Home Cart 0 Sign in  
X

[ CAS No. 112052-11-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 112052-11-6
Chemical Structure| 112052-11-6
Chemical Structure| 112052-11-6
Structure of 112052-11-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 112052-11-6 ]

Related Doc. of [ 112052-11-6 ]

Alternatived Products of [ 112052-11-6 ]

Product Details of [ 112052-11-6 ]

CAS No. :112052-11-6 MDL No. :MFCD08704351
Formula : C11H14O4S Boiling Point : -
Linear Structure Formula :- InChI Key :WWCNXHYRAKUQDB-JTQLQIEISA-N
M.W :242.29 Pubchem ID :13837326
Synonyms :

Calculated chemistry of [ 112052-11-6 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.45
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 58.98
TPSA : 60.98 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.35
Log Po/w (XLOGP3) : 1.62
Log Po/w (WLOGP) : 2.57
Log Po/w (MLOGP) : 1.45
Log Po/w (SILICOS-IT) : 1.57
Consensus Log Po/w : 1.91

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.44
Solubility : 0.875 mg/ml ; 0.00361 mol/l
Class : Soluble
Log S (Ali) : -2.51
Solubility : 0.744 mg/ml ; 0.00307 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.08
Solubility : 0.203 mg/ml ; 0.000839 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.36

Safety of [ 112052-11-6 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 112052-11-6 ]

* 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 [ 112052-11-6 ]

[ 112052-11-6 ] Synthesis Path-Downstream   1~62

  • 1
  • [ 95-56-7 ]
  • [ 112052-11-6 ]
  • 3-(2-Bromo-phenoxy)-tetrahydro-furan [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With potassium hydroxide at 100℃; for 0.5h;
  • 2
  • [ 86087-23-2 ]
  • [ 112052-11-6 ]
YieldReaction ConditionsOperation in experiment
80%
  • 3
  • (2S,3R,4R,5S)-2-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol [ No CAS ]
  • [ 112052-11-6 ]
  • C23H27ClO7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 15h; 6.6.11.11 6.11. Example 11: Synthesis of (2S,3R,4S,5R)-2-r4-Chloro-3-(4-ethoxy-benzyl)- phenyll-tetrahydro-pvran-3,4,5-triolToluene-4-sulfonic acid (S)-(tetrahydro-furan-3-yl) ester (31 mg, 0.126 mmol) was added to a suspension of compound from Example 10, step C (16 mg, 0.042 mmol) and cesium carbonate (46 mg, 0.126 mmol) in 0.22 ml λ/,λ/-dimethylformamide. The reaction vessel was sealed and heated to 800C for 15h. Upon cooling to room temperature, the crude reaction mixture was quenched with 2 ml brine and extracted with ethyl acetate (3 x 2 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (0 to 10% methanol/dichloromethane gradient) provided(2S,3R,4S,5R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-3,4,5-triol as a clear, viscous oil, which upon concentration in dichloromethane was obtained as a white solid (10 mg, 55% yield).1H NMR (400 MHz, Acetone) δ ppm 7.35 - 7.41 (m, 2 H), 7.30 (dd, J=8.34, 2.02 Hz, 1 H), 7.16 (d, J=7.58 Hz, 2 H), 6.83 (d, J=8.59 Hz, 2 H), 4.93 - 5.01 (m, 1 H), 4.74 (d, J=3.79 Hz, 0.5 Ha), 4.42 (d, J=9.60 Hz, 0.5 Ha), 4.33 (d, J=7.58 Hz, 0.5 Hβ), 4.20 (d, J=9.60 Hz, 0.5 Hβ), 4.05 (t, J=2.53 Hz, 2 H), 4.05 (d, J=5.31 Hz, 2 H), 3.93 (dd, J=IO.11, 4.80 Hz, 1 H), 3.75 - 3.89 (m, 2 H), 3.72 (t, J=9.09 Hz, 1 H), 3.50 (t, J=9.09 Hz, 1 H), 3.41 (s, 1.5 Hβ), 3.35 (s, 1.5 Ha), 3.29 - 3.34 (m, 3 H), 2.16 - 2.27 (m, 1 H), 1.97 - 2.04 (m, 1 H). MS (ES+) [M + NH4]+ = 468.
  • 4
  • [ 112052-11-6 ]
  • [ 147081-44-5 ]
  • 1,1-dimethylethyl (3S)-3-[(3R)-tetrahydrofuran-3-ylamino]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate at 100℃; for 48h; 188.b A mixture of 1, 1-DIMETHYLETHYL (3S)-3-AMINO-PYRROLIDINE-1-CARBOXYLATE (0. 95g, 5. 1MMOL), (3S)-tetrahydrofuran-3-yl 4-METHYLBENZENESULFONATE (0.90g, 3. 7mmol) and anhydrous potassium carbonate (0.53g, 3. 8mmol) was stirred and heated at 100°C for 2 days. The reaction mixture was cooled and extracted from water into ethyl acetate. The organic extracts were dried (MgS04), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with methanol/ethyl acetate (0: 100 to 30: 70), to yield the title compound as an oil.
  • 5
  • [ 86087-23-2 ]
  • [ 98-59-9 ]
  • [ 112052-11-6 ]
YieldReaction ConditionsOperation in experiment
100% With 1H-imidazole; dmap In dichloromethane at 20℃; for 16h; 3.1 step 1 (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 3b Under room temperature, the toluene sulfonyl chloride (6.5g, 34 . 0mmol) adding (S)-tetrahydrofuran-3-ol 3a (1.82 ml, 22 . 7mmol) and imidazole (3.86g, 56 . 7mmol) in the dichloromethane solution (60 ml), then adding a catalytic amount of 4-dimethylaminopyridine, at room temperature the resulting reaction system stirring 16 hours. After the reaction is ended, is added to the reaction liquid 20 ml water with 50 ml dichloromethane, stirring, separating, from the organic phase of the first washing water and salt (20 ml × 2), dried anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure, the residue is purified by silica gel column chromatography [petroleum ether/ethyl acetate (v/v)=2/1], to obtain title compound 3b (5.5g, white solid), yield: 100%.
100% With pyridine
99% With trimethylamine hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 4h; 6B (3S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate A solution of (35)-tetrahydrofuran-3-ol (23.6.0 g, 268 mmol), TEA (56 ml, 402 mmol) and trimethylamine hydrochloride (2.6 g, 27 mmol) were stirred in DCM (500 mL) and cooled to 0°C. 4-Methylbenzenesulfonyl chloride (63.8 g, 335 mmol) was added portionwise and the mixture stirred at RT for 4h. TLC (50% EtOAc inheptane) indicated complete consumption of alcohol. Excess 4- methylbenzenesulfonyl chloride was reacted with N, N-dimethylethane-1 , 2-diamine (8.8 ml, 80 mmol). The crude reaction mixture was washed with 1 M HCI (2 x 500 mL) and the organic portion dried (Mg504), filtered and concentrated under reduced pressure to give the title compound 64.6 g (99 % yield) of as orange viscousoil. 1H NMR (500 MHz, Chloroform-d): 6 [ppm] 7.79 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 5.11 (tt, J = 4.7, 2.3 Hz, 1H), 3.91 - 3.78 (m, 4H), 2.45 (5, 3H), 2.12 - 2.07(m, 2H).
99% With pyridine In dichloromethane at 0 - 20℃; for 15h; 8.8-3 4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (Compound 8e) To a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (Compound 8d, 500 mg, 5.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) at 0° C. The solution was stirred at room temperature, then 15 h. later, water and 1N hydrochloric acid were added to separate out the organic layer. The organic layer was washed sequentially with saturated sodium hydrogen carbonate solution, and brine. The solvent was removed by evaporation under reduced pressure to obtain the titled Compound 8e (1.36 g, yield 99%).LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1). 1H-NMR (400 MHz, CDCl3) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H, m), 3.93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m).
95% With trimethylamine hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 16h;
89.1% With dmap; triethylamine In dichloromethane at 20℃; for 3h; Inert atmosphere; 31 Compound 31A (S)-3-hydroxytetrahydrofuran (2.00 g, 22.7 mmol) was dissolved in dichloromethane (20.0 mL) at room temperature and under nitrogen protection.Then, p-toluenesulfonyl chloride (5.19 g, 27.2 mmol), triethylamine (4.59 g, 45.4 mmol) and 4-dimethylaminopyridine (catalytic amount) were sequentially added to the above reaction solution.The reaction system was stirred at room temperature for 3 hours.After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction system to quench.The mixture was extracted with dichloromethane (50 ml×3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and finally the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/3) to obtain 4.90 g of compound 31A as a colorless oil (yield: 89.1%).
85% With citric acid In pyridine 197 4-{(S)-tetrahydrofuran-3-yl}toluenesulphonate Example 197 4-{(S)-tetrahydrofuran-3-yl}toluenesulphonate To a solution of (S)-3-hydroxytetrahydrofuran (2.0 g, 23 mmol) in pyridine (40 ml) at 0° C. was added tosylchloride portionwise (4.8 g, 25 mmol). The solution was stirred at 0° C. for 1 hr and then at room temperature overnight. The pyridine was evaporated in vacuo and the residue was partioned between EtOAc and saturated aquoeus citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2*200 ml) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave an oil (4.5 g, 85%). 1H NMR (CDCl3, 250 MHz): 7.78 (2H, d), 7.35 (2H, d), 5.12 (1H, m), 3.76-3.93 (4H, m), 2.45 (3H, s), 2.01-2.20 (2H, m).
80% Stage #1: (S)-3-hydroxytetyrahydrofurane With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; mineral oil at 25℃; for 15h; 1 Step 1: To a suspension of NaH (673 mg, 28.0 mmol) in THF (20 mL) was added a solution of (S)- tetrahydro-furan-3-ol (2.06 g, 23.4 mmol) in THF (40 mL) drop wise over 30 min with stirring at 0°C. Then a solution of 4-methyl-benzenesulfonyl chloride (5.33 g, 28.1 mmol) in THF (30 mL) was added drop wise. The resulting mixture was kept at 25°C for 15 h. The mixture was quenched with water and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:1 ) gave reagent 2 as a colorless solid (4.50 g, 80%). 1H NMR (CDCI3) 5 7.79 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.10-5.13 (m, 1 H), 3.78-3.84 (m, 4 H), 2.45 (s, 3 H), 2.08-2.12 (m, 2 H).
70% With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20 - 28℃; for 17h; Cooling with ice; 12 Synthesis of Compound 12-c In an ice bath, 1,4-diazabicyclo[2.2.2]octane (4.76 g, 42.43 mmol) and p-toluenesulfonyl chloride (3.09 g, 16.2 mmol) were added into a solution of (S)-tetrahydrofuran-3-methanol (1 mL, 12.48 mmol) in dichloromethane (10 mL) respectively. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour. Additional p-toluenesulfonyl chloride (1 g, 5.25 mmol) was added and the reaction solution was stirred at 28° C. for another 16 hours. The reaction solution was diluted with dichloromethane (30 mL) and washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=30:1) to give 12-c as an oil (2.1 g, yield 70%).
69% With pyridine at 20℃; for 2h; 1 Step 1. (S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a mixture of (5)-tetrahydrofuran-3-ol (1 g, 11.35 mmol) and pyridine (1.8 mL,22.7 mmol) in CH2C12 (20 mL) was addedp-toluenesulfonyl chloride (3.3 g, 17.3 mmol) at room temperature. The reaction mixture was stirred at this temperature for 2 h. After evaporation of the solvents, the crude product was diluted with EtOAc (50 mL), washed with water, then 1 N HC1. The organic layer was dried over Mg504, filtered andconcentrated in vacuo. The residue was purified by flash chromatography on 5i02 (0-50% EtOAc/hexanes) to afford (5)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.9 g, 69% yield) as a colorless oil. MS (ESI): m/z 243.1 [M+Hf ‘H NMR (400 MHz, CDC13) ö 7.81 (d,J= 8.1 Hz, 2H), 7.37 (d,J= 8.1 Hz, 2H), 5.14 (tt,J=4.8, 2.5 Hz, 1H), 3.99-3.75 (m, 4H), 2.48 (s, 3H), 2.17-2.05 (m, 2H).
69% With pyridine In dichloromethane at 20℃; for 2h; 1 Step 1. (S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a mixture of (-toluenesulfonyl chloride (3.3 g, 17.31 mmol). The reaction mixture was stirred at rt for 2 h. After evaporation of the solvent, the crude product was diluted with EtOAc (50 mL), washed with water, and then 1 N HCl. The organic layer was dried over anhydrous MgSCn, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, hexanes: EtOAc, 100:0 to 50:50) to afford (
67.2% With triethylamine In dichloromethane at 25℃; for 16h; Step 1) Synthesis of (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate Add (S) -tetrahydrofuran-3-ol (2.0mL, 25mmol), p-toluenesulfonyl chloride (5.7g, 29.9mmol) and dichloromethane (30mL) to a 100mL single-necked round bottom flask at 25 ° C, then add Triethylamine (7.0 mL, 50.4 mmol), continue to stir the reaction for 16 hours; stop the reaction, add saturated sodium bicarbonate solution (30 mL), separate the liquid, collect the organic phase, spin dry under reduced pressure, and separate by column chromatography / Ethyl acetate (v / v) = 5/1) to give the title compound as a white solid (4.1 g, 67.2%).
65% With trimethylamine hydrochloride; triethylamine In dichloromethane; water at 20℃; Inert atmosphere; Further stages; Intermediate 320: (3S)-oxolan-3-yl 4-methylbenzene-1 -sulfonate A mixture of (3S)-oxolan-3-ol (910 mI, 1 1 mmol), triethylamine (2.4 ml, 17 mmol) and trimethylamine hydrochloride (108 mg, 1.13 mmol) in DCM (14 ml) was cooled to OTD and stirred for 10 minutes. Thereafter 4-methylbenzene-1 -sulfonyl chloride (2.38 g, 12.5 mmol) was added in 2 portions. The solution was stirred at rt overnight under nitrogen. The reaction mixture was treated with N,N-dimethylethylenediamine to consume the unreacted 4- methylbenzene-1 -sulfonyl chloride. Water was added to the mixture. Afterwards the aqueous phase was extracted with DCM (3 x) and concentrated to dryness. The titled compound (1.8 g, 65%) was obtained after silica chromatography purification.
31.82% Stage #1: (S)-3-hydroxytetyrahydrofurane With dmap; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 0 - 55℃; for 1.5h; Step-1 synthesis of S)-THF-3-yl 4-methylbenzenesulfonate (Intermediate AA198-2) To a solution of the Intermediate AA198-1 (4.0 g, 45.45 mmol, 1.0 eq) in DCM (40 mL) at 0° C. were added trimethylamine (6.3 mL, 45.45 mmol) and DMAP (1.6 g, 13.63 mmol, 0.3 eq). After stirring for 10 min at 0° C., 4-toluenesulfonyl chloride (6.4 mL, 45.45 mmol) was added dropwise. After stirring for 30 min at RT and at 55° C. for 1 h, the reaction was diluted with 1N HCl (80 mL) and extracted into DCM (3×40 mL). The combined organic layer was washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to afford Intermediate AA198-2 (3.5 g, 31.82%) as a yellow oil. MS (ES): m/z 243.06 [M+H]+
1.4.2.1 To a solution of the compound (1-D) (68.1 g, 241 mmol) and potassium carbonate (66.5 g, 482 mmol) in DMF (1200 ml) was added (S)-3-tetrahydrofuranol p-toluenesulfonate (synthesized from (S)-3- hydroxytetrahydrofuran and p-toluenesulfonyl chloride) (69.9 g, 289 mmol) under ice-cooling, and the ice bath was removed. The mixture was stirred at room temperature overnight, and then diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate and concentrated in vacuo to give the compound (1-D-l) (94.7 g, quantitatively) .
With pyridine at 20℃; for 4h; 188.a To a stirred solution of (3S)-TETRAHYDROFURAN-3-OL (1.76g, 20mmol) dissolved in dry pyridine (20mL) was added 4-methylbenzenesulfonyl chloride (4.19g, 22mmol). The mixture was stirred at room temperature for 4 h, then was diluted with ethyl acetate and washed with aqueous citric acid. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated IN VACUO. The crude product was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (0: 100 to 30: 70), to yield the title compound as a white solid
With triethylamine In dichloromethane at 0℃; 5A.2 Step 2: Synthesis of (s)-tetrahy enzenesulfonate:To a stirred solution of (s)-tetrahydrofuran-3-ol (about 2.0 g, 22.7 mmol) in DCM (30 ml) triethylamine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0 °C, after ten minutes 4-methylbenzene-l- sulfinothioic chloride (step 1 , about 3.7 ml) was added and stirred for about 6 hours. Completion of the reaction was monitored by TLC, reaction mixture was neutralized with saturated NaHC03 and extracted with DCM, the organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (3.5 g) as light yellow liquid. NMR (300 MHz, CDC13): 2.05-2.12 (m, 2H); 2.46 (s, 3H); 3.77-3.93 (m, 4H); 5.09-5.14 (m, 1H); 7.34-7.81 (m, 4H); ES Mass: (100%), [M+l] 243.
With triethylamine In dichloromethane
With triethylamine In dichloromethane at 20℃; for 8h; 7.1 Step 1: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) and triethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+).
3.7 g With pyridine; dmap In dichloromethane for 16h; 39.1 Step 1 (S)-(+)-3-Hydroxytetrahydrofuran (5.0 g) in dichloromethane (50 mL) is allowed to react in the presence of pyridine (12 mL) and 4-dimethylaminopyridine (0.35 g) with 4-toluenesulfonyl chloride (14.5 g) for 16 h. The mixture is washed with water, dried and the solvent evaporated under vacuum. Purification of the residue by column chromatography (silica gel, dichloromethane:MeOH 100:0 to 90:10 gradient) gives the desired compound (3.7 g). LC (LC METHOD 2): tR=0.49 min; Mass spectrum (ES+): m/z=260 [M+NH4]+.
3.7 g With pyridine; dmap In dichloromethane Step 1:0~~ Brwo 2013/178575 PCT/EP2013/06084483(S)-(+)-3-Hydroxytetrahydrofuran (5.0 g) in dichloromethane (50 ml) is allowed to react inthe presence of pyridine (12 ml) and 4-dimethylaminopyridine (0.35 g) with 4-toluenesulfonyl chloride (14.5 g) for 16 h. The mixture is washed with water, dried and thesolvent evaporated under vacuum. Purification of the residue by column chromatography(silica gel, dichloromethane: MeOH 100: 0 to 90: 10 gradient) gives the desiredcompound (3.7 g).LC (LC METHOD 2): tR = 0.49 min; Mass spectrum (ES+): m/z = 260 [M+NH4f.

Reference: [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN105461762, 2016, A Location in patent: Paragraph 0255; 0257; 0258; 0259
[2]Yang, Chu-Ting; Han, Jun; Liu, Jun; Li, Yi; Zhang, Fan; Gu, Mei; Hu, Sheng; Wang, Xiaolin [RSC Advances, 2017, vol. 7, # 40, p. 24652 - 24656]
[3]Current Patent Assignee: EVOTEC AG; BAYER AG - WO2016/91776, 2016, A1 Location in patent: Page/Page column 144
[4]Current Patent Assignee: ROCHE HOLDING AG; Chugai Pharmaceutical (in: Roche) - US2019/225604, 2019, A1 Location in patent: Paragraph 0410-0413
[5]Williamson, Douglas S.; Smith, Garrick P.; Mikkelsen, Gitte K.; Jensen, Thomas; Acheson-Dossang, Pamela; Badolo, Lassina; Bedford, Simon T.; Chell, Victoria; Chen, I-Jen; Dokurno, Pawel; Hentzer, Morten; Newland, Samantha; Ray, Stuart C.; Shaw, Terry; Surgenor, Allan E.; Terry, Lindsey; Wang, Yikang; Christensen, Kenneth V. [Journal of Medicinal Chemistry, 2021, vol. 64, # 14, p. 10312 - 10332]
[6]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN112778308, 2021, A Location in patent: Paragraph 0933-0938
[7]Current Patent Assignee: ABBVIE INC - US2003/153752, 2003, A1
[8]Current Patent Assignee: H. LUNDBECK A/S - WO2014/49133, 2014, A1 Location in patent: Page/Page column 42
[9]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2018/208604, 2018, A1 Location in patent: Paragraph 0233-0234
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/89670, 2019, A1 Location in patent: Page/Page column 102
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/89665, 2019, A1 Location in patent: Page/Page column 67
[12]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN111072675, 2020, A Location in patent: Paragraph 0255; 0257-0259
[13]Current Patent Assignee: BAYER AG - WO2020/48829, 2020, A1 Location in patent: Page/Page column 437
[14]Current Patent Assignee: CHARLES RIVER LABORATORIES INTERNATIONAL INC; NIMBUS THERAPEUTICS INC; NIMBUS SATURN - US2021/78996, 2021, A1 Location in patent: Paragraph 1014; 1015
[15]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - WO2007/7886, 2007, A1 Location in patent: Page/Page column 68
[16]Current Patent Assignee: ELI LILLY & CO - WO2005/811, 2005, A1 Location in patent: Page/Page column 117
[17]Current Patent Assignee: HETERO DRUGS LIMITED - WO2011/61590, 2011, A1 Location in patent: Page/Page column 36
[18]Location in patent: scheme or table Xin, Yang-Chun; Shi, Shi-Hui; Xie, Dong-Dong; Hui, Xin-Ping; Xu, Peng-Fei [European Journal of Organic Chemistry, 2011, # 32, p. 6527 - 6531]
[19]Current Patent Assignee: CYSTIC FIBROSIS FOUNDATION - US8334292, 2012, B1 Location in patent: Page/Page column 62-63
[20]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2013/324514, 2013, A1 Location in patent: Paragraph 0484
[21]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2013/178575, 2013, A1 Location in patent: Page/Page column 82; 83
  • 6
  • [ 864070-37-1 ]
  • [ 112052-11-6 ]
  • (2S,3R,4R,5S,6R)-2-{4-chloro-3-[4-(tetrahydrofuran-3(R)-yloxy)benzyl]phenyl}-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h; 0.19 g (S)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (S)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature, and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1). Yield: 0.11 g (44% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+.
  • 7
  • [ 915771-04-9 ]
  • [ 112052-11-6 ]
  • N-(1-methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In acetonitrile at 160℃; for 3h; Microwave irradiation; A suspension of 3 -hydroxy-N-(l -methyl- lH-pyrazol-3-yl)-5- [(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (35)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160°C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give N-(l-methyl-lH-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5- [(3i?)-tetrahydrofuran-3-yloxy]benzamide as a white foam. This was dissolved in ethanol (5 mL) and ammonium formate (182 mg, 2.88 mmol) added in one portion. The reaction was blanketed with argon and 10% palladium on activated carbon (30 mg) was added. This mixture was heated in a microwave reactor at 14O0C for 10 minutes, the catalyst filtered off and the volatiles removed in vacuo to give the title product as a white solid (305 mg). 1R NMR δ (de-DMSO): 1.96 - 2.00 (m, 1Η), 2.20 - 2.25 (m, 1Η), 3.74 - 3.85 (m, 6Η), 3.87 - 3.91 (m, IH), 5.06 - 5.08 (m, IH), 6.46 (t, IH), 6.57 (d, IH), 6.97 (s, IH), 7.02 (s, IH), 7.60 (d, IH), 9.74 (s, IH), 10.70 (s, IH); m/z 304 (M+H)+.
  • 8
  • C12H13NO5S [ No CAS ]
  • [ 112052-11-6 ]
  • C16H19NO6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; 1.4.2.1 To a solution of the compound (1-D) (68.1 g, 241 mmol) and potassium carbonate (66.5 g, 482 mmol) in DMF (1200 ml) was added (S)-3-tetrahydrofuranol p-toluenesulfonate (synthesized from (S)-3- hydroxytetrahydrofuran and p-toluenesulfonyl chloride) (69.9 g, 289 mmol) under ice-cooling, and the ice bath was removed. The mixture was stirred at room temperature overnight, and then diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate and concentrated in vacuo to give the compound (1-D-l) (94.7 g, quantitatively) .
  • 9
  • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline [ No CAS ]
  • [ 112052-11-6 ]
  • [ 949152-45-8 ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 27h; 1 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline Example 1 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline 1 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 0.78 g (S)-3-[(4-methylphenyl)sulphonyloxy]-tetrahydrofuran and 0.6 g potassium carbonate are stirred in 10 ml dimethylformamide for 7 hours at 60° C. After the addition of 0.2 g 3-[(4-methylphenyl)sulphonyloxy]-tetrahydrofuran and 0.2 g potassium carbonate the mixture is stirred for another 16 hours at 60° C. After the addition of 0.2 g 3-[(4-methylphenyl)sulphonyloxy]-tetrahydrofuran and 0.2 g potassium carbonate the mixture is again stirred for 4 hours at 60° C. The reaction mixture is cooled, diluted with ethyl acetate and shaken with water and saline solution. The organic phase is dried, evaporated down and the residue is purified by chromatography through a silica gel column with methylene chloride/methanol (98:2 to 90:10). The residue is stirred with diisopropylether and the solid is suction filtered and dried. Yield: 990 mg (83% of theory) Rf value: 0.44 (silica gel; methylene chloride/methanol=9:1) Mass spectrum (ESI+): m/z=446, 448 [M+H]+
  • 10
  • [ 112052-11-6 ]
  • [ 119-36-8 ]
  • [ 1309166-20-8 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In dichloromethane at 20℃; for 6h; 5A.3 Step 3: Synthesis of (S)-methyl 2-(tetrahydrofuran-3-yloxy)benzoate:To a stirred solution of methyl 2-hydroxybenzoate (about 2.0 g, 22.7 mmol) in DCM (50 ml) cesium carbonate (about 2.4 g) was added at room temperature and cooled to about 0 °C, after ten minutes (S)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (step 2, 1.59 g) was added and stirred at room temperature for about 6 hours. Completion of the reaction was monitored by TLC, the reaction mixture was quenched with water and extracted with DCM, the organic layer was dried over Na2S04 and concentrated under reduced pressure to furnish the title compound (0.6 g) as a light yellow liquid. NMR (300 MHz, CDC13): 1.63-2.24 (m, 2H); 2.46 (s, 1 H); 3.88-4.05 (m, 6H); 4.98-5.00 (m, 1 H); 6.88-7.47 (m, 4H); ES Mass: (100%), [M+Na] 245.
  • 11
  • [ 14199-15-6 ]
  • [ 112052-11-6 ]
  • [ 1309166-24-2 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In dichloromethane at 20℃; for 6h; 5B.2 Step 2: Synthesis of ' (S)-me henyl)acetate:To a stirred solution of methyl 2-(4-hydroxyphenyl)acetate (0.5 g, 3.012 in DCM (50 ml) cesium carbonate (2.4 g) was added at room temperature and cooled to 0 after ten minutes (S)-tetrahydrofuran-3-yl methylbenzenesulfonate (0.72 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC, the reaction mixture was quenched with water and extracted with DCM, the organic layer was dried over Na2S04 and concentrated under reduced pressure to furnish the title compound (0.6 g) as a light yellow liquid. NMR (300 MHz, CDC13): 1.32- 1.41 (m, 1H); 2.14-2.19 (m, 2H); 3.54-3.56 (d, J=6 Htz, 2H); 3.69 (s, 3H); 3.89-3.99 (m, 4H); 4.89-4.91 (m, 1H); 6.80-7.20 (m, 4H); ES Mass: (100%), [M+Na] 265
  • 12
  • [ 555-16-8 ]
  • [ 112052-11-6 ]
  • [ 1358604-08-6 ]
YieldReaction ConditionsOperation in experiment
80% With oxygen; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,3-bis(mesityl)imidazolium chloride In tetrahydrofuran at 50℃; for 72h; optical yield given as %ee;
  • 13
  • [ 86087-24-3 ]
  • [ 98-59-9 ]
  • [ 112052-11-6 ]
YieldReaction ConditionsOperation in experiment
83% With triethylamine; In dichloromethane; at 0 - 20℃; for 8h;Product distribution / selectivity; Step 5: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a solution of (R)-tetrahydrofuran-3-ol (3 g, 34.1 mmole) and Et3N (6.9 g, 68.2 mmole) in DCM (40 mL) at 0 C. was added 4-methylbenzene-1-sulfonyl chloride (7.2 g, 37.5 mmole. The mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane) to give the title compound (6.8 g, 83% yield). MS (ESI) m/z: Calc. 242.1 (M+). Found: 243.1 (M++1).
  • 14
  • [ 106-41-2 ]
  • [ 112052-11-6 ]
  • [ 857854-81-0 ]
YieldReaction ConditionsOperation in experiment
97.6% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h; Step 2) Synthesis of (R) -3- (4-bromophenoxy) tetrahydrofuran Add p-bromophenol (3.5g, 20.2mmol), (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (4.1g, 16.9mmol) and N, N-dimethylformamide (20mL) To a 100 mL single-necked round bottom flask, potassium carbonate (4.7 g, 34.1 mmol) was added, and the reaction was carried out at 100 ° C. for 16 hours.The reaction was stopped, and after cooling to room temperature, water (60 mL) was added, followed by addition of dichloromethane (60 mL) for extraction, liquid separation, and the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1) The title compound was obtained as a white solid (4.0 g, 97.6%).
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 15h; 7.2 Step 2: Preparation of (R)-3-(4-bromophenoxy)-tetrahydrofuran A mixture of 4-bromophenol (2.1 g, 12.4 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.5 g, 10.3 mmole) and K2CO3 (4.3 g, 30.9 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (896 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
  • 15
  • [ 112052-11-6 ]
  • [ 269409-70-3 ]
  • [ 1416157-65-7 ]
YieldReaction ConditionsOperation in experiment
30% With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 15h; 17.6 Step 6: Preparation of (R)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (6.3 g, 28.5 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.8 g, 28 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.1 (M+). Found: 291.1 (M++1).
YieldReaction ConditionsOperation in experiment
85% With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20℃; for 1h; Cooling with ice; 30 Synthesis of Compound 28-c General procedure: In an ice bath, to a solution of commercially purchased compound 28-d (1.72 g, 10 mmol) and DAI3CO (2.24g, 20 mmol) in dichloromethane (30 mE) was added slowly TsC1 (2.86 g, 15 mmol). The reaction solution was warmed to normal temperature and stirred for about 1 hour, followed by washing with 2N HC1 solution (30 mE), water (30 mE) and saturated solution of sodium bicarbonate (30 mE) in sequence. The organic phase was dried over anhydrous sodium sulphate and concentrated. The crude product was purified with silica column chromatograph (petroleum ether ethyl acetate10/1 -3/1) to give 28-c (2.94 g, 90%) which was white solid. EC-MS (ESI): m/z344.1 (M+NH4).
68% With triethylamine In dichloromethane at 25℃; for 24h; 2.1 Step 1) Synthesis of oxetan-3-yl 4-methylbenzenesulfonate General procedure: P-toluenesulfonyl chloride (1.0g, 5.2mmol) at 25 ° CAnd triethylamine (2.2mL, 15.7mmol) were added to a 100mL single-necked flask,Add dichloromethane (10mL),Add oxetane-3-ol (0.5g, 6.7mmol) in portions, and continue the reaction for another 24 hours; add water (40mL), then add dichloromethane (20mL), separate the liquid, collect the organic phase, reduce Spin dry and separate by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1 to 5/1) to obtain the title compound as a light yellow solid (1.02g, 85.2%).
With pyridine; dmap In dichloromethane at 0 - 20℃; for 12h; 1 Step 1:
(R)-Tetrahydrofuran-3-yl-4-methylbenzenesulfonate General procedure: Step 1: (R)-Tetrahydrofuran-3-yl-4-methylbenzenesulfonate To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0° C. N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0→95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z=243 [M+H]+.
With pyridine; dmap In dichloromethane at 0 - 20℃; for 12h; 1 Step 1 : (R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate General procedure: To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0°C N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0→95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z = 243 [M+H]+.
With pyridine In dichloromethane at 0 - 20℃; for 12h; 1 Step 4: 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate General procedure: To a solution of 3-(methylsulfonyl)propan-1 -ol (1 .0 g) in dichloromethane (10 mL) and pyridine (1 .5 mL) is added at 0°C p-toluene-sulfonylchloride (1 .38 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated to give the title compound. Yield: 1 .6 g; LC (method 1 ): tR = 0.82 min; Mass spectrum (ESI+): m/z = 293 [M+H]+.
With dmap; triethylamine In dichloromethane at 0 - 25℃; for 16h; Intermediate 7A: 2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate General procedure: Intermediate 7A: 2-oxaspiro[3.3]heptan-6-yl 4-methylbenzenesulfonate 2-oxaspiro[3.3]heptan-6-ol (2.00 g, 17.5 mmol) was dissolved in DCM (50 mL), and DMAP (0.21 g, 1.7 mmol) was added followed by triethylamine (6.1 mL, 44 mmol). The solution was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (3.51 g, 18.4 mmol) was added, and the reaction was stirred for 16 hours at RT. The reaction mixture was washed with a 1N HCl (1*10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (0→80% ethylacetate/heptane) to afford the title intermediate (4.17 g, 14.8 mmol). LCMS: Rt: 0.86 min (LCMS Method 1) MS m/z 269.3 [M+H]+.
With dmap; triethylamine In dichloromethane at 20 - 25℃; Intermediate 5A: (2-oxaspiro[3.3]heptan-6-yl)methyl 4-methylbenzenesulfonate General procedure: To the solution of (2-oxaspiro[3.3]heptan-6-yl)MeOH (50 mg, 0.390 mmol), DMAP (4.77 mg, 0.039 mmol) and triethylamine (0.136 mL, 0.975 mmol) in DCM (5 mL), pTsCl (78 mg, 0.410 mmol) was added. The reaction was stirred at RT overnight and then diluted with DCM and washed with 1N HCl solution, sat. NaHCO3 solution, water and brine then dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by FCC (0-60% EtOAc/heptanes) to yield the title compound (71 mg, 0.226 mmol). LCMS: Rt: 0.92 min (LCMS Method 1). 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.66 (s, 2H), 4.54 (s, 2H), 3.95 (d, J = 5.9 Hz, 2H), 2.48 (s, 3H), 2.46 - 2.27 (m, 3H), 2.01 - 1.89 (m, 2H).

  • 17
  • [ 7463-51-6 ]
  • [ 112052-11-6 ]
  • [ 1447325-52-1 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate at 80℃; for 16h; lntermed iate 39(R)-3-(4-Bromo-3.5-dimethyl-phenoxy)-tetrahydro-furan5 Step 2:4-Bromo-3,5-dimethylphenol (2.0 g), the product from Step 1 (2.7 g) and K2C03 (1.5 g) inN,N-dimethylformamide (1 0 ml) are stirred at 80 oc for 16 h. After cooling the mixture ispartitioned between water and EtOAc, the organic layer washed twice with water and thenwith brine, dried (MgS04) and concentrated. Purification of the residue by columnchromatography (silica gel, dichloromethane : MeOH 98 : 2) gives the desired compound(2.8 g, content ca. 90%).LC (LC METHOD 2): tR = 0.68 min; Mass spectrum (ES+): m/z = 288/290 [M+NH4r
3.7 g With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; 39.2 Step 2 4-Bromo-3,5-dimethylphenol (2.0 g), the product from Step 1 (2.7 g) and K2CO3 (1.5 g) in N,N-dimethylformamide (10 mL) are stirred at 80° C. for 16 h. After cooling the mixture is partitioned between water and EtOAc, the organic layer washed twice with water and then with brine, dried (MgSO4) and concentrated. Purification of the residue by column chromatography (silica gel, dichloromethane:MeOH 98:2) gives the desired compound (2.8 g, content ca. 90%). LC (LC METHOD 2): tR=0.68 min; Mass spectrum (ES+): m/z=288/290 [M+NH4]+.
  • 18
  • [ 35691-93-1 ]
  • [ 112052-11-6 ]
  • [ 1589005-28-6 ]
YieldReaction ConditionsOperation in experiment
63% To a mixture of NaH (475.9 mg, 1 1 .9 mmol) in DMF (5 mL) was added reagent 2 (0.8 g, 4.8 mmol). The mixture was kept at 0C for 30 min. To this mixture was added toluene-4-sulfonic acid (S)-(tetrahydro-furan-3-yl) ester (1 .38 g, 5.7 mmol). The resulting mixture was kept at 25C for 16 h. The solution was quenched with water and the volatiles removed in vacuo. The mixture was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 3:1 ) gave reagent 3 as a solid (0.7 g, 63%) sufficiently pure for the next step
  • 19
  • [ 85290-78-4 ]
  • [ 112052-11-6 ]
  • [ 1589005-17-3 ]
  • [ 1589005-15-1 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 14h; To a mixture of reagent 2 (2.77 g, 1 1.4 mmol) and Cs2C03 (3.1 1 g, 9.5 mmol) in DMF (30 mL) was added 3-methyl-1 H-pyrazole-4-carboxylic acid ethyl ester (1 .47 mL, 9.5 mol). The mix- ture was kept at 80C for 14 h. The mixture was concentrated and the residue was extracted with EtOAc (50 mL). The combined organic layers were washed with water. The organic layer was dried over Na2S04 and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc 3:1 ) gave a mixture of reagents 3 and 4 as a solid (1 .58 g, 62%).
  • 20
  • 4-(3-(3-fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thi oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
67.6% With caesium carbonate In N,N-dimethyl acetamide at 50℃; for 3h; Inert atmosphere; 1.4 Step 4 (R)-4-(3-(3-Fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thio xoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (80 mg, 0.19 mmol) was placed in a reaction flask, followed by addition of (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate If (92 mg, 0.38 mmol, prepared by a method disclosed in US patent application "US2003/153752 A1"), cesium carbonate (186 mg, 0.57 mmol) and 1 mL of N,N-dimethylacetamide successively. The reaction solution was warmed up to 50°C. After reacting for 3 hours, the reaction solution was cooled down to room temperature, mixed with 15 mL of H2O and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound (R)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoim idazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1 (63 mg, yield 67.6%) as a white solid. MS m/z (ESI): 494.4 [M+1] 1H NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.84 (d, 1H), 7.00-7.09 (m, 3H), 5.00-5.03 (m, 1H), 4.12-4.14 (m, 2H), 4.06-4.08 (m, 1H), 3.96-4.01 (m, 1H), 2.23-2.26 (m, 2H), 1.59 (s, 6H).
67.6% With caesium carbonate In N,N-dimethyl acetamide; water at 50℃; for 3h; 1.4 (R)-4-(3-(3-Fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (80 mg, 0.19 mmol) was placed in a reaction flask, followed by addition of (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 1f (92 mg, 0.38 mmol, prepared by a method disclosed in US Patent Application Publication U.S. 2003/153752 A1), cesium carbonate (186 mg, 0.57 mmol), and 1 mL of N,N-dimethylacetamide, successively. The reaction solution was warmed up to 50° C. After reacting for 3 hours, the reaction solution was cooled down to room temperature, mixed with 15 mL of H2O, and extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound (R)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1 (63 mg, yield 67.6%) as a white solid. MS m/z (ESI): 494.4 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.84 (d, 1H), 7.00-7.09 (m, 3H), 5.00-5.03 (m, 1H), 4.12-4.14 (m, 2H), 4.06-4.08 (m, 1H), 3.96-4.01 (m, 1H), 2.23-2.26 (m, 2H), 1.59 (s, 6H).
  • 21
  • 4-(3-(6-hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
40.3% With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; Inert atmosphere; 21 Example 21 (R)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimida zolidin-1-yl)-2-(trifluoromethyl)benzonitrile Example 21 (R)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimida zolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(6-Hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 10c (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 1f (116 mg, 0.48 mmol), cesium carbonate (235 mg, 0.72 mmol) and 3 mL of N,N-dimethylacetamide successively. The reaction solution was warmed up to 60°C and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 5 mL of saturated sodium chloride solution and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by thin layer chromatography with elution system A to obtain the title compound (R)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2 -thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 21(46 mg, yield 40.3%) as a yellow solid.
  • 22
  • 4-(3-(6-hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
40.3% With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; 21 (R)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(6-Hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 10c (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 1f (116 mg, 0.48 mmol), cesium carbonate (235 mg, 0.72 mmol), and 3 mL of N,N-dimethylacetamide, successively. The reaction solution was warmed up to 60° C. and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 5 mL of saturated sodium chloride solution, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with elution system A to obtain the title compound (R)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 21 (46 mg, yield 40.3%) as a yellow solid. MS m/z (ESI): 477.1 [M+1]; 1H NMR (400 MHz, CDCl3): δ 8.09-8.08 (m, 1H), 8.01-7.97 (m, 2H), 7.86-7.84 (m, 1H), 7.54-7.51 (m, 1H), 6.92-6.90 (m, 1H), 5.76-5.60 (m, 1H), 4.09-3.93 (m, 4H), 2.32-2.21 (m, 2H), 1.61 (s, 6H).
  • 23
  • [ 86087-23-2 ]
  • [ 98-09-9 ]
  • [ 112052-11-6 ]
YieldReaction ConditionsOperation in experiment
40% With pyridine at 0 - 20℃; for 1h; 50 Example 50 - Preparation of [(3S-tetrah drofuran-3-yl] 4-methylbenzenesulfonate (I-23) To a solution of (3S-tetrahydrofuran-3-ol (193 μΕ, 2.8 mmol) in pyridine (5 mL) at 0 °C was added benzenesulfonyl chloride (601 mg, 3.4 mmol). The reaction mixture was stirred for 1 hr at 0 °C and overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography with a gradient of 0-30% ethyl acetate in heptane. The pure fractions were collected to give 275 mg [(35)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate as a colorless oil (40%). This material was directly used in the next step.
  • 24
  • 4-((7-hydroxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2-yl)benzamide [ No CAS ]
  • [ 112052-11-6 ]
  • 4-[6-nitro-7-[(3R)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 12h; 51 Preparation of 4-[6-nitro-7-[(3R)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide. A suspension of compound 1-15 (100 mg, 0.25 mmol), potassium carbonate (86 mg, 0.62 mmol) and compound 1-23 (66 mg, 0.27 mmol) in DMF (1 mL) was stirred at 50 °C overnight. About 70% conversion to the desired product was observed. The reaction mixture was stirred for 8 hrs at 60 °C and was stored in the freezer over the weekend. The reaction mixture was stirred for 4 hrs at 60 °C. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCC and brine. The organic layer was dried over Na2S04, concentrated under reduced pressure and purified by silica columnchromatography with a gradient of 0-5% methanol in dichloromethane to give 66 mg 4-[6-nitro- 7- { [(3R)-tetrahydrofuran-3-yl]oxy } quinolin-4-yl]oxy} -N-(pyridin-2-yl)benzamide (56%). LC- MS (Method A) Rt: 5.31 mm; m/z 473.1 (M+H)+.
  • 25
  • [ 192810-12-1 ]
  • [ 112052-11-6 ]
  • methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With caesium carbonate In acetonitrile at 100℃; 7 methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate A mixture of Intermediate 1 (15 g, 4.33 mmo[), Intermediate 6B (20.4 g, 84.4mmo[) and cesium carbonate (42.3 g, 129.8 mmo[) were stirred in acetonitrile (250mL) at 100°C overnight. The cooled reaction mixture was filtered through celite,washed with EtOAc and the filtrate evaporated. The residue was dissolved in EtOAc(200 mL), washed with water (2 x 200 mL), brine (100 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Crude material was purified by Biotage IsoleraTM chromatography (eluting with 1 - 50 % EtOAc in heptane on a 340g prepacked HP-SiC2 column) to give the title compound 18.12g (92 % yield) as colourlessoil.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 7.77 (t, J = 1.5 Hz, 1H), 7.44 (dd, J =2.4, 1.3 Hz, 1H), 7.23 - 7.19 (m, 1H), 4.96 (ddt, J = 6.2, 4.2, 2.0 Hz, 1H), 4.06 -3.86 (m, 7H), 2.33- 2.19 (m, 1H), 2.18-2.05 (m, 1H).
  • 26
  • (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(3-fluoro-4-hydroxyphenyl)methyl]phenyl]-1-(1-hydroxy-1-methylethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
  • [ 112052-11-6 ]
  • (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(3-fluoro-4-tetrahydrofuran-3-yloxyphenyl)methyl]phenyl]-1-(1-hydroxy-1-methylethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
101.8 mg With caesium carbonate In N,N-dimethyl-formamide at 20 - 75℃; for 16h; 12.21 Step 21 (1S, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(3-fluoro-4-tetrahydrofuran-3-yloxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-1-methyl-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane -2, 3, 4-triol 12 Under room temperature, will be sequentially (S)-tetrahydrofuran-3-yl 4-methyl benzene sulfonic acid (98.0 mg, 0 . 40mmol, see example 3 step 1), cesium carbonate (178.8 mg, 0 . 40mmol) adding (1S, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(3-fluoro-4-hydroxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-1-methyl-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane e-2, 3, 4-triol 12u (156.0 mg, 0 . 34mmol) N of, N-dimethylformamide (20 ml) solution, then heating to 75 °C reaction 16 hours. Quenching reaction with saturated ammonium chloride aqueous solution, and adjusting pH=6-7, then adding 60 ml ethyl acetate and 60 ml water, liquid. The separated organic phase is dried with anhydrous sodium sulfate, filtered, concentrated filtrate under reduced pressure, the resulting residues HPLC purification, the title compound 12 (101.8 mg, white solid, HPLC: 96.8%), yield: 56.6%.
  • 27
  • (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-hydroxyphenyl)methyl]phenyl]-1-(1-hydroxy-1-methylethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
  • [ 112052-11-6 ]
  • (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-tetrahydrofuran-3-yloxy-phenyl]methyl]phenyl]-1-(1-hydroxy-1-methylethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
44.5 mg With caesium carbonate In N,N-dimethyl-formamide at 20 - 75℃; for 12h; 3.17 Step 17 (1S, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(4-tetrahydrofuran-3-yl-oxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-1-methyl-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane -2, 3, 4-triol 3 Under room temperature, the cesium carbonate (82 mg, 0 . 25mmol) adding (1S, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(4-hydroxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-1-methyl-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane -2, 3, 4-triol 3q (54.8 mg, 0 . 13mmol) and (S)-tetrahydrofuran-3-yl 4-methyl sulfonate 3b (54.7 mg, 0 . 22mmol) N of, in N-dimethyl formamide solution (20 ml), the resulting mixture is heated to 75 °C stirring 12 hours. After the reaction, to room temperature, filter, in the filtrate by adding 20 ml water, extracted with ethyl acetate (50 ml × 2), combined organic phase of the first washing water and salt (30 ml × 2), dried anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure, the residue is purified by silica gel column chromatography [petroleum ether/ethyl acetate (v/v)=1/3], the title compound 3 (44.5 mg, white oily, HPLC: 97.5%), yield: 70.0%.
  • 28
  • (1R,2S,3S,4R,5S)-5-[4-chloro-3-[(4-hydroxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
  • [ 112052-11-6 ]
  • (1S,2S,3S,4R,5S)-5-[4-chloro-3-[[4-tetrahydrofuran-3-yloxy-phenyl]methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
18 mg With caesium carbonate In N,N-dimethyl-formamide at 20 - 75℃; for 18h; 4.4 Step 4 (1R, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(4-tetrahydrofuran-3-yloxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane -2, 3, 4-triol 4 Under room temperature, will be sequentially (S)-tetrahydrofuran-3-yl 4-methyl benzene sulfonic acid 3b (108.0 mg, 0 . 44mmol, see example 3 step 1), cesium carbonate (164.5 mg, 0 . 50mmol) adding (1R, 2S, 3S, 4R, 5S) - 5 - [4-chloro-3 - [(4-hydroxy-phenyl) methyl] phenyl] - 1 - (1-hydroxy-ethyl) - 6,8-dioxo bicyclo [3.2.1] octane -2, 3, 4-triol 4c (125.4 mg, 0 . 30mmol) N of, N-dimethylformamide (15 ml) solution, then heating to 75 °C reaction 18 hours. Quenching reaction with saturated ammonium chloride aqueous solution, and adjusting pH=6-7, then adding 60 ml water, using ethyl acetate (60 ml × 3) extraction. Combined organic phase dried with anhydrous sodium sulfate, concentrated under reduced pressure, the residue is purified by silica gel column chromatography [petroleum ether/ethyl acetate (v/v)=1/5], to obtain 110 mg of white solid, then preparation HPLC purification, the title compound 4 (18 mg, white oily, HPLC: 83.7%), yield: 12.3%.
  • 29
  • [ 112052-11-6 ]
  • [ 108-95-2 ]
  • (S)-3-phenoxytetrahydrofuran [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 20h; 1 Example 1 Preparation of (S)-3-phenoxytetrahydrofuran In a 500 mL three-necked flaskDMF 300 mL, phenol (309 g, 319 mmol), (R)-p-toluenesulfonic acid 3-tetrahydrofuranyl ester (77.2 g, 319 mmoL), 104 g (319 mmoL) of cesium carbonate, the reaction was allowed to proceed at room temperature for 20 hours. After the reaction, the system was diluted with 1N hydrochloric acid, adjusted to pH = 7-8, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, the obtained filtrate was concentrated under reduced pressure to give a brown crude product. The resulting crude product was recrystallized from 300 mL of isopropanol to give 45.0 g of an off-white solid product, which gave (S)-3-phenoxytetrahydrofuran in 99% purity, the yield was 87%.
  • 30
  • tert-butyl (2S,4R)-4-hydroxy-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxylate [ No CAS ]
  • [ 112052-11-6 ]
  • tert-butyl (2S,4R)-2-(pyrrolidin-1-ylmethyl)-4-(((R)-tetrahydrofuran-3-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
16.8% Stage #1: tert-butyl (2S,4R)-4-hydroxy-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester In N,N-dimethyl-formamide at 20℃; 3 Synthesis of tert-butyl (2S,4R)-2-(pyrrolidin-l-ylmethyl)-4-(((R)-tetrahydrofuran-3-yl) oxy )pyrrolidine-l -carboxylate: To a stirred solution of NaH (1.86 g, 46.66 mmol, 60% in mineral oil w/w) in DMF (10 ml) under N2atmosphere at 0 °C, was added tert-butyl (2S,4R)-4-hydroxy-2-(pyrrolidin- l-ylmethyl)pyrrolidine-l -carboxylate (step 2, 1.8 g, 6.66 mmol) in DMF (15 ml). After 30 minutes (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.6 g, 6.66 mmol) was added and the reaction mixture was slowly allowed to attain to room temperature and stirred for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of saturated NH4C1 solution at 0 °C. The solution was extracted with EtOAc (2x50 mL) and the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by column chromatography with MeOH:DCM (5:95) as an eluent to afford the desired product (0.38 g, yield: 16.8%) as an oil. 1H NMR (300 MHz, CDC13): δ 4.23-4.20 (m, 1H), 4.14-4.08 (m, 2H), 3.92-3.41 (m, 5H), 2.75-2.49 (m, 7H), 2.19-1.71 (m, 8H), 1.46 (s, 9H); ES Mass:341.30 [M+H]+.
  • 31
  • [ 112052-11-6 ]
  • [ 109431-87-0 ]
  • tert-butyl (R)-3-(((R)-tetrahydrofuran-3-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28.1% Stage #1: (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester In N,N-dimethyl-formamide; mineral oil at 20℃; 1 Synthesis of tert-butyl (R)-3-(((R)-tetrahydrofuran-3-yl)oxy)pyrrolidine-l- carboxylate: To a stirred solution of NaH (1.38 g, 36.3 mmol, 60% in mineral oil w/w) in DMF (10 ml) under N2atmosphere at 0 °C, was added tert-butyl (R)-3-hydroxypyrrolidine- l- carboxylate (Intermediate 8-step 1, 3.4 g, 18.0 mmol) in DMF (40 ml). After 30 minutes (S)- tetrahydrofuran-3-yl 4-methylbenzenesulfonate (4.84 g, 21.8 mmol) was added and the reaction mixture was slowly allowed to attain to room temperature and stirred for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of saturated NH4C1 solution at 0 °C. The solution was extracted with EtOAc (2x100 mL) and the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc:hexane (30:70) as an eluent to afford the desired product (0.9 g, yield: 28.1%) as an oil. 1H MR (300 MHz, DMSO-d6): δ 4.22-4.17 (m, 1H), 4.08-4.06 (m, 1H), 3.72-3.56 (m, 4H), 3.28-3.17 (m, 4H), 1.91 -1.82 (m, 4H), 1.39 (s, 9H)
  • 32
  • [ 86087-23-2 ]
  • [ 104-15-4 ]
  • [ 112052-11-6 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: (S)-3-hydroxytetyrahydrofurane With dmap; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: toluene-4-sulfonic acid at 20 - 50℃; for 1.66667h; 5.1 1, Preparation of p-toluenesulfonic acid _ (S) _ tetrahydrofuran-3-ol ester A mixture of 6,61 g (75.22 mmol) of (S) -3-hydroxytetrahydrofuran,8 · 35 g (82 · 51 mmol) of triethylamine and 3.67 g (30.04 mmol)N, N-dimethylaminoP ratio was dissolved in 50 mL of dichloromethane,0 ° C after stirring lOmin,15.73 g (82.51 mmol)P-toluenesulfonyl chloride,Continue to stir lOmin,After warming to room temperature for 30 min,Heated to 50 ° C reflux lh,To the reaction system was added 50 mL of a 2 ml 1 / L HC1 aqueous solution,The organic phase is separated,The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.The resulting black red oily liquid was chromatographed on silica gel (eluting with a 1: 6 by volume mixture of ethyl acetate and petroleum ether)To give colorless liquid p-toluenesulfonic acid (S) -tetrahydrofuran-3-ol17.45 g, the yield was 96%.
  • 33
  • [ 112052-11-6 ]
  • [ 108-95-2 ]
  • (R)-3-phenoxytetrahydrofuran [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 12h; 5.2 2. Preparation of (R) -3-phenoxytetrahydrofuran A solution of 16.91 g (69.79 mmol) of p-toluenesulfonic acid- (S) -tetrahydrofuran-3-ol ester, 9.85 g (104.69 mmol) of phenol in 100 mL of DMF was added 34.31 g (104.68 mmol) of cesium carbonate and heated to 75 After the reaction was carried out for 12 h, distilled water was added and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (a 1: 3 by volume mixture of ethyl acetate and petroleum ether As a eluent) to give 8.19 g of (R) -3-phenoxytetrahydrofuran as a colorless oily liquid in a yield of 71%.
  • 34
  • [ 112052-11-6 ]
  • [ 4559-70-0 ]
  • C16H17O2P [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With N,N,N,N,-tetramethylethylenediamine; lithium methanolate In 1-methyl-pyrrolidin-2-one at 40℃; for 24h;
  • 35
  • 6-(4-hydroxy-1,2-dihydrofuro[3,2-f]quinolin-9-yloxy)-N-methyl-1-naphthamide [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-6-((4-((tetrahydrofuran-3-yl)oxy)-1,2-dihydrofuro[3,2-f] quinolin-9-yl)oxy)-Ν-methyl-1-naphthamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; Inert atmosphere; 12 (R) - 6 - ((4 - ((tetrahydrofuran-3-yl) oxy) - 1,2-dihydro-furo [3,2-f] quinolin-9-yl) oxy)-N-methyl-1-naphthalene carboxamide Under the protection of argon gas, the 6 - (4-hydroxy -1,2-dihydro-furo [3,2-f] quinoline-9-yloxy)-N-methyl-1-naphthalene carboxamide 1p (50 mg, 0 . 13mmol), (S)-tetrahydrofuran-3-yl tosylates 12a (under WO2007007040 relates to the method of preparing) (63 mg, 0 . 26mmol), cesium carbonate (127 mg, 0 . 39mmol) and 2 ml in dimethyl acetamide is put into the reaction bottle, for 60 °C reaction under 2 hours. Cooling, adding 2 ml water, 10 ml ethyl acetate mixed evenly, ethyl acetate extraction (4 ml × 2), combined with the phase, the organic phase is washed by saturated sodium chloride solution, dried anhydrous magnesium sulfate, filtered, filtrate concentrated under reduced pressure, in order to thin-layer chromatography for purification of the resulting product A developing agent system, to obtain the title product (R) - 6 - ((4 - ((tetrahydrofuran-3-yl) oxy) - 1,2-dihydro-furo [3,2-f] quinolin-9-yl) oxy)-N-methyl-1-naphthalene carboxamide 12 (40 mg, pale yellow solid), yield: 68.0%.
  • 36
  • [ 51834-97-0 ]
  • [ 112052-11-6 ]
  • (R)-2-methoxy-5-(tetrahydrofuran-3-oxo)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h; General procedure: In turn, 1c (1.78 g, 14.24 mmol) and (S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonyl ester 3a (3.45 g,14.24 mmol, using a known method ?Guangzhou Chemical Industry, 2012, 40 (16 Prepared from 62-63", dissolved in 20 mL of N,N-dimethylformamide, added potassium carbonate (4.92 g, 35.60 mmol), heated to 95 C, and the reaction was stirred at 90 C.hour.The heating was stopped, the reaction solution was naturally cooled to room temperature, 50 mL of water was added to the reaction solution, extracted with ethyl acetate(40 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (25 mL×3). After drying over anhydrous sodium sulfate, thedesiccant was removedby filtration, and the filtrate was concentrated under reduced pressure to give the crude title product 3b (2.80 g, brown oil). The product was directlyintroduced into the next reactionwithout purification.
  • 37
  • [ 102127-34-4 ]
  • [ 112052-11-6 ]
  • C11H13BrO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 16h; At room temperature, <strong>[102127-34-4]3-methoxy-4-bromophenol</strong> (0.4 g, 1.97 mmol) and cesium carbonate (0.96 g, 2.96 mmol) were added into a solution of compound 12-c (0.57 g, 2.36 mmol) in N,N-dimethylformamide (5 mL) respectively. After the addition, the reaction solution was stirred at 75 C. for 16 hours. The reaction solution was diluted with ethyl acetate (10 mL), washed sequentially with water (10 mL×3) and brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound 12-b (0.55 mg, yield 86%).
  • 38
  • tert-butyl (2R,4R)-4-amino-2-methylpiperidine-1-carboxylate [ No CAS ]
  • [ 112052-11-6 ]
  • C15H28N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With N-ethyl-N,N-diisopropylamine In acetonitrile at 95℃; for 48h; 172 Synthesis of (2R,4R)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172- 16 A mixture of Int-172-1 (1.0 g, 4.6 mmol), Int-172-14 (3.3 g, 14 mmol) and DIPEA (2.44 mL, 14 mmol) in acetonitrile (10 mL) was heated 95oC for 48 h. The mixture was concentrated under reduced pressure and purified by column chromatography using CH2Cl2/MeOH as mobile phase.1.26 g of a pale grey solid was obtained (95 % yield). LCMS: (M+1) m/z = 285.
  • 39
  • 1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-trans-2-methylpiperidin-4-amine [ No CAS ]
  • [ 112052-11-6 ]
  • (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine [ No CAS ]
  • (2S,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 12h; Microwave irradiation; 236 Synthesis of Compounds 236a (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4- amine and 236b (2S,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl-1,2,4-oxadiazol- 5-yl)quinolin-2-yl)-2-methyl-N-((R)-tetrahydrofuran-3-yl)piperidin-4-amine A microwave vessel was charged with 1-(8-fluoro-6-methoxy-4-methyl- 3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-trans-2-methylpiperidin-4-amine (Int- 236-4, 55 mg, 0.14 mmol), (3S)-oxolan-3-yl 4-methylbenzene-1-sulfonate (Int-172-14, 140 mg, 0.56 mmol), diisopropylethylamine (97 μL, 0.56 mmol) and CH3CN (0.9 mL). The mixture was heated at 120 oC in a microwave reactor for 12 hours. The mixture was partitioned between EtOAc and aqueous Na2CO3, drying the organic fraction over sodium sulfate and concentrating to 225 mg of an orange oil. The crude product was purified by column chromatography, eluting from silica gel with a gradient of 0-60% EtOAc/hexanes, followed by a gradient of 0-10% MeOH/DCM to give the mixture of diastereomers as a yellow solid (40 mg, 63% yield). The mixture can be separated to give the individual diasteromers using a phenomenex Lux 5 μ cellulose-2 column (250mmx4.6mm, hexane:ethanol:DEA (80:20:1), 1 mL/min, retention time: 15.7 min, 17.5 min. LCMS: (M+1) m/z = 356.1.
  • 40
  • [ 262586-62-9 ]
  • [ 112052-11-6 ]
  • methyl (R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With potassium carbonate In acetonitrile at 80℃; for 16h; 2 Methyl 6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate Methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (200 mg, 0.71 mmol), iodocyclopentane (0.25 mL, 2.13 mmol) and potassium carbonate (300 mg, 2.13 mmol) in acetonitrile (15 mL) were heated to 80 °C. After 16 h, the reaction mixture was diluted with water (25 mL) and, extracted with ethyl acetate (2 x 25 mL). The organic layer was driedover Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography on Si02 to provide methyl 6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate (211 mg, 85% yield). MS (ESI) m/z: 352.0 [M+Hj+; ‘H NMR (500 MI-Tz, CDC13) ö 8.37 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 7.83 (dd, J=8.8, 2.2 Hz, 1H), 7.59 (s, 1H), 5.15 (dt, J5.6, 3.0 Hz, 1H), 4.10 (s, 3H), 2.18-2.09 (m, 2H), 2.08-2.01 (m, 2H), 1.97-1.88 (m, 2H), 1.81-1.65(m, 2H).
73% With potassium carbonate In acetonitrile at 110℃; for 4h; Sealed tube; 2 Step 2. Methyl (R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate A mixture of methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (208 mg, 0.737 mmol), (+.
  • 41
  • [ 53857-57-1 ]
  • [ 112052-11-6 ]
  • 5-bromo-1-[(3R)-oxolan-3-yl]indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h; 8.8-4 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 80 Step 8-4. 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 80 To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg, 1.52 mmol) was added cesium carbonate (992 mg, 3.05 mmol) and Compound 8e (369 mg, 1.52 mmol) obtained in Step 8-3, and the mixture was stirred at 100° C. for 2 h. After cooling to room temperature, water was added to the reaction solution and extraction was performed using ethyl acetate. The organic layer was washed with water, and the solvent was removed by evaporation under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain the titled Compound 8f (198 mg, yield 49%) as a colorless oil-like product. LC/MS mass spectrometry: m/z 267 ([M+H]+).
  • 42
  • [ 112052-11-6 ]
  • [ 203569-23-7 ]
  • (R)-2-methyl-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
66.5% With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; 5.1 (R)-2-Methyl-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridine 5b 1e (637 mg, 4.0 mmol) was dissolved in 20 mL of N,N-dimethylformamide, then (S)-tetrahydrofuran-3-yl toluene-4-sulfonate 5a (1.45 g, 6.0 mmol, prepared according to the method disclosed in the patent application "WO2014049133") and cesium carbonate (2.61 g, 8.0 mmol) were added, and the reaction solution was stirred at 60° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by CombiFlash rapid preparation instrument with elution system B to obtain the title compound 5b (610 mg, colorless oil, yield: 66.5%).
  • 43
  • [ 1459754-32-5 ]
  • [ 112052-11-6 ]
  • [ 915095-94-2 ]
YieldReaction ConditionsOperation in experiment
90.1% With N-ethyl-N,N-diisopropylamine; potassium iodide; In acetonitrile; at 50 - 55℃;Large scale; First add 70 kg of compound II (0.203 kmol) to 350 kg of acetonitrile solvent, and then add 54.14 kg (0.223 kmol) of the raw material S-3-p-toluenesulfonyloxytetrahydrofuran, 52.51 kg (0.406 kmol) of the base DIEA, and 1.69 kg (0.010kmol) of catalyst potassium iodide, stir evenly and heat to 50-55 C for overnight. After the reaction, the solvent was concentrated under reduced pressure to remove part of the solvent acetonitrile. Then 350kg of water and 350kg of dichloromethane were added for extraction. Chloromethane solvent extraction once, combined organic phases, washed once with 350 kg of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and recrystallized with a mixed solvent of petroleum ether and ethyl acetate to obtain 76.65 kg of a white solid, namely The product engelegrin intermediate (S) -3- (4- (2-chloro-5-iodophenyl) phenoxy) tetrahydrofuran is obtained in a yield of 90.1%.
  • 44
  • 5-(4-fluoro-2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
  • [ 112052-11-6 ]
  • (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
  • (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; Overall yield = 34percent; Overall yield = 39 mg; 54-56 Example 54: 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (mixture of stereoisomers) 5-(4-fluoro-2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1,3,9- triazaspiro[5.5]undecan-2-one (100 mg, 202 pmol, Intermediate 10), (3S)-oxolan-3-yl 4- methylbenzene-1 -sulfonate (63.6 mg, 262 pmol) and potassium carbonate (1 12 mg, 0.81 mmol) were mixed in dimethylformamide (1.2 ml_) and heated to 100 13 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 39.0 mg (34 % yield). LC-MS (Method 4): Rt = 1.16 min; MS (ESIpos): m/z = 566 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.065 (0.64), 0.077 (0.64), 0.094 (0.58), 0.281 (0.55), 0.851 (0.74), 0.890 (1.41), 0.924 (0.89), 1.161 (0.61), 1.191 (1.29), 1.233 (1.60), 1.256 (0.77), 1.323 (1.54), 1.339 (1.04), 1.479 (1.01), 1.516 (0.86), 1.540 (0.68), 1.556 (0.83), 1.576 (1.14), 1.619 (0.55), 1.897 (0.55), 1.913 (0.61), 1.931 (0.77), 1.971 (0.58), 1.984 (0.46), 2.005 (0.61), 2.124 (0.74), 2.139 (1.01), 2.159 (1.32), 2.178 (1.23), 2.195 (1.23), 2.214 (0.95), 2.230 (0.64), 2.248 (0.40), 2.331 (1.29), 2.336 (0.58), 2.427 (0.40), 2.518 (6.48), 2.523 (4.05), 2.673 (1.32), 2.918 (0.80), 2.931 (1.07), 2.940 (1.07), 2.948 (1.26), 2.957 (1.35), 2.984 (1.14), 3.036 (0.80), 3.067 (1.1 1), 3.104 (1.07), 3.1 17 (1.04), 3.129 (1.60), 3.142 (1.35), 3.158 (0.89), 3.186 (0.74), 3.216 (1.38), 3.230 (1.44), 3.250 (1.50), 3.292 (1.57), 3.365 (1.35), 3.393 (2.36), 3.420 (2.73), 3.430 (2.86), 3.460 (3.01), 3.476 (6.51), 3.499 (1.01), 3.571 (16.00), 3.661 (0.92), 3.672 (1.14), 3.681 (2.00), 3.693 (1.84), 3.702 (1.07), 3.721 (2.03), 3.745 (3.96), 3.766 (5.37), 3.781 (2.46), 3.790 (4.05), 3.800 (3.41), 3.809 (1.32), 3.815 (1.44), 3.826 (1.41), 3.848 (1.04), 3.858 (1.20), 3.873 (0.83), 3.884 (0.77), 3.897 (1.07), 3.908 (1.17), 3.922 (0.95), 3.934 (0.83), 4.092 (0.61), 4.127 (0.55), 4.216 (0.89), 4.248 (0.83), 4.921 (1.47), 5.047 (1.20), 5.118 (0.83), 6.362 (2.18), 6.401 (2.21), 6.449 (1.44), 6.476 (0.55), 6.542 (3.22), 6.727 (0.43), 6.741 (1.04), 6.748 (0.92), 6.755 (1.29), 6.762 (1.97), 6.770 (1.29), 6.781 (1.63), 6.795 (1.66), 6.801 (1.87), 6.816 (0.92), 6.823 (1.07), 6.832 (1.04), 6.849 (1.23), 6.879 (2.52), 6.902 (2.98), 6.908 (3.10), 6.930 (0.89), 6.936 (0.83), 7.084 (1.60), 7.104 (3.65), 7.123 (2.55), 7.177 (2.03), 7.195 (5.44), 7.216 (3.62), 7.223 (1.90), 7.228 (1.93), 7.241 (7.80), 7.255 (3.75), 7.277 (0.52), 7.358 (2.00), 7.376 (3.62), 7.395 (1.23), 7.428 (1.84), 7.433 (1.93), 7.445 (1.47), 7.452 (1.29), 7.461 (4.21), 7.468 (3.19), 7.478 (1.90). The title compund was separated into its diastereoisomers by preparative chiral HPLC to give stereoisomer 1 (15 mg, Example 55), and stereoisomer 2 (1 1 mg, Example 56). For the isolation of stereoisomer 1 and stereoisomer 2 the following method was used. Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, column: Cellulose SB 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; Gradient: 20 - 50% B in 20 min; flow 40.0 mUmin; UV 220 nm Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Cellulose SB 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 7 min; flow 1.4 mUmin; temperature: 25 1C; DAD 220 nm. Example 55, Example 56 (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one Example 55 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 1) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 54. Analytical chiral FIPLC (method see Example 54): Rt = 3.3 min; ee > 99.9% Optical rotation (method OR1) = 38.3°+/- 0.76i;DMS O). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.260 (0.54), 0.282 (0.81), 0.312 (0.54), 0.795 (0.27), 0.851 (1.48), 0.883 (0.87), 1.006 (0.27), 1.026 (2.76), 1.042 (2.82), 1.061 (0.27), 1.083 (0.34), 1.137 (0.34), 1.160 (0.94), 1.192 (1.41), 1.214 (1.14), 1.232 (2.82), 1.259 (0.74), 1.324 (2.29), 1.337 (1.55), 1.375 (0.47), 1.583 (1.01), 1.616 (0.81), 1.897 (0.81), 1.914 (0.81), 1.931 (0.94), 1.957 (0.47), 1.971 (0.81), 1.986 (0.74), 2.004 (1.01), 2.019 (0.47), 2.158 (0.47), 2.177 (1.21), 2.192 (1.41), 2.213 (1.41), 2.229 (0.87), 2.247 (0.40), 2.331 (2.82), 2.336 (1.34), 2.518 (16.00), 2.522 (10.08), 2.673 (2.82), 2.678 (1.21), 2.882 (0.40), 2.908 (0.67), 2.934 (0.47), 3.036 (1.08), 3.066 (1.55), 3.135 (0.74), 3.157 (1.14), 3.185 (0.81), 3.216 (1.88), 3.228 (2.02), 3.250 (2.08), 3.290 (2.02), 3.374 (0.87), 3.405 (1.55), 3.418 (1.88), 3.430 (1.28), 3.474 (6.12), 3.573 (1 1.16), 3.685 (0.67), 3.721 (2.69), 3.746 (4.84), 3.759 (2.96), 3.766 (3.63), 3.780 (3.16), 3.787 (2.82), 3.809 (1.48), 3.829 (0.34), 3.847 (1.34), 3.858 (1.61), 3.873 (1.14), 3.884 (1.08), 3.897 (1.48), 3.908 (1.68), 3.922 (1.34), 3.933 (1.14), 4.092 (0.81), 4.125 (0.81), 4.345 (0.34), 4.355 (0.34), 5.045 (1.48), 5.120 (1.14), 5.320 (0.13), 6.357 (3.16), 6.440 (2.02), 6.525 (2.69), 6.734 (0.74), 6.741 (1.21), 6.749 (0.94), 6.755 (1.82), 6.762 (2.76), 6.770 (1.68), 6.777 (1.28), 6.783 (1.55), 6.791 (0.81), 6.832 (1.41), 6.849 (1.68), 6.877 (2.08), 6.883 (2.08), 6.906 (2.76), 6.912 (2.29), 6.931 (1.21), 6.936 (1.14), 7.206 (1.41), 7.224 (2.08), 7.228 (2.42), 7.241 (1 1.23), 7.255 (5.45), 7.276 (0.81), 7.365 (1.61), 7.376 (2.02), 7.385 (1.95), 7.417 (0.67), 7.424 (1.08), 7.431 (1.34), 7.438 (1.41), 7.445 (1.34), 7.452 (1.68), 7.462 (6.12), 7.468 (4.71), 7.478 (2.76). Example 56 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 2) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 54. Analytical chiral HPLC (method see Example 54): Rt = 3.9 min; ee = 98.4% Optical rotation (method OR1) = -32.1°+/- 0.28i;DM SO). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.60), 0.016 (0.70), 0.033 (1.07), 0.044 (1.02), 0.063 (0.83), 0.078 (0.60), 0.820 (0.56), 0.862 (1.53), 0.893 (1.39), 0.995 (2.64), 1.010 (2.74), 1.040 (0.42), 1.171 (1.07), 1.202 (4.03), 1.225 (1.48), 1.451 (1.67), 1.484 (1.39), 1.510 (1.16), 1.525(1.30), 1.542(1.16), 1.557 (0.83), 2.073 (0.51), 2.093 (1.11), 2.108 (1.58), 2.128 (1.62), 2.143(1.11), 2.163 (0.60), 2.301 (2.04), 2.487 (12.71), 2.491 (7.84), 2.642 (2.09), 2.898 (1.30), 2.908(1.30), 2.917(1.81), 2.925 (2.18), 2.937 (1.25), 2.951 (1.81), 2.984 (0.93), 3.073 (1.53), 3.085(1.53), 3.098 (2.04), 3.110 (1.67), 3.334 (1.67), 3.361 (2.60), 3.405 (3.43), 3.429 (4.22), 3.448 (4.92), 3.467 (1.44), 3.538 (16.00), 3.630 (1.21), 3.641 (1.30), 3.650 (2.41), 3.662 (2.32), 3.672(1.16), 3.683(1.02), 3.710 (1.95), 3.735 (4.68), 3.759 (3.90), 3.769 (3.99), 3.784 (1.86), 3.794(1.95), 3.804(1.02), 3.819 (0.42), 4.182 (1.39), 4.216 (1.30), 4.889 (2.32), 5.026 (0.42), 6.367 (3.48), 6.438 (0.79), 6.505 (4.27), 6.690 (0.46), 6.695 (0.51), 6.743 (1.11), 6.749 (1.44), 6.764 (2.32), 6.770 (2.74), 6.785 (1.25), 6.792(1.44), 6.827 (0.51), 6.842 (2.55), 6.848 (2.60), 6.871 (2.69), 6.877 (2.46), 7.053 (2.46), 7.073 (5.61), 7.092 (3.90), 7.146 (2.97), 7.163 (8.35), 7.184 (5.24), 7.302 (0.70), 7.327 (2.27), 7.345 (3.43), 7.363 (1.58), 7.397(1.95), 7.402(1.76), 7.410 (1.02), 7.414 (0.97).
  • 45
  • 5-(4-fluoro-2-hydroxyphenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
  • [ 112052-11-6 ]
  • (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triaza-spiro[5.5]undecan-2-one [ No CAS ]
  • (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triaza-spiro[5.5]undecan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; Overall yield = 60percent; Overall yield = 69 mg; 57-59 Example 57: 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triaza- spiro[5.5]undecan-2-one (mixture of stereoisomers) (4-fluoro-2-hydroxyphenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triazaspiro[5.5]- undecan-2-one (100 mg, 208 mihoI, Intermediate 15), (3S)-oxolan-3-yl 4-methylbenzene-1 - sulfonate (75.5 mg, 312 pmol) and potassium carbonate (1 15 mg, 0.831 mmol) were mixed in dimethylformamide (1.2 ml_) and heated to 100 13 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 69.0 mg (60 % yield). LC-MS (Method 4): Rt = 1.08 min; MS (ESIpos): m/z = 552 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.154 (1.23), 1.202 (1.60), 1.237 (3.36), 1.269 (2.88), 1.359 (3.73), 1.383 (3.25), 1.533 (2.19), 1.567 (1.87), 1.596 (2.03), 1.632 (1.65), 1.834 (1.07), 1.853 (1.01), 1.867 (1.28), 1.921 (1.23), 1.935 (1.81), 1.953 (2.13), 1.966 (2.29), 1.997 (1.12), 2.187 (1.71), 2.203 (2.51), 2.221 (2.93), 2.238 (2.35), 2.518 (1 1.52), 2.523 (7.68), 2.839 (0.64), 2.949 (1.49), 3.039 (0.91), 3.1 19 (1.12), 3.152 (2.13), 3.184 (2.88), 3.226 (1.60), 3.285 (4.16), 3.314 (2.72), 3.344 (8.80), 3.363 (3.84), 3.376 (5.17), 3.489 (0.80), 3.521 (2.19), 3.544 (4.32), 3.554 (5.39), 3.584 (5.28), 3.594 (4.96), 3.653 (12.91), 3.680 (2.29), 3.714 (4.16), 3.722 (4.27), 3.728 (4.21), 3.743 (4.91), 3.755 (8.96), 3.764 (7.89), 3.778 (9.39), 3.793 (9.07), 3.834 (4.48), 3.845 (4.96), 3.859 (2.40), 3.871 (2.72), 3.878 (3.04), 3.889 (2.99), 3.903 (2.40), 3.915 (2.24), 3.948 (2.24), 3.986 (2.67), 4.023 (1.12), 5.060 (3.04), 5.102 (1.71), 6.441 (8.00), 6.666 (7.36), 6.732 (1.81), 6.738 (2.35), 6.753 (4.85), 6.759 (4.69), 6.766 (3.79), 6.773 (4.91), 6.781 (2.72), 6.788 (1.97), 6.793 (1.81), 6.885 (3.95), 6.891 (4.1 1), 6.898 (3.63), 6.908 (3.36), 6.915 (4.16), 6.920 (4.05), 6.927 (3.41), 7.207 (7.57), 7.215 (16.00), 7.226 (12.64), 7.253 (13.92), 7.259 (1 1.25), 7.280 (4.69), 7.331 (2.67), 7.339 (5.23), 7.345 (5.28), 7.354 (4.64), 7.363 (5.12), 7.376 (2.40), 7.382 (1.60). The title compund was separated into its diastereoisomers by preparative chiral HPLC to give stereoisomer 1 (25 mg, Example 58), and stereoisomer 2 (27 mg, Example 59). For the isolation of stereoisomer 1 and stereoisomer 2 the following method was used. Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, column: Chiralpak IA 5m 250x30mm; eluent A: hexane; eluent B: 2- propanol; isocratic: 20% B; flow 40.0 mL/min; UV 220 nm Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-Propanol; gradient: 20-50% B in 7min; fluss 1.4 mL/min; temperature: 25 1C; DAD 220 nm. Example 58, Example 59 (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9- triazaspiro[5.5]undecan-2-one (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9- triazaspiro[5.5]undecan-2-one Example 58 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9- triazaspiro[5.5]undecan-2-one (stereoisomer 1) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 57. Analytical chiral FIPLC (method see Example 57): Rt = 2.8 min; ee > 99.9% 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.795 (0.90), 0.810 (0.85), 0.851 (1.35), 0.899 (0.55), 0.967 (3.31), 0.994 (0.45), 1.006 (0.75), 1.034 (0.55), 1.084 (0.95), 1.107 (6.92), 1.136 (1.45), 1.144 (2.36), 1.154 (3.36), 1.172 (1.96), 1.190 (2.16), 1.209 (2.71), 1.233 (5.57), 1.259 (3.06), 1.268 (2.76), 1.303 (1.76), 1.352 (4.61), 1.388 (1.86), 1.537 (1.61), 1.570 (1.40), 1.595 (1.61), 1.629 (1.35), 1.936 (1.35), 1.950 (1.86), 1.966 (2.46), 1.980 (2.01), 1.996 (1.45), 2.186 (2.06), 2.207 (2.41), 2.221 (2.31), 2.242 (1.61), 2.256 (0.65), 2.518 (16.00), 2.522 (10.63), 2.933 (1.20), 2.967 (1.66), 2.995 (0.85), 3.116 (0.95), 3.146 (1.55), 3.183 (1.20), 3.226 (1.66), 3.285 (3.91), 3.373 (4.01), 3.385 (3.36), 3.488 (0.70), 3.516 (1.50), 3.553 (4.21), 3.594 (5.32), 3.652 (10.78), 3.680 (2.76), 3.713 (4.56), 3.755 (7.97), 3.778 (9.43), 3.793 (5.77), 3.813 (2.46), 3.877 (3.71), 3.886 (3.81), 3.903 (3.16), 3.914 (2.81), 3.954 (2.01), 5.061 (2.46), 5.104 (2.16), 6.439 (4.97), 6.650 (4.66), 6.658 (5.22), 6.738 (1.45), 6.752 (3.21), 6.759 (3.06), 6.766 (2.56), 6.773 (3.26), 6.788 (1.35), 6.885 (2.41), 6.891 (2.71), 6.899 (2.56), 6.905 (2.46), 6.913 (2.71), 6.920 (2.71), 6.927 (2.51), 6.934 (2.16), 7.215 (9.33), 7.226 (12.19), 7.254 (9.43), 7.259 (8.13), 7.282 (3.41), 7.331 (2.21), 7.345 (3.91), 7.354 (3.61), 7.363 (4.01), 7.376 (1.86), 7.382 (1.15). Example 59 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9- triazaspiro[5.5]undecan-2-one (stereoisomer 2) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 57. Analytical chiral HPLC (method see Example 57): Rt = 3.4 min; ee = 92% 1H-NMR (400 MHz, DMSO-d6) d [ppml: 0.776 (0.47), 0.795 (0.88), 0.810 (0.82), 0.836 (0.99), 0.850(1.46), 0.859 (0.99), 0.899 (0.47), 0.967 (3.39), 0.995 (0.41), 1.005 (0.76), 1.034 (0.58), 1.084 (0.76), 1.109 (2.69), 1.124 (0.93), 1.135 (2.51), 1.144 (3.27), 1.154 (4.79), 1.172 (2.74), 1.185(1.17), 1.209 (2.28), 1.232 (5.90), 1.259 (3.45), 1.288(1.64), 1.320(1.28), 1.352(1.46), 1.381 (2.92), 1.415 (1.69), 1.527(1.40), 1.561 (1.23), 1.599 (1.23), 1.631 (0.99), 1.820(0.64), 1.834(1.11), 1.851 (1.05), 1.868(1.23), 1.882 (0.76), 1.920 (0.88), 1.936 (0.93), 1.953(1.05), 1.969 (0.82), 2.183 (0.47), 2.204(1.11), 2.219(1.52), 2.231 (1.40), 2.238 (1.58), 2.246 (1.40), 2.253(1.34), 2.264(1.17), 2.280 (0.76), 2.336(1.11), 2.518(16.00), 2.522 (10.69), 2.678 (1.11), 2.902 (0.53), 2.920 (1.28), 2.950 (1.69), 2.979 (0.76), 3.126 (0.70), 3.154(1.46), 3.183 (2.16), 3.271 (2.45), 3.287 (2.04), 3.361 (3.45), 3.377 (3.27), 3.488 (0.53), 3.504 (0.76), 3.520 (1.28), 3.544 (3.45), 3.584 (3.85), 3.605 (1.52), 3.646 (5.14), 3.653 (5.49), 3.694 (0.64), 3.721 (3.68), 3.727 (3.85), 3.743 (4.55), 3.749 (4.38), 3.764 (6.66), 3.791 (5.31), 3.834 (4.50), 3.844 (4.96), 3.859 (2.34), 3.870 (2.28), 3.945 (1.05), 3.989 (1.69), 4.021 (1.11), 5.038 (2.04), 5.051 (1.87), 5.067 (1.69), 6.435 (4.73), 6.663 (4.61), 6.732 (0.99), 6.738 (1.34), 6.753 (2.69), 6.759 (2.63), 6.766 (2.04), 6.773 (2.57), 6.780 (1.52), 6.787 (1.1 1), 6.879 (2.10), 6.885 (2.51), 6.891 (2.34), 6.897 (2.04), 6.908 (2.34), 6.914 (2.51), 6.919 (2.28), 6.926 (1.75), 7.206 (5.84), 7.214 (9.58), 7.230 (4.96), 7.251 (8.29), 7.258 (5.96), 7.268 (5.14), 7.329 (1.81), 7.338 (3.21), 7.345 (2.57), 7.351 (2.39), 7.359 (2.69), 7.375 (1.17), 7.381 (0.82).
  • 46
  • 5-(4-fluoro-2-hydroxyphenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
  • [ 112052-11-6 ]
  • (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
  • (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; Overall yield = 75percent; Overall yield = 43 mg; 60-62 Example 60: 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one (mixture of stereoisomers) (5-(4-fluoro-2-hydroxyphenyl)-9-{2-methyl-2-[3-(trifluor,3,9- triazaspiro[5.5]undecan-2-one (50.0 mg, 101 pmol, Intermediate 16), (3S)-oxolan-3-yl 4- methylbenzene-1 -sulfonate (36.8 mg, 152 pmol) and potassium carbonate (56 mg, 0.405 mmol) were mixed in dimethylformamide (0.6 ml_) and heated to 100 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 43.0 mg (75 % yield). LC-MS (Method 4): Rt = 1.16 min; MS (ESIpos): m/z = 564 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.438 (0.78), 0.932 (1.62), 0.948 (1.98), 0.983 (1.86), 1.309 (6.71), 1.469 (7.37), 1.941 (1.86), 2.074 (0.48), 2.152 (1.68), 2.172 (3.18), 2.187 (3.96), 2.207 (3.54), 2.221 (2.40), 2.243 (1.08), 2.518 (16.00), 2.523 (10.43), 2.539 (1.26), 2.729 (1.02), 2.888 (4.01), 3.143 (4.13), 3.174 (5.27), 3.203 (5.09), 3.501 (1.56), 3.737 (7.55), 3.762 (10.97), 3.804 (4.49), 3.814 (4.91), 3.830 (3.60), 4.036 (1.08), 4.993 (2.58), 5.029 (3.12), 6.359 (1 1.33), 6.487 (6.83), 6.500 (6.17), 6.739 (3.12), 6.758 (5.45), 6.775 (3.18), 6.867 (4.31), 6.872 (4.55), 6.895 (6.41), 6.901 (5.57), 6.920 (2.34), 7.177 (2.10), 7.278 (4.31), 7.380 (9.41), 7.396 (8.21), 7.582 (4.79), 7.595 (7.19), 7.613 (4.31). The title compund was separated into its diastereoisomers by preparative chiral HPLC to give stereoisomer 1 (15 mg, Example 61), and stereoisomer 2 (15 mg, Example 62). For the isolation of stereoisomer 1 and stereoisomer 2 the following method was used. Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, column: Chiralpak IA 5m 250x30mm; eluent A: hexane; eluent B: 2- propanol; isocratic: 20% B; flow 40.0 mL/min; UV 220 nm Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20-50% B in 7min; flow 1.4 mL/min; temperature: 25 1C; DAD 220 nm. Example 61, Example 62 (5R)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one (5S)-5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one Example 61 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 1) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 60. Analytical chiral FIPLC (method see Example 60): Rt = 2.5 min; ee > 99.9% 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.430 (0.36), 0.775 (0.30), 0.794 (0.72), 0.813 (0.54), 0.833 (0.54), 0.851 (0.90), 0.859 (0.90), 0.899 (0.60), 0.967 (3.19), 0.994 (0.84), 1.006 (0.96), 1.009 (0.72), 1.034 (0.54), 1.083 (0.84), 1.107 (14.38), 1.144 (1.98), 1.208 (1.68), 1.232 (3.19), 1.259 (2.89), 1.275 (2.59), 1.352 (1.62), 1.388 (1.92), 1.485 (2.47), 1.601 (0.66), 1.986 (0.24), 2.181 (0.84), 2.331 (2.65), 2.336 (1.20), 2.518 (16.00), 2.522 (10.05), 2.673 (2.71), 2.678 (1.26), 2.876 (1.08), 3.032 (0.60), 3.143 (1.32), 3.172 (2.1 1), 3.202 (1.80), 3.504 (0.66), 3.698 (1.02), 3.736 (2.53), 3.761 (4.15), 3.804 (1.86), 3.813 (1.92), 3.829 (1.14), 4.152 (0.42), 4.992 (1.38), 6.357 (3.31), 6.494 (3.13), 6.739 (0.96), 6.757 (1.68), 6.777 (0.96), 6.867 (2.35), 6.873 (2.35), 6.895 (2.41), 6.901 (2.23), 7.178 (0.72), 7.279 (1.44), 7.379 (4.99), 7.582 (2.53), 7.600 (1.98). Example 62 5-(4-fluoro-2-[(3R)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 2) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 60. Analytical chiral HPLC (method see Example 60): Rt = 3.5 min; ee = 96.8% 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.514 (0.39), 0.776 (0.45), 0.794 (0.89), 0.813 (0.78), 0.832 (1.00), 0.851 (1.45), 0.859 (1.00), 0.967 (1.78), 1.006 (1.1 1), 1.034 (0.72), 1.083 (0.84), 1.107 (1.67), 1.135 (0.89), 1.144 (1.34), 1.153 (1.45), 1.172 (1.17), 1.190 (1.00), 1.208 (1.39), 1.232 (5.02), 1.259 (2.45), 1.310 (2.95), 1.352 (2.51), 1.389 (1.95), 1.460 (2.73), 1.938 (1.06), 1.984 (0.33), 2.152 (0.56), 2.173 (1.23), 2.187 (1.62), 2.207 (1.45), 2.221 (1.00), 2.242 (0.50), 2.331 (2.45), 2.518 (16.00), 2.522 (9.87), 2.673 (2.51), 2.763 (0.33), 2.776 (0.39), 2.920 (1.06), 3.124 (1.56), 3.218 (1.51), 3.504 (0.95), 3.758 (2.56), 3.829 (1.00), 4.041 (0.50), 5.031 (1.67), 6.354 (3.62), 6.479 (3.51), 6.758 (1.62), 6.894 (1.39), 6.920 (1.34), 7.177 (0.61), 7.273 (1.28), 7.396 (4.40), 7.595 (2.73), 7.613 (2.23).
  • 47
  • [ 112052-11-6 ]
  • [ 123-08-0 ]
  • (R)-4-((tetrahydrofuran-3-yl)oxy)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 14h; 6.1 Step 2) Synthesis of 3- (oxetan-3-yloxy) benzaldehyde General procedure: M-hydroxybenzaldehyde (1.5g, 12.3mmol),Oxetan-3-yl 4-methylbenzenesulfonate (2.0g, 8.7mmol) and N, N-dimethylformamide (10mL) were added to a 100mL single-necked round bottom flask, and potassium carbonate (2.6 g, 18.8 mmol), reaction at an oil bath at 100 ° C for 14 hours; stop the reaction, cool to room temperature, add water (50 mL) to quench, then add ethyl acetate (30 mL), separate the liquid, collect the organic phase, and spin dry under reduced pressure , Column chromatography separation and purification (petroleum ether / ethyl acetate (v / v) = 8/1) to give the title compound as a yellow oil (1.1g, 70%).
  • 48
  • [ 1062642-68-5 ]
  • [ 112052-11-6 ]
  • tert-butyl ((R)-2-(5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidine-1(6H)-yl)-1-phenylethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; 4.1 Step 8) (R)-Methyl 4-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoro (Methyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyrate General procedure: Add (R)-tert-butyl(2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl- 2,6-dioxo-2,3-dihydropyrimidine-1(6H)-yl)-1-phenylethyl)carbamate (0.5g, 0.79mmol) andN,N-dimethylformamide (8.0mL) was added to a 100mL single-neck round bottom flask, potassium carbonate (221mg, 1.58mmol) andMethyl 4-bromobutyrate (286mg, 1.58mmol), react at 70°C for 12 hours;Stop the reaction, add water (50mL) after cooling to room temperature, and then add ethyl acetate for extraction (50mL×2),The organic phases were combined, spin-dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a viscous liquid (456 mg, 79%).
  • 49
  • C22H16Cl2F4N4O3 [ No CAS ]
  • [ 112052-11-6 ]
  • C26H22Cl2F4N4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 18h; 37.1 The first step Compound 13-2 (250.0 mg, 470.56 mmol) was dissolved in N,N-dimethylformamide (4 mL), and to the reactionsolution were added potassium carbonate (130.0 mg, 941.11 mmol) and compound M-1 (171.0 mg, 705.83 mmol). Thereaction solution was stirred at 110 °C for 18 hours. The solvent was concentrated under reduced pressure, and theresidue was isolated by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to afford compound37-2. LC-MS: m/z = 601.3 [M+H]+.
  • 50
  • (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-ol [ No CAS ]
  • [ 112052-11-6 ]
  • C25H21F4N5O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.08% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; 201 (R)-4-(2-(1,1-dioxidothiomorpholino)ethyl)-8-(4-fluorophenyl)-3-oxo-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide Potassium carbonate (47.7 mg, 0.345 mmol) was added to a mixture of (R)-6-(4- fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-ol (64.4 mg, 0.150 mmol) and (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (41.8 mg, 0.172 mmol) in DMF (Volume: 3 ml). Stirring went on at 60 °C for 16 h. The reaction mixture was allowed to cool down to rt, then it was quenched by the addition of formic acid (0.017 ml, 0.450 mmol). Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 100:0 to 50:50 A/B, A: water/acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 +0.1% HCOOH) then DP chromatography (Biotage Isolera, 11 g NH cartridge, gradient elution from 0 to 40% ethyl acetate in dichloromethane) yielded 6-(4-fluorophenyl)-8-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)- 1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (8.3 mg, 0.017 mmol, 11.08 % yield) as a white powder. LCMS (Method 5): Method 50.74 min, 500.0 [M+H]+, CSH method 2 min. 1H NMR (400 MHz, DMSO-d6) d ppm 9.16 (s, 2 H), 8.61 (d, J=6.6 Hz, 1 H), 8.42 (s, 1 H), 8.21 (d, J=1.3 Hz, 1 H), 7.84 - 8.01 (m, 2 H), 7.51 (d, J=1.3 Hz, 1 H), 7.38 (t, J=8.8 Hz, 2 H), 5.67 (t, J=7.0 Hz, 1 H), 5.35 - 5.50 (m, 1 H), 3.85 - 4.04 (m, 3 H), 3.79 (d, J=4.4 Hz, 1 H), 2.19 - 2.37 (m, 1 H), 2.03 - 2.17 (m, 1 H), 1.72 (d, J=7.0 Hz, 3 H).
  • 51
  • C22H28N4O [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
16 mg With caesium carbonate In acetonitrile at 95℃; for 16h; 1.P Example 1P Example 1P (R)-2-(pyrimidin-5-yl)-6-(4-(2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane (R)-2-(1-(2-(pyrimidin-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)phenol (Intermediate 6G, 80 mg, 0.219 mmol), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (Intermediate 7C, 61.2 mg, 0.252 mmol), and Cs2CO3 (286 mg, 0.878 mmol) were dissolved in MeCN (5 mL) to give a yellow solution. The solution was stirred at 95° C. for 16 hrs and the solvent was then removed under reduced pressure. The crude mixture was diluted with EtOAc and washed with water. The organic phase was separated, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by FCC (0-10% MeOH (1% 7N NH3 in MeOH)/DCM) and preparative HPLC (XBridge 30*50 mm 35-60% MeCN/H2O (5 mM NH4OH)) to afford the title compound (16 mg, 0.036 mmol). LCMS: Rt: 0.64 min (LCMS Method 1) MS m/z 435.5. [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.00 (s, 2H), 7.23-7.12 (m, 2H), 6.95-6.87 (m, 2H), 5.09-5.02 (m, 1H), 4.01-3.81 (m, 8H), 3.22 (s, 3H), 3.00 (s, 1H), 2.81 (s, 1H), 2.39-2.20 (m, 3H), 2.16-1.92 (m, 4H), 1.89-1.56 (m, 6H).
  • 52
  • [ 321601-48-3 ]
  • [ 112052-11-6 ]
  • methyl (R)-6-bromo-3-((tetrahydrofuran-3-yl)oxy)picolinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
67.2% With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; Step-3 Synthesis of methyl (R)-6-bromo-3-((THF-3-yl)oxy)picolinate (Intermediate AA198-5) To a solution of Intermediate AA198-4 (4.0 g, 17.24 mmol) and Intermediate AA198-2 (5.4 g, 22.41 mmol, 1.5 eq) in DMF (20 mL) was added potassium carbonate (7.1 g, 51.72 mmol, 3.0 eq). After stirring at 90° C. for 16 h, the reaction was diluted with ice cold water (250 mL) and extracted into ethyl acetate (3×80 mL). The combined organic layer was washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 17% ethyl acetate in hexane to afford Intermediate AA198-5 (3.5 g, 67.20%) as a yellow oil. MS (ES): m/z 302.9 [M+H]+.
  • 53
  • tert-butyl 3-(4-hydroxy-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [ No CAS ]
  • [ 112052-11-6 ]
  • tert-butyl 3-(4-(((R)-tetrahydrofuran-3-yl)oxy)-7-(thiazol-2-yl)benzo[d]oxazol-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34 mg With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; 324.a (a) (((2-nitro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene General procedure: 5 g of 2-nitroresorcinol was dissolved in N,N-dimethylformamide (88 mL), and then benzylbromide (8.4 mL, 2.2equivalents) and caesium carbonate (25 g, 2.4 equivalents) were added thereto, followed by stirring at room temperaturefor 12 hours. The formation of the product was confirmed by TLC, and then ethyl acetate was added thereto. The organicphase was washed by 1% aqueous solution of hydrochloric acid and then washed again by distilled water. The organicphase was dried over anhydrous magnesium sulfate, followed by filtration. Hexane was added to the residue obtainedby vacuum concentration of the filtrate and the precipitated solid was collected by filtration, thus obtaining 10 g of thetitle compound. MS (ESI) m/z: 336 (M+H)+
  • 54
  • (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol [ No CAS ]
  • [ 112052-11-6 ]
  • (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
27 mg With caesium carbonate In acetonitrile at 80℃; for 1.33333h; 2CC Example 2CC: (S)-7-(4-(3,5-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)piperidin-1-yl)-2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane (S)-2-(1-(2-(1,3,4-oxadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)piperidin-4-yl)-4,6-difluorophenol (Intermediate 4C, 32 mg, 0.082 mmol), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (Intermediate 5C) 22 mg, 0.090 mmol) and cesium carbonate (106 mg, 0.326 mmol) were suspended in acetonitrile (0.8 mL). The reaction was stirred at 80 °C for 80 minutes then cooled at room temperature and diluted with EtOAc and water. The aq layer was extracted with EtOAc, and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The residue was purified by FCC (0-20% MeOH(10% NH4OH)/EtOAc) to afford the title compound (27 mg, 0.058 mmol) as a white solid. LCMS: Rt: 1.98 min (LCMS Method 4); MS m/z 463.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 6.94 - 6.75 (m, 2H), 5.03 - 4.94 (m, 1H), 4.35 - 4.23 (m, 2H), 4.17 (q, J = 8.6 Hz, 2H), 4.10 - 3.99 (m, 2H), 3.96 - 3.86 (m, 2H), 3.80 - 3.69 (m, 2H), 3.15 - 2.98 (m, 3H), 2.95 - 2.84 (m, 1H), 2.55 (dd, J = 13.0, 7.4 Hz, 1H), 2.27 - 2.08 (m, 5H), 1.85 - 1.56 (m, 4H).
  • 55
  • [ 610-81-1 ]
  • [ 112052-11-6 ]
  • C10H12N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; 31 Compound 31B At room temperature, compound 31A (3.00 g, 12.4 mmol) was dissolved in N,N-dimethylformamide (30.0 mL).Subsequently, 4-amino-3-nitrophenol (2.29 g, 14.9 mmol) and cesium carbonate (8.07 g, 24.8 mmol) were sequentially added to the above solution.The reaction system was heated to 80 degrees Celsius and stirred for 16 hours.After LCMS monitoring showed that the raw materials disappeared, the reaction system was cooled to room temperature, and water (100 mL) was added to the reaction solution to quench.The mixture was extracted with ethyl acetate (100 ml × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (200 ml × 3 times), then dried with anhydrous sodium sulfate, filtered, and the filtrate was finally reduced Concentrate under pressure.The obtained residue was slurried with ether (50 ml), filtered, and the obtained filter cake was dried to obtain 1.75 g of brown solid compound 31B (crude).
  • 56
  • 4-chloro-3-hydroxy-5-nitrobenzamide [ No CAS ]
  • [ 112052-11-6 ]
  • C11H11ClN2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
77 mg With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 12h; 22.1 Example 22: Synthesis of S-15 Step 1: Add (S)-3-hydroxytetrahydrofuran p-toluenesulfonate (260mg), potassium iodide (30mg) and potassium carbonate (300mg) to the solution of S-2 (190mg) in DMF (6mL), and react at 70 12h, poured into water, extracted with EA, washed the EA layer with saturated brine, spin-dried the solvent and column chromatography to obtain S-15-1 (77mg).
  • 58
  • 7-bromo-8-hydroxy-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylic acid methyl ester [ No CAS ]
  • [ 112052-11-6 ]
  • (S)-methyl 7-bromo-8-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.4% With Cs2CO3 In N,N-dimethyl-formamide at 95℃; for 1h; 20.3 (S)-Methyl 7-bromo-8-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylate 20d Compound 20c (500 mg, 1.73 mmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (845 mg, 2.6 mmol) and 1 g (461 mg, 1.9 mmol) were added, and the reaction was heated to 95° C. for 1 hour. Cooled, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 20d (500 mg), yield: 80.4%.
  • 59
  • 2-methylfuro[2,3-h]quinazoline-4,6-diol [ No CAS ]
  • [ 112052-11-6 ]
  • (S)-2-methyl-6-((tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
60.4% With Cs2CO3 In N,N-dimethyl-formamide at 60℃; for 1h; 1.6 (S)-2-Methyl-6-((tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-ol 1h Compound 1f (250 mg, 1.2 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium carbonate (753 mg, 2.3 mmol) and 1 g (420 mg, 1.7 mmol) were added, Journal of Medicinal Chemistry, 2011, 54, 4092-4108), heated to 60 °C for 1 hour. Cooled, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (200 mg), yield: 60.4%.
  • 60
  • 7-bromo-8-hydroxy-4-methyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate methyl ester [ No CAS ]
  • [ 112052-11-6 ]
  • (R)-7-bromo-4-methyl-5-nitro-8-((tetrahydrofuran-3-yl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
78.6% With Cs2CO3 In N,N-dimethyl-formamide at 90℃; for 2h; 77.8 (R)-7-Bromo-4-methyl-5-nitro-8-((tetrahydrofuran-3-yl)oxy)-3,4-dihydro-2H-benzo[b][1,4 ]oxazine-6-carboxylate methyl ester 77i Compound 77h (0.9 g, 2.5 mmol) and compound 1 g (942 mg, 3.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (1.69 g, 5.2 mmol) was added, and the reaction was carried out at 90°C for 2 hours . The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 77i (850 mg), yield: 78.6%.
  • 61
  • 2-methylfuro[3,2-h]quinazoline-4,6-diol [ No CAS ]
  • [ 112052-11-6 ]
  • (S)-2-methyl-6-((tetrahydrofuran-3-yl)oxy)furo[3,2-h]quinazolin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
50.3% With Cs2CO3 In N,N-dimethyl-formamide at 60℃; for 1h; 7.8 (S)-2-Methyl-6-(tetrahydrofuran-3-yl)oxy)furo[3,2-h]quinazolin-4-ol 7i Compound 7h (0.06 g, 277.53 μmol) was dissolved in N,N-dimethylformamide (5 mL), compound 1 g (0.07 g, 288.90 μmol) and cesium carbonate (0.18 g, 552.45 μmol) were added in sequence, and the mixture was heated at 60° C. Heat and stir for 1 hour. Cooled, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 7i (79 mg), yield: 50.3%.
  • 62
  • 4-chloro-3-hydroxy-5-nitrobenzamide [ No CAS ]
  • [ 112052-11-6 ]
  • (S)-4-chloro-3-nitro-5-((tetrahydrofuran-3-yl)oxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56.3% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; General synthesis procedure of compounds 24a~24e: General procedure: To a 50 mLround bottom flask was added 4-chloro-3-hydroxy-5-nitrobenzamide(17) (2.0 g, 9.23 mmol, 1.0 eq) and K2CO3 (2.5 g, 18.46 mmol, 2.0eq) in DMF (10 mL). N-(3-Chloropropyl) morpholine (1.67 g, 10.16mmol, 1.1 eq) (for 24a), 2-bromopropane (1.3 mL, 13.85 mmol, 1.5 eq) (for 24b), (chloromethyl)cyclopropane (1.70 g, 9.23 mmol, 1.0 eq) (for24c), (chloromethyl)cyclopropane (1.25 g, 13.85 mmol, 1.5 eq) (for24d), 50a (3.37 g, 13.85 mmol, 1.5 eq) (for 24e) was added next andstirred at 70 °C for 2 h. The resulting mixture was dissolved in 100 mL ofwater and washed with ethyl acetate (3 × 50 mL). The combined organicswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gelchromatography (eluent: DCM/MeOH (v/v) = 20/1-5/1) to provide24a~24e, as yellow solids.
Same Skeleton Products
Historical Records