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Chemical Structure| 1388842-44-1
Chemical Structure| 1388842-44-1
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Product Details of [ 1388842-44-1 ]

CAS No. :1388842-44-1 MDL No. :MFCD30537662
Formula : C13H7F6N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :YPMUIQDGERASRJ-UPHRSURJSA-N
M.W : 351.20 Pubchem ID :86703006
Synonyms :

Safety of [ 1388842-44-1 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1388842-44-1 ]

* 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 [ 1388842-44-1 ]
  • Downstream synthetic route of [ 1388842-44-1 ]

[ 1388842-44-1 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 1388842-44-1 ]
  • [ 1421919-75-6 ]
YieldReaction ConditionsOperation in experiment
98.9% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at -10℃; for 1.5 h; Synthesis of (Z)-3 -(3 -(3 , 5 -bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol- 1 -y 1) - 1 -(3 ,3 - difluoroazetidin- 1 -yl)prop-2-en- 1 -one: To a 3-L, four-necked, round-bottomed flask equipped with nitrogen inlet, addition funnel, thermometer socket, mechanical stirrer was added (Z)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l-yl)acrylic acid (100 g, 1.0 eq.) in DCM (1.8 L, 18 V). The reaction mixture was cooled to -lOoC. To the cooled solution, were added HOBT (4.4 g, 0.1 eq.), EDC-HC1 (80.6 g, 1.5 eq.) and 3,3-difluoroazetidine hydrochloride (44 g, 1.2 eq.). To the resulting mixture at -10 oC, was added DIPEA (72 mL, 1.5 eq) dropwise over a period of 1.5 hours. The progress of the reaction was monitored by HPLC analysis which showed the completion of the reaction at the end of DIPEA addition. The reaction temperature was slowly raised to 15 °C to 20 °C (~ 2h). The reaction mixture was quenched with 1L ice-water slurry. The organic layer was separated and the aqueous layer was extracted with DCM (400 mL x 2). The organic layer was washed with saturated brine solution (2 x 500 ml), dried over anhydrous Na2S04 (lOg) and concentrated under reduced pressure (~35 °C) to afford crude compound. The crude compound thus obtained was dissolved in 5 vol. of DIPE and stirred at rt for 30 min. and then filtered. Crude weight was 100 g (yield = 82.39 percent) [Cis-85.07percent by HPLC, Trans- 14.36percent by HPLC].The crude compound thus obtained was further purified by recrystallisation with ethyl acetate according to the following procedure. To a 500-mL, four-necked, round-bottomed flask equipped with mechanical stirrer, thermometer socket and stopper was added 100 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)-l-(3,3-difluoroazetidin-l- yl)prop-2-en-l-one. To this compound at rt was added ethyl acetate (7 volumes) under stirring. However, compound was not completely soluble. Hence, the resulting solution was heated to 60 oC to obtain a clear solution and was then slowly cooled to -30 oC. At -30 oC, solution was stirred for 20 min. and filtered under suction. The compound obtained was dried under vacuum at 40-45 °C for 3 h - 4hrs to yield the product as a white solid. (Cis- 98.9percent by HPLC); (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l-yl)-l-(3,3- difiuoroazetidin-l-yl)prop-2-en-l-one. 1H NMR (300 MHz, CDC13) δ 9.57(s, 1H), 8.56(s, 2H), 7.90 (s, 1H), 7.18-7.21 (d, J = 10.8 Hz, 1H), 5.61-5.65 (d, J = 10.8 Hz, 1H), 4.39- 4.45(m, 4H).
Reference: [1] Patent: WO2013/19548, 2013, A1, . Location in patent: Page/Page column 86-87
  • 2
  • [ 288315-03-7 ]
  • [ 1388842-44-1 ]
  • [ 1421919-75-6 ]
YieldReaction ConditionsOperation in experiment
33% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 25℃; (Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H- 1,2,4-triazol- l-yl)acrylic acid (8) (30 g, 85.47 mmol) was dissolved in CH2C12 (600 mL) and cooled to 0 °C. 3,3- Difluoroazitidine hydrochloride (13.29 g, 102. 56 mmol), EDCI (14.24 g, 128.20 mmol) and HOBt (13.78 g, 102.56 mmol) were added at 0 °C followed by a dropwise addition of DIPEA (21.74 mL, 102.56 mmol) over 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 4, transferred into water (250 mL) and extracted with CH2C12 (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (0.5 percent MeOH in CH2C12) to give (Z)-3-(3-(3,5- bis(trifluoromethyl)phenyl)- 1 H- 1 ,2,4-triazol- 1 -yl)-l -(3,3 -difiuoroazetidin- 1 -yl)prop-2-en- 1 - one (9) (Yield: 12 g, 33percent). 1H NMR (400 MHz, CDC13) δ 9.63 (s, 1H), 8.61 (s, 2H), 7.95 (s, 1H), 7.26 (d, J= 10.4 Hz, 1H), 5.68 (d, J= 10.8 Hz, 1H), 4.46-4.60 (m, 4H). LCMS: m/z 427.39 [M+H]+, tR = 3.04 min
Reference: [1] Patent: WO2014/205393, 2014, A1, . Location in patent: Paragraph 00326
  • 3
  • [ 1388842-44-1 ]
  • [ 54608-52-5 ]
  • [ 1393477-72-9 ]
YieldReaction ConditionsOperation in experiment
83% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In ethyl acetate; acetonitrile at 0 - 25℃; for 3 h; In a 3-L, 3-necked, round-bottomed flask were charged 60.0 gr (Z)-3-(3-(3,5- bis(trifluoromethyl)phenyl)- 1 H- 1,2, 4-triazol- 1 -yl)acrylic acid (SLN- 105, prepared according to examples 27), Ethyl acetate (0.42 lit, 7V) and Acetonitrile (0.3 lit,5V) at 20-25°C. Charged 2-hydrazino pyrazine (19.8 gr, 1.05 eq) then cooled to 0 to 5°C. Charged EDC .HC1 (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) (49. lgr 1 .Seq) at 0 to 5°C. The reaction mass was stirred for 3hrs and monitored by HPLC (till SLN-105 NMT 1.0percent). Once the reaction completes, charge water (0.2lit, 2V) and stirred for 15-30 mm at 15-20°C, settled and separated the organic layer. Collected the organic layer and washed with sodium bicarbonate solution (0.Slit, SV). Finally washed the organic layer with water (0.2lit, 2 V) and combined the collected organic layer containing the product. The solvent is distilled off under vacuum at 50 to 60°C for 30 mm. To the obtained solid, added absolute Ethanol (0.6lit, 1OV) and stirred for 30mm at 20-25°C then cooled to 0-5°C and stirred for 1 hr at 0-5°C. Filtered the compound under vacuum at 20-25°C and washed with Ethanol (0.2lit, 2V). The wet cake was dried at 55-60°C under vacuum (600 to 700 mm Hg) for 4 hrs. (Yield 83percent).
16% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at -40℃; for 0.5 h; Example 2: Synthesis of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol- 1 -yl)-N'-(pyrazin-2-yl)acr lohydrazide (1-3 .A 50-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylic acid (0.200 g) in 1 :1 CH2C12: AcOEt (25 mL). 2-Hydrazinopyrazine (0.062 g) was added at -40 °C followed by T3P (50percent) (0.432g) and DIPEA (0.147 g). The reaction mixture was stirred for 30 min at -40 °C before being concentrated under reduced pressure (35 °C, 20 mmHg). The crude oil was purified by preparative TLC using 5percent MeOH in CH2C12 as mobile phase (under ammonia atmosphere) to afford 40 mg (yield: 16percent) of (Z)-3-(3-(355-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l- yl)-N'-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ ,10.53 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.53 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 7.92-7.93 (d, J=2.8 Hz, 1H), 7.51-7.53 (d, J=10.4 Hz, 1H), 6.07-6.10 (d, J=10.4 Ηζ,ΙΗ); LCMS for CnHi2F6N70 [M+H]+ predicted: 444.31, found: 444.49 (RT 2.70 min, purity: 95.78percent).
7 g With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate; acetonitrile at 0℃; for 2.5 h; Example-4: Preparation of Selinexor (0507) (0508) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86percent. Yield : 7 g
Reference: [1] Patent: WO2018/129227, 2018, A1, . Location in patent: Paragraph 00196; 00197; 00215; 00216; 00218
[2] Patent: WO2013/19548, 2013, A1, . Location in patent: Page/Page column 56-57
[3] Drugs of the Future, 2014, vol. 39, # 10, p. 685 - 692
[4] Patent: WO2017/118940, 2017, A1, . Location in patent: Page/Page column 61
  • 4
  • [ 4930-98-7 ]
  • [ 1388842-44-1 ]
  • [ 1392136-43-4 ]
YieldReaction ConditionsOperation in experiment
48% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at -40℃; for 0.5 h; Example 3: Synthesis of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4- -yl)-N'-(pyridin-2-yl)acrylohydrazide hydrochloride (1-4).A 500-mL, 3 -necked, round-bottomed flask was charged with a suspension of (Z)-3- (3-(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l-yl)acrylic acid (10 g, 1.0 eq.) in 1 : 1 CH2C12:AcOEt (200 mL). 2-Hydrazinopyridine (3.1 1 g) was added at -40°C. T3P (50percent in ethylacetate) (21.75 g) was added dropwise followed by DIPEA (7.36 g) and the reaction mixture was stirred for 30 min at -40 °C before being concentrated under reduced pressure (35 °C, 20 mm Hg) to afford a crude brown oil that was purified by column chromatography (the compound eluted with 1.3percent MeOH in CH2C12). Fractions containing desired compound were combined to afford 6.0 g (yield: 48percent) (Z)-3-(3-(3,5-bis-(trifluoromethyl)phenyl)-lH- 1 ,2,4-triazol- 1 -yl)-N'-(pyridin-2-yl)acrylohydrazide. 1H NMR (400MHz, DMSO-d6) δ ,10.41(s, 1H), 9.66 (s, 1H), 8.59 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.06-8.08 (d, J=5.2 Hz, 1H), 7.48-7.53 (m, 1H), 7.49-7.52 (d, J=10.4, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (d,J=8.4Hz,lH), 6.07-6.09 (d, J=10.4, 1H). LCMS for Ci8Hi2F6N60 [M+H]+ predicted: 443.33, found: 443.44 (RT 2.45 min, purity: 100percent).
Reference: [1] Patent: WO2013/19548, 2013, A1, . Location in patent: Page/Page column 57
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