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[ CAS No. 1226781-80-1 ] {[proInfo.proName]}

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Chemical Structure| 1226781-80-1
Chemical Structure| 1226781-80-1
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Product Details of [ 1226781-80-1 ]

CAS No. :1226781-80-1 MDL No. :MFCD20687608
Formula : C6H9N3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :BUJWKBIFOTURDW-UHFFFAOYSA-N
M.W : 187.22 Pubchem ID :57518503
Synonyms :

Calculated chemistry of [ 1226781-80-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.5
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.99
TPSA : 72.37 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.24 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.67
Log Po/w (XLOGP3) : -1.12
Log Po/w (WLOGP) : -0.31
Log Po/w (MLOGP) : -0.13
Log Po/w (SILICOS-IT) : -0.5
Consensus Log Po/w : -0.28

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.54
Solubility : 54.3 mg/ml ; 0.29 mol/l
Class : Very soluble
Log S (Ali) : 0.09
Solubility : 231.0 mg/ml ; 1.23 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -1.33
Solubility : 8.82 mg/ml ; 0.0471 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.48

Safety of [ 1226781-80-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1226781-80-1 ]

* 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.

  • Downstream synthetic route of [ 1226781-80-1 ]

[ 1226781-80-1 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 657428-42-7 ]
  • [ 124-63-0 ]
  • [ 1226781-80-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester With sodium hydride In acetonitrile; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: methanesulfonyl chloride In acetonitrile; mineral oil at 20℃; Cooling with ice; 5.A; 5.B Intermediate 5; 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole; Step A: tert-Butyl 1-(methylsulfonyl)]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (A) and tent-butyl 2-(methylsulfonyl)]-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (B); A suspension of N-Boc-pyrazolopyrrolidine (Intermediate 3, Step B) (27.16 g, 130 mmol) in anhydrous acetonitrile (1.0 L) was charged in a 2.0 L three-neck flask fitted with a thermometer and an addition funnel and then treated with sodium hydride (60% dispersion in oil, 6.23 g, 156 mmol) while under nitrogen atmosphere in one portion. The reaction mixture was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and methanesulfonyl chloride (25.2 mL, 324 mmol) was slowly added via addition funnel The ice bath was then removed and the mixture was stirred 1 h at room temperature. The reaction mixture was quenched with water (500 mL) and the layers were separated. The aqueous layer was then extracted with 2×500 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a mixture of products A and B as colorless syrups. NMR in CD3OD indicated a 1:1 mixture of two products, in which the proton on the pyrazole ring in product A appeared at 7.70 ppm while the proton in product B appeared at 7.95 pm. LC-MS: 288.08 (M+1).; Step B: 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole; Trifluoroacetic acid (200 mL) was added slowly to a solution containing intermediates A and B prepared in the previous step (48.4 g, 168 mmol) in dichloromethane (400 mL) at 0° C. After addition, the cooling bath was removed and the reaction was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure and the resulting trifluoroacetate salt was then neutralized with 500 mL of 25% methanol and 2.5% ammonium hydroxide in dichloromethane. After removal of solvent, the desired Intermediate 5 was obtained after chromatography on a Biotage column (2×340 g) eluting with 2.5-12.5% methanol and 0.25-1.25% ammonium hydroxide in dichloromethane. LC-MS: 109.85 (M+1).
  • 2
  • [ 951127-24-5 ]
  • [ 1226781-80-1 ]
  • [ 1226781-88-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl ((2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate; 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In methanol for 0.5h; Stage #2: With decaborane In methanol at 20℃; for 18h; 2.A Example 2; (2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine; Step A: tert-Butyl {(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate; A mixture of Intermediate 1 (516 mg, 1.5 mmol) and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 5) (280 mg, 1.5 mmol) in anhydrous methanol (70 ml) was stirred for 30 min before adding decaborane (54.8 mg, 0.45 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and purified on 40M Biotage silica column eluting with 0-10% ethyl acetate in dichloromethane to wash out the minor isomer and 1.25% methanol in dichloromethane to elute the title compound which was obtained as a white solid. LC/MS: 517.05 (M+1).
  • 3
  • [ 951127-25-6 ]
  • [ 1226781-80-1 ]
  • [ 1226781-87-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic acid 1,1-dimethylethyl ester; 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In methanol at 20℃; for 2h; Stage #2: With decaborane In methanol at 20℃; 1.A Example 1; (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine; Step A: tert-Butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5 (4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate; A mixture of Intermediate 2 (26.3 g, 80 mmol) and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 5) (15.07 g, 80 mmol) in anhydrous methanol (1.5 L) was stirred at room temperature for 2 h. To the resulting white suspension was added decaborane (2.95 g, 24.15 mmol) and the mixture was stirred at room temperature overnight. Methanol was removed and the residue was purified on two 65i Biotage columns eluting with 5-50% ethyl acetate in dichloromethane to afford the title compound as a white solid. LC-MS: 499.10 (M+1).
  • 4
  • [ 1226781-80-1 ]
  • [ 1350652-30-0 ]
  • C23H30F2N4O4S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxothiepan-3-yl]carbamate With titanium(IV) isopropylate In dichloromethane; dimethyl sulfoxide at 0℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; dichloromethane; dimethyl sulfoxide at 50℃; for 3h; 4.A To a solution of fer/-butyl [(2J,3S)-2-(2,5-difluorophenyl)-5-oxothiepan-3- yljcarbamate (mtermediate 3) (55 mg, 0.1.5 mmols) and 2-(methylsulfonyl)-2,4>5,6- te1iahydropyrrolo[3,4-c]pyra2ole (Intermediate 19) (35 mg, 0.19 mmol) in DCM (1.5 mL) and DMSO (100 μL) was added titanium(IV) isopropoxide (135 μ, 0.46 mmol). The reaction was stirred for 10 min at 0 °C, then sodium cyanoborohydride (462 μ, 0.46 mmol, 1M in THF) was added and the reaction was heated to 50 °C for 3 h. The reaction mixture was concentrated to approximately 0.5 mL and purified by preparative thin layer chromatography (2 x 1000 micron PTLC plates using 10% MeOH (containing 2 N N) in DCM as a developing solvent). The major band was removed, eluted with 1:1 methanol/DCM and evaporated. Examination of the oil by .H NMR showed an approximately 4: 1 mixture of diastereomeric amines at C-5.
  • 5
  • [ 1226781-80-1 ]
  • [ 1350652-34-4 ]
  • C37H36F2N4O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; (6S,7R)-7-(2,5-difluorophenyl)-6-(tritylamino)oxepan-4-one With titanium(IV) isopropylate In dichloromethane at 0℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; dichloromethane at 20 - 50℃; for 19h; 1.A To a 0 °C solution of (65,7ii)-7-(2,5-diiluorophenyl)^-(tritylamino)oxepan-4-one(Intermediate 5) (150 mg, 0.31 mmol) and 2-(memylsulfonylV2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole (Intermediate 19) (64 mg, 0.34 mmol) in DCM (3 mL) was added titanium(TV) isopropoxide (91 μ, 0.31 mmol). The reaction was stirred for 10 min at 0 °C, then sodium cyanoborohydride (3 0 μ,, 0. 1 mmol, 1M in THF) was added. The reaction was heated to 50 °C for 1 h, then cooled to rt for 18 h and concentrated to approximately 1 mL. The resulting solution was purified by preparative thin layer chromatography (4 x 1000 micron FTLC plates using 10% methanol (containing 2N N) in DCM as a developing solvent). The major band was removed, eluted with 1:1 methanol/DC and evaporated. Examination of the oil by 1H NMR showed an approximately 4:1 mixture of diastereomeric amines at C-5.
  • 6
  • [ 1226781-80-1 ]
  • C14H18FNO4S [ No CAS ]
  • C20H27FN4O5S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole With triethylamine In N,N-dimethyl acetamide for 0.166667h; Stage #2: C14H18FNO4S With acetic acid In N,N-dimethyl acetamide at 20℃; for 0.5h; Stage #3: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 0 - 20℃; for 2h; 1.9 Step 9. Preparation of Compound 9 To a mixture of amine (0.053 g, 0.152 mmol, 1.2 equiv) in dimethylacetamide (2 mL) was added triethylamine (0.038 g, 0.380 mmol, 3 equiv) and stirred for 10 min. Then compound 8 (0.040 g, 0.126 mmol, 1 equiv) and acetic acid (0.038 g, 0.634 mmol, 5 equiv) were added and the mixture was stirred for 30 min at room temperature. To the resulting solution, sodiumtriacetoxy borohydride (0.032 g, 0.152 mmol, 1.2 equiv) was added at 0 °C and allowed to stir at room temperature for 2 h. The mixture was poured into water and then extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography (60- 65 % ethyl acetate in hexane) to obtain compound 9 as white solid. 1H NMR (400 MHz, CDCI3): δ 7.75 (s, IH), 7.19 (dd, J= 3.92 Hz, J= 5.40 Hz, IH), 6.74 (d, J=5.52 Hz, IH), 4.57-4.49 (m, 2H), 4.27 (d, J=11.6 Hz, IH), 3.96-3.80 (m, 5H), 3.31 (s, 3H), 2.54-2.50 (m, IH), 1.34 (s, 9H). Mol. formula C2oH27FN405S2, calcd. mol. wt.486.58).
  • 7
  • [ 1226781-80-1 ]
  • C15H18F2N2O4 [ No CAS ]
  • C21H27F2N5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole With triethylamine In tetrahydrofuran; methanol for 0.166667h; Stage #2: C15H18F2N2O4 With titanium(IV) tetraethanolate In tetrahydrofuran; methanol at 20℃; for 12h; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran; methanol at 0 - 20℃; for 3h; 2.8 Step 8: Synthesis of Compound 9 To a solution of amine (0.526 g, 1.52 mmol, 2.5 equiv) in methanohtetrahydrofuran (3 mL:5 mL) was added triethylamine (0.254 mL, 1.8 mmol, 3 equiv) and stirred for 10 min. To this, 8 (0.200 g, 0.6 mmol, 1 equiv) was added followed by titaniumtetraethoxide (0.306 mL, 1.46 mmol, 2.4 equiv) and the mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated and diluted with methanol (lOmL). Sodium triacetoxyborohydride (0.308 g, 1.46 mmol, 2.4 equiv) was added at 0 °C and the mixture was stirred at room temperature for 3 h and concentrated. The reaction mixture was neutralized with aqueous ammonia (3 mL) and then extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2S04, filtered and concentrated. The residue obtained was purified by flash chromatography (70- 80 % ethyl acetate in hexane) to obtain 9 as white solid. Mol. formula C2iH27F2N505S, calcd. mol. wt. 499.53. Observed mass : 500.3 (M+l).
  • 8
  • [ 773837-37-9 ]
  • [ 951127-25-6 ]
  • [ 1226781-80-1 ]
  • [ 1548337-32-1 ]
  • [ 1548337-36-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic acid 1,1-dimethylethyl ester With sodium metabisulfite In water at 20℃; for 1h; Stage #2: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In ethanol; water for 4h; Stage #3: sodium cyanide In ethanol; water at 50℃; for 48h; 2.1; 3.1 Synthesis of Compound 1 & 2 (Step 1) To a suspension ofM2 (0.95 g, 2.8 mmol) in water (8.67 mL) was added sodiummetabisulfite (0.55 g, 2.8 mmol) and stirred a room temperature for 1hour. A solution ofM3*(0.52 g, 2.8 mmol) in ethanol (8.67 mL) was added to the above reaction mixture and continuedthe stirring for further 4 hours. Neat NaCN (0.14 g, 2.8 mmol) was added to the above reaction mixture in one portion and heated the reaction mixture at 50 °C for 2 days. Reaction mixture wasconcentrated under vacuum to remove most of the ethanol. The crude mixture was extracted withCHCh (50 x 3 mL ). The combined organic layer was washed with water, dried over N a2S04,filtered, concentrated and purified by flash chromatography to obtain 1 and 2 as solids. Compound 1: 1H NMR (300 MHz, CDCh): o 7.77 (s, 1H), 7.26- 7.35 (m, 1H), 7.00 (t, J = 5.76 Hz, 2H), 4.57 (t, J = 9.88 Hz, 2H), 4.32 - 4.39 (m, 1H), 3.85 - 4.09 (m, 5H), 3.60 ( d, J = 11.34Hz, 1H), 3.34 (s, 3H), 2.63-2.74 (m, 1H), 2.02-2.15 (m, 1H), 1.31 (s, 9H).Compound 2: 1H NMR (300 MHz, CDCh): o 7.28- 7.36 (m, 2H), 7.00 (t, J = 5.85 Hz, 2H),4.55 (d, J = 8.97 Hz, 2H), 4.37 (dd, J= 2.65, 11.25 Hz, 1H), 3.88-4.07 (m, 5H), 3.60 (d, J =11.34 Hz, 1H), 2.71 (td, J = 3.45, 12.49 Hz, 1H), 1.97- 2.12 (m, 1H), 1.31 (s, 9H).; Molecular Formula: CzzHzsFzNs03; LCMS purity: 94.48%; Expected: 445.2; Observed: 446.0 (M+ 1 ).(*Preparation ofM3: M3.PhS03H (1.0 g, 2.8 mmol) was dissolved in minimum volume ofMeOH:CHCh (1: 1) and passed through a column [Orochem 5 g, 10 ml, Amino (NH2)] usingMeOH as eluent. Organics were concentrated under vacuum to get free M3, which was useddirectly without further purification.)
  • 9
  • [ 1226781-80-1 ]
  • C17H20F2N4O*3C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium metabisulfite / water / 1 h / 20 °C 1.2: 4 h 1.3: 48 h / 50 °C 2.1: methylmagnesium bromide / tetrahydrofuran; diethyl ether / 1 h / -78 - 20 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C
  • 10
  • [ 1226781-80-1 ]
  • C18H22F2N4O3S*2C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium metabisulfite / water / 1 h / 20 °C 1.2: 4 h 1.3: 48 h / 50 °C 2.1: methylmagnesium bromide / diethyl ether / 1 h / -78 - 20 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 2.3: 1 h / 0 °C 3.1: dichloromethane / 2 h / 0 - 20 °C
  • 11
  • [ 1226781-80-1 ]
  • [ 1544022-38-9 ]
  • C27H28F2N4O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C21H19F2NO3 With N,N-dimethyl acetamide; triethylamine for 0.333333h; Stage #2: With acetic acid for 0.333333h; Stage #3: With sodium tris(acetoxy)borohydride 2.15 Synthesis of 16 To a solution of 15 (200 mg, 0.53 mmol) in DMAc (2 mL) was added Ml (555 mg, 1.6 mmol) followed by EtsN (0.22 mL, 1.6 mmol) and stirred it for 20 minutes. AcOH (0.15 mL, 2.7 mmol) was added to the reaction mixture and continued the stirring for 20 minutes. NaBH(OAc)3 (341 mg, 1.6 mmol) was added to the reaction mixture and continued the stirring for over night. The reaction mixture was quenched with NH4OH and extracted with EtOAc. Combined organics were concentrated under vacuum. Crude mixture was purified by silica gel chromatography afforded 16. XH NMR (400 MHz, CDC13): δ 7.75 (s, 1H), 7.38 - 7.18 (m, 5 H), 7.09 - 6.95 (m, 2 H), 6.91 (br. s., 1 H), 5.03 - 4.90 (m, 2 H), 4.71 - 4.60 (m, 1H), 4.20 - 3.90 (m, 4 H), 3.78 - 3.57 (m, 2 H), 3.30 (s, 3 H), 2.94 - 2.84 (m, 1 H), 2.16 (br. s., 1 H), 1.59 - 1.41 (m, 3 H), 1.00 - 0.85 (m, 2 H).; Molecular Formula: C27H28F2 404S; LCMS purity: 96.47%; Expected: 542.2; Observed: 543.0 (M+l).
  • 12
  • [ 1226781-82-3 ]
  • [ 1226781-80-1 ]
YieldReaction ConditionsOperation in experiment
95% With benzenesulfonic acid; In Isopropyl acetate; for 48h;Large scale; Step (4) The distilled pale yellow wet product IV was dissolved in isopropyl acetate 35kg, and then added dropwise with acid solution at roomtemperature (benzenesulfonic acid 7.7kg and 14kg isopropyl acetate), stirring2d, suction filtration to give a pale gray solid, at 40 deg. C vacuum dried togive a pale gray solid after 10h 7.78kg, 95% yield, purity 98.2%.
80.5% With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h; 3a (2.1 g, 7.3 mmol) was dissolved in dichloromethane (25 ml), and trifluoroacetic acid (5 ml) was added thereto at 0C, followed by reaction at 0C for 2 hours. The reaction solution was dried by rotary evaporation, and the reaction was quenched by addition of aqueous ammonia (2 ml), followed by purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1) to obtain a white solid 3b (1.1 g, yield 80.5%). 1H NMR (400 MHz, MeOD): delta 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H).
80.5% With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h; 3a(2.1g, 7.3mmol) dissolved in dichloromethane (25 ml) in, at 0 C added to trifluoroacetic acid (5 ml), the reaction of the 0 C under 2 hours. The reaction the fluid turns on lathe stem, plus ammonia water (2 ml) quenching the reaction, silica gel column chromatography for purification (dichloromethane/methanol (v/v)=50:1), to obtain white solid3b(1.1g, 80.5% yield).
With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h; A solution of 2E (2.1 g, 7.3 mmol)Was dissolved in dichloromethane (25 mL)Cooled to 0 C, trifluoroacetic acid (5 mL) was added,Reaction for 2 hours.The reaction solution was concentrated, quenched by addition of aqueous ammonia (2 mL), and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give intermediate 2 as a white solid.

  • 13
  • [ 1226781-80-1 ]
  • C11H9F2NO4 [ No CAS ]
  • C17H18F2N4O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
94.9% With lithium borohydride In N,N-dimethyl-formamide at -15℃; for 1h; Inert atmosphere; Large scale; 4 Preparation of Compound (8) General procedure: Under nitrogen, at room temperature to 50L reactor was added 1.8kg (7.0mol) of the compound (6) and 1.57kg (8.4mol) of the compound (7) in 20L of anhydrous DMA.After stirring for one hour cooled to -10 deg.] C, sodium borohydride was slowly added 114g (3.0mol), keeping the temperature below -10°C, TLC monitoring completion of the reaction, water was slowly added aqueous ammonia 2.0kg and 10kg, warmed to room temperature, filtered to give compound (8) crude, the crude product was recrystallized from methanol to give compound (8) masterwork 2.87kg (6.7mol), a yield of 95.7%. Purity by HPLC: 99.2%. According to the method of Example 1, the reaction of DMF anhydrous solvent substitution; the reaction temperature was -15°C ; reducing agent used in replace of lithium borohydride, the final compound (8) purified product yield was 94.9%.Purity by HPLC: 99.8%.
  • 15
  • 6a-hydroxy-3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 1226781-80-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 1 h / 20 - 30 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C
  • 16
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30.6% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20 - 30℃; for 3h; Inert atmosphere; 4.1 Step 1:
tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(triflu oromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (4a)
Intermediate 3 (3 g, 7.26 mmol) and 3b (1.76 g, 9.44 mmol) were added to 100 ml toluene, and the reaction was allowed to proceed in an open round-bottom flask in a 140°C oil bath until the solvent was evaporated to dryness. In a N2 atmosphere, the residue was cooled to room temperature and re-dissolved in 1,2-dichloroethane (30 ml), and tri(acetoxy)sodium borohydride (4.62 g, 21.8 mmol) and acetic acid (0.87 g, 14.5 mmol) were added sequentially, followed by reaction at room temperature for 3 hours. The reaction was quenched by addition of a saturated sodium bicarbonate solution (30 ml) to the reaction solution, which was allowed to be partitioned. The aqueous phase was extracted with ethyl acetate (30 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a white oily liquid 4a (1.3 g, yield 30.6%).
  • 17
  • [ 1226781-80-1 ]
  • (2R,3S,5R,6S)-2-(2,5 difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 - 30 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 - 30 °C
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / toluene; 1,2-dichloro-ethane / 3 h / 20 - 140 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere
  • 18
  • [ 1226781-80-1 ]
  • (2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 - 30 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 - 30 °C
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / toluene; 1,2-dichloro-ethane / 3 h / 20 - 140 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C
  • 19
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 60% 2: 5.9% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20 - 30℃; for 3h; Inert atmosphere; 3.3 Step 3:
tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5( 2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c)
Intermediate 1 (490 mg, 1.24 mmol) and 3b (254 mg, 1.36 mmol) were added to 10 ml toluene, and the reaction was allowed to proceed in an open round-bottom flask in a 140°C oil bath until the solvent was evaporated to dryness. In a N2 atmosphere, the residue was cooled to room temperature and re-dissolved in 1,2-dichloroethane (15 ml), and tri(acetoxy)sodium borohydride (1.05 mg, 4.96 mmol) and acetic acid (149 mg, 2.48 mmol) were added sequentially, followed by reaction at room temperature for 3 hours. The reaction was quenched by addition of a saturated sodium bicarbonate solution (20 ml) to the reaction solution, which was allowed to be partitioned. The aqueous phase was extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a white oily liquid 3c (455 mg, yield 60%) and a white solid 3d (45 mg, yield 5.9%).
1: 60% 2: 5.9% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane; toluene at 20 - 140℃; for 3h; Inert atmosphere; 3.3 tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c) Intermediate 1(490 mg, 1.24 mmol) and 3b (254 mg, 1.36mmol) in toluene is added to the 10 ml, 140 °C oil bath temperature in the round bottom flask open reaction to the solvent to dryness. in the nitrogen atmosphere, the remainder of the cooling to the room temperature, re-dissolved in 1,2- dichloroethane (15 ml), is added in sodium triacetoxyborohydride (1.05 mg, 4.96mmol) and acetic acid (149 mg, 2.48mmol), react at room temperature for 3 hours. To add saturated sodium bicarbonate solution in the reaction solution (20 ml) quenching the reaction, layered, ethyl acetate (20mL × 2) extracting the aqueous phase, combined with the organic phase, dried with anhydrous sodium sulfate, concentrated. Silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) separation and purification, to obtain white oily liquid3c(455 mg, yield 60%) and the white solid3d (45 mg, 5.9% yield).
  • 20
  • tert-butyl 6a-hydroxy-2,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ No CAS ]
  • [ 1226781-80-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 1 h 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 1 h 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C
  • 21
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate In chloroform for 4h; Reflux; Dean-Stark; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 5 - 20℃; for 5h; Inert atmosphere;
30.6% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h; Inert atmosphere; 4.1 tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (4a) Intermediate 3 (3 g, 7.26 mmol) and 3b (1.76 g, 9.44 mmol) were added 20 to 100 mL of toluene, and the round bottom flask was exposed to a solvent at a 140 ° C oil bath temperature Evaporated to dry. In a nitrogen atmosphere, the residue was cooled to room temperature and the residue was redissolved in 1,2_ Dichloroethane (30 mL), followed by the addition of tris (acetoxy) borohydride (4.62 g, 21.8 mmol) and acetic acid (0.87 g, 14.5 mmol) were added and reacted at room temperature for 3 hours. to The reaction solution by adding saturated sodium bicarbonate solution (30 mL) quenching reaction, stratification, with B 25 acid ethyl ester (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. Sand column chromatography (petroleum ether / ethyl acetate (ν / ν) = 3: 1) was isolated and purified to give A white oily liquid 4a (1.3 g, yield 30.6%).
  • 22
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • (2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: chloroform / 4 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere
  • 23
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3R,4R)-2-(2,5-difluorophenyl)-4-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42.6% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R,4R)-2-(2,5-difluorophenyl)-4-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl acetamide at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 20℃; for 24h; 1 Step 2:(2R, 3R, 4R, 5S) -2- (2,5-difluorophenyl) -4-fluoro-5- (2- (methylsulfonyl) pyrrolo [3,4-c] Azo-5 (2H, 4H, 6H) -yl) tetrahydro-2H-pyran-3-yl) carbamate (1c) Under nitrogen protection,A mixture of 1b (345 mg, 1 mmol) and intermediate 2 (206 mg, 1.1 mmol)Was dissolved in N, N-dimethylacetamide (6 mL)A mixture of hydrobenzene sulfonic acid (222 mg, 1.2 mmol)The mixture was stirred at room temperature for 1 hour,Sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 24 hours.Water (60 mL) and aqueous ammonia (6 mL) were added to the reaction system to precipitate a solid which was isolated by filtration and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2: 1) , Yield 1c (220 mg, yield 42.6%).
  • 24
  • [ 1226781-80-1 ]
  • C14H14F2O4 [ No CAS ]
  • C20H23F2N3O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.1% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C14H14F2O4 In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; Large scale; Stage #2: With sodium tetrahydroborate In N,N-dimethyl acetamide; water at -10℃; Large scale; Preparation of compound (5) Under nitrogen protection,Add to the 50L reactor at room temperature2.56 kg (9.0 mol) Compound (3)And 1.85 kg (9.9 mol) of compound (4) in 20 L of anhydrous DMA.After stirring for one hour, the temperature was lowered to -10 ° C,Slowly add sodium borohydride 114 g (3.0 mol)And 0.2 L of water, keeping the temperature below -10 ° C, After TLC monitoring reaction is complete,Slowly add ammonia 2.0kg and water 10kg,Warmed to room temperature and filtered to give crude compound (5)The crude product was recrystallized from methanol to give 3.73 kg (8.2 mol) of product (5)Yield 91.1%. Purity by HPLC: 98.2%.
  • 25
  • [ 1226781-80-1 ]
  • C17H18F5NO4 [ No CAS ]
  • tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C17H18F5NO4 In chloroform for 5h; Dean-Stark; Reflux; Stage #2: With acetic acid; sodium triacetoxyborodeuteride In chloroform; 1,2-dichloro-ethane at 20 - 35℃; for 3h; 2.1 First Step: tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol- 5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate (2B) Compound 2A and Compound 1C were synthesized by referring to WO2015192701 method. Compound 1A (395mg, 1.00mmol) and Compound 1C (281mg, 1.50mmol) were added to a reaction flask containing chloroform (10mL),Heat and stir to reflux, Dean-Starks water separation reaction for 5 hours. The heating was stopped at the end of the reaction, and after the reaction solution stopped boiling, 1,2-dichloroethane (5 mL) was added to dilute the reaction solution. Under nitrogen atmosphere, the reaction system was stirred and cooled to 515, and sodium deuterated triacetoxyborohydride (333mg, 1.50mmol) and acetic acid (0.026mL, 1.5mmol) were added in sequence. After the addition, the temperature was raised to 20 ~35°C, react for 3 hours. After the reaction was completed, water (5 mL) was slowly added, stirred for 5 minutes, left to stand for separation, and the aqueous layer was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography of the residue (petroleum ether/ethyl acetate (v/v)=4:1) to obtain N-[(2R, 3S, 5R, 6S)-5-deutero-2-(2,5-di Fluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-C]pyrazopyrimidin-5-yl)-6-(trifluoromethyl)tetrahydropyridinepyran-3-yl] tert-butyl carbamate (2B), white solid (400 mg, yield: 71%).
  • 26
  • [ 1226781-80-1 ]
  • C17H17F6NO4 [ No CAS ]
  • tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydropyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51.3% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C17H17F6NO4 In chloroform for 5h; Reflux; Dean-Stark; Stage #2: With acetic acid; sodium triacetoxyborodeuteride In chloroform; 1,2-dichloro-ethane at 20 - 35℃; for 3h; Inert atmosphere; 3.1 First step: tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl) -2-(2,4,5-trifluorophenyl)tetrahydropyran-3-yl]carbamate (3B) Compound 2A and Compound 1C were synthesized by referring to WO2015192701 method. Compound 3A (413mg, 1.00mmol) and Compound 1C (281mg, 1.50mmol) were added to a reaction flask containing chloroform (10mL), Heat and stir to reflux, Dean-Starks water separation reaction for 5 hours. The heating was stopped at the end of the reaction, and after the reaction solution stopped boiling, 1,2-dichloroethane (5 mL) was added to dilute the reaction solution. Under nitrogen atmosphere, the reaction system was stirred and cooled to 515, and sodium deuterated triacetoxyborohydride (333mg, 1.50mmol) and acetic acid (0.026mL, 1.5mmol) were added in sequence. After the addition, the temperature was raised to 20 ~35°C, react for 3 hours. After the reaction was completed, water (5 mL) was slowly added, stirred for 5 minutes, left to stand for separation, and the aqueous layer was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography of the residue (petroleum ether/ethyl acetate (v/v)=4:1) to obtain N-[(2R, 3S, 5R, 6S)-5-deutero-5-(2-methylsulfonate) Acyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro Pyran-3-yl] tert-butyl carbamate (3B),White solid (300 mg, yield: 51.3%).
  • 27
  • [ 1226781-80-1 ]
  • tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C
  • 28
  • [ 1226781-80-1 ]
  • tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(1-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere
  • 29
  • [ 1226781-80-1 ]
  • tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
  • 30
  • [ 1226781-80-1 ]
  • (2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere
  • 31
  • [ 1226781-80-1 ]
  • 5-deuterio-2-(trideuteriomethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
In deuteromethanol; water-d2 at 75 - 80℃; for 2h; Microwave irradiation; 1.2 Second Step: 5-deuterio-2-(trideuteriomethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole Compound 1C was synthesized with reference to the method of WO2015192701. Compound 1C (1.4 g, 7.49 mmol) was dissolved in a mixed solvent of heavy water (12 mL) and deuterated methanol-d1 (6 mL), and reacted in a microwave at 80° C. for 1 hour. After the reaction was stopped, it was concentrated, and the residue was added with a mixed solvent of heavy water (14 mL) and deuterated methanol-d1 (6 mL). The reaction was carried out at 75° C for 1 hour in a microwave, and the reaction was monitored by LC-MS. After the reaction, the reaction solution was concentrated to obtain crude 5-deutero-2-(deuterated methanesulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (1D), used directly in the next reaction.
  • 32
  • [ 1226781-80-1 ]
  • C12H10F5NO2 [ No CAS ]
  • tert-butyl N-((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With sodium tris(acetoxy)borohydride; acetic acid In chloroform; 1,2-dichloro-ethane at 20 - 90℃; for 3h; Inert atmosphere; 1.1 Combine compound 1a (340mg, 1.7mmol) and compound 1b(680mg, 1.7mmol) was added to 20mL chloroform,React at 90°C for 1 hour until the solvent evaporates to dryness.The remainder was redissolved in 1,2-dichloroethane (15mL),In a nitrogen atmosphere,Add sodium tris(acetoxy)borohydride (1.1g, 5.2mmol) and acetic acid (150mg, 2.5mmol) in sequence,React at room temperature for 3 hours.Add saturated sodium bicarbonate solution (20 mL) to the reaction solution to quench the reaction,Stratification,Extract the aqueous phase with ethyl acetate (20mL×2), combine the organic phases,Dry with anhydrous sodium sulfate,concentrate.Separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-1/1),To obtain compound 1c,White solid (500mg, yield 50%).
  • 33
  • [ 1226781-80-1 ]
  • C12H9F6NO2 [ No CAS ]
  • C26H28F6N2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With sodium tris(acetoxy)borohydride In chloroform; 1,2-dichloro-ethane at 20 - 90℃; for 3h; Inert atmosphere; 2.1 Compound 1a (320 mg, 1.6 mmol) and compound 2b (670 mg, 1.6 mmol) were added to 20 mL of chloroform, and reacted at 90° C. for 1 hour until the solvent was evaporated. The residue was redissolved in 1,2-dichloroethane (15mL), and in a nitrogen atmosphere, sodium tris(acetoxy)borohydride (1.0g, 4.9mmol) and acetic acid (150mg, 2.5mmol) were added sequentially, React at room temperature for 3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) to the reaction solution, the layers were separated, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-1/1) gave compound 2c as a white solid (500 mg, yield 52%).
  • 34
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-4-fluoro-5-oxotetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-4-fluoro-5-oxotetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
  • 35
  • [ 1226781-80-1 ]
  • (2R,3S,5R,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C
  • 36
  • [ 1226781-80-1 ]
  • (2R,3S,5S,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 5 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C
  • 37
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S,6R)-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: chloroform / 5 h / Reflux; Dean-Stark 2: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere
  • 38
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere
  • 39
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere
  • 40
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: chloroform / 5 h / Reflux; Dean-Stark 2: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere
  • 41
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S,5S,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 5 °C / Inert atmosphere
  • 42
  • [ 1226781-80-1 ]
  • (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine 2,2,2-trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: ethyl acetate / 3 h / 20 °C
  • 43
  • [ 1226781-80-1 ]
  • (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2,6 dihydropyrrolo[3,4-c]pyrazol-5(4H)yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 5 h / 20 °C
  • 44
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In chloroform for 3h; Reflux; Dean-Stark; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 5 - 20℃; for 5h; Inert atmosphere;
  • 45
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate [ No CAS ]
  • tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 85% 2: 6% In chloroform for 5h; Reflux; Dean-Stark;
  • 46
  • [ 36082-50-5 ]
  • [ 1226781-80-1 ]
  • C10H9BrClN5O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In ethanol at 0℃; for 2h; Inert atmosphere; 1 Synthesis of compound 7: Take a 100ml three-necked flask, add 1.23g 5-bromo-2,4-dichloropyrimidine, add 5ml ethanol to dissolve it,Put it in a refrigerator under the protection of nitrogen, add 0.54g of triethylamine at 0,Take 1.5g of 2,4,5,6-tetrahydro-2-(methylsulfonyl)pyrrolo[3,4-C]pyrazole, add 20ml of ethanol to dissolve it,Add dropwise to the above reaction solution at 0°C, and solids will precipitate in the reaction solution. After the dropwise addition, continue the low-temperature reaction for 2h.TLC detected that the reaction of the raw materials was complete, the reaction was stopped, and 1.74 g of off-white solid was obtained by suction filtration with a yield of 85%.
  • 47
  • [ 1226781-80-1 ]
  • C14H12ClN5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 1 h / 80 °C / Inert atmosphere
  • 48
  • [ 1226781-80-1 ]
  • C21H15F4N5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 1 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 °C / Inert atmosphere
  • 49
  • [ 1226781-80-1 ]
  • C17H12ClF4N5O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 2 h / Inert atmosphere
  • 50
  • [ 1226781-80-1 ]
  • tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
  • ((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(4H)-yl)tetrahydro-2H-pyran-3-yl)tert-butyl carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 20℃; for 24h; Inert atmosphere; 1.2 tert-butyl((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol -5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate Under the protection of nitrogen, the tert-butyl((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamic acid Ester 1b (345mg, 1mmol) and 2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (206mg, 1.1mmol, synthesized with reference to WO2017031918A1), dissolved in N,N-dimethylacetamide (6mL), add benzenesulfonic acid hydrate (222mg, 1.2mmol), stir at room temperature for 1 hour, add sodium triacetoxyborohydride (276mg, 1.3mmol), stir at room temperature for reaction 24 Hour. Water (60mL) and ammonia (6mL) were added to the reaction system, the solid was precipitated, and the crude product was filtered out. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain ( (2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole -5(4H)-yl)tetrahydro-2H-pyran-3-yl)tert-butyl carbamate 1c (103 mg, yield 20.0%).
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