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Chemical Structure| 1049037-18-4 Chemical Structure| 1049037-18-4

Structure of 1049037-18-4

Chemical Structure| 1049037-18-4

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Product Details of [ 1049037-18-4 ]

CAS No. :1049037-18-4
Formula : C9H15F3O2
M.W : 212.21
SMILES Code : O=C(OC(C)(C)C)CCCC(F)(F)F

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Application In Synthesis of [ 1049037-18-4 ]

* 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.

  • Downstream synthetic route of [ 1049037-18-4 ]

[ 1049037-18-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 1049037-18-4 ]
  • [ 1401067-00-2 ]
  • [ 1401067-01-3 ]
  • [ 1401067-02-4 ]
YieldReaction ConditionsOperation in experiment
Intermediate S-1I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate, and Intermediate S-1J: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate To a cold (-78 C.), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The mixture was then warmed to 0 C. to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol). The material was azeotroped twice with benzene (the RotoVap air inlet was fitted with a nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C., was added the LDA solution (21.0 mL, 10.5 mmol) and the mixture was stirred at -78 C. for 10 min, then warmed to 0 C. for 10 min., and then cooled to -78 C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C. and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 C. for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate and stirred at -78 C. for an additional 5 min, at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum was replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C.) with rapid swirling and with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was then poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2*). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP SiO2 120 g). Concentration of the appropriate fractions provided a mixture of Intermediate S-1I and Intermediate S-1J (2.87 g, 66%) as a pale yellow viscous oil. 1H NMR showed the product was a 1.6:1 mixture of diastereomers S-1I:S-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDCl3) δ ppm 4.43-4.54 (2H, m), 4.23-4.35 (5H, m), 4.01 (1H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1H, ddd, J=9.41, 7.28, 3.64Hz), 2.74 (1H, ddd, J=10.29, 6.27, 4.02Hz), 2.37-2.48 (2H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3H, m), 1.92-2.20 (8H, m), 1.64-1.91 (5H, m), 1.47 (18H, s), 0.88-0.98 (12H, m).
To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol)in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (I4.7mL, 36.8 mmol), then warmed to 0 octo give a 0.5M solution ofLDA. A separate vesselwas charged with Intermediate S-IB (2.45 g, 9.17 mmol), the material was azeotropedtwice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completelyIS exclude humidity) then toluene (I5.3 mL) was added. This solution was added to a flaskcontaining dry lithium chloride (I.96 g, 46.2 mmol). To the resultant mixture, cooled to-78 C, was added LDA solution (21.0 mL, I0.5 mmol) and stirred at -78 oc for IO min,warmed to 0 oc for I 0 min then recooled to -78 C. To a separate reaction vesselcontaining Intermediate S-IA (3.4I g, I6.07 mmol), also azeotroped twice with benzene,20 was added toluene (I5.3 mL), cooled to -78 C. Next, LDA (37.0 mL, I8.5 mmol) wasadded and the resulting solution was stirred at -78 oc for 25 min. At this time the enolatederived from the ester was transferred via cannula into the solution of the oxazolidinoneenolate, stirred at -78 oc for an additional 5 min. The septum was removed and solidpowdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the25 reaction vessel and the septum replaced. The vessel was immediately removed from thecold bath and immersed into a warm water bath ( 40 C) with rapid swirling with aconcomitant color change from the initial turquoise to brown. The reaction mixture wasstirred for 20 min, was poured into 5% aqueous NH40H (360 mL) and extracted withEtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flashchromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solventA/B=hexanes/EtOAc, REDISEP Si02 I20g). Concentration of appropriate fractionsprovided a mixture oflntermediates S-IC and S-ID (2.87 g, 66%) as pale yellow viscous5 oil. 1 H NMR showed the product was a I. 6: I mixture of diastereomers S-IC: S-ID asdetermined by the integration ofthe multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz,CDCb) 8 ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.0I (I H, ddd, J=9.54, 6.27, 3.5IHz), 2.84 (I H, ddd, J=9.4I, 7.28, 3.64 Hz), 2.74 (I H, ddd, J=I0.29, 6.27, 4.02 Hz),2.37-2.48 (2 H, m, J=I0.38, 6.98, 6.98, 3.5I, 3.5I Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8IO H, m), 1.64-1.9I (5 H, m), I.47 (I8 H, s), 0.88-0.98 (I2 H, m).
Preparation A-i C: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2-oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate,[00144j To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol)in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (i4.7mL, 36.8 mmol), and then the mixture was warmed to 0 c to give a 0.5M solution ofLDA. A separate vessel was charged with Preparation A-iB (2.45 g, 9.i7 mmol), thematerial was azeotroped twice with benzene (the RotoVap air inlet was fitted withnitrogen inlet to completely exclude humidity), and then toluene (i5.3 mL) was added.This solution was added to a flask containing dry lithium chloride (i .96 g, 46.2 mmol).To the resultant mixture, cooled to -78 c, was added the above LDA solution (2i.O mL,iO.5 mmol) and the mixture was stirred at -78 c for iO mm, warmed to 0 c for iO mmand then cooled to -78 c. To a separate reaction vessel containing Preparation A-iA(3.4i g, i6.07 mmol), also azeotroped twice with benzene, was added toluene (i5.3 mL).The mixture was cooled to -78 c and LDA (37.0 mL, i8.5 mmol) was added, and theresulting solution was stirred at -78 c for 25 mm. At this time, the enolate derived fromthe ester was transferred via cannula into the solution of the oxazolidinone enolate andstirred at -78 c for an additional 5 mm. The septum was removed and solid powderedbis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reactionvessel and the septum replaced. The vessel was immediately removed from the cold bathand immersed into a warm water bath (40 C) with rapid swirling with a concomitantcolor change from the initial turquoise to brown. The reaction mixture was stirred for 20mm, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). Thecombined organics were washed with brine, dried (Na2SO4), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography (Teledyneisco combiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 i2Og).concentration of appropriate fractions provided Preparation A-it (2.87 g, 66%) as a paleyellow viscous oil. ‘H NMR showed the product was a i .6: i mixture of diastereoisomersic:iD as determined by the integration of the multiplets at 2.74 and 2.84 ppm: ‘H NMR(400 MHz, cDcl3) ö ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.Oi (i H, ddd, J9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J=i0.29, 6.27,4.02 Hz), 2.37-2.48 (2 H, m, J10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m),1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).
To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol), then warmed to 0 C to give a 0.5 M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C, was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 C for 10 min, warmed to 0 C for 10 min, and then recooled to -78 C. To a separate reaction vessel containing Intermediate S-IG (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 C for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 C for an additional 5 min at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided a mixture of S-1I and S-1J (2.87 g, 66%) as pale yellow viscous oil. 1H NMRshowed the product was a 1.6: 1 mixture of diastereomers S-1LS-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDC13) δ ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J=9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J=10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).
Intermediate S-i I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2- oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate, and Intermediate S-i J: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3 -((S)-4-isopropyl-2- oxooxazolidine-3 -carbonyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate[00147j To a cold (-78 C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The reaction mixture was warmed to 0 C to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted withnitrogen inlet to completely exclude humidity) then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 C, was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 C for 10 mm, warmed to 0 C for 10 mm then recooled to -78 C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), alsoazeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 C and LDA (37.0 mL, 18.5 mmol) was added, the resulting solution was stirred at -78 C for 25 mm. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 C for an additional 5 mm at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 C) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 mm, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics werewashed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP Si02 120g). Concentration of appropriate fractions provided a mixture of Intermediates S-lI and S-1J (2.87 g, 66%) aspale yellow viscous oil. ‘H NMR showed the product was a 1.6:1 mixture ofdiastereomers S-i I: S-i J as determined by the integration of the multiplets at 2.74 and2.84 ppm: ‘H NMR (400 MHz, CDC13) ö ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m),4.01 (1 H, ddd, J9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J10.38, 6.98, 6.98, 3.51, 3.51 Hz),2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.9 1 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12H, m).
A 0.5 M solution of LDA was prepared by the addition of a solutionof 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold(-78 C) solution of diisopropylamine (5.3 mL, 37.2 mmol) inTHF (59 mL) under N2. The solution was stirred at 0 C for 15min. A solution of <strong>[1401067-00-2](S)-4-isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one</strong> (2.45 g, 9.2 mmol) in toluene (15.3 mL)was added with stirring to dry LiCl (1.96 g, 46.2 mmol). Themixture was cooled to -78 C, and the freshly prepared 0.5 Msolution of LDA (21.0 mL, 10.5 mmol) was added. The reactionmixture was stirred at -78 C for 10 min, at 0 C for 10 min, andcooled to -78 C. Meanwhile, the freshly prepared 0.5 M solutionof LDA (37.0 mL, 18.5 mmol) was added to a cold (-78 C)solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1mmol) in toluene (15.3 mL). After 25 min of stirring at -78 C, this reaction mixture was transferred via cannula into the cold(-78 C) LiCl/enolate solution. After an additional 5 min of stirringat -78 C, solid powdered bis(2-ethylhexanoyloxy)copper(9.02 g, 25.8 mmol) was rapidly added to the reaction vesselthrough a funnel, and the flask was rapidly recapped with aseptum. The vessel was immediately removed from the coldbath and immersed into a warm (40 C) water bath with rapidswirling. The reaction mixture changed from the initial turquoiseto a dark green then to a brown color. After 20 min ofstirring, the reaction mixture was poured into 5% aq NH4OH(360 mL) and extracted with EtOAc (2 × 150 mL). The combinedorganic layer was washed with brine, dried (Na2SO4), filtered,and concentrated under reduced pressure. The residue waspurified by flash chromatography (Teledyne ISCO CombiFlashRf, 0-60% EtOAc in hexanes, RediSep silica gel, 120 g). Concentrationof appropriate fractions provided the product tert-butyl(2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as apale yellow oil. 1H NMR indicated that the product was a 1.6:1mixture of diastereomers, as determined by integration of themultiplets at 2.74 and 2.84 ppm. 1H NMR (400 MHz, CDCl3): δ =4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54,6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H,ddd, J = 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m), 2.20-2.37 (3 H,m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m).

  • 2
  • [ 1049037-18-4 ]
  • [ 1401067-00-2 ]
  • [ 1401067-03-5 ]
  • [ 1401067-04-6 ]
YieldReaction ConditionsOperation in experiment
Intermediate S-1: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and Intermediate S-1E: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid [0289] [0290] To a cool (0 C.), stirred solution of Intermediate S-1I and Intermediate S-1J (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) were sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol). The mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. To the reaction mixture were added saturated NaHCO3 (45 mL) and saturated Na2SO3 (15 mL), and then the mixture was partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3×). The aqueous phase was acidified to pH1-2 with 1N HCl, extracted with DCM (3×) and then EtOAc (1×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide a mixture of Intermediates S-1 and S-1E (3.00 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 2.76-2.84 (1H, m, diastereomer 2), 2.64-2.76 (3H, m), 2.04-2.35 (8H, m), 1.88-2.00 (4H, m), 1.71-1.83 (4H, m), 1.48 (9H, s, diastereomer 1), 1.46 (9H, s, diastereomer 2); 1H NMR showed a 1.7:1 mixture of S-1E:S-1F by integration of the peaks for the t-butyl groups.
 

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