* 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] Patent: WO2008/98104, 2008, A1, . Location in patent: Page/Page column 191-192
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
2
[ 24065-33-6 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
3
[ 35475-03-7 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
4
[ 1047644-88-1 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
5
[ 1047630-52-3 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
6
[ 114873-01-7 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
7
[ 944470-56-8 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
8
[ 1201923-48-9 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
9
[ 1047630-72-7 ]
[ 1047644-62-1 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
10
[ 1047644-62-1 ]
[ 1047645-82-8 ]
Yield
Reaction Conditions
Operation in experiment
73.6%
With hydrogenchloride In 1,4-dioxane; tert-butyl methyl ether; acetonitrile at 40 - 42℃;
Preparation of: CrystallineN-{(1S)-2-Amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride5 mL of MTBE was added to 213.9 mg of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide amorphous free-base (0.500 mMol.). The mixture was heated to 40° C. with magnetic stirring for 1 hour. A solution of 4M HCl in 1,4-dioxane (1 eq; 125.1 uL) was added in four equal portions. After addition of the first portion (0.25 eq), the mixture was heated to 42° C. and 1 mL of acetonitrile was added to dissolve all of the solid material. After the remainder of the HCl solution was added, some solid material appeared. The slurry was stirred at 42° C. for 4 hours, then was cooled slowly to 22° C. overnight with 90 minute holds at 35° C., 30° C., and 25° C. The white solid material was filtered and dried at 50° C. under vacuum with a slow nitrogen bleed overnight. The yield was 73.6percent (0.3685 mmol; 170.90 mg) of the HCl salt. The solid was found to be 1:1 stoichiometric HCl salt by ion chromatography, and to be crystalline by the Powder X-Ray Diffraction (PXRD) pattern depicted in FIG. 2 and as characterized by diffraction peaks below, and to have a melting point of 211° C.PXRD Peaks (Values Given in Degrees Two-Theta with d-Spacing in Parenthesis): 7.2(12.20) 14.4(6.16) 17.9(4.94) 18.5(4.79) 20.8(4.26) 21.5(4.12) 22.4(3.96) 22.9(3.88) 23.7(3.75) 24.5(3.63) 24.7(3.61) 25.1(4.12) 25.7(3.46) 27.3(3.26) 28.2(3.16) 28.8(3.10) 30.4(2.94) 32.4(2.76) 32.7(2.73) 35.2(2.55) 36.1(2.48) 40.0(2.25) 41.3(2.18) 41.7(2.16) Instrument: PANalytical X'Pert-Pro MPD with Johansson Kα1 monochromator, using X'Celerator detector Key Operating Parameters:Radiation: Cu (Kα1), 1.540598 angstroms (monochromatic)Detector: X'CeleratorTension: 45 kVCurrent: 40 mAStart angle: 2.0° 2ψ End angle: 52.0° 2ψ Step size: 0.02° Time/step: 40.0 secScan speed: 0.05°/sec Incident beam: 2° fixed anti-scatter slit, and programmable divergence slit Diffracted beam: 0.02 rad soller slit, and programmable anti-scatter slit Samples prepared on silicon zero background sample holder.
With hydrazine; In tetrahydrofuran; methanol; at 20℃; for 24.0h;
To a 250 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1- methyl-1 H-pyrazol-5-yl)-N-{(1 S)-2-(1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)-1 -[(3- fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (9 g, 16.15 mmol) and hydrazine (15.69 ml, 323 mmol) in tetrahydrofuran (THF) (75 ml) and methanol (75 mL). After 24 h at RT, the precipitate was filtered, the filtrate was concentrated, and the crude product was purified on a silica gel column [CHCI3/MeOH/NH4OH, 90:9:1 ] to give the title compound as a white solid. <n="193"/>The free base product was treated with 4M HCI in dioxane (15 ml_). After 5 min, the product solution was concentrated and dried under vacuum to afford the product (6.5 g, 91 %) as an HCI salt: LCMS (ES) m/z 428 (M+H)+, 1H NMR (400 MHz, CD3OD) delta ppm 7.75 (s, 1 H), 7.60 (s, 1 H), 7.32 (m, 1 H) 7.14 (m, 2H), 6.98 (m, 1 H), 4.54 (m, 1 H), 3.78 (s, 3H), 3.24 (m, 2H), 3.02 (m, 2H).
With hydrogenchloride; In 1,4-dioxane; tert-butyl methyl ether; acetonitrile; at 40 - 42℃;Product distribution / selectivity;
Preparation of: CrystallineN-{(1S)-2-Amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride5 mL of MTBE was added to 213.9 mg of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide amorphous free-base (0.500 mMol.). The mixture was heated to 40 C. with magnetic stirring for 1 hour. A solution of 4M HCl in 1,4-dioxane (1 eq; 125.1 uL) was added in four equal portions. After addition of the first portion (0.25 eq), the mixture was heated to 42 C. and 1 mL of acetonitrile was added to dissolve all of the solid material. After the remainder of the HCl solution was added, some solid material appeared. The slurry was stirred at 42 C. for 4 hours, then was cooled slowly to 22 C. overnight with 90 minute holds at 35 C., 30 C., and 25 C. The white solid material was filtered and dried at 50 C. under vacuum with a slow nitrogen bleed overnight. The yield was 73.6% (0.3685 mmol; 170.90 mg) of the HCl salt. The solid was found to be 1:1 stoichiometric HCl salt by ion chromatography, and to be crystalline by the Powder X-Ray Diffraction (PXRD) pattern depicted in FIG. 2 and as characterized by diffraction peaks below, and to have a melting point of 211 C.PXRD Peaks (Values Given in Degrees Two-Theta with d-Spacing in Parenthesis): 7.2(12.20) 14.4(6.16) 17.9(4.94) 18.5(4.79) 20.8(4.26) 21.5(4.12) 22.4(3.96) 22.9(3.88) 23.7(3.75) 24.5(3.63) 24.7(3.61) 25.1(4.12) 25.7(3.46) 27.3(3.26) 28.2(3.16) 28.8(3.10) 30.4(2.94) 32.4(2.76) 32.7(2.73) 35.2(2.55) 36.1(2.48) 40.0(2.25) 41.3(2.18) 41.7(2.16) Instrument: PANalytical X'Pert-Pro MPD with Johansson Kalpha1 monochromator, using X'Celerator detector Key Operating Parameters:Radiation: Cu (Kalpha1), 1.540598 angstroms (monochromatic)Detector: X'CeleratorTension: 45 kVCurrent: 40 mAStart angle: 2.0 2theta End angle: 52.0 2theta Step size: 0.02 Time/step: 40.0 secScan speed: 0.05/sec Incident beam: 2 fixed anti-scatter slit, and programmable divergence slit Diffracted beam: 0.02 rad soller slit, and programmable anti-scatter slit Samples prepared on silicon zero background sample holder.
With hydrogenchloride; In 1,4-dioxane; for 0.08333330000000001h;
1 , 1 -dimethylethyl {(2S)-2-([5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 ml_, 1 :2) and stirred at 25 0C. After 30min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1 % NH4OH)) affording the free base of the title compound.The free base, as a solution in MeOH, was then treated with excess 4M HCI in dioxane affording the title compound (43 mg, 44%-2 steps) as the HCI salt: LCMS (ES) m/z 478 (M+H)+, 1H NMR (400 MHz, DMSO-d6) delta ppm 9.10 (d, J=8.84 Hz, 1 H) 8.06 (s, 4 H) 7.75 (s, 1 H) 7.70 (d, J=7.83 Hz, 1 H) 7.54 - 7.61 (m, 2 H) 7.43 (t, J=7.45 Hz, 1 H) 4.47 (t, J=8.84 Hz, 1 H) 3.78 (s, 3 H) 2.98 - 3.12 (m, 4 H).
Stage #1: methyl (2S)-2-[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophen-2-yl]formamido}-3-(3-fluorophenyl)propanoate With ammonia In methanol at 25 - 30℃; for 18h; Inert atmosphere;
Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 70 - 75℃; for 48h; Inert atmosphere;
3-4 Example three:
Under the protection of nitrogen, N-[(1S)-1-[(3-fluorophenyl)methyl]-2-methyl acetate]-5-chloro-4-(4-chloro-1- Methyl-1H-pyrazol-5-yl)-2-thiophenebenzamide (IV) (2.28g, 5mmol) was dissolved in 25mL of methanol, and a methanol solution of ammonia gas (2M, 7.5mL, 15mmol) was added dropwise, After dripping, stir at 25-30°C for 18 hours. After concentration, the obtained product was dissolved in 30 mL of tetrahydrofuran. Under the protection of nitrogen, lithium tetrahydroaluminum (1.52g, 40mmol) was added, the temperature was raised to 70-75°C, and the reaction was continued for 48 hours. Cool, quench the reaction with ice water, extract three times with ethyl acetate, combine the organic phases, wash sequentially with saturated brine and water, and dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized with ethanol to obtain 1.6 g of white solid frescitin (I), the yield was 75.0%.
With sodium tetrahydroborate; nickel(II) chloride hexahydrate; ethanol at 25 - 30℃; for 6h; Inert atmosphere;
5 Embodiment five:
Under the protection of nitrogen, add nickel dichloride hexahydrate (0.12g, 0.5mmol), sodium borohydride (0.38g, 10mmol) and 25mL of ethanol into the reaction flask. After stirring for 30 minutes at 2530, add N- [(1S)-2-(3-Fluorophenyl)methyl-2-acetonitrile]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2 -Thiophene benzamide (VII) (2.11g, 5mmol) in 25mL ethanol solution, stirred at 25-30°C for 2 hours.Additional sodium borohydride (0.38 g, 10 mmol) was added, and the reaction was continued for 4 hours.Filter and concentrate under reduced pressure.The residue was recrystallized from ethanol to obtain 1.9 g of white solid fresceti (I) with a yield of 89.0%.