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[ CAS No. 33024-60-1 ] {[proInfo.proName]}

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Chemical Structure| 33024-60-1
Chemical Structure| 33024-60-1
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Product Details of [ 33024-60-1 ]

CAS No. :33024-60-1 MDL No. :MFCD00100881
Formula : C5H12ClNO Boiling Point : No data available
Linear Structure Formula :- InChI Key :KWZSCXIYGVEHOB-UHFFFAOYSA-N
M.W : 137.61 Pubchem ID :44118693
Synonyms :

Calculated chemistry of [ 33024-60-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 34.79
TPSA : 35.25 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.49
Log Po/w (WLOGP) : 0.93
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 0.82
Consensus Log Po/w : 0.49

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.0
Solubility : 13.7 mg/ml ; 0.0996 mol/l
Class : Very soluble
Log S (Ali) : -0.8
Solubility : 21.8 mg/ml ; 0.159 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.34
Solubility : 62.6 mg/ml ; 0.455 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.41

Safety of [ 33024-60-1 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P305+P351+P338 UN#:
Hazard Statements:H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33024-60-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 33024-60-1 ]

[ 33024-60-1 ] Synthesis Path-Downstream   1~23

  • 1
  • 4-methyl-1H-indazole-5-carboxylic acid [ No CAS ]
  • [ 33024-60-1 ]
  • 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52.7% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 4h; Tetrahydro-2H-pyran-4-ylamine monohydrochloride (228 mg, 1.66 mmol), triethylamine (0.5 ml, 3.59 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (367 mg, 1.91 mmol) and hydroxybenzotriazole (190 mg, 1.41 mmol) were added to a solution of 4-methyl-1H-indazole-5-carboxylic acid (225 mg, 1.28 mmol) in N,N-dimethylformamide (5.5 ml), and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution. A small amount of the insoluble material was collected by filtration and then dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (41 mg). The filtrate was extracted with ethyl acetate and chloroform, and the combined organic layer was dehydrated over magnesium sulfate and then filtered. The filtrate was concentrated and the resulting residue was suspended in chloroform. The resulting suspension was filtered and the precipitate was dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (134 mg, 52.7percent).1H-NMR (DMSO-d6) delta; 1.45-1.58 (m, 2H), 1.76-1.80 (m, 2H), 2.58 (s, 3H), 3.33-3.42 (m, 2H), 3.84-4.03 (m, 3H), 7.29 (d, J=8.6Hz, 1H), 7.35 (d, J=8.6Hz, 1H), 8.13 (d, J=7.9Hz, 1H), 8.19 (d, J=0.9Hz, 1H), 13.11 (br, 1H).
  • 2
  • 6-methyl-1H-indazole-5-carboxylic acid [ No CAS ]
  • [ 33024-60-1 ]
  • 6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); Tetrahydro-2H-pyran-4-ylamine monohydrochloride (0.0402 g, 0.292 mmol), triethylamine (0.07 ml, 0.5 mmol), 1-hydroxybenztriazole (0.0460 g, 0.340 mmol) and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (0.0606 g, 0.316 mmol) were added to a solution of 6-methyl-1H-indazole-5-carboxylic acid (0.0437 g, 0.248 mmol) in N,N-dimethylformamide (2 ml) and stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform (x 3), and the extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by replacement with toluene (three times), whereby a solid was precipitated. The solid obtained was suspended in ethyl acetate and stirred to be washed, and then it was collected by filtration and dried under reduced pressure to obtain 6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (0.0587 g, 91percent).1H-NMR (DMSO-d6) delta; 1.46-1.58 (2H, m), 1.75-1.82 (2H, m), 2.44 (3H, s), 3.39 (2H, td, J=1.9, 11.6Hz), 3.83-3.90 (2H, m), 3.91-4.02 (1H, m), 7.35 (1H, m), 7.73 (1H, s), 8.06 (1H, s), 8.23 (1H, d, J=7.7Hz), 13.01 (1H, br).
  • 3
  • (2R,3R,4R,5R)-4-(acetoxy)-2-(6-chloro-9H-purin-9-yl)-5-(prop-2-ynyl)tetrahydrofuran-3-yl acetate [ No CAS ]
  • [ 33024-60-1 ]
  • C21H25N5O6 [ No CAS ]
  • [ 674367-58-9 ]
YieldReaction ConditionsOperation in experiment
12%; 36% With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 2.5h; Intermediate [II] (43mg, 0. [114MMOL)] was reacted with 4-amino-tetrahydropyran hydrochloride salt (31 mg, 0. [23MMOL)] according to general procedure C (0. [45MMOL] DIPEA in isopropanol, heated for 2.5hours). Purification by preparative HPLC gave the desired product (purine N-9 linked to the 1-position of ribose) as a yellow gum, [(18MG,] 0.041 mmol, 36percent). m/z 444 [(MH +),] LCMS retention time 2.64min. The isomeric product (purine [N-7-LINKED)] was also obtained as a gum, (6mg, 0. [014MMOL,] 12percent). m/z 444 (MH +), LCMS retention time 2.52min.
  • 4
  • [ 674367-27-2 ]
  • [ 33024-60-1 ]
  • [ 674367-41-0 ]
YieldReaction ConditionsOperation in experiment
79% With N-ethyl-N,N-diisopropylamine; In propanal, 2-; at 90℃; for 6h; Intermediate I (459mg, 1. [3MMOL),] [DIPEA] (1. [1 ML)] and 4-aminotetrahydropyran hydrochloride (219mg, 1. [6MMOL)] were heated in 2-propanal in a reacti-vial at [90°C] for 6 hours. The mixture was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, dried [(NA2SO4),] filtered and evaporated. The residue was purified by chromatography on silica using [BIOTAGENo., ]with cyclohexane containing ethyl acetate (60-80percent) as eluant, to give the desired intermediate (427mg, 79percent) as a white solid. LC/MS R5 2.70 min, mass spectrum [M/Z 430 [MH+].] An ice cold mixture of TFA-water (9: 1) (5mL) was added to the acetonide derivative (427mg, [1.] [OMMOL).] The mixture was left to stand at [0°C] overnight (17 hours) then added dropwise to a saturated solution of sodium bicarbonate, and extracted with ethyl acetate, dried [(NA2SO4),] filtered and evaporated. The residue was purified by chromatography on silica using [BIOTAGE,] with ethyl acetate containing ethanol (0-10percent) as eluant, to give the title compound (104mg, 27percent). 'H [NMR No. ] (DMSO) 1.56-1. 90 [(4H,] m), 3.36-3. 46 (2H, m), 3.49 [(1 H,] t), 3.63 [(1 H,] dd), 3.73 (1H, dd), 3.85-3. 94 (2H, m), 4.01-4. 07 (1H, m), 4.12-4. 17 (1H, m), 4.20 (2H, s), 4.26-4. 41 [(1 H,] m), 4.54-4. 62 (1H, m), 5.31 [(1 H,] d, OH), 5.52 (1H, d, OH), 5.91 (1H, d), 7.79 (1H, br. s, NH), 8.23 [(1 H,] s), 8.33 [(1 H,] s).
  • 5
  • [ 675111-72-5 ]
  • [ 33024-60-1 ]
  • N-benzyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 16h; Intermediate 17 (0. 031g, 0.1 mmol) was dissolved in acetonitrile (lml). [4-AMINOTETRAHYDROPYRAN HYDROCHLORIDE] (Intermediate 8A, [0.] [015G,] 0.11 mmol) and N, N- diisopropylethylamine (0. [08ML,] 0.5 mmol) were added and the mixture stirred under nitrogen at [85°C] for 16h, then concentrated in vacuo. The residue was partitioned between dichloromethane (DCM) and water. The layers were separated and the organic layer was concentrated in vacuo to afford Example 21 (0.027g). LCMS showed [MH+ =] [380] ; [TRET = 2. 92 MIN.]
  • 6
  • [ 33024-60-1 ]
  • [ 30720-25-3 ]
  • [ 675112-01-3 ]
YieldReaction ConditionsOperation in experiment
Intermediate 1 (2. [5G)] was dissolved in acetonitrile [(15ML).] 4-Aminotetrahydropyran hydrochloride [(1.] [LG)] and N, N-diisopropylethylamine (9. [4ML)] were added and the mixture stirred under nitrogen at [85°C] for 16h. A trace of starting material remained, so an additional portion of 4-aminotetrahydropyran hydrochloride [(O.] [L] lg) was added and stirring continued at [85°C] for a further [16H.] The mixture was then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was washed with further water [(2X20ML)] then dried [(NA2S04)] and concentrated in vacuo. The residue was further purified by chromatography using Biotage (silica, 90g), eluting with cyclohexane: ethyl acetate to afford Example 3 (2.45g). LCMS showed MH+ [= 319] ; TRET = 2. [90MIN.]
  • 7
  • [ 33024-60-1 ]
  • [ 41095-07-2 ]
  • [ 675114-55-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 24h;Product distribution / selectivity; Alternative preparation of ethyl 1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H- pyrazolo[3,4-b]pyridine-5-carboxylate: 4-Aminotetrahydro-2/-/-pyran hydrochloride (e.g. see Intermediate 8A of WO 2004/024728 A2, 0.413g, 3.0mmol) is added to a mixture of ethyl 4-chloro-1-ethyl-6- methyl-1/-/-pyrazolo[3,4-]pyhdine-5-carboxylate (0.268g, LOmmol) and DIPEA (0.87ml, delta.Ommol) in MeCN (3ml). The resulting mixture is heated at 85 0C for 24 hours.Volatiles are removed in vacuo and the residue is dissolved in chloroform (1.5ml) and applied to a SPE cartridge (silica, 5g). The cartridge is eluted successively with Et2O, EtOAc and EtOAc-MeOH (9:1). Fractions containing the desired product (which might be contaminated with starting material) are combined and concentrated in vacuo. Further purification using a SPE cartridge (silica, 5g) eluting with EtOAc-cyclohexane (1 :3) affords ethyl 1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1/-/-pyrazolo[3,4- ]pyridine-5-carboxylate.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 24h; 4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0. [413G,] 3. 0mmol) was added to a mixture of Intermediate 51 (0.268g, [L.] Ommol) and N, N-diisopropylethylamine (0. [87ML,] [5.] [0MMOL)] in acetonitrile (3ml). The resulting mixture was heated at [85 °C FOR] 24 hours. Volatiles were removed in vacuo and the residue was dissolved in chloroform (1. [5ML)] and applied to a SPE cartridge (silica, 5g). The cartridge was eluted successively with [ET20,] EtOAc and EtOAc-MeOH (9/1). Fractions containing the desired product were combined and concentrated in vacuo to give the desired product contaminated with starting material (Intermediate [51).] Further purification using a SPE cartridge (silica, 5g) eluting with ethyl acetate-cyclohexane (1/3) afforded Example 189 (0.248g). LCMS showed [MH+ =] 333; [TRET] = 2.75min.
  • 8
  • [ 675112-44-4 ]
  • [ 33024-60-1 ]
YieldReaction ConditionsOperation in experiment
N, N-dibenzyltetrahydro-2H-pyran-4-amine (20. [5G)] was dissolved in ethanol [(210ML)] and hydrogenated over 10percent palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture was filtered and the filtrate was adjusted to pH 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gave a solid which was triturated with diethyl ether to give the product as a white solid (9. [23G). 1H] NMR [(400MHZ] in d6-DMSO, [27°C,] [SPPRN)] 8.24 (br. s, 3H), 3.86 (dd, 12,4Hz, 2H), 3.31 (dt, 2, [12HZ,] 2H), 3.20 (m, 1H), 1.84 (m, 2H), 1.55 (dq, 4, [12HZ,] 2H).
N,N-dibenzyltetrahydro-2H-pyran-4-amine (20.5 g) is dissolved in ethanol (210 ml) and hydrogenated over 10percent palladium on carbon catalyst (4 g) at 100 psi for 72 h at room temperature. The reaction mixture is filtered and the filtrate is adjusted to pH 1 with 2M-hydrogen chloride in diethyl ether. Evaporation of solvents gives a residue (which may be a solid) which is triturated with diethyl ether to give the product (which may be a solid).
Step 2: Tetrahydro-2H-pyran-4-amine hydrochloridelambda/,lambda/-dibenzyltetrahydro-2H-pyran-4-amine (20.5g) is dissolved in ethanol (210ml) and hydrogenated over 10percent palladium on carbon catalyst (4g) at 100 psi for 72h at room temperature. The reaction mixture is filtered and the filtrate is adjusted to pH 1 with 2M- hydrogen chloride in diethyl ether. Evaporation of solvents gives a residue (which may be a solid) which is triturated with diethyl ether to give the product (which may be a solid).
  • 9
  • [ 299901-56-7 ]
  • [ 33024-60-1 ]
  • C22H30N4O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
A DMF (12 ml) solution of the compound of Reference Example 3 (340 mg) was mixed with tetrahydropyran-4-ylamine hydrochloride (367 mg) and potassium carbonate (672 mg), and the mixture was stirred in an oil bath of 50°C for 36 hours. After completion of the reaction, the reaction mixture was mixed with water and extracted with ethyl acetate. The insoluble matter was filtered, and the water layer was extracted with ethyl acetate. The organic layer was washed with water and then extracted with 1 M hydrochloric acid aqueous solution. The water layer was washed with chloroform, and then the water layer was adjusted to basic (pH 9 - 11) with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting product was made into hydrochloride in the usual way and recrystallized from ethanol to obtain the title compound (77 mg).1H-NMR (DMSO-d6); 0.97 (s, 9 H), 1.71 (ddd, 2 H), 2.06 - 2.12 (m, 2 H), 3.27 - 3.38 (m, 3 H), 3.43 (br, 2 H), 3.47 (br, 3 H), 3.94 (dd, 2 H), 4.28 - 4.32 (m, 2 H), 7.66 (d, 1 H), 7.79 (d, 1 H), 8.24 (s, 1 H), 9.11 (s, 1 H), 9.32 - 9.54 (m, 2 H) MS (FAB +); 415 (M + 1).
  • 10
  • [ 33024-60-1 ]
  • (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-tetrahydro-2H-pyran-4-ylprop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
46.5% Example 71 (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-N-tetrahydro-2H-pyran-4-ylprop-2-enamide To a solution of (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propenoate (300 mg, 0.759 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0796 ml, 0.912 mmol), the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (184 mg, 1.51 mmol), triethylamine (0.560 ml, 4.01 mmol) and THF (3 ml), the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane and ethyl acetate. Yield (amount) 173 mg, yield (rate) 46.5percent 1H-NMR (CDCl3) delta: 1.26-1.62 (2H, m), 1.84-1.90 (2H, m), 2.57 (3H, s), 2.75 (3H, s), 3.38-3.49 (2H, m), 3.92-4.10 (3H, m), 5.54 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 15.8 Hz), 6.92 (1H, s), 7.20-7.45 (11H, m), 8.05 (1H, s). IR (KBr) cm-1; 3300, 2215, 1657, 1618, 1591, 1547, 1426, 1335, 912, 735, 698.
  • 11
  • [ 33024-60-1 ]
  • (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)prop-2-enamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
66.7% Example 79 (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (250 mg, 0.570 mmol) in THF (2.5 ml) were added DMF (0.025ml) and oxalylchloride (0.060 ml, 0.680 mmol), the mixture was stirred at room temperature for 1 hour and the solvent distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[33024-60-1]tetrahydro-2H-pyran-4-ylamine hydrochloride</strong> (136 mg, 1.13 mmol), triethylamine (0.472 ml, 3.39 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate. Yield (amount) 200 mg, yield (rate) 66.7percent 1H-NMR (CDCl3) delta: 1.43-1.58 (2H, m), 1.87-1.92 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.42-3.50 (2H, m), 3.94-4.05 (3H, m), 5.56 (1H, d, J = 7.8 Hz), 6.78 (1H, d, J = 15.3 Hz), 6.91-7.21 (9H, m), 7.43 (1H, d, J = 15.3 Hz), 7.92 (1H, s). IR (KBr) cm-1; 3277, 2924, 2216, 1661, 1607, 1549, 1510, 1231, 1161, 1013, 837, 801, 733.
  • 12
  • [ 29943-42-8 ]
  • [ 33024-60-1 ]
YieldReaction ConditionsOperation in experiment
With ammonium formate;palladium 10% on activated carbon; In methanol; water; at 20℃; Reference Example 17 Tetrahydro-2H-pyran-4-ylamine hydrochloride To a solution of tetrahydro-4H-pyran-4-one (4.30 g, 43.0 mmol) in methanol (112 ml) was added an aqueous solution (12.5 ml) of ammonium formate (25 g, 400 mmol). Insolubles were completely dissolved and then 10percent palladium carbon (5.1 g) was added thereto, which was stirred at room temperature overnight. After the insolubles were filtrated off to obtain a filtrate, which was concentrated, and to the residue was added ethanol (100 ml) and concentrated hydrochloric acid (7.5 ml). The solvent was distilled off under reduced pressure to give an objective product, which was collected by filtration and washed with ether. 1H-NMR (DMSO-d6) delta: 1.54-1.74 (2H, m), 1.82-1.98 (2H, m), 3.27-3.38 (3H, m), 3.87-3.94 (2H, m), 9.05 (3H, bs). IR (KBr) cm-1; 2966, 1377, 1163, 1088, 1015, 986, 862.
  • 13
  • [ 862997-24-8 ]
  • [ 33024-60-1 ]
  • C22H30F3N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 5; Intermediate 9 (192 mg, 0.538 mmol) was combined with 4-aminotetrahydropyran hydrochloride (81. 4 mg, 0.592 mmol) and diisopropylethylamine (113 VL, 0.946 mmol) in Ti (OiPr) 4 (3.5 mL). The resulting solution was stirred overnight at room temperature. Sodium borohydride (41 mg, 1.1 mmol) and methanol (2 mL) were added and the mixture was stirred at room temperature for 30 min. Water was added and the solid was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the crude product was extracted with EA (x3) and purified by preparative TLC (10percent MeOH/DCM) to give 12.5 mg of the title compound.
  • 14
  • [ 862997-48-6 ]
  • [ 33024-60-1 ]
  • C27H37F6N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Molecular sieve; Step D; To a mixture of the compound described in Step C, Example 2 (240 mg, 0.455 mmol), 4- amino tetrahydrofuran HC1 salt (63 mg, 0.455 mmol), molecular sieve (9i, 200 mg), DIEA (7011L, 0.455 mmol) in DCM (15 mL), was added sodium triacetoxyborohydride (482 mg, 2.275 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction was diluted with DCM, filtered through celite, and evaporated i7l vacuo. The residue was purified by preparative TLC (1000 micron, eluant: 6percent MeOH : 94percent DCM) to afford two separate single isomers (isomer 1, less polar, 75 mg, 28percent ; isomer 2, more polar, 58 mg, 22percent).
  • 15
  • [ 38041-19-9 ]
  • [ 33024-60-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; butan-1-ol;Product distribution / selectivity; To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 30.0 g (158.7 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 3.0 g (0.70 mmol calculated as palladium atom) of 5percent by weight palladium/carbon (50percent wet product) and 150 ml of ethanol, and the mixture was reacted at 75°C for 24 hours under hydrogen atmosphere (0.1 MPa. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 15.9 g (Reaction yield: 72percent) of 4-aminotetrahydropyran was found to be formed. Then, 200 ml of n-butyl alcohol and 17.4 g (166.8 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the mixture was concentrated under reduced pressure to obtain 14.3 g (Isolation yield: 65percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).; To a flask having an inner volume of 100 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.0 g (5.55 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesized in the same manner as in Example 2(1), 6.2 ml of ethanol, 1.2 ml (1.20 mmol) of 1 mol/l aqueous sodium hydroxide solution and 1.5 g (10 mmol) of copper (I) oxide, and the mixture was reacted at 65°C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. When the concentrate was analyzed (internal standard method) by gas chromatography, 0.47 g (Reaction yield: 50percent) of 4-aminotetrahydropyran was found to be formed. Then, 5 ml of n-butyl alcohol and 10 ml (12.0 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the resulting mixture was concentrated under reduced pressure to obtain 0.42 g (Isolation yield: 45percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).
With hydrogenchloride; In water;Industry scale;Product distribution / selectivity; To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 5873 g (115 mol) of 98percent aqueous hydrazine solution and 2072 ml of ethanol, and the mixture was heated to 75°C with stirring. Then, a solution in which 2136 g (11.5 mol) of tetrahydropyranyl-4-methanesulfonate with a purity of 70percent had been dissolved in 2072 ml of ethanol was gradually added dropwise to the mixture, and the mixture was reacted at the same temperature for 4 hours with stirring. After completion of the reaction, the mixture was cooled to room temperature to obtain a reaction mixture comprising 4-hydrazinotetrahydropyran as a main product. Then, to a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 414.4 g (4.6 mol calculated as nickel atom) of 65percent by weight developed Raney nickel and 2072 ml of water, and the mixture was heated up to 60°C with stirring. Then, the reaction mixture was gradually added dropwise, and the resulting mixture was reacted at 80°C for 2 hours with stirring. After completion of the reaction, the reaction mixture was cooled up to 40°C, Raney nickel was filtered off, and the filtrate was concentrated under reduced pressure to obtain 818.0 g of the reaction solution containing 4-aminotetrahydropyran as a main product. To a flask having an inner volume of 20 L, made of glass and equipped with a stirring device, a thermometer, a dropping funnel, a reflux condenser and a distillation device under reduced pressure were charged the above reaction solution, 2072 ml (10.9 mol) of tetraethylenepentamine and 4100 ml of n-butyl alcohol, and the mixture was stirred at 80°C for 2 hours under reduced pressure. Then, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Thereafter, 4100 ml of n-butyl alcohol was added again, 4-aminotetrahydropyran and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. This operation was repeated to three times to obtain 15000 ml of a distilled solution in total. To the distilled solution was added 575 ml (6.90 mol) of conc. hydrochloric acid, and then, the mixture was concentrated under reduced pressure. To the concentrate was again added 8200 ml of n-butyl alcohol, and water and n-butyl alcohol were removed by azeotropic distillation under reduced pressure. Then, 7460 ml of n-butyl alcohol and 3730 ml of ethanol were added to the residue, and the resulting mixture was once heated up to 115°C and stirred, then, it was gradually cooled to -5°C and stirred for 30 minutes. After the filtration, the filtrate was washed with cooled toluene and dried to obtain 788.9 g (Isolation yield based on tetrahydropyranyl-4-methanesulfonate: 50percent) of 4-aminotetrahydropyran hydrochloride with a purity of 99percent (internal standard method by gas chromatography) as white needle-like crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride were the same as those in Example 2(2).
  • 16
  • 1-(tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride [ No CAS ]
  • [ 33024-60-1 ]
YieldReaction ConditionsOperation in experiment
To a flask having an inner volume of 500 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 60.0 g (392 mmol) of 4-hydrazinotetrahydropyran hydrochloride with a purity of 99percent and synthesised in the same manner as in the above-mentioned (1), 12.0 g of a developed Raney nickel, 120 ml of ethanol and 120 ml of water, and the mixture was reacted at 75°C for 24 hours under hydrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Then, 200 ml of n-butyl alcohol and 50 ml (600 mmol) of 12 mol/l hydrochloric acid were added to the concentrate, and the mixture was concentrated under reduced pressure to obtain 38.5 g (Isolation yield: 70percent) of 4-aminotetrahydropyran hydrochloride with a purity of 98percent (areal percentage by gas chromatography) as white crystals. Physical properties of the 4-aminotetrahydropyran hydrochloride are as follows. CI-MS(m/e); 102 (M+1-HCl) 1H-NMR (DMSO-d6, delta (ppm)); 1.52 to 1.66 (2H, m), 1.84 to 1.90 (2H, m), 3.15 to 3.45 (3H, m), 3.84 to 3.89 (2H, m), 8.38 (3H, brs)
  • 17
  • benzoic acid 3R,4R-bis-benzoyloxy-5R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-2R-yl ester [ No CAS ]
  • [ 6192-52-5 ]
  • [ 33024-60-1 ]
  • [ 77-76-9 ]
  • {2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; N-ethyl-N,N-diisopropylamine; In methanol; isopropyl alcohol; acetone; {2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol A mixture of benzoic acid 3R,4R-bis-benzoyloxy-5R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-2R-yl ester (8.25 g), tetrahydro-pyran-4-ylamine hydrochloride (1.92 g) and diisopropylethylamine (5.5 ml) in isopropanol (100 ml) was stirred under reflux, under nitrogen for 1.5 h. The solution was concentrated in vacuo and the residue was treated with potassium carbonate (4.5 g) in methanol (150 ml). After 24 h at 21° C. more potassium carbonate (4.5 g) was added and stirring was continued at 21° C. for 64 h. The solvent was evaporated in vacuo and the residue was absorbed on silica prior to purification by flash chromatography (250 g), with dichloromethane:methanol:ammonia (90:10:1) eluant to give an off-white foam (3.7 g). This material was dissolved in acetone (60 ml) and treated with para-toluenesulphonic acid monohydrate (2.0 g) and 2,2-dimethoxypropane (6 ml) and the resulting mixture was stirred at 22° C. overnight. The white suspension was concentrated in vacuo and the residue was partitioned between 8percent aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to a foam which was purified by flash chromatography over silica (100 g) with ethyl acetate eluant to give the title compound as a colourless foam (3.49 g). TLC Silica (ethyl acetate) Rf=0.23.
  • 18
  • methanolic ammonia [ No CAS ]
  • acetic acid 4R-acetoxy-2R-(6-chloro-purin-9-yl)-5R-trifluoromethoxymethyl-tetrahydro-furan-3R-yl ester [ No CAS ]
  • [ 33024-60-1 ]
  • [ 223761-50-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; EXAMPLE 1 N-(Tetrahydro-pyran-4-yl)-5'-O-trifluoromethyladenosine Acetic acid 4R-acetoxy-2R-(6-chloro-purin-9-yl)-5R-trifluoromethoxymethyl-tetrahydro-furan-3R-yl ester (170 mg), was heated under reflux with tetrahydro-pyran-4-ylamine hydrochloride (235 mg) and diisopropylethylamine (0.35 ml) in isopropanol (8 ml) for 20 h. After cooling, the solvent was removed in vacuo and saturated methanolic ammonia (15 ml) added and the solution allowed to stand at 22° C. for 3 h. The solvent was evaporated in vacuo and the crude product which was triturated with ether (6 ml) to afford the title compound as a colourless powder (96 mg). Mass spectrum m/z 420 (MH+); Microanalysis Found: C,45.7; H,4.9; N,16.3. C16H20F3N5O5 requires C,45.8; H,4.8; N,16.7percent.
  • 19
  • {2,2-dimethyl-6R-[6-chloro-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]
  • [ 33024-60-1 ]
  • {2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3AR,6AR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In methanol; isopropyl alcohol; {2,2-Dimethyl-6R-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol A solution of {2,2-dimethyl-6R-[6-chloro-purin-9-yl]-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol (2.00 g), tetrahydro-pyran-4-ylamine hydrochloride (926 mg) and diisopropylethylamine (2.67 ml) in propan-2-ol (15 ml) was heated under reflux under nitrogen for 24 h and left to cool to room temperature. The amber solution was concentrated under vacuum to give a brown oil which was purified by flash chromatography over silica (115 g) with ethyl acetate:methanol (195:5) eluant. This afforded the title compound as a white foam (2.2 g). TLC SiO2 (Methanol:ethyl acetate 5:195), Rf=0.30.
  • 20
  • [ 61128-73-2 ]
  • aluminum nickel [ No CAS ]
  • [ 33024-60-1 ]
YieldReaction ConditionsOperation in experiment
89% With hydrogenchloride; In 1,4-dioxane; methanol; ethanol; Step 2. Preparation of perhydro-2H-pyran-4-ylamine Hydrochloride. A mixture of 4-(hydroxyimino)-3,5,6-trihydro-2H-pyran (43.4 mmol) and Raney Nickel (200 mg) in ethanol was hydrogenated (90 psi) at room temperature for 3 days. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated. The residue was dissolved in MeOH, and treated with HCl (4 N in dioxane, 60 mmol), and concentrated to give perhydro-2H-pyran-4-ylamine hydrochloride (89percent).
  • 21
  • [ 253126-77-1 ]
  • [ 33024-60-1 ]
  • [ 7087-68-5 ]
  • (2R,3R,4S,5R)-2-(2H-Pyrazol-3-yl)-5-(6-tetrahydro-pyran-4-ylamino-purin-9yl)-tetrahydro-furan-3,4-diol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In methanol; dichloromethane; isopropyl alcohol; EXAMPLE 29 (2R,3R,4S,5R)-2-(2H-Pyrazol-3-yl)-5-(6-tetrahydro-pyran-4-ylamino-purin-9yl)-tetrahydro-furan-3,4-diol (2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furan-3,4-diol (35 mg) was dissolved in isopropanol (3 ml), N,N-di-isopropylethylamine (0.12 ml) and tetrahydro-pyran-4-ylamine hydrochloride (46 mg) were added, and the resulting solution was heated under reflux under nitrogen for 17 h. The solvent was removed in vacuo, the residue dissolved in methanol (10 ml), and 8percent sodium bicarbonate (3 ml) added, followed by silica gel (3 g). The solvents were removed in vacuo and the residue added to a flash column of silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4:1) afforded the title compound as a clear viscous gum (5.2 mg). LCMS (system A) Rt=3.34 min. Mass spectrum m/z 388 (MH+)
  • 22
  • [ 3056-18-6 ]
  • [ 96042-30-7 ]
  • [ 33024-60-1 ]
  • [ 253126-46-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In methanol; ethanol; isopropyl alcohol; 2-Chloro-N-(tetrahydro-pyran-4-yl)-adenosine A mixture of acetic acid 4R-acetoxy-5R-acetoxymethyl-2R-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3R-yl ester (10 g), diisopropylethylamine (5.7 ml), and 4-amino tetrahydropyran hydrochloride (2.02 g), in isopropanol (200 ml) was heated at 50° for 4 h. The cooled mixture was evaporated in vacuo, the residue re-dissolved in methanol (200 ml) and ammonia gas bubbled through the solution for 2 h. The mixture was stirred at 22° C. overnight, and evaporated in vacuo to give a brown oily solid. Purification by flash chromatography on silica gel (Merck 9385), eluding with 75:8:1 DCM:EtOH:880 NH3 to 50:8:1 DCM:EtOH:880NH3, gave the title compound as a pale brown oily solid (7.81 g). LC/MS (System B) Rt 2.24 min. Mass spectrum m/z 3.86 [MH+].
  • 23
  • methanolic ammonia [ No CAS ]
  • Acetic acid 4S-acetoxy-2R-(2,6-dichloro-purin-9-yl)-5S-fluoromethyl-tetrahydro-furan-3R-yl ester [ No CAS ]
  • [ 33024-60-1 ]
  • [ 223774-69-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; EXAMPLE 3 2-Chloro-5'-deoxy-5'-fluoro-N-(tetrahydro-pyran-4-yl)-adenosine Acetic acid 4S-acetoxy-2R-(2,6-dichloro-purin-9-yl)-5S-fluoromethyl-tetrahydro-furan-3R-yl ester (50 mg) was heated at 55-58° C. with 4-aminotetrahydropyran hydrochloride (33 mg) and diisopropylethylamine (0.125 ml) in isopropanol (5 ml) for 21 h. On cooling to room temperature, methanolic ammonia (4 ml) was added, and the mixture was allowed to stand at room temperature (22° C.) overnight (16 h). The mixture was evaporated to dryness in vacuo to give the crude product which was purified by solid phase extraction (5 g, Varian Mega Bondelut cartridge, aminopropyl bonded phase, eluding with (i) CHCl3, (ii) acetone, to give the title compound (47 mg).
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