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[ CAS No. 239087-08-2 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 239087-08-2
Chemical Structure| 239087-08-2
Chemical Structure| 239087-08-2
Structure of 239087-08-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 239087-08-2 ]

CAS No. :239087-08-2 MDL No. :MFCD00082477
Formula : C8H5BrF4 Boiling Point : -
Linear Structure Formula :- InChI Key :RINUERVPFANASB-UHFFFAOYSA-N
M.W : 257.02 Pubchem ID :2737573
Synonyms :

Calculated chemistry of [ 239087-08-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 44.24
TPSA : 0.0 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.56
Log Po/w (XLOGP3) : 3.46
Log Po/w (WLOGP) : 5.16
Log Po/w (MLOGP) : 4.53
Log Po/w (SILICOS-IT) : 4.28
Consensus Log Po/w : 4.0

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.82
Solubility : 0.0386 mg/ml ; 0.00015 mol/l
Class : Soluble
Log S (Ali) : -3.14
Solubility : 0.185 mg/ml ; 0.000722 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.82
Solubility : 0.00385 mg/ml ; 0.000015 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.07

Safety of [ 239087-08-2 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:1759
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 239087-08-2 ]

* 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.

  • Downstream synthetic route of [ 239087-08-2 ]

[ 239087-08-2 ] Synthesis Path-Downstream   1~96

  • 1
  • [ 51-20-7 ]
  • [ 239087-08-2 ]
  • [ 830346-32-2 ]
YieldReaction ConditionsOperation in experiment
A suspension of 5-bromouracil (31.0 g) in 300 mL OF DICHLOROETHANE is treated with N,O-bis (trimethylsilyl) acetamide (80 mL). The reaction mixture is heated under nitrogen. The solution is cooled to ambient temperature, 2-fluoro-6- (trifluoromethyl) benzyl bromide (50 g) is added and the reaction mixture is heated overnight under the nitrogen. The reaction is cooled, quenched with MEOH, and partitioned between dichloromethane and water. The organic layer is washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product is triturated with ether, filtered, and washed with ether three times providing 40.7 g of 5- bromo-1-[2-fluoro-6-(trifluoromethyl) benzyl] pyrimidine-2,4 (1H, 3H)-DIONE 5A. MS (CI) m/z 366.0, 368.0 (MH+).
A suspension of 5-bromouracil (31.0 g) in 300 mL of dichloroethane is treated with N, 0-BIS (trimethylsilyl) acetamide (80 mL). The reaction mixture is heated under nitrogen. The solution is cooled to ambient temperature, 2-fluoro-6- (trifluoromethyl) benzyl bromide (50 g) is added and the reaction mixture is heated overnight under the nitrogen. The reaction is cooled, quenched with MEOH, and partitioned between dichloromethane and water. The organic layer is washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product is triturated with ether, filtered, and washed with ether three times providing 40.7 g of 5- BROMO-L- [2-FLUORO-6- (TRIFLUOROMETHYL) BENZYL] PYRIMIDINE-2, 4 (IH, 3H)-DIONE IA. MS (CI) mlz 366. 0, 368. 0 (MH+).
EXAMPLE 2 5-BROMO-1 -[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]PYRIMIDINE-2,4(lH,311(at)-DIONE Step 2A: Preparation of 5-bromo-l-r2-fluoro-6- (trifluoromethyl) benzyl]pyrimidine-2,4(1H,3H)-dione 2-1; A suspension of 5-bromouracil (3.1 g, 16.2 mmol) in 100 mL of anhydrous acetonitrile is treated with NO-bis(trimethylsilyl)acetamide (8 mL, 32.4 mmol). The reaction mixture is heated at 80 C under nitrogen for 2 hours. The solution is cooled to ambient temperature and a solution of 2-fluoro-6- (trifluoromethyl) benzyl bromide (5.0 g, 19.4 mmol) in acetonitrile (20 mL) is added and the reaction mixture is heated overnight under nitrogen. The reaction is cooled, quenched with MeOH, and partitioned between dichloromethane and water. The organic layer is washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product is triturated with ether, filtered, and washed with ether three times providing 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]pyrimidine- 2,4(1H,3H)-dione 2-1. NMR (CDCl3) No. 8.72 (s, 1H), 7.64 - 7.37 (3H, m), 7.21 (1H, s), 5.18 (s, 2H), MS (CI) m/z 366.8, 368.8 (MH+).
  • 2
  • [ 4956-05-2 ]
  • [ 239087-08-2 ]
  • [ 867060-68-2 ]
  • 3
  • [ 632628-01-4 ]
  • [ 239087-08-2 ]
  • [ 632626-78-9 ]
  • 4
  • [ 947403-77-2 ]
  • [ 239087-08-2 ]
  • C15H20N3O4CH2C6H3FCF3 [ No CAS ]
  • 5
  • [ 239087-08-2 ]
  • {2-[6-bromo-2-(2-fluoro-6-trifluoromethyl-benzyl)-3,5-dioxo-2,5-dihydro-3<i>H</i>-[1,2,4]triazin-4-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 6
  • [ 239087-08-2 ]
  • 4-(2-amino-2-phenyl-ethyl)-6-(2-chloro-3-methoxy-phenyl)-2-(2-fluoro-6-trifluoromethyl-benzyl)-2<i>H</i>-[1,2,4]triazine-3,5-dione [ No CAS ]
  • 7
  • [ 239087-08-2 ]
  • 4-(2-amino-2-phenyl-ethyl)-6-(2-fluoro-3-methoxy-phenyl)-2-(2-fluoro-6-trifluoromethyl-benzyl)-2<i>H</i>-[1,2,4]triazine-3,5-dione [ No CAS ]
  • 8
  • [ 239087-08-2 ]
  • {2-[6-(2-fluoro-3-methoxy-phenyl)-2-(2-fluoro-6-trifluoromethyl-benzyl)-3,5-dioxo-2,5-dihydro-3<i>H</i>-[1,2,4]triazin-4-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 9
  • [ 239087-08-2 ]
  • {2-[6-(2-chloro-3-methoxy-phenyl)-2-(2-fluoro-6-trifluoromethyl-benzyl)-3,5-dioxo-2,5-dihydro-3<i>H</i>-[1,2,4]triazin-4-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 10
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-5-phenyl-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 11
  • [ 239087-08-2 ]
  • [ 830345-95-4 ]
  • 12
  • [ 239087-08-2 ]
  • [ 876621-30-6 ]
  • 13
  • [ 239087-08-2 ]
  • {2-[5-bromo-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 14
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-fluoro-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 15
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-chloro-4-methyl-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 16
  • [ 239087-08-2 ]
  • [ 855230-38-5 ]
  • 17
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 18
  • [ 239087-08-2 ]
  • [ 830346-45-7 ]
  • 19
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-chloro-phenyl)-1-(2-methanesulfonyl-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 20
  • [ 239087-08-2 ]
  • {2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-5-phenyl-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 21
  • [ 239087-08-2 ]
  • [ 855230-52-3 ]
  • 22
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-isopropoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 23
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-5-(2-trifluoromethyl-phenyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 24
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(3-ethoxy-2-fluoro-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 25
  • [ 239087-08-2 ]
  • [ 830346-38-8 ]
  • 26
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-(2-chloro-4-trifluoromethyl-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 27
  • [ 239087-08-2 ]
  • [ 879876-80-9 ]
  • 28
  • [ 239087-08-2 ]
  • {2-[5-(2-fluoro-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 29
  • [ 239087-08-2 ]
  • {2-[5-(2-chloro-4-methyl-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 30
  • [ 239087-08-2 ]
  • 3-(2-amino-2-phenyl-ethyl)-5-[2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-1<i>H</i>-pyrimidine-2,4-dione [ No CAS ]
  • 31
  • [ 239087-08-2 ]
  • [ 1062642-64-1 ]
  • 32
  • [ 239087-08-2 ]
  • {2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 33
  • [ 239087-08-2 ]
  • {2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 34
  • [ 239087-08-2 ]
  • [ 830346-44-6 ]
  • 35
  • [ 239087-08-2 ]
  • [ 879877-97-1 ]
  • 36
  • [ 239087-08-2 ]
  • {2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-5-(2-trifluoromethyl-phenyl)-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 37
  • [ 239087-08-2 ]
  • {2-[5-(3-ethoxy-2-fluoro-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 38
  • [ 239087-08-2 ]
  • {2-[5-(2-fluoro-3-isopropoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 39
  • [ 239087-08-2 ]
  • {2-[5-(2-chloro-4-trifluoromethyl-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 40
  • [ 239087-08-2 ]
  • {2-[5-[2-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2<i>H</i>-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 41
  • [ 239087-08-2 ]
  • [ 830346-43-5 ]
YieldReaction ConditionsOperation in experiment
88% To a suspension of 5- (2-chloro-3-methoxyphenyl) pyrimidine- 2,4 (1H, 3H)-DIONE 3e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis (trimethylsilyl) acetamide (4.3 mL, 17.4 mmol), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3- trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition OF MEOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-CHLORO-3-METHOXYPHENYL)-1-[2- fluoro-6- (trifluoromethyl) benzyl] pyrimidine-2,4 (1H, 3R)-DIONE 3f (3.3 g, 88 %) as a white solid. MS (CI) M/Z 429.0, 431. 0 (MH+).
  • 42
  • [ 496929-95-4 ]
  • [ 239087-08-2 ]
  • [ 496929-96-5 ]
YieldReaction ConditionsOperation in experiment
399 mg (76%) With potassium carbonate; In N,N-dimethyl-formamide; Step 6D {2-[3-(2-Fluoro-3-methoxy-phenyl)-5-(2-fluoro-6-trifluoromethyl-benzyl)-2,4,6-trioxo-[1,3,5]triazinan-1-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester {2-[3-(2-Fluoro-3-methoxy-phenyl)-2,4,6-trioxo-[1,3,5]triazinan-1-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (370 mg) was dissolved in 7 mL of anhydrous DMF. To this solution was added K2CO3 (2.0 eq, 226 mg) and <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (1.0 eq, 222 mg). The reaction was complete by LC/MS after 14 hours. The DMF was removed in vacuo. The residue was partitioned between EtOAc and H2O. The EtOAc layer was collected and the aqueous layer was extracted with EtOAc (2*20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 30% EtOAc/hexanes to yield 399 mg (76%). Rf=0.36 in 30% EtOAc/hexanes. 1H NMR (CDCl3) delta: 7.51 (d,1H), 7.39 (m,1H), 7.27 (d,1H), 7.15 (dt,1H), 7.06 (dt,1H), 6.88 (dt,1H), 5.42 (q,2H), 5.15 (bs,1H), 4.14 (q,2H), 3.9 (s,3H), 1.4 (s,9H), 1.39 (d,6H).
  • 43
  • [ 1030369-40-4 ]
  • [ 239087-08-2 ]
  • [ 1030369-46-0 ]
YieldReaction ConditionsOperation in experiment
75% 1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydride tetrahydrofuran and the temperature was lowered to -78 C 3.6 ml (1.8 M, 2.0 equivalent) of lithium diisopropyl amide (LDA) was slowly added thereto. Then, 561 mg (2.2 mmol) of 2-chloro~5-trifluoromethylbenzylbromide was added to the reaction solution, and the temperature was slowly raised to room temperature. After 30 more minutes of reaction, the reaction was terminated by ammonium chloride solution, and the organic solvent was extracted by using ethylacetate and sodium chloride solution, which was dried over magnesium sulfate to eliminate moisture of the organic layer. After filtering, the solvent was distillated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1068 mg (yield: 75%) of the target compound (EIMS : 713.1 [M+H] +) .
  • 44
  • [ 1030367-80-6 ]
  • [ 239087-08-2 ]
  • [ 1030367-86-2 ]
YieldReaction ConditionsOperation in experiment
81% 489 mg (1 mmol) of the compound S2 was dissolved in 20 ml of anhydride tetrahydrofuran and the temperature was lowered to -78C 1.8 ml (1.8 M1 2.0 equivalent) of lithium diisopropyl amide (LDA) was slowly added thereto. Then, 514 mg (2.0 mmol) of 2-chloro-5-trifluoromethylbenzylbromide was added to the reaction solution, and the temperature was slowly raised to room temperature. After 30 more minutes of reaction, the reaction was terminated by ammonium chloride solution, and the organic solvent was extracted by using ethylacetate and sodium chloride solution, which was dried over magnesium sulfate to eliminate moisture of the organic layer. After filtering, the solvent was distillated under reduced pressure, and the residue was purified by silica gel column chromatography to give 538 mg (yield: 81%) of the target compound (EIMS: 665.2 [M+H] +) .
  • 45
  • N-{(R)-2-[5-(2-fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamide [ No CAS ]
  • [ 239087-08-2 ]
  • [ 830346-50-4 ]
YieldReaction ConditionsOperation in experiment
91% Uracil 3b (14.5 g, 30.9 mmol), sodium carbonate (50.0 g, 106 mmol), sodium bromide (25.0 g, 102.9 mmol), anhydrous DMF (200 mL), and 2-flouro-6- trifluoromethylbenzyl bromide (12.0 g, 46.7 mmol) in 50 mL toluene were heated at 70- 90 0C for 10 hours (HPLC showed all of the 3b was consumed). The mixture was cooled to room temperature and was slowly charged with 170 mL of cone. HCl solution. (Optionally, the solid carbonate and sodium bromide can be filtered off before the addition of the HCl resulting in the use of less HCL solution). The solution was heated at 60 0C for 10 hours. The pH of the solution was adjusted to 7-8 by slowly adding solid sodium carbonate. 600 mL of DI water was added and the solution was extracted with 2 x 250 mL isopropyl acetate. The phases were separated and the organic layer was washed with 2 x 100 mL of DI water. The organic layer was concentrated to 150 mL and was extracted with 150 mL 10% phosphoric acid. The aqueous layer was agitated with 450 mL of isopropyl acetate and the mixture was neutralized with saturated sodium bicarbonate solution to pH 7. The phases were separated and the organic layer was washed with 2 x 100 mL of water then dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated at 10 mm and 50-60 0C to give 15.8 g of Ie as sticky oil with >98% HPLC peak are at 254 urn (tR = 6.61 min,HPLC method 1). The yield was 91%. The oil can be triturated with hexane to further remove some of the impurities.
  • 46
  • [ 830346-42-4 ]
  • [ 239087-08-2 ]
  • [ 830346-43-5 ]
YieldReaction ConditionsOperation in experiment
88% To a suspension of 5- (2-CHLORO-3-METHOXYPHENYL) pyrimidine- 2,4 (1H, 3H)-dione 7e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis (trimethylsilyl) acetamide (4.3 mL, 17.4 MMOL), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3- trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition OF MEOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-chloro-3-methoxyphenyl)-1-[2- fluoro-6- (trifluoromethyl) benzyl] pyrimidine-2,4 (1H, 3H)-DIONE 7f (3.3 g, 88 %) as a white solid. MS (CI) M/Z 429.0, 431. 0 (MH+).
  • 47
  • [ 1249343-86-9 ]
  • [ 239087-08-2 ]
  • [ 1253186-49-0 ]
YieldReaction ConditionsOperation in experiment
Example 29: 2,6-Difluoro-Lambda/-(1-{r2-fluoro-6-(trifluoromethyl)phenvnmethyl)-1H- pyrazol-3-yl)benzamide; A solution of 2,6-difluoro-Lambda/-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (4.59 g, 20.6 mmol) in THF (45 ml) was cooled to 5 0C under nitrogen. A solution of 1.0 M lithium bis(trimethylsilyl)amide in THF (20.6 ml, 20.6 mmol) was added dropwise maintaining the temperature below 10 0C. After 10 minutes a solution of <strong>[239087-08-2]2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene</strong> (5.29 g, 20.6 mmol, JRD fluorochemicals Ltd) in THF (9 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched using 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried with magnesium sulphate, filtered and solvent removed in vacuo. The crude material was dissolved in DCM and applied to a 330 g silica cartridge. The cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min. The required fractions were combined and evaporated in vacuo, to give the title compound as a white solid (6.75 g). The white solid (6.75 g) was dissolved in ethyl acetate (70 ml) and heated to 50 0C. Cyclohexane (280 ml) was then added dropwise over 20 min. The solution was left to cool to room temperature overnight. White crystals formed which were filtered, washed with the same solvent mixture (50 ml) and dried in an oven at 40 0C to give the title compound as a white solid (5.07 g). LCMS: (System 3) MH+ = 400, tRET = 1.10 min. 1H NMR (400 MHz, Chloroform-d) delta = 8.17 (1 H, br, s), 7.59 - 7.46 (2 H, m), 7.44 - 7.31 (2 H, m), 7.28 (1 H, d, J = 2.5 Hz), 6.98 (2 H, t, J= 8.0 Hz), 6.84 (1 H, d, J = 2.5 Hz), 5.40 (2 H, s).
  • 48
  • [ 1250009-98-3 ]
  • [ 239087-08-2 ]
  • [ 1253187-52-8 ]
YieldReaction ConditionsOperation in experiment
With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; Example 120: 2-Chloro-Lambda/-(1-fr2-fluoro-6-(trifluoromethyl)phenvnmethyl)-1H- pyrazol-3-yl)benzamide; 1.0 M lithium bis(trimethylsilyl)amide (100 mul, 0.1 mmol, Aldrich) was slowly added to a solution of 2-chloro-Lambda/-1 H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 45)(22 mg, 0.1 mmol) in THF (400 mul). The resulting solution was then transferred to a solution of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (26 mg, 0.1 mmol, Aldrich ) in THF (200 mul) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+ = 398, tRET = 2.96 min. Similarly prepared were
  • 49
  • [ 1249109-42-9 ]
  • [ 239087-08-2 ]
  • [ 1253187-60-8 ]
YieldReaction ConditionsOperation in experiment
With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; Example 128 : Lambda/-(1-U2-fluoro-6-(trifluoromethyl)phenyllmethyl)-1H-pyrazol-3- yl)-2-methylbenzamide; 1.0 M lithium bis(trimethylsilyl)amide (100 mul, 0.1 mmol, Aldrich) was slowly added to a solution of 2-methyl-Lambda/-1 H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 46)(22 mg, 0.1 mmol) in THF (400 mul). The resulting solution was then transferred to a solution of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (26 mg, 0.1 mmol, Aldrich) in THF (200 mul) and stirred for 1 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 (Method D) column using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 3) MH+ = 378, tRET =1.13 min.
  • 50
  • [ 2075-46-9 ]
  • [ 239087-08-2 ]
  • [ 1373128-29-0 ]
YieldReaction ConditionsOperation in experiment
4-Nitropyrazole (Aldrich; 4.974 g, 44.0 mmol) was dissolved in DMF (100 ml) and potassium carbonate (9.12 g, 66.0 mmol) was added. The reaction mixture was allowed to stir at ambient temperature under nitrogen for approximately 5 minutes. 2- (Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (Aldrich; 1 1.31 g, 44.0 mmol) in DMF (25 ml) was then added over a period of approximately 5 minutes and the reaction was left to stir overnight.The reaction mixture was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer was washed with water (2 x 250 ml) and dried over sodium sulfate. The solvent was then evaporated under vacuum to give the title compound (12.52 g) as an oil; LCMS (System 3): MNH4+ = 307, tRET = 1 06 min.
Intermediate 1 : 1-[2-Fluoro-6-(trifluoromethyl)phenyl]methyl}-4-nitro-1 H- pyrazole4-Nitropyrazole (Aldrich; 4.974 g, 44.0 mmol) was dissolved in DMF (100 ml) and potassium carbonate (9.12 g, 66.0 mmol) was added. The reaction mixture was allowed to stir at ambient temperature under nitrogen for approximately 5 minutes. 2- (Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (Aldrich; 1 1.31 g, 44.0 mmol) in DMF (25 ml) was then added over a period of approximately 5 minutes and the reaction was left to stir overnight.The reaction mixture was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer was washed with water (2 x 250 ml) and dried over sodium sulfate. The solvent was then evaporated under vacuum to give the title compound (12.52 g) as an oil; LCMS (System 3): MNH4+ = 307, tRET = 1 06 min.
  • 51
  • [ 239087-08-2 ]
  • [ 1373128-30-3 ]
  • 52
  • [ 239087-08-2 ]
  • [ 1373128-32-5 ]
  • 53
  • [ 239087-08-2 ]
  • [ 1373128-25-6 ]
  • 54
  • [ 239087-08-2 ]
  • [ 1373128-26-7 ]
  • 55
  • [ 1153946-38-3 ]
  • [ 239087-08-2 ]
  • [ 1373128-25-6 ]
YieldReaction ConditionsOperation in experiment
A solution of 2,6-difluoro-/V-1/-/-pyrazol-4-ylbenzamide (for a preparation see intermediate 2; 22 mg, 0.1 mmol) in DMF (0.4 ml) was treated with potassium tert- butoxide (1 1 mg, 0.1 mmol) and allowed to stand at room temperature for 10 min. A solution of 1-(bromomethyl)-2-phenoxybenzene (Maybridge; 26 mg, 0.1 mmol) in acetonitrile (0.2 ml) was finally added and the solution left to stand for 16 h at room temperature. The solvent was removed and then the crude mixture was dissolved in a 1 : 1 mixture of DMSO: methanol (0.6 ml) and the solution purified by MDAP on Sunfire C18 (Method D). The appropriate fraction was concentrated in vacuo to give the title compound (2.6 mg); LCMS (System 1): MH+ = 406, tRET = 3.46 min.
  • 56
  • 5-[4-(tetr-butyldimethylsilanyloxy)-3-methyl-phenylsulfanyl-methyl]-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [ No CAS ]
  • [ 239087-08-2 ]
  • C33H34F7NOS2Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: A stirred solution of 6 (300 mg, 0.59 mmol) in anhydrous THF (5 ml) was cooled to -78 C in dryice-acetone bath under N2 atmosphere. 2.0 M lithiumdiisopropylamide (619 mul, 1.24 mmol) was added dropwise to reaction mixture at -78 C. The reaction mixture was stirred at -78 C for 30 min. A solution of benzyl bromide (77 mul, 0.65 mmol) in THF (1 ml) was added dropwise at -78 C. After the mixture was stirred at same temperature for further 30 min, it was quenched by adding sat. NH4Cl solution. The mixture was diluted by ethyl acetate and the organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to give crude compound. The crude compound was purified by column chromatography on silica gel (n-hexnane/ethylacetate = 10/1) to obtain 7a as colorless oil (265 mg, 75%).
  • 57
  • [ 1332494-96-8 ]
  • [ 239087-08-2 ]
  • [ 1332495-16-5 ]
YieldReaction ConditionsOperation in experiment
73% With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃; for 0.5h; [Example 23] Preparation of Compound S23 [Show Image][Step C] Compound S3 (732 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the temperature was lowered to -78 C. Then, lithium diisopropylamide (LDA, 1.8 mL, 1.8 M, 2.0 equivalents) was slowly added. After adding 2-fluoro-5-trifluoromethylbenzyl bromide (514 mg, 2.0 mmol), the temperature was slowly raised to room temperature. After further reacting for 30 minutes, the reaction was terminated with aqueous ammonium chloride solution. The organic solvent was extracted with ethyl acetate and brine, and the organic layer was dried with magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by silica gel column chromatography yielded the target compound (534 mg, yield: 73 %). (FABMS: 734 [M+H] +).
  • 58
  • [ 1332494-97-9 ]
  • [ 239087-08-2 ]
  • [ 1332495-17-6 ]
YieldReaction ConditionsOperation in experiment
70% With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃; for 0.5h; [Example 24] Preparation of Compound S24 [Show Image][Step C] Compound S4 (779 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the temperature was lowered to -78 C. Then, lithium diisopropylamide (LDA, 1.8 mL, 1.8 M, 2.0 equivalents) was slowly added. After adding 2-fluoro-5-trifluoromethylbenzyl bromide (514 mg, 2.0 mmol), the temperature was slowly raised to room temperature. After further reacting for 30 minutes, the reaction was terminated with aqueous ammonium chloride solution. The organic solvent was extracted with ethyl acetate and brine, and the organic layer was dried with magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by silica gel column chromatography yielded the target compound (545 mg, yield: 70 %). (FABMS: 782 [M+H]+) .
  • 59
  • [ 1454273-42-7 ]
  • [ 239087-08-2 ]
  • [ 1454273-43-8 ]
YieldReaction ConditionsOperation in experiment
46% With potassium carbonate; In 1-methyl-pyrrolidin-2-one; for 2h; General procedure: 1'-benzyl-lH-spiro[mro[3,4-d]pyrimidin-5,4'-piperidine]-2,4(3H,7H)-dione (4) (130 g, 0.416 mol) obtained in Step D and potassium carbonate (114 g, 0.832 mol) were suspended in 1 -methyl-2-pyrrolidinone (325 niL), and 2-fluoro-6-(trifluoromethyl) benzylbromide (107 g, 0.416 mol) was slowly added thereto. The resulting mixture was stirred for 2 hrs, and added with ethyl acetate (1300 mL) and deionized water (1300 mL). The organic layer was separated and the aqueous layer was further extracted once with ethyl acetate (650 mL). The organic layer was washed once with a saturated aqueous solution of sodium chloride (2000 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. Methyl tert butyl ether (MTBE, 300 mL) was added to the resulting solid from the concentration process, stirred for 2 hrs, followed by Alteration. The filted solid was washed with MTBE (200 mL) to obtain the title compound as white solid (92.7 g, yield: 46%). NMR (600MHz, CDC13) delta 1.56 (2H, d), 2.25 (2H, m), 2.35 (2H, m), 2.75 (2H, m), 3.50 (2H, s), 4.66 (2H, s), 5.12 (2H, s), 7.21 -7.24 (1 H, m), 7.27-7.30 (3H, m), 7.33-7.34 (2H, m), 7.47 (1H, m), 7.54 (1H, d), 8.11 (1H, s)
46% With sodium chloride; potassium carbonate; In 1-methyl-pyrrolidin-2-one; water; ethyl acetate; for 2h; 1'-benzyl-1H-spiro[furo[3,4-d]pyrimidin-5,4'-piperidine]-2,4(3H,7H)-dione (4) (130 g, 0.416 mol) obtained in Step D and potassium carbonate (114 g, 0.832 mol) were suspended in 1-methyl-2-pyrrolidinone (325 mL), and <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzylbromide</strong> (107 g, 0.416 mol) was slowly added thereto. The resulting mixture was stirred for 2 hrs, and added with ethyl acetate (1300 mL) and deionized water (1300 mL). The organic layer was separated and the aqueous layer was further extracted once with ethyl acetate (650 mL). The organic layer was washed once with a saturated aqueous solution of sodium chloride (2000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Methyl tert butyl ether (MTBE, 300 mL) was added to the resulting solid from the concentration process, stirred for 2 hrs, followed by filteration. The filted solid was washed with MTBE (200 mL) to obtain the title compound as white solid (92.7 g, yield: 46%). 1H NMR (600 MHz, CDCl3) delta 1.56 (2H, d), 2.25 (2H, m), 2.35 (2H, m), 2.75 (2H, m), 3.50 (2H, s), 4.66 (2H, s), 5.12 (2H, s), 7.21-7.24 (1H, m), 7.27-7.30 (3H, m), 7.33-7.34 (2H, m), 7.47 (1H, m), 7.54 (1H, d), 8.11 (1H, s)
  • 60
  • [ 672906-60-4 ]
  • [ 239087-08-2 ]
  • 1,3-bis[5-(2-trifluoromethyl-6-fluorobenzyl(ethyl)amino)pentyl]-6-methyluracil [ No CAS ]
  • 61
  • 5-(2-fluoro-3-methoxyphenyl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ No CAS ]
  • [ 239087-08-2 ]
  • 5-(2-fluoro-3-methoxyphenyl)-7-(2-fluoro-6-(trifluoromethyl)benzyl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.7% With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 30℃; for 20h; Step 1 5-(2-fluoro-3-methoxyphenyl)-7-(2-fluoro-6-(trifluoromethyl)benzyl)-3-methyl-2-(4-nitrophe nyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione 5-(2-fluoro-3-methoxyphenyl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6 (5H,7H)-dione 1d (1.90 g, 4.62 mmol), <strong>[239087-08-2]2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene</strong> (1.31 g, 5.10 mmol), potassium iodide (844 mg, 5.08 mmol) and potassium carbonate (702 mg, 5.09 mmol) were dissolved in 54 mL of N,N-dimethylformamide successively. After stirring for 20 hours at room temperature, the reaction was stopped and the reaction solution was concentrated under reduced pressure. The residues were added with water and ether to slurrying for 1 hour, and filtered. The filter cake was washed with ether (10 mL x 3) and dried to obtain the title compound 5-(2-fluoro-3-methoxyphenyl)-7-(2-fluoro-6-(trifluoromethyl)benzyl)-3-methyl-2-(4-nitrophe nyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione 6a (1.91 g, white solid), yield 70.7%. MS m/z (ESI): 588.1 [M+1]
  • 62
  • 5-(6-methoxypyridazin-3-yl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ No CAS ]
  • [ 239087-08-2 ]
  • 7-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(6-methoxypyridazin-3-yl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
465 mg With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃; for 2h; Step 3 7-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(6-methoxypyridazin-3-yl)-3-methyl-2-(4-nitrophen yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione <strong>[239087-08-2]2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene</strong> (purchased from Sinopharm Chemical Reagent Co., Ltd., product number XW239870821) (308 mg, 1.20 mmol) was dissolved in 20 mL of N,N-dimethyl formamide, and added with the crude 5-(6-methoxypyridazin-3-yl)-3-methyl-2-(4-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5 H,7H)-dione 12b (395 mg, 1 mmol) and potassium carbonate (276 mg, 2mmol) successively. After reacting for 2 hours at room temperature, the reaction solution was stopped. The reaction solution was poured into 100 mL of water, and filtered. The filter cake was dried to obtain the title compound 7-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(6-methoxypyridazin-3-yl)-3-methyl-2-(4-nitrophen yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione 12c (465 mg, yellow solid ), yield: 81.4%. MS m/z (ESI): 570.0 [M-1]
  • 63
  • [ 1421631-92-6 ]
  • [ 239087-08-2 ]
  • C33H54F4N13(1+)*Br(1-) [ No CAS ]
  • 64
  • [ 239087-08-2 ]
  • 1,2-di-(2-fluoro-6-(trifluoromethyl)phenyl)ethane [ No CAS ]
  • 65
  • C33H54F4N13(1+)*Br(1-) [ No CAS ]
  • [ 239087-08-2 ]
  • 1,2-di-(2-fluoro-6-(trifluoromethyl)phenyl)ethane [ No CAS ]
  • 66
  • [ 121-44-8 ]
  • [ 239087-08-2 ]
  • C11H14F4N(1+)*Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% In acetonitrile; at 20℃; for 1h; Trimethylamine (1.28 mL, 5.4 mmol, 4.2 M in ethanol) was added to a solution of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (700 mg, 2.72mmol) in acetonitrile and the solution was stirred at r.t. for 1 h. The volatiles were evaporated under reduced pressure, the residue was dissolved in CH2Cl2 and Et2O was slowly added. The precipitated bromide salt was collected by filtration (840 mg, 2.65 mmol, 98%). This salt (632 mg, 2 mmol) was dissolved in chloroform and AgOTs (837mmol, 3 mmol) was added. The resulting reaction mixture was stirred for 30 min, then filtered through a bed of Celite. The solvent was removed under reduced pressure to afford the tosylate salt 1f. Yield: 572 mg (1.4 mmol, 70%); white solid.
  • 67
  • [ 239087-08-2 ]
  • 1-fluoro-2-(4-methoxybenzyl)-3-(trifluoromethyl)benzene [ No CAS ]
  • 68
  • [ 239087-08-2 ]
  • 1-(2-fluoro-6-(trifluoromethyl)phenyl)-N,N,N-trimethylmethanaminium tosylate [ No CAS ]
  • 69
  • [ 616-47-7 ]
  • [ 239087-08-2 ]
  • 1-(2-trifluoromethyl-6-fluorophenylmethyl)-3-methylimidazolium bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% In dichloromethane; at 20℃; for 96h; General procedure: 1-Methylimidazole (0.57 g, 6.93 mmol) was added to 2,6-difluorophenylmethyl bromide (1.45 g, 6.99 mmol) in dichloromethane (30 cm3 ). The mixture was left at ambient temperature for 96 h. The solvent was removed by rotary evaporation affording the product as a white powder. Yield 1.89 g (94%). MS: C11H11F2N2 requires 209.0890; found [M - Br]+ 209.0913. 1 H (CDCl3/(CD3)2SO): delta = 10.07 (1 H, s, N2CH), 7.43 (1 H, t, 3 JHH = 1.8 Hz, HCCH), 7.34 (1 H, m, Hpara), 7.18 (1 H, t, 3 JHH = 1.8 Hz, HCCH), 6.29 (2 H, m, Hmeta), 5.50 (2 H, s, CH2), 3.98 (3 H, s, CH3). 13C{1 H} NMR (CDCl3/(CD3)2SO): delta = 162.8 (dd, 1 JCF = 252 Hz, 3 JCF = 6 Hz, CF), 137.7 (s, N2CH), 132.5 (t, 2 JCF = 10 Hz, Cpara), 124.1 (s, CHCH), 121.6 (s, CHCH), 112.3 (dm, 2 JCF = 24 Hz, Cmeta), 109.2 (t, 2 JCF = 18 Hz, Cipso), 41.0 (t, 3 JCF, NCH2), 36.7 (NCH3). 19F (CDCl3/(CD3)2SO): delta = -113.80 (2 F, m).
  • 70
  • [ 239087-08-2 ]
  • 4-(2-{(S)-1-amino-3-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)butyric acid [ No CAS ]
  • 71
  • [ 239087-08-2 ]
  • 4-(2-{(S)-1-amino-3-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethylbenzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-propyl}-phenoxy)butyric acid sodium salt [ No CAS ]
  • 72
  • [ 239087-08-2 ]
  • [ 869984-39-4 ]
  • 73
  • [ 239087-08-2 ]
  • [ 869984-40-7 ]
  • 74
  • [ 239087-08-2 ]
  • [ 869984-41-8 ]
  • 75
  • [ 239087-08-2 ]
  • C37H38F5N3O8 [ No CAS ]
  • 76
  • [ 239087-08-2 ]
  • [ 869984-42-9 ]
  • 77
  • [ 15018-56-1 ]
  • [ 239087-08-2 ]
  • [ 830346-48-0 ]
YieldReaction ConditionsOperation in experiment
81% With potassium carbonate; In N,N-dimethyl-formamide; at 75 - 85℃; Add to the three-necked flask5-bromo-6-methylpyrimidine-2,4(1H,3H)-dione 1 (20.50 g, 100 mmol)And <strong>[239087-08-2]2-(bromomethyl)-1-fluoro-3-trifluoromethylbenzene</strong> 2 (25.70 g, 100 mmol)And N,N-dimethylformamide (103 mL),After stirring and stirring, potassium carbonate (27.64 g, 200 mmol) was added.After stirring uniformly, the mixture was heated to 75 to 85 C to react overnight. Water (205 mL) was added to the end of the reaction to precipitate a large amount of solid, which was filtered and dried to give Compound 3 (30.88 g, 81%).
  • 78
  • [ 239087-08-2 ]
  • [ 1150560-59-0 ]
  • 79
  • [ 239087-08-2 ]
  • (R)-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2-(2-oxopyrrolidin-1-yl)-2-phenylethyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione [ No CAS ]
  • 80
  • [ 239087-08-2 ]
  • [ 834153-87-6 ]
  • 81
  • methyl 3-((4-(methoxymethoxy) phenyl) (phenyl) amino)-3-oxopropanoate [ No CAS ]
  • [ 239087-08-2 ]
  • methyl 3-(2-fluoro-6-(trifluoromethyl) benzyl)-3-((4-(methoxymethyl) phenyl) (phenyl) amino)-3-oxopropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With Rhodinyl iodide; potassium hydroxide; In toluene; at -10 - 20℃; for 1h;Inert atmosphere; General procedure: To a stirred solution of amide compound 4 (0.200 gr, 0.60 mmol)in Toluene (4 mL) at 5-10 C 50% KOH solution (0.23 mL,6.68 mmol) was added and stirring was continued for 10-15 min.The reaction mixture was turned to blue colour then reactionmixture was taken to 0 C, 4-bromobenzyl bromide (0.165 gr,0.66 mmol) in 1mL toluene was added drop wise slowly followedby catalytic amount (19 mg) of TBAI was added, then the biphasicreaction mixturewas allowed to rt and stirring was continued untilcompletion starting material (amide compound 10), monitored byTLC. After completion of starting material the biphasic reactionmixture was diluted with water (5 mL) and extracted with ethylacetate (2 20 mL), the combined organic layer was washed withbrine and dried over anhydrous Na2SO4. The solvent was removedunder reduced pressure, and the crude product was subjected toflash column chromatography (3-5% ethyl acetate-hexane) to givecorresponding alkylated compound 10j (0.268 gr, 89%) as colourless liquid; IR (neat): 2955, 2917, 2850, 2826, 2790,1745,1667,1506,1440, 1199, 1233, 1151, 1077, 732 cm1; 1H NMR (400 MHz, CDCl3)delta 7.43 (d, J 7.9 Hz, 2H), 7.33-7.25 (m, 2H), 7.19-7.07 (m, 2H),7.06-6.58 (m, 7H), 5.14 (d, J 17.4 Hz, 2H), 3.81-3.71 (m, 4H), 3.46 (d, J 22.0 Hz, 3H), 3.28 (t, J 12.0 Hz, 1H), 3.13 (dd, J 13.5, 4.6 Hz,1H); 13C NMR (150 MHz, CDCl3) delta 169.60, 168.54, 156.91, 142.27,137.30, 136.10, 131.53 (2 C), 131.24, 129.88, 129.69, 128.92, 128.59,128.14, 127.47, 126.43, 126.11, 120.67, 117.06, 116.59, 94.43, 56.23,52.64, 51.35, 34.74 ppm; ESI-MS: m/z 498 [M].
  • 82
  • C15H12N4O2S [ No CAS ]
  • [ 239087-08-2 ]
  • N-(3-bromo-1-methyl - 1H-indol-2-yl)-N-(2-fluoro-6-(trifluoromethyl)benzyl)benzenesulfonamide [ No CAS ]
  • 83
  • [ 626-48-2 ]
  • [ 239087-08-2 ]
  • [ 830346-47-9 ]
YieldReaction ConditionsOperation in experiment
89% With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 18h; In the reactor, 1.0 g, 1.0 equiv. as shown in Formula IV2-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene was dissolved in 10 mL of DMF.To this was added 1.2 equiv. 6-methyluracil as shown in Formula V, 1.8 equiv. potassium carbonate,0.1equiv. of TBAI, the system is heated to 70 ° C for 18h;After the reaction was completed, the reaction mixture was concentrated to dryness, and the concentrate was washed with a mixture of dichloromethane and 1N aqueous hydrochloric acid.The organic phase is separated, and the organic phase is washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine.Subsequently, it is dried over sodium sulfate and spin-dried to obtain 0.89 equiv. of the polysubstituted pyrimidine derivative as shown in Formula I.The yield was 89percent.
  • 84
  • C12H11FN2O3 [ No CAS ]
  • [ 239087-08-2 ]
  • [ 1150560-59-0 ]
YieldReaction ConditionsOperation in experiment
83% With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; at 80℃; for 18h; S2, synthesis of the compound of formula X: Weigh 1.0 g, 1.0 equiv. of the compound of formula VIII in the reactor, after dissolving by adding 10 mL of 1,4-dioxane, based on the compound of formula VIII, 1.2equiv. of the compound of formula IX is added to the reactor in turn, after 1.8equiv. of base, 0.1equiv. of catalyst, The reaction system is heated to 70 C, and the reaction is kept for 18 hours. After the reaction is completed, The reaction solution was concentrated to dryness. The concentrated residue was partitioned between dichloromethane and 1.0 N aqueous hydrochloric acid. Separating the organic phase, after washing the organic phase with a saturated aqueous solution of sodium hydrogencarbonate and brine, The organic phase was dried over sodium sulfate and concentrated. The concentrate is separated by column chromatography to obtain a compound of formula X in a yield of 83%.
78.5% With potassium tert-butylate; In acetonitrile; at 75 - 85℃; Compound II (4.8 g, 19.2 mmol) was placed in a 100 ml three-necked flask,Potassium tert-butoxide 50 mmol,40ml acetonitrile,<strong>[239087-08-2]2-fluoro-6-trifluoromethylbenzyl bromide</strong> (28.1 mmol),Heated to 75-85 C and reacted for 10-11 hours,After the reaction was completed, 40 ml of water was added to precipitate a white solid.Filtration and drying gave 6.45 g of intermediate 1 with a yield of 78.5%.
  • 85
  • C26H29FN2O5 [ No CAS ]
  • [ 239087-08-2 ]
  • C34H33F5N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In tetrahydrofuran; at 50℃; for 12h; 7.5 g of the above intermediate V, 8.2 g of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> and 4.4 g of potassium carbonate were added to the reaction flask, and then 35 mL of tetrahydrofuran was added thereto, and the mixture was heated to 50 C for 12 h, and washed into 100 mL of water. A large amount of solid was precipitated, filtered, and dried to give 9.4 g of Intermediate VII, weight yield 125%, HPLC purity 97%.
  • 86
  • C17H19FN2O5 [ No CAS ]
  • [ 239087-08-2 ]
  • [ 1150560-59-0 ]
YieldReaction ConditionsOperation in experiment
83.6% With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 3h; Add DMF (10 mL) to the three-necked flask,Compound IX (1.1 g, 3 mmol),2-trifluoromethyl-6-fluoro-benzyl bromide (0.8 g, 3 mmol), potassium carbonate (0.87 g, 6 mmol), TBAI (0.011 g, 0.03 mmol).The temperature was raised to 75 C, and the reaction was stirred for 3 hours.The reaction was stopped, extracted with ethyl acetate (20 mL) and water (20 mL x 3), and dried over anhydrous magnesium sulfate.The resulting solution was added dropwise to 10 mL (4.76 mol / L) of ethyl acetate in a hydrogen chloride solution. After the dropwise addition was completed, the reaction was stopped by stirring at 30 C for 16 hours.Wash with water, dry the organic phase, concentrate,Compound X (1.1 g, 83.6%) was obtained.
  • 87
  • tert-butyl (2,5-dimethyl-4-nitrophenyl)carbamate [ No CAS ]
  • [ 239087-08-2 ]
  • tert-butyl (2,5-dimethyl-4-nitrophenyl)(2-fluoro-6-(trifluoromethyl)benzyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of tert- butyl (2,5-dimethyl-4-nitrophenyl)carbamate (0.5 g, 1.89 mmol) in anhydrous N,N- dimethylformamide (10 mL), sodium hydride (68 mg, 2.8 mmol, 60% in mineral oil) was added at 0 C, and the reaction mixture was stirred for 15 min, followed by addition of 2-(bromomethyl)-l-fluoro-3- (trifluoromethyl)benzene (0.58 g, 2.253 mmol). The resulting reaction mixture was allowed to stir at 25 C for 2 h. After completion of the reaction, the reaction mixture was poured into an ice cold aqueous ammonium chloride solution, further diluted with water (30 mL) and extracted three times with ethyl acetate (25 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain crude tert- butyl (2,5-dimethyl-4- nitrophenyl)(2-fluoro-6-(trifluoromethyl)benzyl)carbamate (0.8 g, 96 % yield), which was used for the next step.
  • 88
  • [ 142253-56-3 ]
  • [ 239087-08-2 ]
  • tert-butyl 3-(((2-fluoro-4-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.3% To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg, 534 i.imol) in dryTHF (2.67 mL) was added potassium tert-butoxide 1.65 M solution in THF (340 1.iL, 561 i.imol)and the turbid reaction mixture was stirred at RT for 15 mm followed by addition of <strong>[239087-08-2]1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene</strong> (137 mg, 534 i.imol). The reaction mixture was then stirred at room temperature for 3 h. The crude reaction was diluted with ethyl acetate and extracted with sat. aq. NaHCO3 solution, the organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried oversodium sulfate and evaporated down to dryness to yield a clear oil. The crude was immobilizedon Isolute and purified by column chromatography eluting with 0 to 30 % EtOAc in heptanes to afford tert-butyl 3 -(((2 -fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine- 1 -carboxylate (158 mg, 413 imol, 77.3 % yield) as a colorless oil. MS (ESI): mlz = 308.1 [M-56+H]
  • 89
  • [ 141699-55-0 ]
  • [ 239087-08-2 ]
  • tert-butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.9% With potassium tert-butylate; In tetrahydrofuran; at 25℃; for 12h;Inert atmosphere; To a solution of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (1000.0 mg, 3.89 mmol, CAS RN239087-08-2) and tert-butyl 3-hydroxyazetidine-1-carboxylate (673.92 mg, 3.89 mmol, CAS RN141699-55-0 ) in dry THF (10 mL) at 25 C, was added t-BuOK (5.84 mL, 5.84 mmol; 1.0 M in dryTHF) and the mixture was stirred at 25 C for 12 h. The mixture was poured into H20 (10 mL) andextracted three times with EA (20 mL each). The combined organic layers were combined, dried overanhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, purified by flash chromatography on silica gel (gradient PE : EA = 10: 1 to 2: 8) to give the title compound as colorless oil (1100 mg, 80.9%). MS (ESI): m/z = 294.0 [M-56+H].
80.9% With potassium tert-butylate; In tetrahydrofuran; at 25℃; for 12h; To a solution of <strong>[239087-08-2]2-fluoro-6-(trifluoromethyl)benzyl bromide</strong> (1000.0 mg, 3.89 mmol, CAS RN 239087-08-2) and tert-butyl 3-hydroxyazetidine-l-carboxylate (673.92 mg, 3.89 mmol, CAS RN 141699-55-0 ) in dry THF (10 mL) at 25 C, was added t-BuOK (5.84 mL, 5.84 mmol; 1.0 M in dry THF) and the mixture was stirred at 25 C for 12 h. The mixture was poured into H20 (10 mL) and extracted three times with EA (20 mL each). The combined organic layers were combined, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated under reduced pressure, purified by flash chromatography on silica gel (gradient PE : EA = 10 : 1 to 2 : 8) to give the title compound as colorless oil (1100 mg, 80.9%). MS (ESI): m/z = 294.0 [M-56+H]+.
  • 90
  • [ 239087-08-2 ]
  • (4aR,8aS)-6-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ No CAS ]
  • 91
  • [ 239087-08-2 ]
  • 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine trifluoroacetate [ No CAS ]
  • 92
  • [ 239087-08-2 ]
  • 3 -((2-fluoro-6-(trifluoromethyl)benzyl)sulfonyl)azetidine 2,2,2-trifluoroacetate [ No CAS ]
  • 93
  • [ 239087-08-2 ]
  • 3-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)azetidine trifluoroacetate [ No CAS ]
  • 94
  • [ 941585-25-7 ]
  • [ 239087-08-2 ]
  • tert-butyl 3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (0.400 g, 2.11 mmol) in dry THF (5 mL) was added potassium tert-butoxide 1M solution in THF (2.22 mL, 2.22 mmol) and the reaction mixture was stirred at RT for 15 mm followed by addition of 2-(bromomethyl)-1- fluoro-3-(trifluoromethyl)benzene (CAS RN 23 9087-08-2). The reaction mixture was thenstirred at RT for 14 h. The crude reaction was diluted with EtOAc and extracted with aq. 1 M NaHCO3 solution, the organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO4 and evaporated down to dryness to yield the crude product (805 mg) which was used in the next step without further purification. MS (ESI): mlz = 310.2 [M-56+H].
In tetrahydrofuran; at 20℃; for 14h; To a solution oftert-butyl 3-mercaptoazetidine-l-carboxylate (0.400 g, 2.11 mmol) in dry THF (5 mL) was added potassium tert-butoxide 1M solution in THF (2.22 mL, 2.22 mmol) and the reaction mixture was stirred at RT for 15 min followed by addition of 2-(bromom ethyl)- 1- fluoro-3-(trifluoromethyl)benzene (CAS RN 239087-08-2). The reaction mixture was then stirred at RT for 14 h. The crude reaction was diluted with EtOAc and extracted with aq. 1 M NaHCCh solution, the organic phase was collected and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaS04 and evaporated down to dryness to yield the crude product (805 mg) which was used in the next step without further purification. MS (ES1): m/z = 310.2 [M-56+H]+
  • 95
  • [ 941585-25-7 ]
  • [ 239087-08-2 ]
  • tert-butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfonyl]azetidine-1-carboxylate [ No CAS ]
  • 96
  • [ 142253-56-3 ]
  • [ 239087-08-2 ]
  • tert-butyl 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.3% To a solution of tert-butyl 3-(hydroxymethyl)azetidine-l -carboxylate (100 mg, 534 pmol) in dry THF (2.67 mL) was added potassium tert-butoxide 1.65 M solution in THF (340 pL, 561 pmol) and the turbid reaction mixture was stirred at RT for 15 min followed by addition of 1- (bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene (137 mg, 534 pmol). The reaction mixture was then stirred at room temperature for 3 h. The crude reaction was diluted with ethyl acetate and extracted with sat. aq. NaHCCh solution, the organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield a clear oil. The crude was immobilized on Isolute and purified by column chromatography eluting with 0 to 30 % EtOAc in heptanes to afford tert-butyl 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-l-carboxylate (158 mg, 413 pmol, 77.3 % yield) as a colorless oil. MS (ESI): m/z = 308.1 [M-56+H]+
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