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Product Details of [ 764667-65-4 ]

CAS No. :764667-65-4 MDL No. :MFCD11111443
Formula : C16H12F6N4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :QAEDTLFWHIEVPK-UHFFFAOYSA-N
M.W : 406.28 Pubchem ID :9887588
Synonyms :
Chemical Name :1-(3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione

Calculated chemistry of [ 764667-65-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 28
Num. arom. heavy atoms : 11
Fraction Csp3 : 0.38
Num. rotatable bonds : 6
Num. H-bond acceptors : 10.0
Num. H-bond donors : 0.0
Molar Refractivity : 84.74
TPSA : 68.09 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.98 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.35
Log Po/w (XLOGP3) : 1.13
Log Po/w (WLOGP) : 4.14
Log Po/w (MLOGP) : 2.85
Log Po/w (SILICOS-IT) : 3.65
Consensus Log Po/w : 2.82

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.97
Solubility : 0.44 mg/ml ; 0.00108 mol/l
Class : Soluble
Log S (Ali) : -2.15
Solubility : 2.85 mg/ml ; 0.00702 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.07
Solubility : 0.00347 mg/ml ; 0.00000853 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.96

Safety of [ 764667-65-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 764667-65-4 ]

* 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.

  • Upstream synthesis route of [ 764667-65-4 ]
  • Downstream synthetic route of [ 764667-65-4 ]

[ 764667-65-4 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 209995-38-0 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With cycl-isopropylidene malonate; N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 20 - 40℃;
Stage #2: With pivaloyl chloride In ISOPROPYLAMIDE at 0 - 5℃; for 1 - 3 h;
Stage #3: at 40 - 70℃;
2,4, 5-TRIFLUOROPHENYLACETIC acid (2-1) (150 g, 0.789 MOL), Meldrum's acid (125 g, 0.868 mol), and 4- (DIMETHYLAMINO) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 mL) was added in one portion at room temperature to dissolve the solids. N, N-DIISOPROPYLETHYLAMINE (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 °C. The reaction mixture was aged at 5 °C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 °C. The reaction solution was aged at 70 °C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 ML) was then added dropwise at 20-45 °C. The batch was seeded and aged at 20-30 °C for 1-2 h. Then an additional 525 mL of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 °C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAC (300 mL), followed by an additional two batches of 20percent aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89percent.
Reference: [1] Patent: WO2005/3135, 2005, A1, . Location in patent: Page 12-13
[2] Patent: WO2006/81151, 2006, A1, . Location in patent: Page/Page column 14-15
  • 2
  • [ 2033-24-1 ]
  • [ 209995-38-0 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20 - 50℃; for 2 - 3 h;
Stage #2: at 40 - 70℃;
Stage #3: With sodium hydrogencarbonate In N,N-dimethyl acetamide; water at 20 - 45℃;
2,4,5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and DMAP (7.7 g, 0.0063 mol) were charged into a 5 L three-neck flask. DMAc (525 mL) was added in one portion at room temperature. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature below 50 C. The reaction was aged at 45-50 C for 2-3 h. Triazole hydrochliride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 C. The batch was seeded and aged at 20 - 30 C for 1-2 h. Then the additional 525 mL of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was further cooled to 0-5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAc (300 mL), followed by an aditional two batches of 20percent aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product was 89percent.In CD3CN solutiob, 2-3 exists as a 4:3 mixture of amide rotamers (hindered rotation around the Nitrogen-Carbonyl bond). Severe overlap of signals does not permit unequivocal assignment of each rotamer. Assignments are grouped (when necessary) and rotamers (major/minor/both) denoted. Complexity due to 19F spin-spin coupling does not permit assignment of all 13C resonances, therefore, select 13C data are presented. The structure shown is the major rotamer in solution. 1H-NMR (400 MHz, CD3CN): δ 7.23-7.07 (overlaping m, 2H, both), 4.91 (s, 2H, major), 4.81 (s, 2H, minor), 4.16 (t, J = 5.6 Hz, 2H, major), 4.11 (t, J = 5.6 Hz, 2H, minor), 4.00 (t, J = 5.6 Hz, 2H, minor), 3.92 (s, 2H, major), 3.91 (s, 2H, minor), 3.83 (t, J = 5.6 Hz, 2H, major), 3.80 (s, 2H, major), 3.78 (s, 2H, major), 3.91 (s, 2H, minor) ppm. 13C NMR (100 MHz, CD3CN, selected data): δ 201.43 (both), 167.37 (minor), 167.27 (major), 151.88 (major), 151.53 (minor), 48.88 (minor), 48.81 (major), 44.65 (major), 44.19 (minor), 43.86 (minor), 43.08 (major), 43.00 (both), 39.82 (major), 38.81 (minor) ppm.
Reference: [1] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 8798 - 8804
[2] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 10-11
[3] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 10
[4] Patent: US2006/270722, 2006, A1, . Location in patent: Page/Page column 18
[5] Patent: WO2011/25932, 2011, A2, . Location in patent: Page/Page column 17-18
  • 3
  • [ 157911-56-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
89.5%
Stage #1: With magnesium In tetrahydrofuran at 35 - 45℃; for 2.16667 h;
Stage #2: at 0 - 5℃; for 4 h;
Example 1 was replaced with 16.5 grams of potassium carbonate12 grams of sodium carbonate from step 1,The rest with Example 1,36.4 grams of white crystals4-oxo-4- [3- (trifluoromethyl) -5,6- dihydro [1,2,4] triazolo [4,3- a] pyrazin-7 (8H) 1- (2,4,5-trifluorophenyl) -2-butanone (II),Yield 89.5percent (calculated as compound of formula III),Liquid phase purity of 99.95percent.
Into a 500 ml dry four-necked flask was added20 grams of tetrahydrofuran,3.5 g magnesium powder,0.5 g of 2,4,5-trifluoro-1-bromomethylbenzene,40-45 ° C slightly stirred to trigger Grignard reaction,While maintaining 35-45 ° C, 26.5 grams (0.118 moles)2,4,5-trifluoro-1-bromomethylbenzene and100 g of tetrahydrofuran,About 70 minutes dripping is completed,After that, the reaction was stirred at 45 ° C for 1 hour,Cooled to 20-25 ° C,The obtained 2,4,5-trifluoro-1-bromomethyl-phenyl Grignard reagent was transferred to a pressure-equalizing dropping funnel,Was added dropwise to a solution of 3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 , 3-a] pyrazin-7 (8H) yl] propionitrile (IV) in toluene,About 2 hours after the addition was completed,After 0-5 ° C the reaction was stirred for 2 hours,Add 20 g saturated aqueous ammonium chloride solution,200 grams of saturated salt water,The layers were separated, the aqueous layer was extracted three times with 150 g of toluene,The combined toluene layer.Toluene was recovered under reduced pressure,To the resulting light yellow solid was added1.0 grams of activated carbon,30 grams of methanol,The reaction was stirred at 60 ° C for 1 hour,Filtered while still hotThe filtrate was cooled to 0-5 ° C,Filtration and drying gave 35.6 g of white crystals4-oxo-4- [3- (trifluoromethyl) -5,6- dihydro [1,2,4] triazolo [4,3- a] pyrazin-7 (8H) 1- (2,4,5-trifluorophenyl) -2-butanone (II),Yield 87.6percent (calculated as compound of formula III),Liquid phase purity of 99.96percent
Reference: [1] Patent: CN104987338, 2017, B, . Location in patent: Paragraph 0023; 0049; 0050; 0051; 0052; 0055; 0056
  • 4
  • [ 1151240-88-8 ]
  • [ 486460-21-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
82% With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1 h; Potassium tert-butoxide (2.24 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran in a 100 mL single-necked flask.Stir at room temperature for one minute. Then compound III (1.91 g, 10 mmol) was added in sequence.Compound II (2.60 g, 10 mmol) was stirred at room temperature for 60 min.Thereafter, the reaction solvent tetrahydrofuran was distilled off under reduced pressure, and then 50 mL of water and 50 mL of dichloromethane were added.The organic phase was extracted and the organic phase was dried with anhydrous sodium sulfate and evaporatedThe crude product was recrystallized from dichloromethane and cyclohexane to give 3.33 g of Compound IV.The yield was 82percent and the purity was 99percent.
Reference: [1] Patent: CN108178761, 2018, A, . Location in patent: Paragraph 0032; 0038; 0039; 0061-0066
  • 5
  • [ 764667-64-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
98.1% With 4-methyl-morpholine In ethyl acetate for 6 h; Reflux A round bottom flask is charged with 3-trifluoromethyl-5,6,7,8-tetrahydro- 1 ,2,4-thazolo[4,3a]pyrazine hydrochloride (144.6 g) and ethyl acetate (2000 ml_) at 28°C, then N-methylmorpholine (67.2 g) is added. 5-[1 -hydroxy-2-(2,4,5- trifluorophenyl)ethyledine]-2,2-dimethyl-1 ,3 dioxane-4,6-dione (200 g) is added and the mixture is heated to reflux for 6 hours. The mixture is slowly cooled to room temperature. Water (1000 ml_) is added, the mixture is stirred for 15 minutes, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (200 ml_). The two organic layers are combined and solvent is distilled at 37°C. Toluene (400 ml_) is added to the residue and stirred for 3 hours. The solid is filtered, washed with toluene (200 ml_), and dried under reduced pressure at 500C for 12.5 hours, to afford the title compound. (252.0 g, 98.1 percent yield).
93.3% With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 4 h; A mixture of 5-(1 -hydroxy-2-(2,4,5-thfluorophenyl)-ethylidene)-2,2-dimethyl-1 ,3- dioxane-4,6-dione (10 g), 3-trifluoromethyl-5,6,7,8-tetrahydro-1 ,2,4-triazolo[4,3-a]pyrazine hydrochloride (7.2 g), diisopropyl ethylamine (4.5 g), and isopropyl acetate (100 ml_) are heated to about 85 0C and stirred for about 4 hours. The reaction mass is then cooled to about 3O0C and quenched with water (90 ml_). The organic layer is separated, washed with 5percent sodium chloride solution (3x50 ml_) and distilled off completely under vacuum to afford 12 g of the title compound. (Yield: 93.3percent; purity by HPLC: 95.7percent)
92% With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 3.5 h; 2,4,5-Trifluorophenylacetic acid (2-1) (11.4 g, 60 mmol) was dissolved in THF (60 mL) and 1,1'-carbonyldiimidazole (10.7 g, 66 mmol) was added over 5 min. The mixture was warmed to 51 C, Meldrum's acid (9.51 g, 66 mmol) was added, and the mixture was aged for 3 h. The reaction mixture was diluted with IPAc (60 mL) and water (60 mL), and the pH was adjusted to 2.4 with concentrated hydrochloric acid (11.5 mL). The aqueous layer was separated, and the orgnic layer was washed at 36 C with 0.1 N HCl (60 mL). The organic layer was concentrated, flushed with IPAc, and the residue was slurried in 2:1 heptane/IPAc (70 mL). the mixture was cooled over an ice-bath, then filtered, rinsing the solid with 2:1 heptane/IPAc. After drying, the Meldrum's acid adduct was obtained as a solid (15.1 g) in 80percent yield.The Meldrum's acid adduct (22.1 g, 70 mmol) and the triazole hydrochloride 1-4 (16.0 g, 70 mmol) were sluuried in IPAc (220 mL) and N,N-diisopropylethylamine (12.8 mL) was added. After aging for 3.5 h at 85 C, water (175 mL) was added and the mixture was transferred to a separatory funnel with a 40-mL rinse with IPAc. The aqueous layer was separated and the organic layer was washed with water (100 mL). The organic layer was partially concentrated under reduced pressure to give a 65 g of solution of the ketoamide 2-3 in IPAc. n-Heptane (30 mL) was added at roo temperature, followed by seed crystals of ketoamide. Additional heptane (20 mL) was added dropwise, and the mixture was stirred overnight. Additional heptane (50 mL) was added slowly and after aging for 2 h, the solids were filtered and washed with 2.2:1 heptane/IPAc (30 mL). After drying, the ketoamide 2-3 was obtained in 92percent yield (26.3 g).
89% With sodium hydrogencarbonate In ISOPROPYLAMIDE at 20 - 45℃; Step A: Preparation of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4, 3- ALPYRAZIN-7 (8H)-YLL-1-(2, 4, 5-TRIFLUOROPHENYL) BUTAN-2-ONE (2-3) 2,4, 5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4- (dimethylamino) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 ML) was added in one portion at room temperature to dissolve the solids. NN-DIISOPROPYLETHYLAMINE (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 °C. The reaction mixture was aged at 5 °C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 °C. The reaction solution was aged at 70 °C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20-45 °C. The batch was seeded and aged at 20-30 °C for 1-2 h. Then an additional 525 ML of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 °C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAC (300 mL), followed by an additional two batches of 20percent aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89percent.
89%
Stage #1: at 70℃;
Stage #2: With sodium hydrogencarbonate In ISOPROPYLAMIDE; water at 20 - 30℃; for 3 - 5 h;
2,4, 5-TRIFLUOROPHENYLACETIC acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0. 868 mol), and 4- (DIMETHYLAMINO) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 ML) was added in one portion at room temperature to dissolve the solids. N, N-diisopropylethylamine (282 ML, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 °C. The reaction mixture was aged at 5 °C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 °C. The reaction solution was aged at 70 °C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 ML) was then added dropwise at 20-45 °C. The batch was seeded and aged at 20-30 °C for 1-2 h. Then an additional 525 mL of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 °C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAC (300 mL), followed by an additional two batches of 20percent aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89percent.
89%
Stage #1: at 70℃;
Stage #2: With sodium hydrogencarbonate In ISOPROPYLAMIDE; water at 20 - 30℃; for 3 - 5 h;
2,4, 5-TRIFLUOROPHENYLACETIC acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0. 868 mol), and 4- (DIMETHYLAMINO) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 ML) was added in one portion at room temperature to dissolve the solids. N, N-diisopropylethylamine (282 ML, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 °C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 °C. The reaction mixture was aged at 5 °C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 °C. The reaction solution was aged at 70 °C for several h. 5percent Aqueous sodium hydrogencarbonate solution (625 ML) was then added dropwise at 20-45 °C. The batch was seeded and aged at 20-30 °C for 1-2 h. Then an additional 525 mL of 5percent aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 °C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20percent aqueous DMAC (300 mL), followed by an additional two batches of 20percent aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89percent.

Reference: [1] Patent: WO2011/25932, 2011, A2, . Location in patent: Page/Page column 17
[2] Patent: WO2009/85990, 2009, A2, . Location in patent: Page/Page column 28
[3] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 12
[4] Patent: WO2004/85378, 2004, A1, . Location in patent: Page 16
[5] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 12-13
[6] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 12-13
[7] Journal of the American Chemical Society, 2004, vol. 126, # 40, p. 13002 - 13009
[8] Journal of the American Chemical Society, 2004, vol. 126, # 40, p. 13002 - 13009
[9] Patent: WO2005/97733, 2005, A1, . Location in patent: Page/Page column 23
[10] Patent: WO2006/33848, 2006, A1, . Location in patent: Page/Page column 11
[11] Patent: WO2007/35198, 2007, A2, . Location in patent: Page/Page column 10-11
[12] Patent: WO2007/50485, 2007, A2, . Location in patent: Page/Page column 34-35
[13] Patent: WO2009/84024, 2009, A2, . Location in patent: Page/Page column 23
[14] Patent: WO2005/72530, 2005, A1, . Location in patent: Page/Page column 11-12
[15] Patent: WO2010/32264, 2010, A2, . Location in patent: Page/Page column 27
[16] Patent: WO2010/122578, 2010, A2, . Location in patent: Page/Page column 53
[17] Patent: WO2006/119260, 2006, A2, . Location in patent: Page/Page column 43-44
  • 6
  • [ 2033-24-1 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With 1,1'-carbonyldiimidazole In Isopropyl acetate at 45℃; for 0.166667 h;
Stage #2: at 20 - 40℃; for 25.5 h;
Stage #3: at 90℃; for 12 h;
To 45 mL of IPAc was added the trifluorophenylacetic acid (5 g), CDI (4.3 g), and the resulting mixture was heated to 45 C for 10 min. The reaction was allowed to cool to 20 C and degassed. Meldrum's acid (4.2 g) was added and the mixture was aged 24 h at 20 C, and then 1.5 h at 40 C. The triazole hydrochloride 1-4 (6 g) was added and the reaction mixture was stirred for 12 h at 90 C. The reaction mixture was washed with water (2 x 50mL). The solution ontained 7.8 g pf the product 2-3 (71percent yield).
69%
Stage #1: With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 45℃; for 0.166667 h;
Stage #2: at 20 - 50℃; for 25 h;
Stage #3: at 90℃; for 12 h;
To 25 mL of DMAc was added the trifluorophenylacetic acid (5 g), CDI (4.3 g), and the resulting mixture was heated to 45 C for 10 min. The reaction was allowed to cool to 20 C and degassed. Meldrum's acid (4.2 g) was added and the mixture was aged 24 h at 20 C and then 1 h at 50 C. The triazole hydrochloride 1-4 (6 g) was added and the reaction mixture was stirred for 12 h at 90 C. The reaction mixture was cooled to 50 C and water (40 mL) was added crystallizing the product. The slurry was cooled to 20 C and stirred for 12 h and water (35 mL) was added over 3 h. After 2 h, the solid was isolated by filtration and dried to give 7.4 g of 2-3 (69percent yeild).
Reference: [1] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 13
[2] Patent: WO2004/83212, 2004, A1, . Location in patent: Page 12-13
  • 7
  • [ 2033-24-1 ]
  • [ 486460-21-3 ]
  • [ 209995-38-0 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
84%
Stage #1: With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 50 - 55℃;
Stage #2: With trifluoroacetic acid In N,N-dimethyl acetamide at 55℃; for 6 h;
In 2000 mL of three necked flask , 150g(0.789mil)2,4,5- Trifluorophenylacetic acid,125g(0.86mol) isopropylidene malonate and 7.7g(63mol)DMAP(4-dimethylaminopyridine) were addded , plus 525 ml DMA (N,N- Dimethylacetamide) was dissolved with magnetic stirring .296mL(1.696mol)DIPEA(N,N-Diisopropylethylamine) was added at room temperature . The oil bath was heated to a reaction temperature of 50 ° C and 107 mL (0.868 mol) of pivaloyl chloride was added dropwise,Keeping the temperature above 55 ° C (1-2h). After completion of the dropwise addition at 55 ° C for 2 h, 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine (0.789 mol) was added, followed by 18 mL (0.237 mol) of trifluoroacetic acid was added dropwise, keeping the temperature at 55° C for 6 h. After cooling, 625 mL of 5percent sodium bicarbonate solution was added, after adding 5g of the compound shown in the formula I keep temperature at 20 ~ 30 ° C and stirring for 2h,add 5percent of sodium bicarbonate solution dropwise for 3 h, Stir at room temperature until no more solids are produced, after cooling to 5 ° C for 1 h, filtered and washed using three times with 200 mL of 20percent DMA solution, washed with 400 mL of water and vaccum drying to obtain 269 g of solid which was tested as a compound of formula I in 84percent yield,m/z:407.15[M+H]+.
Reference: [1] Patent: CN104447753, 2017, B, . Location in patent: Paragraph 0059; 0060
  • 8
  • [ 764667-64-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
115 g
Stage #1: With 4-methyl-morpholine In ethyl acetate at 10℃; for 20 h;
Stage #2: for 6 h; Reflux
Step (i) Preparation of 4-oxo-4-r3-(trifluoromethyl)-5,6-dihvdrori,2,41triazolor4,3,alpyrazin-7(8H)- yll-l-(2A5-trifluorophenyl)butane-2-one To a mixture of 3-trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3a]pyrazine hydrochloride (75.7 g) and ethyl acetate (1 ltr) was added N-methylmorpholine (35.2 ml) and stirred the reaction mixture for about 10 min at room temperature. To this, 5-[l-hydroxy-2- (2,4,5-trifluorophenyl)ethyledine]-2,2-dimethyl-l,3 dioxane-4,6-dione (100 g) was added and stirred for about 10 min at room temperature and heated the reaction mixture to reflux temperature and maintained at the same temperature for about 6 hours. Cooled the reaction mixture to 25-30°C and DM water (750 ml) was added. The reaction mass was stirred for about 10 minutes and separated the organic layer from aqueous layer. Washed the organic layer with DM water and separated the organic layer. Dried the organic layer over anhydrous Na2S04 and concentrated under vacuum at 50-55°C. Toluene (280 ml) was added to the residue, stirred for about 1 hour. Filtered the solid obtained, washed the cake with toluene and suck dried to get 115.0g of title compound.
Reference: [1] Patent: US2010/317856, 2010, A1, . Location in patent: Page/Page column 11
[2] Patent: US2011/213149, 2011, A1, . Location in patent: Page/Page column 12
[3] Patent: WO2015/162506, 2015, A1, . Location in patent: Page/Page column 16-17
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Reference: [1] Patent: US2011/213149, 2011, A1,
[2] Patent: US2011/213149, 2011, A1,
[3] Patent: WO2006/119260, 2006, A2,
[4] Patent: WO2005/30127, 2005, A2,
[5] Patent: WO2005/20920, 2005, A2,
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Reference: [1] Patent: WO2012/63085, 2012, A2, . Location in patent: Page/Page column 109
[2] Patent: US2013/225594, 2013, A1, . Location in patent: Paragraph 0399
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  • [ 486460-21-3 ]
  • [ 764667-64-3 ]
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Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 40, p. 13002 - 13009
  • 12
  • [ 1253055-91-2 ]
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Reference: [1] Patent: WO2010/122578, 2010, A2, . Location in patent: Page/Page column 43
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  • [ 1176895-65-0 ]
  • [ 764667-65-4 ]
Reference: [1] Patent: US2011/213149, 2011, A1,
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Reference: [1] Patent: CN108178761, 2018, A,
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Reference: [1] Patent: CN108178761, 2018, A,
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YieldReaction ConditionsOperation in experiment
79.8% With ammonia In methanol at 25 - 65℃; Example 1;Preparation of (Z)-3-amino-l-(3-(trifluoromethyl)-5,6-dihvdro-ri,2,41triazolor4,3-alpyrazin- 7(8H)-yl)-4-(2A5-trifluorophenyl)but-2-en-l-one.To the mixture of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3,-a]pyrazin- 7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-one (427.0g) (prepared as per US 7,326,708 B2 (or) J.Am.Chem.Soc. 2009,131,8798-8804) and methanol (1000ml) was purged dry ammonia gas (53.6g) at 25-30°C, heated to reflux (60-65°C) and maintained the reaction mass at the same temperature for about 3.0-4.0 hrs. Cooled the reaction mass to 0-5°C, filtered the precipitated solid and washed with chilled methanol. Dried the wet cake at 60-65°C to obtain 340.0g of the title compound. Molar yield 79.8percent; purity by HPLC: 98.99percent.
Reference: [1] Journal of the American Chemical Society, 2009, vol. 131, # 25, p. 8798 - 8804
[2] Patent: WO2016/110750, 2016, A1, . Location in patent: Page/Page column 15; 16
[3] Patent: WO2004/85378, 2004, A1, . Location in patent: Page 16
[4] Patent: WO2005/97733, 2005, A1, . Location in patent: Page/Page column 23-24
[5] Patent: WO2006/81151, 2006, A1, . Location in patent: Page/Page column 14; 15
[6] Patent: WO2006/33848, 2006, A1, . Location in patent: Page/Page column 11-12
[7] Patent: WO2007/35198, 2007, A2, . Location in patent: Page/Page column 11-12
[8] Patent: WO2007/50485, 2007, A2, . Location in patent: Page/Page column 35
[9] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 13
[10] Patent: WO2005/30127, 2005, A2, . Location in patent: Page/Page column 9-11
[11] Patent: WO2005/3135, 2005, A1, . Location in patent: Page 12-13
[12] Patent: WO2005/72530, 2005, A1, . Location in patent: Page/Page column 11-13
[13] Patent: WO2010/122578, 2010, A2, . Location in patent: Page/Page column 53
[14] Patent: US2006/270722, 2006, A1, . Location in patent: Page/Page column 18
[15] Patent: WO2006/119260, 2006, A2, . Location in patent: Page/Page column 43-44
[16] Patent: WO2005/30127, 2005, A2, . Location in patent: Page/Page column 9-11
[17] Patent: WO2005/20920, 2005, A2, . Location in patent: Page/Page column 13
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Reference: [1] Synthetic Communications, 2013, vol. 43, # 24, p. 3281 - 3286
[2] Synthetic Communications, 2013, vol. 43, # 24, p. 3281 - 3286
[3] Patent: WO2005/30127, 2005, A2,
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