 4-6-dichloro-yl) ethanone 535 mg (example 29 step 1,2), (S) - ( -) - 1- (4-fluorophenyl) ethylamine 391 mg, (±)-2,2'- bis (diphenylphosphino) -1,1'-binaphthyl 262 mg, were added successively cesium carbonate 1.28g and palladium acetate 63 mg, under an argon atmosphere and stirred for 3 hours at 0.89 C..The reaction mixture was purified by silica gel column chromatography to give the title compound 132mg as a pale yellow powder.
With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 24h;
(S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate 5.0 g of <strong>[65515-28-8]methyl 2,6-dichloronicotinate</strong> was dissolved in 50 ml of dimethylformamide, and 4.39 g of (S)-(-)-1-(4-fluorophenyl)ethylamine, 6.27 g of diisopropylethylamine and 150 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at 60 C. for 24 hours. The reaction solution was cooled, and then diluted with ethyl acetate, and washed in turn with water and brine, and the organic layer was dried, over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.83 g of the objective compound as white powder.
With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 24h;
step 1 (S ) -6-chloro-2- [1- (4-fluorophenyl) ethylamino] methyl nicotinatewas dissolved <strong>[65515-28-8]2,6-dichloro-nicotinic acid methyl ester</strong> 5.0 g N, the N- dimethylformamide 50 ml, (S) - (-) - 1- (4-fluorophenyl) ethylamine 4.39 g, N, N-diisopropylethylamine 6.27g and 4-dimethylaminopyridine 150mg was added, and stirred for 24 hours at 60 C..The reaction mixture was cooled, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 2.83g as a white powder.
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane; at 70℃; for 7h;Inert atmosphere;
(S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]isonicotinate 8.3 g of <strong>[42521-09-5]methyl 2,6-dichloroisonicotinate</strong>, 6.1 ml of (S)-(-)-1-(4-fluorophenyl)ethylamine, 20.5 g of cesium carbonate, 2.1 g of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 505 mg of palladium acetate were added in turn to 100 ml of degassed 1,4-dioxane, and the mixture was stirred at 70 C. for 7 hours under argon atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 4.4 g of the objective compound as pale yellow powder.
With bis[2-(diphenylphosphino)phenyl] ether; sodium t-butanolate;palladium diacetate; In toluene; at 80℃; for 1h;Inert atmosphere;
Step 1 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-methylpyridine-2-amine 500 mg of 2,6-dichloro-4-iodopyridine, 0.51 ml of trimethylboroxine, 1.0 g of potassium carbonate and 208 mg of tetrakis(triphenylphosphine)palladium were added in turn to 6 ml of degassed dimethylformamide, and the mixture was stirred at 110 C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 330 mg of a pale yellow solid. The obtained solid was dissolved in 6 ml of degassed toluene, 253 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 147 mg of bis[2-(diphenylphosphino)phenyl]ether, 244 mg of sodium t-butoxide and 40 mg of palladium acetate were added in turn thereto, and the mixture was stirred at 80 C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 100 mg of the objective compound as colorless oil.
With palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; sodium t-butanolate; In toluene; at 80℃; for 1h;
Step 1 (S) 6-chloro -N- [1- (4- fluorophenyl) ethyl] -4-methyl-2-aminedegassed N, the N- dimethylformamide 6 ml, 2,6-dichloro-4-iodopyridine 500mg , trimethylboroxine 0.51 ml, were added successively potassium carbonate 1.0g and tetrakis (triphenylphosphine) palladium 208 mg, under an argon atmosphere and stirred for 3 hours at 110 C..The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give a pale yellow solid 330 mg.This was dissolved in toluene 6ml degassed, (S) - (-) - 1- (4-fluorophenyl) ethylamine 253 mg, bis [2- (diphenylphosphino) phenyl] ether 147 mg, sodium t- butoxide 244mg and successively added palladium acetate 40 mg, under an argon atmosphere and stirred for 1 hour at 80 C..The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 100mg as a colorless oil.
With sodium t-butanolate;palladium diacetate; In 1,4-dioxane; at 100℃; for 10h;Inert atmosphere;
(S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl carbamate 390 mg of t-butyl 2,6-dichloropyridin-4-yl carbamate, 220 mul of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 243 mg of bis[2-(diphenylphosphino)phenyl]ethyl ether, 199 mg of sodium t-butoxide and 67 mg of palladium acetate were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 100 C. for 10 hours under argon atmosphere. 118 mul of acetic acid was added to the reaction solution, and then the mixture was diluted with ethyl acetate. The reaction mixture was filtrated by celite to remove precipitates, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the objective compound as a white amorphous solid.
With sodium t-butanolate; In 1,4-dioxane; at 89℃; for 10h;Inert atmosphere;
, (S) - (- ) - 1- (4-fluorophenyl) ethylamine 220 mul, bis [2- (diphenylphosphino) phenyl] ether 243 mg, sodium t- butoxide 199mg and sequentially added palladium acetate 67 mg, under an argon atmosphere and stirred for 10 hours at 0.89 C..After the addition of acetic acid 118mul to the reaction mixture, and the mixture was diluted with ethyl acetate.Remove insolubles through Celite filtration, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title compound 210mg as white amorphous
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 2h;Inert atmosphere;
Step 2 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine 257 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine obtained by Step 1, 164 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 66 mg of 2-(di-t-butylphosphino)biphenyl, 271 mg of sodium t-butoxide and 25 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85 C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 240 mg of the objective compound as pale yellow powder. MS (ESI) m/z 331 (M+H)
With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 85℃; for 2h;Inert atmosphere;
Step 2 (S)-6-chloro-N- [1- (4- fluorophenyl) ethyl] -4- (1-methyl -1H- pyrazol-4-yl ) pyridin-2-aminein deaerated toluene 6 ml, obtained in step 1 2,6-dichloro-4- (1-methyl -1H- pyrazol-4-yl) pyridine 257mg, (S) - (- )1- (4-fluorophenyl) ethylamine 164 mg, 2-(di -t- butyl phosphino) biphenyl 66 mg, successively adding sodium t- butoxide 271mg and palladium acetate 25 mg, under an argon atmosphere, stirred for 2 hours at 85 C. did.The reaction mixture was purified by silica gel column chromatography to give the title compound 240mg as a pale yellow powder.MS (ESI) yd / z 331 (M +H)+
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃; for 1.5h;Inert atmosphere;
Step 2 (S)-N2-[1-(4-Fluorophenyl)ethyl]-4-(oxazol-5-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine 630 mg of 5-(2,6-dichloropyridin-4-yl)oxazole obtained by Step 1, 408 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 182 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1.9 g of cesium carbonate and 66 mg of palladium acetate were added in turn to 30 ml of degassed toluene, and the mixture was stirred at 100 C. for 1.5 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 600 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)pyridine-2-amine as pale yellow powder.
With palladium diacetate; caesium carbonate; at 100℃; for 1.5h;Inert atmosphere;
(S)-N 2 - [1-(4- fluorophenyl) ethyl] -4- (5-oxazol-yl) -N. 6- (pyrazin -2 - yl) pyridine-2,6-diaminein deaerated toluene 30 ml, obtained in step 1 5- (2,6-dichloro-4-yl) oxazole 630 mg, (S) - (-) - 1- (4-fluoro-phenyl) ethylamine 408mg, 2,2'- bis (diphenylphosphino) -1,1'-binaphthyl 182mg, sequentially added cesium carbonate 1.9g and palladium acetate 66mg, under an argon atmosphere, at 100 and stirred for 1.5 hours.The reaction mixture was purified by silica gel column chromatography, (S)-6-chloro -N- [1- (4- fluorophenyl) ethyl] -4-pale (oxazol-5-yl) pyridin-2-amine 600mg It was obtained as a yellow powder
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 1.5h;Inert atmosphere;
Step 3 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2-amine 100 mg of 2,6-dichloro-4-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine obtained by Step 2, 44 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 17 mg of 2-(di-t-butylphosphino)biphenyl, 70 mg of sodium t-butoxide and 6 mg of palladium acetate were added in turn to 3 ml of degassed toluene, and then the mixture was stirred at 85 C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil.
With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 85℃; for 1.5h;
Step 3 (S)-6-chloro-N- [1-(4- fluorophenyl) ethyl] -4- (1 - [2- (trimethylsilyl) ethoxy] methyl}-lH-pyrazol-4-yl) pyridine 2-aminein deaerated toluene 3 ml, obtained in step 2 2,6-dichloro-4- (1 - [2- (trimethylsilyl) ethoxy] methyl}-lH-pyrazol-4-yl) pyridine 100mg , (S) - (-) - 1- (4-fluorophenyl) ethylamine 44 mg, were added successively 2- (di -t- butyl phosphino) biphenyl 17 mg, sodium t- butoxide 70mg and palladium acetate 6 mg, argon below, and the mixture was stirred for 1.5 hours at 85 .The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 70mg as a colorless oil.
(S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 1h;Inert atmosphere;
Step 5 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2-amine 100 mg of 2,6-dichloro-4-(1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine obtained by Step 4, 45 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 17 mg of 2-(di-t-butylphosphino)biphenyl, 70 mg of sodium t-butoxide and 7 mg of palladium acetate were added in turn to 3 ml of degassed toluene, and then the mixture was stirred at 85 C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 130 mg of the objective compound as brown oil.
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 2h;Inert atmosphere;
Step 3 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine-2-amine 145 mg of 2,6-dichloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine obtained by Step 2, 87 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 34 mg of 2-(di-t-butylphosphino)biphenyl, 109 mg of sodium t-butoxide and 13 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and then the mixture was stirred at 85 C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 59 mg of the objective compound as pale yellow powder.
With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 85℃; for 2h;Inert atmosphere;
Step 3 (S)-6-chloro-N- [1- (4- fluorophenyl) ethyl] -4- (1-isopropyl -1H- pyrazol-4-yl) pyridin-2-aminein degassed toluene 6ml , obtained in step 2 2,6-dichloro-4- (1-isopropyl -1H- pyrazol-4-yl) pyridine 145mg, (S) - (- ) - 1- (4-fluorophenyl) ethylamine 87 mg, 2- (di -t- butyl phosphino) biphenyl 34 mg, successively adding sodium t- butoxide 109mg and palladium acetate 13 mg, under an argon atmosphere, and stirred for 2 hours at 85 C..The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 59mg as a pale yellow powder.
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 80℃; for 0.25h;Inert atmosphere;
Step 2 (S)-6-Chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine 130 mg of 2,6-dichloro-4-(cyclopropylmethoxy)pyridine, 92 mg of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 36 mg 2-(di-t-butylphosphino)biphenyl, 144 mg of sodium t-butoxide and 14 mg of palladium acetate were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 80 C. for 15 minutes under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the objective compound as colorless oil.
With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 80℃;Inert atmosphere;
Step 2 (S)-6-chloro-4-(cyclopropylmethoxy)-N-[ 1 - (4- fluorophenyl) ethyl] pyridin-2-aminein deaerated toluene 2 ml, 2,6-dichloro -4 - (cyclopropylmethoxy) pyridine130 mg, (S) - (-)-1 - (4- fluorophenyl) ethylamine 92 mg, 2-(di -t- butyl phosphino) biphenyl 36 mg, sodium t- butoxide144 mg and palladium acetate1sequentially added 4mg, under an argon atmosphere, at 801and the mixture was stirred for 5 minutes.The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound1was obtained 22mg as a colorless oil.
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In tetrahydrofuran; at 60℃; for 10h;Inert atmosphere;
Step 3 (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine-2-amine 225 mg of 2,6-dichloro-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine, 104 mul of <strong>[66399-30-2](S)-(-)-1-(4-fluorophenyl)ethylamine</strong>, 68 mg of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 359 mg of cesium carbonate and 17 mg of palladium acetate were added in turn to 5 ml of degassed tetrahydrofuran, and the mixture was stirred at 60 C. for 10 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate, and filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 118 mg of the objective compound as pale yellow powder.
With Novozym 435 at 23℃; for 3h; Molecular sieve; Enzymatic reaction; optical yield given as %ee; enantioselective reaction;
4.3. Preparative-scale solvent-free kinetic resolution of rac-1a-i
General procedure: One of the amines rac-1a-i (2 mmol) and isopropyl methoxyacetate (2 mmol) were added into a reaction vessel containing Novozym 435 (25 mg) and molecular sieves (4 Å, 50 mg). The reaction mixture was shaken (170 rpm) at room temperature (23 °C) if not otherwise stated. The reaction was stopped by filtering off the enzyme at (50 +/- 0.5)% conversion. Isolation of the products was performed by silica gel chromatography using a mixture of hexane and ethylacetate and/or mixture of dichloromethane and methanol as eluent.
General procedure: At first, borane/THF (25 mL, 25 mmol) was added to a solution of (S)-valinol (1.29 g, 12.5 mmol) in THF (10 mL) at 0 C, and the mixture was stirred for 5 h in an ice-water bath. A solution of 13 (2.55 g, 10 mmol) in THF (10 mL) was then added dropwise and the mixture was stirred for 24 h at room temperature. Next, borane/THF (50 mL, 50 mmol) was added, the mixture was gently refluxed for 24 h, then cooled, acidified with 2 M hydrochloric acid, and stirred for 24 h at room temperature. It was then concentrated under vacuum, alkalized with 20% aqueous sodium hydroxide, and extracted with ethyl acetate (3 × 50 mL). The organic solution was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was removed and the product was isolated by flash chromatography, silica gel, dichloromethane-methanol-triethylamine 9:1:0.1, 1.12 g, 74%
With pyridoxal 5'-phosphate In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 24h; Resolution of racemate; Enzymatic reaction; enantioselective reaction;
2.4 Kinetic resolution of rac-1a-d
General procedure: All experiments were carried out keeping the protein content constant (8 mg mL-1) if not otherwise stated. One of the substrates rac-1a-d (50 mM), sodium pyruvate (50 mM) and pyridoxal-5′-phosphate monohydrate (0.2 mg mL-1) in phosphate buffer (1 mL, 0.1 M, pH 7.5) containing IPA or DMSO as a possible cosolvent (10, v/v-%) was added to a 2 mL Eppendorf tube, containing the ω-transaminase sol-gel catalyst (25 or 50 mg). The reaction was shaken (170 rpm) at 30 °C. After 24 h the reaction was stopped by centrifuging the mixture and removing the solution by pipette. The solid catalyst was reused while conversion was monitored by taking a sample (5 μL) from the solution and diluting it with the HPLC eluent (500 μL). The sample was filtered and analyzed for conversion by HPLC. A sample (400 μL) for ee(S)-1 analysis was taken, and aqueous NaOH (2 M, 50 μL) was added followed by the extraction of the amine into ethyl acetate (400 μL). The organic phase (300 μL) was dried with Na2SO4, and after filtration the amine in the sample (200 μL) was derivatized with acetic anhydride (10 μL) to determine the enantiomeric excess of (S)-1 by GC.
N-[(S)-1-(4-fluorophenyl)ethyl]-(R)-2-(2,4-dichlorophenoxy)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: To solutions of 2-(2,4-dichlorophenoxy)propanoic acid(100 mg, 0.43 mmol) in DMF (2 mL) were added 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate(HATU; 200 mg, 0.53 mmol), the correspondingbenzylamines (0.50 mmol), and diisopropylethylamine (100 lL,0.57 mmol). The resulting mixtures were stirred at room temperaturefor 16 h, then poured into water (20 mL). The aqueousmixtures were then stirred at room temperature until solids precipitate.The solids were filtered, rinsed with water, and dried toprovide solids that were recrystallized from CH2Cl2/hexane to providethe products 27a-p. With the exception of 27d and 27e, theremaining compounds were isolated as inseparable mixtures ofdiastereomers; where possible, the matched pairs of NMR signalsare noted.
(S)-1-(4-chlorophenyl)-3-(1-(4-fluorophenyl)ethyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
In dichloromethane; at 20℃; for 1h;Inert atmosphere;
The (S) -1- (4- fluorophenyl) ethanamine (4.6mg, 0.033mmol) was dissolved in 1.2mL of anhydrous dichloromethane,Under nitrogen was added rapidly chlorophenyl isocyanate (5.1mg, 0.033mmol), stirred for 1 hour at room temperature, produce a large amount of white solid, TLC detection was done after the reaction was complete, after that diluted petroleum ether is added and filtered to give a white solid (S) -1- (4 -chlorinePhenyl) -3- (1- (4-fluorophenyl) ethyl) urea 9.1mg, 94% yield.
(S)-2-amino-N-(1-(4-fluorophenyl)ethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h;
In 100 ml of methylene chloride solution containing 3 g of 2-amino acid (21.7 mmol) was added 16.5 g of benzotriazole -N, N, N ', N'- tetramethyluronium hexafluorophosphate salt (43.4 mmol, 2.0 equiv.), 3.02 g (S) -1- (4- fluorophenyl) ethylamine (21.7 mmol, 1.0 equiv.), and 10.97 g of triethylamine (0.11 mole, 5.0 eq.). After the reaction mixture was stirred at room temperature for 18 hours and filtered off the solvent, the residual material was purified through column chromatography (petroleum ether / ethyl acetate = 2: 1) to obtain 4.2 g of the desired product, yield 74% .
pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
In a round bottom flask fitted with magnetic stirrer, 4-pentynoic acid (1.5 g, 15.3 mmol) and (S)-1 -(4-fluoro-phenyl)-ethylamine (1 .8 ml, 16.83 mmol) were dissolved in DCM (50 ml) and then treated with Hunig's base (5.4 ml, 30.6 mmol) and HBTU (1 1 .6 g, 30.6 mmol). This mixture was allowed to stir overnight at r.t. Reaction crude was concentrated under reduced pressure and purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with 40% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (3.21 g, 96%).LCMS Method: 1 , RT: 3.78 min, Ml: 220 [M+1]
6-bromo-4-cyclopropyl-1,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
[ 66399-30-2 ]
4-cyclopropyl-6-(((S)-1-(4-fluorophenyl)ethyl)amino)-1,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In toluene; at 85℃;Sealed tube; Microwave irradiation; Inert atmosphere;
General procedure: To a solution of compound 93 (0.12 g, 0.41 mmol), sodium tert-butoxide (0.145 g, 1.51 mmol), phenylmethanamine (0.13 mL, 1.16 mmol) in toluene (5 mL) at room temperature were added palladium acetate (6 mg, 0.025 mmol) and tBu3P (0.017 mL, 0.07 mmol). The mixture was sealed in a microwave tube and heated to 85 C overnight. The reaction was monitored by TLC. Upon completion, the mixture was extracted with EtOAc (3 * 20 mL). The combined organic fractions were washed with brine, dried with Na2SO4, then concentrated by evaporation under reduced pressure. Purification by silica gel column chromatography (gradient elution, gradient 0-25% EtOAc/60-90 C petroleum ether) gave compound 32 as a yellow soild (0.077 g, 0.24 mmol, 59% yield).
(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ca. 100%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50℃; for 5h;
A solution of 4,6-dichloropyrimidine (500 mg, 3.36 mmol) and <strong>[66399-30-2](S)-1-(4-fluorophenyl)ethan-1-amine</strong> (467 mg, 3.36 mmol) in isopropanol (10 mL) was added DIPEA (1.75 mL, 10.07 mmol). The solution was stirred for 5 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)pyrimidin-4-amine compound 2 (865 mg, 100%) as thick orange liquid. The compound was used for the next step without further purification. MS (ESI): Calcd. for C12H11ClFN3: 251, found 252 (MH+).
(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-5-methylpyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 24h;
A solution of 4,6-dichloro-5-methylpyrimidine (500 mg, 3.07 mmol) and <strong>[66399-30-2](S)-1-(4-fluorophenyl)ethan-1-amine</strong> (427 mg, 3.07 mmol) in THF (5 mL) was added DIPEA (1.60 mL, 9.20 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-methylpyrimidin-4-amine compound 3 (482 mg, 59%) as light brown solid. The compound was used for the next step without further purification. MS (ESI): Calcd. for C13H13ClFN3: 265, found 266 (MH+).
(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+).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 105℃; for 2h;
The solution of compound 5 (150 mg, 0.58 mmol), (S)-1-(4-fluorophenyl)ethanamine (80 mg, 0.58 mmol) and DIPEA (0.15 ml, 0.86 mmol) DMSO (3.5 mL) was stirred at 105 C. for 2 hours. TLC was checked and the starting material was consumed. The reaction mixture was added to half-saturated ammonium chloride in water (80 mL) and stirred for 30 min, then cooled with ice bath. The solids were collected by filtration, washed by water. The crude product was triturated with MeOH and the solids were collected by filtration to give the product compound 26 as yellow solids. (87 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) delta 12.12 (br, 1H), 10.90 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.42 (m, 2H), 7.16 (m, 2H), 5.69 (s, 1H), 5.45 (m, 1H), 2.00 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.79 (m, 2H); ESI-MS: calcd for (C23H29N7O3) 363, found 364 (MH+).
4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile[ No CAS ]
[ 66399-30-2 ]
(S)-6-chloro-4-((1-(4-fluorophenyl)ethyl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 5h;Inert atmosphere;
To a solution of 4,6-dichloro-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (1000 mg, 4.72mmol) in NMP (lOmL) was added (S)-l-(4-fluorophenyl)ethan-l -amine (1312 mg, 9.43mmol) and triethylamine (715.1 mg, 7.08 mmol) under nitrogen. The mixture was stirred at 100 C. After 5hrs, the mixture was cooled to 15 C, then water was added. After stirring for 0.5 h, the mixture was filtered. The solid was dissolved into toluene and concentrated under reduced pressure, twice. The residue was washed with petroleum ether, and the solid was dried under vacuum to give (S)-6-chloro-4-((l-(4-fluorophenyl)ethyl)amino)-lH-pyrrolo[2,3- b]pyridine-5-carbonitrile (910 mg, 2.89 mmol, 61% yield).
4,6-dichloro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile[ No CAS ]
[ 66399-30-2 ]
(S)-6-chloro-4-((1-(4-fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With triethylamine; In ethanol; at 20℃; for 16h;
To a solution of 4,6-dichloro-lH-pyrazolo[3,4-b]pyridine-5- carbonitrile (200.0 mg, 0.94 mmol) in ethanol (10 mL) was added (S)-l-(4-fluorophenyl)ethan- l-amine (261.3 mg, 1.88 mmol) and triethylamine (285.0 mg, 2.82 mmol) at ambient temperature and stirred at ambient temperature for 16 hours. Solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (S)-6-chloro-4-((l-(4- fluorophenyl)ethyl)amino)-lH-pyrazolo[3,4-b]pyridine-5-carbonitrile (200 mg, 67% yield) as a solid. LCMS ESI (+) m/z 316 (M+H).
6-(naphthalen-2-yl)-4-oxo-3-(propan-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylic acid[ No CAS ]
[ 66399-30-2 ]
N-[(1S)-1-(4-fluorophenyl)ethyl]-6-(naphthalen-2-yl)-4-oxo-3-(propan-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
6-(naphthalen-2-yl)-4-oxo-3-(propan-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (Intermediate 19A, 200 mg, 576 pmol) was dissolved in DMF (14.0 ml), and (1S)-1-(4-fluorophenyl)ethanamine (80.1 mg, 576 pmol), N,N-diisopropylethylamine (300 pi, 1.7 mmol) and HA- TU (241 mg, 633 pmol) were added. The mixture was stirred at RT overnight. The reaction mix- ture was diluted with water and dichloromethane, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (Meth- od P12) to afford the title compound. Yield: 144 mg (53% of theory). LC/MS [Method 33]: Rt = 1.45 min; MS (ESIpos): m/z = 469 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): d [ppm] = 11.66 (s, 1H), 8.76 (d, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 8.02 (d, 1H), 8.00-7.94 (m, 2H), 7.92-7.82 (m, 1H), 7.63-7.55 (m, 2H), 7.51-7.42 (m, 2H), 7.20-7.13 (m, 2H), 5.21-5.13 (m, 1H), 4.12-4.02 (m, 1H), 1.48 (d, 3H), 1.40-1.26 (m, 6H).
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