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CAS No. : | 285-69-8 | MDL No. : | MFCD00800639 |
Formula : | C4H6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AIUTZIYTEUMXGG-UHFFFAOYSA-N |
M.W : | 86.09 | Pubchem ID : | 67511 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 19.28 |
TPSA : | 21.76 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.1 cm/s |
Log Po/w (iLOGP) : | 1.42 |
Log Po/w (XLOGP3) : | -0.39 |
Log Po/w (WLOGP) : | -0.22 |
Log Po/w (MLOGP) : | -0.57 |
Log Po/w (SILICOS-IT) : | 1.41 |
Consensus Log Po/w : | 0.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.13 |
Solubility : | 64.1 mg/ml ; 0.745 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.4 |
Solubility : | 215.0 mg/ml ; 2.49 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.1 |
Solubility : | 109.0 mg/ml ; 1.27 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.49 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P280-P370+P378-P303+P361+P353-P403+P235 | UN#: | 1993 |
Hazard Statements: | H225 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran at 0 - 20℃; | Step 1 : To the solution of 24a (5.04g, 0.072mol) in 15OmL of DCM was added 85percent mCPBA(18.86g, 0.093mol) at O0C using ice-water bath. The mixture was stirred over weekend at r.t. and the precipitate was filtered off. The filtrated was washed successfully with saturated aqueous NaH CO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of white solid and yellow oil (5.24g, 84.6percent). |
84.6% | With mCPHA In dichloromethane at 0 - 20℃; | Example 24 Preparation of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-tetrahydro-furan-3-yl)-amide Preparation of 4-Amino-tetrahydro-furan-3-ol Step 1: To the solution of 24a (5.04 g, 0.072 mol) in 150 mL of DCM was added 85percent mCPHA(18.86 g, 0.093mol) at 0° C. using ice-water bath. The mixture was stirred over weekend at r.t. and the precipitate was filtered off. The filtrated was washed successfully with saturated aqueous NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of white solid and yellow oil (5.24 g, 84.6percent). |
66% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 48 h; | 2,4-Dihydrofuran (7) (5.3 mL, 71.3 mmol) was added to a 500 mL round bottom flask containing CH2Cl2 (250 mL). mCPBA was added and the solution stirred at ambient temperature for two days. The solution was washed twice with aqueous Na2S2O3, then sat. Na2CO3 and dried over Na2SO4. The organic layer was then concentrated to afford the epoxide as a colorless oil (3.7 g, 66percent). |
57% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 15 h; Reflux | To a solution of 2,5-dihydrofuran SM 1 (5.0 g, 71 mmol) in DCM (100 mL) was added mCPBA (18.9 g, 109 mmol) at 0 °C, then the reaction mixture was stirred at reflux for 15 h. Quenched with water and extracted with EtOAc, dried and evaporated to give compound 1 (3.5 g, 57percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With ammonium hydroxide In isopropyl alcohol at 80℃; for 15 h; | To a solution of compound 1 (0.3 g, 3.5 mmol) in isopropanol (5 mL) and ammonium hydroxide (10 mL) was stirred at 80 °C for 15 h. Quenched with water and extracted with EtOAc, dried and evaporated to give compound 2 (0.36 g, 100percent). LC-MS: m/z = 104.0 [M+H] |
96.8% | With ammonia; water In isopropyl alcohol at 80℃; for 18 h; | Step 2: A mixture of crude 24b (300mg, 3.49mmol) obtained from last step, i- PrOH (3mL) and 26percent NH4OH (1OmL) was heated at a sealed tube at 800C for 18hs. A small amount of solid was filtered off and the filtrate was evaporated to give the crude 24c (0.348g, 96.8percent). |
96.8% | With ammonia In water; isopropyl alcohol at 80℃; for 18 h; | Step 2: A mixture of crude 24b (300 mg, 3.49 mmol) obtained from last step, i-PrOH (3 mL) and 26percent NH4OH (10 mL) was heated at a sealed tube at 80° C. for 18 hs. A small amount of solid was filtered off and the filtrate was evaporated to give the crude 24c (0.348 g, 96.8percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With 3-chloro-benzenecarboperoxoic acid; In tetrahydrofuran; at 0 - 20℃; | Step 1 : To the solution of 24a (5.04g, 0.072mol) in 15OmL of DCM was added 85% mCPBA(18.86g, 0.093mol) at O0C using ice-water bath. The mixture was stirred over weekend at r.t. and the precipitate was filtered off. The filtrated was washed successfully with saturated aqueous NaH CO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of white solid and yellow oil (5.24g, 84.6%). |
84.6% | With mCPHA; In dichloromethane; at 0 - 20℃; | Example 24 Preparation of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-tetrahydro-furan-3-yl)-amide Preparation of 4-Amino-tetrahydro-furan-3-ol Step 1: To the solution of 24a (5.04 g, 0.072 mol) in 150 mL of DCM was added 85% mCPHA(18.86 g, 0.093mol) at 0 C. using ice-water bath. The mixture was stirred over weekend at r.t. and the precipitate was filtered off. The filtrated was washed successfully with saturated aqueous NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of white solid and yellow oil (5.24 g, 84.6%). |
71% | a) Preparation of 3,4-epoxytetrahydrofuran The title product is obtained from 58 g (0.83 mol) of 2,5-dihydrofuran, which is available commercially from Aldrich Chimie (Strasbourg), according to the method described in Journal of Pharmaceutical Sciences 59 (1970) 1676-1679. Mass obtained: 54 g. Yield: 71%. |
66% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 48h; | 2,4-Dihydrofuran (7) (5.3 mL, 71.3 mmol) was added to a 500 mL round bottom flask containing CH2Cl2 (250 mL). mCPBA was added and the solution stirred at ambient temperature for two days. The solution was washed twice with aqueous Na2S2O3, then sat. Na2CO3 and dried over Na2SO4. The organic layer was then concentrated to afford the epoxide as a colorless oil (3.7 g, 66%). |
57% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0℃; for 15h;Reflux; | To a solution of 2,5-dihydrofuran SM 1 (5.0 g, 71 mmol) in DCM (100 mL) was added mCPBA (18.9 g, 109 mmol) at 0 C, then the reaction mixture was stirred at reflux for 15 h. Quenched with water and extracted with EtOAc, dried and evaporated to give compound 1 (3.5 g, 57%). |
49.4% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 14h; | 2,5-dihydrofuran (80.00 g, 1.14 mol, 86.02 ml) was dissolved in 1000 ml dichloromethane, into which was thenadded m-chloroperoxybenzoic acid (277.74 g, 1.37 mol) batchwise, and the mixture was reacted at room temperaturefor 14 h. When TLC detected that the reaction has been completed, the solid was filtered off, the filtrate was washedwith a saturated solution of sodium sulfite until the starch-KI paper didn?t become blue anymore, and then washed witha saturated solution of sodium bicarbonate until the PH of the solution =7~8. The organic phase was dried over anhydroussodium sulfate, filtered and the solvent was removed by rotatory evaporation to give 48.50 g yellow product Example19A without being further purified, with a yield of 49.4%. 1HNMR (400 MHz, CHLOROFORM-d) delta 3.99 (d, J=10.29 Hz, 2H), 3.77 (s, 2H), 3.63 (d, J=10.54 Hz, 2H). |
With m-chloroperoxybenzoic acid; In dichloromethane; | EXAMPLE 44 3,6-dioxabicyclo[3.1.0]hexane (44) STR60 To a stirred mixture of 13.1 g (188 mmoles) of 2,5-dihydrofuran and 450 ml of dichloromethane was added 38.2 g (221 mmoles) of m-chloroperoxybenzoic acid. After stirring for 20 hours, the mixture was filtered and the separated solid washed with dichloromethane. The filtrate was washed with saturated aqueous sodium bicarbonate containing Na2 S2 O3 and then saturated aqueous sodium carbonate, and dried over sodium sulfate. The mixture was filtered and evaporated. Distillation of the residue first at atmospheric pressure and then under vacuum gave 6.7 g of the title compound as a liquid, b.p. 40-45 C. (15 mm). The structure was supported by 1 H NMR. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; | EXAMPLE 196 3,6-Dioxabicyclo[3.1.0]hexane A 0 C. solution, under argon, of 5 g of 2,5-dihydrofuran in 85 ml of methylene chloride is treated with 13.54 g of 85% m-chloroperbenzoic acid. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is filtered and the filtrate stirred for 10 minutes with saturated sodium carbonate and the two layers separated. The organic layer is dried and concentrated in vacuo to give an oil. The oil is distilled under vacuum (water aspirator) to give 3.93 g of the desired epoxide. 1 H NMR(CDCl3): delta4.03(d,2H,J=10.5 Hz); 3.81(s,2H); 3.66(d,2H,J=10.5 Hz). MS(CI):m/z 87(M+ +H). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Step 1To a stirred solution of 3,4-dihydro-2H-Pyrane [99] (5.0 g, 72 mmol) in DCM (150 ml), m- CPBA (18.86 g, 93 mmol) was added portionwise under stirring at 0 C. The resulting white precipitate was stirred at RT for 72 h. The progress of the reaction was monitored by TLC. After 72 h, the precipitate was removed by filtration, and the organic layer was washed with saturated aqueous Na2S203 (100 ml x 2) followed by saturated aqueous NaHC03 solution (100 ml x 1). The DCM layer was dried over anhydrous Na2S04, evapourated to yield 3,6- dioxabicyclo[3.1.0]hexane [100] as a colorless gel (2.80 g, 43%) and used directly in the next step. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 48h; | Step 6) 3,6-dioxabicyclor3.1.01hexane [0173] To a solution of 2,5-dihydrofuran(5.3 niL, 71.3 mmol) in DCM (250 mL) was added m-CPBA (24.6 g,142.6 mmol). The reaction was stirred at rt for 48 h, then filtered through a pad of Celite, which was washed with DCM (50 mL). The filtrate was washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo to afford crude product as colorless oil (4.12 g, 67%). GC-MS m/z:86 (M); NMR (400 MHz, CDC13) delta (ppm): 3.65-3.65 (d, J= 10.5 Hz,2H), 3.80 (s, 2H), 4.02-4.04 (d, J= 10.5 Hz, 2H). | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 12h; | m-CPBA (88 g, 509.95 mmol, 1.20 equiv) was added in several batches into a solution of 2,5- dihydrofuran (30 g, 428.02 mmol, 1.00 equiv) in dichloromethane (300 mL) at --0C. After 12 h at room temperature the resulting solution was diluted with saturated Na2SO3 and stirred for 0.5 h at room temperature. The resulting mixture was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum at low temperature. This resulted in the title compound (30 g, crude) as colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-methylene-tetrahydro-furan-3-ol (61 ) is prepared from a starting compound 3,6-Dioxa- bicyclo[3.1.0]hexane (60) as shown in Figure I E. It is used in a Mitsunobu type reaction with p-CN- phenol (50) to form compound 62. Dihydroxylation with OsO4, followed by oxidation with NaClO4 in the presence of TEMPO radical (2,2,6,6-tetramethylpiperidinyloxy) forms acid 64. Compound 64 <n="140"/>using thionyl chloride and 4-cyano-3-trifluoromethyl-aniline yields compound XXl, as presented inFigure IE. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonium hydroxide; In ethanol; dichloromethane; | Preparation of (+-)-trans-4-[4-(4-chlorobenzyl)-piperazin-1-yl]-tetrahydrofuran-3-ol Following General Procedure A, 1-(4-chlorobenzyl)-piperazine (500 mg, 2.37 mmol) was alkylated with <strong>[285-69-8]3,6-dioxa-bicyclo[3.1.0]hexane</strong> (2.04 g, 23.7 mol) (Barili, P. L.; Berti, G.; Mastrorilli, E.; Tetrahedron 1993, 49, 6263) in EtOH (3 mL) at 90° C. for 2 d. Chromatography of the crude product with 100percent CH2Cl2 followed by 40:0.95:0.05-10:0.95:0.05 CH2Cl2:MeOH:NH4OH gave the product (615 mg, 87percent) as a yellow solid: MS m/z 297 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With ammonium chloride; In methanol; | a trans-4-Azido-3-hydroxy tetrahydrofuran 3,4-Epoxytetrahydrofuran (9 g, 105 mmol) was added to a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95percent, 200 ml). The reaction was heated to 75° C. and stirred for 20 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate, dried and evaporated under reduced pressure to afford the title compound as a colourless oil, 10 g, 74percent yield. 1 H NMR delta(CDCl3) 4.32 (m, 1H), 4.09 (dd, 1H, J=4.8, 9.9 Hz), 3.99 (dd, 1H, J=4.3, 10.1 Hz). 3.94 (m, 1H), 3.81 (dd, 1H, J=2.1, 9.9 Hz), 3.73 (dd, 1H, J=1.8, 10.1 Hz), 2.72 (d, 1H, J=4.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium azide; ammonium chloride; In methanol; water; at 75℃; for 20h; | NaN3 (11.2 g, 172 mmol) and NH4Cl (3.6 g, 64.5 mmol) were added to 80 mL 95percent MeOH in H2O and stirred until most dissolved. The above epoxide (3.7 g, 43 mmol) was added and the solution was heated at 75° C. for 20 h. It was then cooled to room temperature and filtered to remove excess NaN3. The filtrate was diluted with water and extracted four times with EtOAc, dried over Na2SO4, and concentrated to afford azido alcohol 8 as a tan oil (4.3 g, 78percent) |
74% | With ammonium chloride; In methanol; | a trans-3-azido-4-hydroxytetrahydrofuran <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (9 g, 105 mmol) was added to a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95percent, 200 mL). The reaction was heated to 75° C. and stirred for 20 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a colorless oil (10 g, 74percent). 1H NMR d (CDCl3) 4.32 (m, 1H), 4.09 (dd, 1H, J=4.8, 9.9 Hz), 3.99 (dd, 1H, J=4.3, 10.1 Hz), 3.94 (m, 1H), 3.81 (dd, IH, J =2.1, 9.9 Hz), 3.73 (dd, IH, J =1.8, 10.1 Hz), 2.72 (d, IH, J =4.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; water; | 6. N-(3,5-Dichloropyridin-4-yl)-3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzamide 400 mg (1.2 mmol) of N-(3,5-dichloropyridin-4-yl)-3-hydroxy-4-methoxybenzamide (starting compound A16) and 540 mg (3.85 mmol) of potassium carbonate are stirred under a nitrogen atmosphere at RT for 1 h in 5 ml of dimethylformamide. The mixture is heated to 120° C. and 115 mg (1.3 mmol) of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> are added to the reaction mixture 4*at an interval of 6 h in each case. The mixture is concentrated, 50 ml of water are added, it is acidified with 2 N HCl and extracted with 3*50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel [toluene/ethyl acetate=1:2]. The product-containing fractions are concentrated and the residue is crystallized from diethyl ether. 130 mg of the title compound of m.p. 183-185° C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; water; ethyl acetate; toluene; | 3-(4-Hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile 50 g (335 mmol) of 3-hydroxy-4-methoxybenzonitrile and 92 g (670 mmol) of potassium carbonate are suspended in 900 ml of dimethylformamide and the mixture is stirred at RT for 1 h. 32 g (368 mmol) of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> are then added dropwise and the mixture is stirred at 90° C. for 6 h. The solvent is evaporated in vacuo and the residue is partitioned between 500 ml of ethyl acetate and 500 ml of water. The phases are separated, the aqueous phase is extracted with 4*250 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is recrystallized in 400 ml of toluene. 62 g of the title compound of m.p. 147-149° C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With nitrogen; benzyl alcohol; | Example 2 To a flask fitted with a condenser and nitrogen inlet was added <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (20 g, 0.23 mol), isobutyronitrile (100 ml, 5 vol), benzyl alcohol (124 g, 1.15 mol, 5 eq.) and finally magnesium perchlorate (10.3 g, 0.046 mol, 0.2 eq). The solution was heated at 100° C. for 24 hours. After cooling to room temperature, the reaction was quenched with water (1000 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*400 mL). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-benzyloxy-4-hydroxytetrahydrofuran was isolated by column chromatography to give 29 g (66percent yield) of a clear colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.9% | With nitrogen; In dichloromethane; | Example 1 To a 10-L flask fitted with a double surface condenser, overhead stirrer and nitrogen inlet was added <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (750 g, 8.71 mol), dichloromethane (3750 ml, 5 vol) and allyl alcohol (2530 g, 43.56 mol, 5 eq.). The solution was cooled to between 0° and 5° C. and boron trifluoride diethyletherate (61.8 g, 0.436 mol, 0.05 eq.) was added dropwise whilst maintaining the temperature below 10° C. After addition was complete the solution was allowed to warm to room temperature at which point the reaction slowly exothermed to reflux. After 3 hours 1 H NMR analysis showed that no epoxide remained and the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The phases were separated and the organic phase was washed with a further portion of saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The combined aqueous washes were extracted with CH2 Cl2 (5*750 ml, 1 vol). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-allyloxy-4-hydroxytetrahydrofuran (I) was isolated by reduced pressure distillation (bp 94° C. at; 3 mbar) to give 1004.0 g (79.9percent yield) of a clear colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; | EXAMPLE 19 trans-4-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]tetrahydro-3-furanol (19) STR48 3,5-Bis(1,1-dimethylethyl)benzenethiol (0.0078 mole) and the title compound of Example 18 (0.0074 mole) are added to a degassed (Argon) solution of 50percent sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction is heated to reflux for 24 hours. The reaction is cooled to room temperature and poured into water (125 ml). The solution is made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts are dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator. The product is purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 197 trans-(+-)-Tetrahydro-4-hydroxy-3-furancarbonitrile To 5.0 g of product from Example 196 is added 29 ml of 1M diethylaluminum cyanide at room temperature. The reaction is exothermic. The mixture is stirred for 3 hours, quenched very carefully with ethyl alcohol, as the evolved gas is hydrogen cyanide, cooled to 0° C. and stirred until the reaction warms up to room temperature. The reaction is then flushed with argon for 10 minutes, concentrated in vacuo to about 15 ml, and filtered through a pad of diatomaceous earth. The pad is washed with methyl alcohol and diethyl ether. The combined organic layers are refiltered and concentrated in vacuo to give 0.383 g of the desired product. 1 H NMR(CDCl3): delta4.69(m,1H); 4.22(dd,1H,J=7.3 and 9.12 Hz); 4.05(m,2H); 3.8(dd,1H,J=2.71 and 10.11 Hz); 3.06(m,1H); 2.83(br s,1H,OH). MS(CI): m/z 114(M+ +H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 1 : frans-4-Phenyltetrahydro-3-furanol <n="25"/>Copper iodide (1.26g, 6.61 mmol), phenyl magnesium bromide (3M in Et2O, 31.5ml, 94.49mmol) and dry tetrahydrofuran (10ml) were placed in a flask under nitrogen atmosphere. The mixture was cooled to 00C and a solution of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (8.13g, 94.49mmol) in tetrahydrofuran (20ml) was added dropwise. The reaction was stirred for 3 hours, diluted with saturated solution of NH4CI and then extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated to dryness to give the title compound (16.32g) as crude material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With lithium perchlorate; In acetonitrile; at 20℃; for 3h; | Example 21; beta-toeaSjTaRVSetauoro-pyridin^-yl^-foeexahydro^^-dioxa-T-aza-inden- 7-yl)-3-methyl-3H-pyrimidin-4"one; (3RS. 4SR)-4-((lR)-l-Phenvl-ethvlamino)-tetrahvdro-furan-3-ol; To a solution of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (10 g, 116 mmol) and(i?)-phenylethylamine (14.8 ml, 116 mmol) in acetonitrile (100 ml), anhydrous lithium perchlorate (12.3 g, 116 mmol) was added at room temperature and the mixture was refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, the solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The flash silica gel column chromatography (eluent; 10percent methanol in chloroform) was performed to isolate (3RS, 4SR)-4-((lR)-l-phenyl-ethylamino)- tetrahydro-furan-3-ol (11 g, 53 mmol, 46 percent) as partially crystallized yellowish oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate A4: rra"s-4-pent-4-en-l-yltetrahvdrofuran-3-olTo a mixture of CuI (1.66 g, 8.71 mmol) in THF (100 mL) at -5°C, a 0.5M solution of bromo(pent-4-en-l-yl)magnesium (116 mL, 5.81 mmol) was added. The solution was stirred for 1 hour and cooled to -20°C. 3,6-Dioxabicyclo[3.1.0]hexane (5.0 g, 58.1 mmol) was added dropwise, and the reaction mixture was slowly warmed to RT and stirred for 15 hours. The reaction mixture was quenched with NH4Cl(aq.) and extracted with Et2O (3x). The combined organics were washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified on SO2 (gradient elution, 10-100percent EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) delta 5.83 - 5.75 (m, 1 H); 5.04 - 4.95 (m, 2 H); 4.14 - 4.07 (m, 3 H); 3.85 (m, 1 H); 3.70 (m, 1 H); 3.44 (m, 1 H); 2.07 (m, 3 H); 1.45 (m, 3 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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64% | n-Butyllithium (1.6 M in hexane; 0.239 mol) is added dropwise to a solution of 3,4-dibromo-2,5-dimethylthiophene (0.239 mol) in 325 ml of THF which has been cooled to -78° C. and the mixture is stirred for 30 minutes. 3,4-Epoxytetrahydrofuran (0.217 mol) and boron trifluoride etherate (0.217 mol) are added dropwise to this solution. The reaction solution is warmed to 0° C. and stirred for a further 3 hours. It is subsequently hydrolyzed with saturated ammonium chloride solution and the aqueous phase is extracted twice with tert-butyl methyl ether. After drying, the solvent is removed under reduced pressure and the crude product is purified by chromatography. The product is obtained as an oil in a yield of 64percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 110℃; | A stirred mixture of methyl 5-hydroxy-4'-methylbiphenyl-3-carboxylate (370 mg, 1.4 mmol), potassium carbonate (421 mg, 3.05 mmol), DMSO (8 mL), and <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (260 mg, 3.0 mmol) was heated at 1 10 0C overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In 1,4-dioxane; at 90℃; for 120h;Inert atmosphere; | A solution of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (10.3 g, 120 mmol) in 1 ,4- dioxane (30 ml_) was treated with propane-2-sulfonamide (17.7 g, 144 mmol), benzyltriethylammonium chloride (2.72 g, 12.0 mmol) and potassium carbonate (1.65 g, 12 mmol), and the mixture was heated at 9O0C for 5 days.The reaction mixture was then filtered, concentrated in vacuo and purified via silica gel chromatography (Gradient: 20percent to 60percent ethyl acetate in heptane) to afford Lambda/-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide. Yield: 18.5 g, 88.4 mmol, 74percent. LCMS m/z 210.1 (M+1). 1H NMR (400 MHz, CDCI3) delta1.37 (d, J=6.6 Hz, 3H), 1.39 (d, J=6.6 Hz, 3H), 3.21 (septet, J=6.7 Hz, 1 H),3.69 (m, 2H), 3.81 (m, 1 H), 4.09 (m, 2H), 4.38 (m, 1 H), 4.97 (d, J=8.3 Hz, 1 H).13C NMR (I OO MHZ, CDCI3) delta 16.41 , 16.65, 54.1 1 , 61.93, 71.45, 73.46, 77.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate;N-benzyl-N,N,N-triethylammonium chloride; In 1,4-dioxane; for 120h;Reflux; Inert atmosphere; | 3,6-Dioxabicyclo[3.1.0]hexane (1.90 g, 22.1 mmol), propane-2- sulfonamide (prepared according to the method of D. C. Johnson, Il and T. S. Widlanski, Tetrahedron Letters 2004, 45, 8483-8487) (3.13 g, 25.4 mmol), potassium carbonate (584 mg, 4.23 mmol) and benzylthethylammonium chloride (963 mg, 4.23 mmol) were suspended in dioxane (10 ml_) and heated at reflux for 120 hours. The reaction was cooled to room temperature, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 40percent to 80percent ethyl acetate in heptane), to afford trans-N-{4- hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide as a solid. Yield: 3.76 g, 18.0 mmol, 81 percent. 1H NMR (400 MHz, CDCI3) delta 1.38 (d, J=6.7 Hz, 3H), 1.40 (d, J=6.7 Hz, 3H) 2.91 (d, J=3.6 Hz, 1 H), 3.22 (septet, J=6.8 Hz, 1 H), 3.67- 3.71 (m, 2H), 3.82 (m, 1 H), 4.08-4.12 (m, 2H), 4.40 (m, 1 H), 4.77 (d, J=8.4 Hz, 1 H), 13C NMR (100 MHz, CDCI3) delta 16.44, 16.69, 54.18, 62.06, 71.47, 73.50, 77.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;N-benzyl-N,N,N-triethylammonium chloride; In 1,4-dioxane; for 18h;Reflux; Inert atmosphere; | 3,6-Dioxabicyclo[3.1.0]hexane (100 g, 1.16 mol), 4-bromophenol (241.1 g, 1.39 mol), cesium carbonate (492 g, 1.51 mol) and benzylthethylammonium chloride (52.9 g, 0.23 mol) were suspended in dioxane (1 L) and heated at reflux for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, then washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic portions were dried over sodium sulfate, filtered and concentrated in vacuo, to provide crude product, which solidified on standing. This was used without purification in the next step. Yield: 354 g, >100percent, assumed quantitative. Material from a smaller-scale experiment carried out in similar fashion was purified by silica gel chromatography for characterization (Gradient: 10percent to 35percent ethyl acetate in heptane), to afford frans-4-(4-bromophenoxy)tetrahydrofuran-3-ol as a solid. 1H NMR (400 MHz, CDCI3) delta 2.09 (br d, J=4.5 Hz, 1 H), 3.83 (m, 1 H), 3.91 (dd, J=10.3, 2.1 Hz, 1 H), 4.05 (dd, J=10.1 , 4.0 Hz, 1 H), 4.26 (dd, J=10.4, 4.9 Hz, 1 H), 4.41 (br s, 1 H), 4.67 (m, 1 H), 6.81 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 20h;Inert atmosphere; | Example 3A; rac-trans-4-[4-Hydroxytetrahydrofuran-3-yl]oxy}benzaldehyde 6.00 g (49.1 mmol) of 4-hydroxybenzaldehyde were initially charged in 16 ml of DMF, 6.34 g (73.7 mmol) of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> and 551 mg (4.91 mmol) of potassium tert-butoxide were added and the mixture was stirred under argon at 120° C. for 20 h. The reaction mixture was then stirred into 200 ml of water, and the resulting suspension was extracted with 300 ml of ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue obtained was chromatographed on silica gel using the mobile phase dichloromethane/methanol (100:1).Yield: 4.10 g (40percent of theory)LC-MS (Method 9): Rt=1.32 min; MS (ESIpos): m/z=209 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): delta=9.89 (s, 1H); 7.89 (d, 2H); 7.18 (d, 2H); 5.57 (d, 1H); 4.81 (d, 1H); 4.24 (br. t, 1H); 4.09 (dd, 1H); 3.93 (dd, 1H); 3.80 (d, 1H); 3.61 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.70 g, 24.0 mmol) produced in Reference Example 1(1b) and <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (1.03 g, 12.0 mmol) were dissolved in dichloromethane (5.0 mL). To the resulting mixture, a boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added at room temperature, followed by stirring for 16 hours. More boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added, followed by further stirring for two hours. Triethylamine (1.82 g, 18.0 mmol) was then added, and the resulting reaction liquid was directly purified by basic silica gel column chromatography (hexane : ethyl acetate, 100 : 0 - 0 : 100, ethyl acetate : methanol, 100 : 0 - 95 : 5, V/V) to give the desired title compound (2.14 g, yield 49percent). 1H-NMR (CDCl3) delta: 1.51-1.59 (2H, m), 1.80-1.88 (2H, m), 1.90 (1H, d, J = 5.2 Hz), 3.16-3.23 (2H, m), 3.48-3.54 (1H, m), 3.58-3.64 (2H, m), 3.66-3.70 (2H, m), 3.70-3.76 (2H, m), 3.78-3.87 (2H, m), 3.93-3.97 (2H, m), 4.04-4.09 (1H, m), 4.29-4.33 (1H, m), 5.12 (2H, s), 7.29-7.38 (5H, m). MS (EI+) m/z: 366 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | boron trifluoride diethyl etherate; In dichloromethane; at 20℃; for 3h; | (18a)Trans-4-[2-(benzyloxy)ethoxy]tetrahydrofuran-3-olInto dichloromethane (5.0 mL), 2-benzyloxyethanol (7.07 g, 46.5 mmol) and <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (1.0 g, 11.6 mmol) were dissolved, to which a boron trifluoride-diethyl ether complex (0.08 g, 0.58 mmol) was added at room temperature, followed by stirring for three hours.To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with dichloromethane.The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate, 100 : 0 - 0 : 100, V/V) to give the desired title compound (2.28 g, yield 82percent).1H-NMR (CDCl3) delta: 3.61-3.65 (2H, m), 3.69-3.77 (4H, m), 3.93-3.96 (1H, m),3.97 (1H, dd, J = 10.1, 4.6 Hz), 4.07 (1H, dd, J = 10.1, 4.6 Hz), 4.30-4.34 (1H, m), 4.57 (2H, s), 7.27-7.38 (5H, m).MS (EI+) m/z: 239 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | copper(l) iodide; In tetrahydrofuran; at 0 - 20℃; for 3h; | Intermediate 42 (1-42)Trans-4-Phenyltetrahydrofuran-3-ol trans3,4-Epoxytetrahydrofuran (3.9 g, 45.30 mmol) in dry THF (9 mL) was added dropwise to a stirred suspension of phenylmagnesium bromide (15.1 mL, 45, 30 mmol), Cul (604.13 mg, 3.17 mmol) and dry THF (5 mL) under nitrogen at 0°C and the mixture was stirred at RT for 3 h. The mixture was diluted with sat. aq. H4CI and extracted with EtOAc. The organic layer was separated, dried (Na2S04), filtered and evaporated in vacuo.A second batch was obtained according to the above procedure reacting 3,4-epoxy- tetrahydrofuran (1.0 g, 11.62 mmol), phenylmagnesium bromide (3.872 mL,11.62 mmol), Cul (155.67 mg, 0.813 mmol) and dry THF (total volume of 3.6 mL). The residues obtained from the above two batches was mixed and purified by flash chromatography (silica; DCM in MeOH 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to give 1-42 (5.5 g, 74percent) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18%; 18% | With caesium carbonate; In ISOPROPYLAMIDE; at 120℃; for 22h;Sealed tube; | Example 44:N-(7-((3S,4S)-4-hydrox tetrahydrofuran-3-yloxy)isoquinolin-3-yl)cyclopropanecarboxamideandN-(7-((3R,4R)-4-hydrox>tetrahydrofuran-3-yloxy)isoquinolin-3-yl)cyciopropanecarboxamideA mixture of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (59.4 mg, 0.260 mmol ),3.4-epoxytetrahydrofuran ( 128.4 mg. 1 .4 1 mmol ). and cesium carbonate ( 1 2.4 mg. 0.5598 mmol ) in N.N-dimethylacetamide (3.0 mL, 32 mmol ) was stirred in a sealed tube at 120 °C for 22 hours. The reaction mixture was poured into dichloromethane, washed with water, dried over MgS04, filtered, and evaporated in vacuo to yield a mixture of trans-stereoisomers. The crude products were purified and the enantiomers are separated via chiral supercritical fluid chromotagraphy to yield 14.4 mg ( 18percent) of one enantiomer and 14.5 mg ( 18percent) of the other enantiomer.Enantiomer No. 1 :LCMS (ESI): RT (min) = 3.216, M +H = 315.1, method = E; MR (400 MHz, DMSO-d6) delta 10.75 (s, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.50 (s, 1H), 7.36 (dd, J = 9.0, 2.3 Hz, 1H), 5.53 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.30 (s, 1 H). 4. 13 (dd, J = 10.2, 4.2 Hz, 1H), 3.95 (dd, J = 9.5, 4.5 Hz, 1H), 3.84 (d, J = 10.2 Hz, 1H), 3.62 (d, J = 9.5 Hz, 1H), 2.13 - 1.94 (m, 1H), 0.92 - 0.72 (m, 4H). Enantiomer No.2:LCMS (ESI): RT (min) = 3.215, M +H = 315.1, method = E; Iota N R (400 MHz, DMSO-d6) delta N MR (400 MHz, DMSO) delta 10.75 (s, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 9.0, 2.4 Hz, 1H), 5.53 (d, J = 3.7 Hz, 1H), 4.80 (d, J = 3.9 Hz, 1H), 4.30 (s, 1 H ). 4. 13 (dd, J = 10.2, 4.2 Hz, 1H), 3.95 (dd, J = 9.5, 4.5 Hz, 1H), 3.84 (d, J = 10.2 Hz, 1H), 3.62 (d, J = 9.5 Hz, 1H), 2.09 1 .98 (m. I H). 0.89 0.75 (m. 4H ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; In ipa; at 80℃; for 16h;Sealed tube; | Step 2Liquid NH3 was added to a stirred solution of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> [100] (1.0 g, 1 1 mmol) in IPA (10 ml) a sealed tube. The reaction mixture was heated 80 °C for 16 h. The progress of the reaction was monitored by TLC. After 16 h, the reaction vessel was cooled to RT and solvent was evaporated on vacuum to yield a brown gel. The crude gel product was washed with n-hexane (50 ml) followed by diethyl ether (50 ml), to yield (3S,4R)-4- aminotetrahydrofuran-3-ol [101] as a light brown gel (0.90 g, 75percent).ESIMS: 104.2 (M+ + 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 75℃; for 48h; | [00194] Step 1 : To a solution of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (57.4 g, 0.67 mol) in ethanol (344 mL) was added diallylamine (194 g, 2.00 mol). The reaction mixture was heated to 75°C. After 2 days, the reaction mixture was cooled and concentrated under reduced pressure to afford tr n5-4-(diprop-2-en-l-ylamino)tetrahydrofuran-3-ol. The material was used without further purification. | |
In methanol; at 72℃; for 48h; | Step (i): trans-4-[Bis(prop-2-en-l-yl)amino]oxolan-3-ol To the solution of 3,6-dioxabicyclo [3.1.0] hexane (CAS Number 285-69-8; 20.0 g, 232.5 mmol) in methanol (60 ml) was added di-allyl amine (CAS Number; 124-02-7; 67.7 g, 697.5 mmol). The reaction mixture was stirred at 72°C for 48 hours and then concentrated in vacuo to afford the title compound.1H NMR (400 MHz, DMSO-d): delta ppm 2.00-2.20 (m, IH), 3.05-3.17 (m, 5H), 3.41-3.44 (m, IH), 3.49-3.54 (m, IH), 3.80-3.87 (m, 2H), 4.10-4.19 (m, IH), 5.02-5.05(m, IH), 5.09- 5.19 (m, 3H), 5.78-5.85 (m, 2H)MS ES+: 184 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24 mg | at 140℃; for 7h;Microwave irradiation; | Example 554-f1-(2,4-Difluoro-3-phenoxy-phenyl)-propylamino1-tetrahvdro-furan-3-ol. hydrochlorideA mixture of 1-(2,4-difluoro-3-phenoxy-phenyl)-propylamine prepared as described in Example 3 (50 mg, 0.19 mmol) and <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong>(16 mg, 0.19 mmol) was heated under microwave irradiation at 140 °C for a total of 6 hours with further and 3,4- epoxytetrahydrofuran(16 mg, 0.19 mmol) added ever hour. The material was purified by preparative hplc to give the title compound (24 mg) as a 2:3 mixture of diastereomers. 1H NMR (400 MHz, Me-d3-OD): 7.50-7.39 (1 H, m), 7.39-7.24 (3H, m), 7.16-7.06 (1 H, m), 6.95 (2H, d), 4.57-4.18 (2H, m), 4.13-3.96 (2H, m), 3.94-3.62 (1 H, m), 3.62-3.53 (1 H, m), 2.04 (2H, d), 0.95-0.83 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.78 g | In isopropyl alcohol; at 90℃; for 120h; | (1) Synthesis of t-butyl 2-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]hydrazinecarboxylate <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (3.33 mL) and t-butyl carbazate (6.14 g) were dissolved in 2-propanol (15 mL), and the solution was heated to 90° C. After three days, t-butyl carbazate (6.3 g) was further added. After heating with stirring for further two days, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding chloroform and brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 50percent to 100percent) to give the title compound (5.78 g). ESI-MS m/z 241 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | Step 7) 4-(4-iodo-lH-pyrazol-l-yl)tetrahydrofuran-3-ol [0174] To a solution of 4-iodo-lH-pyrazole (10.8 g, 57.6 mmol) in anhydrous THF (60 mL) was added LDA (31.2 mL, 62.4 mmol) at -78 °C.The mixture was stirred at -40 °C for 1 h, followed by the addition of a solution of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (4.12 g, 48 mmol) in THF (50 mL). The reaction was sitrred at rt for lh,then heated to 80 °C and continued to stir for 36 h. The solution was cooled to rt, then quenched with H20 (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The resulted residue was purified bya silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (5 g, 37percent). LC-MS (ESI, pos. ion) m/z: 281 [M + H]+; 1H NMR (400 MHz, CDC13) delta (ppm): 3.44 (s, 1H), 3.79-3.82 (dd, J= 2.8, 10.0 Hz, 1H), 4.15- 4.22 (m, 2H), 4.29-4.33 (m, 1H), 4.55 (s, 1H), 4.75-4.78 (m, 1H), 7.53 (s, 1H), 7.55 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.17% | With water; potassium carbonate; In acetonitrile; at 100℃; for 20h; | Example 27: (2R, 75R)-2-[(l-Aminoisoquinolin-6-yl)amino]-8-fluoro-7- [(3R,^5)-4- hydroxyoxolan-3-yl]oxy}-4,15,17-trimethyl-13-oxa-4, l 1- diazatricyclo[14.2.2.16' 10]henicosa-l(18),6,8, 10(21),16, 19-hexaene-3, 12-dione; trifluoroacetic acid -Fluoro-6-((methylamino)methyl)-4-nitrophenol [00333] To a solution of 17C (2.65 g, 14.32 mmol) in MeOH (100 mL), methylamine (33percent in EtOH, 1.960 mL, 15.75 mmol) was added dropwise and stirred rt for 1 h. The reaction mixture was cooled to 0 °C, sodium borohydride (0.596 g, 15.75 mmol) was added portionwise and the mixture was stirred at rt for lh. The reaction was quenched with 0.5 N HC1, extracted with EtOAc (3x20 mL), washed with water, brine, dried ( a2S04). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography to give 27A (3.8 g, 18.98 mmol, 133percent yield) yellow solid. MS (ESI) m/z: 201.2 (M+H)+. -fluoro-2-hydroxy-5-nitrobenzyl(methyl)carbamate [00334] To a flask containing 27A (1.6 g, 7.99 mmol), DIEA (2.088 ml, 11.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (2.19 g, 8.79 mmol). The mixture was stirred at rt for lh. The reaction was quenched with FLjO and then extracted with EtOAc (3x). The organic layer was washed with brine, dried over a2S04 and concentrated. The crude was purified by flash column chromatography (0-60percent EtOAc/hexanes) to give 27B (1.8 g, 5.38 mmol, 67.4percent yield). MS (ESI) m/z: 335.2 (M+H)+. 27C: Benzyl 3-fluoro-2-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-5- nitrobenzyl(methyl)carbamate [00335] 27B (680 mg, 2.034 mmol) was mixed with <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (876 mg, 10.17 mmol), and K2CO3 (1546 mg, 1 1.19 mmol) in acetonitrile (1 mL) and H2O (1 mL) in a sealed tube. The mixture was stirred at 100 °C for 20 h. The reaction was quenched with H2O then extracted with EtOAc (2x) and concentrated. The residue was purified by flash column chromatography (0-90percent EtOAc/hexanes) to give a mixture of diastereomers as yellow oil. The diastereomers were further separated by a prep chiral HPLC equipped with a OJ Column to give the first peak 27C (181 mg, 0.431 mmol, 21.17percent yield). The relative stereochemistry of hydroxy ether is trans however absolute stereochemistry is undetermined. MS (ESI) m/z: 421.2 (M+H)+. 27D: (3S,4R)-4-(2-((((Benzyloxy)carbonyl)(methyl)amino)methyl)-6-fluoro-4- nitrophenoxy)tetrahydrofuran-3 -yl 4-nitrobenzoate [00336] Intermediate 27C (250 mg, 0.595 mmol) was mixed with 4-nitrobenzoic acid (447 mg, 2.68 mmol), PPh3 (741 mg, 2.82 mmol) in THF (1.5 mL) and stirred at rt for 10 min. The reaction was cooled to 0 °C, then DIAD (0.589 mL, 2.97 mmol) was added. After stirring at rt for 16 h, the reaction was quenched with H2O and extracted with EtOAc (2x). The organic extracts were washed with brine, dried ( a2S04) and concentrated. The residue was purified by flash column chromatography to give 27D (268 mg, 0.471 mmol, 79percent yield) as a white foam. The relative stereochemistry of hydroxyether is cis however absolute stereochemistry is undetermined. MS (ESI) m/z: 570.4 (M+H)+. 27E: Benzyl 3-fluoro-2-(((3R, 45)-4-hydroxytetrahydrofuran-3-yl)oxy)-5- nitrobenzyl(methyl)carbamate [00337] To 27D (250 mg, 0.439 mmol) in MeOH (5 mL) was added KOH (0.878 mL, 0.878 mmol) and the reaction was stirred at rt for 2 h. The reaction was concentrated and acidified with IN HCl after addition of ( . The sample was extracted with EtOAc (2x) and the extracts was washed with sat. NaHCC^ and brine. The solvent was removed and the residue was purified by flash column chromatography (0-60percent EtOAc/hexanes) to afford 27E (172 mg, 0.409 mmol, 93percent yield). MS (ESI) m/z: Al l A (M+H)+. NMR (400 MHz, CDCI3)) delta ppm 7.83 - 8.07 (m, 2 H) 7.33 (s, 5 H) 5.14 (s, 2 H) 4.92 - 5.03 (m, 1 H) 4.78 (d, J=7.91 Hz, 1 H) 4.70 (d, J=14.94 Hz, 1 H) 4.49 - 4.60 (m, 1 H) 4.39 (d, J=6.15 Hz, 1 H) 4.06 - 4.19 (m, 1 H) 3.90 - 4.03 (m, 2 H) 3.65 - 3.78 (m, 1 H) 2.84 (s, 3 H). 27F: Benzyl 2-(((3R,^5)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)oxy)-3- fluoro-5-nitrobenzyl(methyl)carbamate [00338] To 27E (171 mg, 0.407 mmol) in DMF (3 mL) was added TBS-C1 (307 mg, 2.034 mmol) and imidazole (138 mg, 2.034 mmol). The reaction was stirred at rt for 16 h, then quenched with H2O and extracted with EtOAc (2x). The solvent was removed and the residue was purified by flash column chromatography (0-60percent EtOAc/hexanes) to give 27F (215 mg, 0.402 mmol, 99percent yield). MS (ESI) m/z: 535.4 (M+H)+. 27G: 4-(((3R,^5)-4-((tert-Butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)oxy)-3-fluoro-5- ((methylamino)methyl)aniline [00339] To 27F (138 mg, 0.372 mmol, 93percent yield) in MeOH (5 mL) was added 10percent Pd/C (50 mg) and the mixture was hydrogenated (1 atm) for 4 h at rt. The mixture was filtered and concentrated to give 27G (138 mg, 0.372 mmol, 93percent yield) as a colorless oil. MS (ESI) m/z: 371.4 (M+H)+. 27H: tert-Butyl N- {6-[([(5-amino-2- { [(3R, ^5)-4-[(tert-butyldi... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation; | A mixture of Cs2C03 (34 mg, 0.105 mmol), 3-chloro-6-(1 H-pyrazol-4- yl)isoquinoline (16 mg, 0.070 mmol) and <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (Preparation 37, 24 mg, 0.279 mmol) in DMF (3 mL) was stirred at 120°C under microwave irradiation for 60 minutes. The reaction was cooled, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with 50-75percent EtOAc/cyclohexane to give the title compound as white solid (10 mg, 46percent). 1 H NMR (500 MHz, MeOD) delta 9.01 (s, 1 H), 8.31 (d, = 0.80 Hz, 1 H), 8.1 1 (d, J = 0.80 Hz, 1 H), 8.09 (d, J = 8.78 Hz, 1 H), 8.06 (d, J = 2.02 Hz, 1 H), 7.93 (dd, J = 1.68, 8.62 Hz, 1 H), 7.86 (s, 1 H), 4.84 (ddd, J = 2.32, 3.54, 6.13 Hz, 1 H), 4.61 (dt, J = 2.64, 5.24 Hz, 1 H), 4.34 (dd, J = 6.32, 9.92 Hz, 1 H), 4.23 (dd, J = 4.56, 9.16 Hz, 1 H), 4.20 (dd, J = 3.04, 9.36 Hz, 1 H), 3.79 (dd, J = 3.04, 9.76 Hz, 1 H). LCMS (ESI) Rt = 2.38 minutes MS m/z 316 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With water; In acetonitrile; at 23℃; for 24h; | A dram vial equipped with a stir bar and screw cap was charged with oligomeric cyclic (R,R)-(salen)Co(III) triflate 4a (n=1?2) (20.0 mg, 0.025 mmol), <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (S104) (87 mg, 1.0 mmol), CH3CN (0.30mL), and H2O (22 muL, 1.22 mmol), respectively, and the reaction was stirred for 24 h at room temperature. At 24 h, pyridinium p-toluenesulfonate (19 mg, 0.076 mmol) was added to quench the catalyst and ensure complete oxidation to Co(III). The reaction mixture was diluted to 20mL with EtOAc and agitated vigorously to ensure complete dissolution of precipitated product. The resulting mixture was concentrated to ca. 1?2 mL by rotary evaporation. The product solution was pipetted away from precipitated catalyst and applied directly to a silica gel column. The product was then purified by flash chromatography on silica gel (100percent EtOAc). The resulting product was dried over Na2SO4, and solvent was removed via rotary evaporation to give 80 mg (76percent) of a light-brown oil in approximately 95percent purity by 1H NMR analysis that crystallized to a light brown solid upon standing. The yield was uncorrected. Observe 99percent ee as determined by chiral GC analysis of the bis(trifluoroacetate) derivative [obtained by treating product with neat trifluoroacetic anhydride, followed by evaporation of excess trifluoroaceticanhydride under a stream of N2; ChiraldexTM gamma- TA, 70 °C, isothermal, tR (minor) = 4.4 min; tR(major) = 8.7 min]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium(IV) isopropylate; at 130℃; for 2h;Microwave irradiation; | Step 1: Ti(OiPr)4 (1.0 mL, 3.48 mmol) was added to a solution of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (1.5 g, 17.4 mmol) in benzylamine (2.0 mL). The mixture was irradiated in a microwave reactor at 130° C. for 2 hours. It was cooled to room temperature, and 50 mL of saturated aqueous NH4Cl solution and 20 mL of EtOAc were added to the reaction. The mixture was stirred for 10 minutes. The resulting gummy precipitate was filtered over a celite bed, and the filtrate was extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography on a C-18 column (0-100percent CH3CN/water) to afford trans-4-(benzylamino)tetrahydrofuran-3-ol. MS APCI calc'd for C11H15NO2 [M+H]+194. found 194. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In ethanol; at 100℃; for 1.5h;Microwave irradiation; | 4'-Hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde 3d (226 mg, 1 mmol), <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> 13a (600 mg, 6.97 mmol) and potassium carbonate (180 mg, 1.30 mmol) were dissolved in 1 mL of ethanol. The reaction mixture was reacted at 100 °C for 90 minutes under microwave condition. The resulting mixture was added with 10 mL of ethyl acetate, filtered and washed with ethyl acetate (10 mL*3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4'-(((3R,4R)/(3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-2',6'-dimethylbiphenyl-3-carb aldehyde 13b (312 mg, yield 100percent) as a yellow slime. MS m/z (ESI): 313.1 [M+1] |
100% | With potassium carbonate; In ethanol; at 100℃; for 1.5h;Inert atmosphere; Microwave irradiation; | 4?-Hydroxy-2?,6?-dimethylbiphenyl-3-carbaldehyde 3d (226 mg, 1 mmol), <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> 13a (600 mg, 6.97 mmol) and potassium carbonate (180 mg, 1.30 mmol) were dissolved in 1 mL of ethanol. The reaction mixture was reacted at 100° C. for 90 minutes under microwave conditions. The resulting mixture was mixed with 10 mL of ethyl acetate, filtered, and washed with ethyl acetate (10 mL×3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4?-(((3R,4R)/(3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-2?,6?-dimethylbiphenyl-3-carbaldehyde 13b (312 mg, yield 100percent) as a yellow slime. MS m/z (ESI): 313.1 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 75℃; for 48h;Autoclave; | Step 1: synthesis ofInt-2a A Parr autoclave reactor was charged with <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (57.4 g, 0.67 mol, diallylamine (194.3 g, 2.0 mol), and ethanol (344.4 mL). The mixture was heated to 75 °C and stirred for two days. The reaction mixture was cooled and the solvent was removed under reduced pressure to provide compound Int-2a, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In N,N-dimethyl-formamide; at 150℃; for 1h;Microwave irradiation; | A 8 mL microwave vial was charged with Intermediate C2 (100 mg, 0.2923 mmol), 3,4- epoxy tetrahydrofuran (50.3 mg, 0.5846 mmol, Combi blocks) and CsF (26.6 mg, 0.0292mmol) in DMF (2 mL). The capped vial was irradiated in a microwave reactor at 150 00 for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (5 mL). The organic phase was washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude product was purified by MD Auto-Prep HPLC (method A) to getthe pure title product as off white solid as mixture of enantiomers. 1H NMR (400 MHz,DMSO-d6): 6 7.49-7.44 (m, 1 H), 7.35-7.31 (m, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.09 (t, J =12.0 Hz, 1H), 5.49-5.47 (m, 1H), 4.83 (s, 1H), 4.80 (s, 1H), 4.76 (d, J = 3.6 Hz, 1H),4.54-4.47 (m, 2H), 4.18 (br s, 1H), 4.03-3.99 (m, 1H), 3.74-3.69 (m, 2H), 3.53-3.49 (m,1H), 2.84 (s, 1.6H), 2.80 (s, 1.4H), 2.62 (s, 1.5H), 2.56 (s, 1.5H). LCMS: (Method A)429.0 (M+H), Rt. 3.3 mm, 92.8 percent (Max). HPLC: (Method A) Rt. 3.3 mm, 94.8 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In N,N-dimethyl-formamide; at 150℃; for 1h;Microwave irradiation; | A 8 mL microwave vial was charged with Intermediate Cl (100 mg, 0.27 mmol), <strong>[285-69-8]3,4-epoxy tetrahydrofuran</strong> (47.8 mg, 0.55 mmol, Combi blocks) and CsF (4.22 mg, 0.03mmol) in DMF (2 mL). The capped vial was irradiated in a microwave reactor at 150 00 for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (5 mL). The organic phase was washed with water (3 mL) and brine (3 mL). The organic layer was dried over anhydrous sodiumsulphate and evaporated. The crude product was purified by MD Auto-Prep (Method A) to get the title product as white solid as mixture of two enantiomers. 1H NMR (400 MHz, DMSO-d6): 6 7.37 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 11.2 Hz, 1H), 6.92 (t, J = 12.0 Hz, 1H), 5.54 (s, 1H), 4.83-4.79 (m, 3H), 4.55-4.49 (m, 2H), 4.19 (s, 1H), 4.00 (d, J = 10.0 Hz, 1 H), 3.72 (d, J = 8.8 Hz, 2H), 3.52 (br s, 1 H), 2.85 (s, 1 .7H), 2.82 (s, 1 .3H), 2.63 (s,1.4H), 2.57 (s, 1.6H). LCMS: (Method A) 447.0 (M+H), Rt. 3.4 mm, 97.7 percent (Max). HPLC: (Method A) Rt. 3.5 mm, 99.5 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In N,N-dimethyl-formamide; at 150℃; for 1h;Microwave irradiation; | Example 26 (anti)-(3-chloro-2,4-dimethyl-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-8(9H)-yl)(4-fluoro-2-((4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)methanone A 8 mL microwave vial was charged with Intermediate C1 (100 mg, 0.27 mmol), <strong>[285-69-8]3,4-epoxy tetrahydrofuran</strong> (47.8 mg, 0.55 mmol, Combi blocks) and CsF (4.22 mg, 0.03 mmol) in DMF (2 mL). The capped vial was irradiated in a microwave reactor at 150 °C for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (5 mL). The organic phase was washed with water (3 mL) and brine (3 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude product was purified by MD Auto-Prep (Method A) to get the title product as white solid as mixture of two enantiomers. 1H NMR (400 MHz, DMSO-d6): delta 7.37 (d, J = 7.2 Hz, 1 H), 7.19 (d, J = 11.2 Hz, 1 H), 6.92 (t, J = 12.0 Hz, 1 H), 5.54 (s, 1 H), 4.83-4.79 (m, 3H), 4.55-4.49 (m, 2H), 4.19 (s, 1 H), 4.00 (d, J = 10.0 Hz, 1 H), 3.72 (d, J = 8.8 Hz, 2H), 3.52 (br s, 1 H), 2.85 (s, 1.7H), 2.82 (s, 1.3H), 2.63 (s, 1.4H), 2.57 (s, 1.6H). LCMS: (Method A) 447.0 (M+H)+, Rt. 3.4 min, 97.7 percent (Max). HPLC: (Method A) Rt. 3.5 min, 99.5 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In N,N-dimethyl-formamide; at 150℃; for 1h;Microwave irradiation; | Example 21 (anti)-(3-chloro-2,4-dimethyl-7H-pyrrolo[3',4':3,4]pyrazolo[1,5-a]pyrimidin-8(9H)-yl)(2-((4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)methanone SGN010041-01 A 8 mL microwave vial was charged with Intermediate C2 (100 mg, 0.2923 mmol), <strong>[285-69-8]3,4-epoxy tetrahydrofuran</strong> (50.3 mg, 0.5846 mmol, Combi blocks) and CsF (26.6 mg, 0.0292 mmol) in DMF (2 mL). The capped vial was irradiated in a microwave reactor at 150 °C for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (5 mL). The organic phase was washed with water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude product was purified by MD Auto-Prep HPLC (method A) to get the pure title product as off white solid as mixture of enantiomers. 1H NMR (400 MHz, DMSO-d6): delta 7.49-7.44 (m, 1 H), 7.35-7.31 (m, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.09 (t, J = 12.0 Hz, 1 H), 5.49-5.47 (m, 1 H), 4.83 (s, 1 H), 4.80 (s, 1 H), 4.76 (d, J = 3.6 Hz, 1 H), 4.54-4.47 (m, 2H), 4.18 (br s, 1 H), 4.03-3.99 (m, 1 H), 3.74-3.69 (m, 2H), 3.53-3.49 (m, 1 H), 2.84 (s, 1.6H), 2.80 (s, 1.4H), 2.62 (s, 1.5H), 2.56 (s, 1.5H). LCMS: (Method A) 429.0 (M+H)+, Rt. 3.3 min, 92.8 percent (Max). HPLC: (Method A) Rt. 3.3 min, 94.8 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; ammonium chloride; In ethanol; water; for 24h;Reflux; | Step (i): trans-4-Azidooxolan-3-ol A mixture of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (5.0 g, 58 mmol), ethanol (540 ml), water (108 ml), sodium azide (11.3 g, 174 mmol) and ammonium chloride (9.3 g, 174 mmol) was heated to reflux for 24 hours. The reaction was allowed to cool to room temperature and partially concentrated in vacuo before water (50 ml) was added and the residue extracted with ethyl acetate. The combined organics were washed with brine and dried (sodium sulphate) and the solvent was removed in vacuo to afford the title compound which was used without further purification.1H NMR (CDC13): delta ppm 3.20 - 3.40 (br s, 1 H), 3.70 (d, / = 10.0 Hz, 1 H), 3.78 (d, / = 10.0 Hz, 1 H), 3.91 - 3.95 (m, 1 H), 3.95 - 3.99 (m, 1 H), 4.03 - 4.94 (m, 1 H), 4.29 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step i): trans-4-(l,3-Benzothiazol-2-ylmethyl)oxolan-3-ol To a stirred solution of 2-methyl-l,3-benzothiazole (CAS number 120-75-2 ; 7.0 g, 46.979 mmol) in dry THF (150 ml) at -78°C was added n-BuLi (2.5 M in hexane; 37.6 ml, 93.959 mmol) dropwise. The reaction was stirred at -78°C for 2 hours. To this was then added dropwise over 30 minutes <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (CAS number 285-69-8; 6.1 g, 70.469 mmol) as a solution in dry THF (100 ml) and boron trifluoride diethyl etherate (8.9 ml, 70.469 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 mins and then quenched with saturated (aq.) ammonium chloride (200 ml) and extracted with diethyl ether (250 ml x 3). The organics were washed with water (250 ml), brine (250 ml), dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0 - 5percent ethyl acetate / n-hexane) to afford the title compound.1H NMR (400 MHz, DMSO-d): delta ppm 3.04-3.18 (m, 2H), 3.48-3.54 (m, 2H), 3.86-3.96 (m, 2H), 4.09-4.15 (m, 1H), 5.11-5.12 (m, 1H), 7.40-7.49 (m, 1H), 7.48-7.51 (m, 1H), 7.94-7.96 (m, 1H), 8.06-8.08 (m, 1H)MS ES+: 236 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With copper(l) iodide; In tetrahydrofuran; at 0 - 5℃; for 3h;Inert atmosphere; | Bromo(prop-2-en-1-yl)magnesium (300 mL, 2.06 mol, 2.00 equiv) was added dropwise into a mixture of <strong>[285-69-8]3,6-dioxabicyclo[3.1.0]hexane</strong> (12.9 g, 149.84 mmol, 1.00 equiv) and CuT (2.85 g, 14.96 mmol, 0.10 equiv) in tetrahydrofuran (100 mL) at 0-5°C under nitrogen. The resulting solution was stirred for 3 h at 0°C, quenched by NH4C1 (aq.), and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:6) to afford the title compound (5 g, 26percent) as light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine tris(hydrogen fluoride); at 120℃; | A mixture of 3,6-dioxa-bicyclo[3.1 .0]hexane (1 .OOg; 12 mmol) and triethylamine trihydrofluoride (2.81 g; 17 mmol) is stirred at 12000 over night. The mixture is allowed to cool to RT, quenched with saturated sodium bicarbonate solution and stirred for 1 h, then extracted with DCM/2-propanol (5:1). The organic layer is separated, dried and evaporated to yield the crude product which is further reacted without chromatographicpurification.Yield: 510 mg (60percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.1% | With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 0.5h;Inert atmosphere; | Step 3 4-(3-(4-((4-Hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimid azolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 14c (2.38 g, 5.87 mmol) was placed in a reaction flask, followed by addition of cesium carbonate (2.86 g, 8.81 mmol), 20 mL of N,N-dimethylacetamide and 3,4-epoxy-tetrahydrofuran (0.61 g, 7.05 mmol) successively. The reaction solution was warmed up to 120°C. After reacting for 0.5 hour, the reaction solution was mixed with 100 mL of water and extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (30 mL*3) and saturated sodium chloride solution (30 mL*3), 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 B to obtain the crude compound. The crude compound was seperated by HPLC method to obtain the title product 4-(3-(4-(((3R,4R/3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-ox o-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 14 (350 mg, yield 12.1percent) as a white solid. |
12.1% | With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 0.5h; | 4-(3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 14c (2.38 g, 5.87 mmol) was placed in a reaction flask, followed by addition of cesium carbonate (2.86 g, 8.81 mmol), 20 mL of N,N-dimethylacetamide and 3,4-epoxy-tetrahydrofuran (0.61 g, 7.05 mmol), successively. The reaction solution was warmed up to 120° C. After reacting for 0.5 hour, the reaction solution was mixed with 100 mL of water and extracted with ethyl acetate (100 mL). The organic phases were combined, washed with water (30 mL*3) and saturated sodium chloride solution (30 mL*3), 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 B to obtain the crude compound. The crude compound was separated by HPLC to obtain the title product 4-(3-(4-(((3R,4R/3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 14 (350 mg, yield 12.1percent) as a white solid. MS m/z (ESI): 492.3 [M+1]; 1H NMR (400 MHz, CDCl3): delta 8.03-8.01 (m, 2H), 7.90-7.88 (m, 1H), 7.28-7.26 (m, 2H), 7.12-7.10 (m, 2H), 4.81-4.80 (m, 1H), 4.53-4.52 (m, 1H), 4.37-4.33 (m, 1H), 4.14-4.10 (m, 1H), 4.02-3.99 (m, 1H), 3.91-3.89 (m, 1H), 1.62 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.3% | With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 2h;Inert atmosphere; | Example 7 4-(3-(3-Fluoro-4-(((3R,4R/3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimet hyl-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 (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of 3,4-epoxy-tetrahydrofuran (24 mg, 0.28 mmol), cesium carbonate (115 mg, 0.35 mmol) and 4 mL of N,N-dimethylacetamide successively. The reaction mixture was warmed up to 120°C. After reacting for 1 hour, the reaction solution was supplemented with 3,4-epoxy-tetrahydrofuran(100 mg, 1.16 mmol) and stirred at 120°C for another 1 hour. The reaction solution was mixed with 30 mL of H2O and extracted with ethyl acetate (30 mL). The organic phases were combined, washed with water (15 mL*3) and saturated sodium chloride solution (15 mL*3), 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 and subsequent elution system B to obtain the title compound 4-(3-(3-fluoro-4-(((3R,4R/3S,4S)-4 -hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 7 (40 mg, yield 33.3percent) as a white solid. |
33.3% | With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 2h; | 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of 3,4-epoxy-tetrahydrofuran (24 mg, 0.28 mmol), cesium carbonate (115 mg, 0.35 mmol), and 4 mL of N,N-dimethylacetamide, successively. The reaction mixture was warmed up to 120° C. After reacting for 1 hour, the reaction solution was supplemented with 3,4-epoxy-tetrahydrofuran (100 mg, 1.16 mmol), and stirred at 120° C. for another 1 hour. The reaction solution was mixed with 30 mL of H2O and extracted with ethyl acetate (30 mL). The organic phases were combined, washed with water (15 mL*3) and saturated sodium chloride solution (15 mL*3), 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 and subsequently with elution system B to obtain the title compound 4-(3-(3-fluoro-4-(((3R,4R/3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 7 (40 mg, yield 33.3percent) as a white solid. MS m/z (ESI): 510.3 [M+1]; 1H NMR (400 MHz, CDCl3): delta 8.00-7.96 (m, 2H), 7.85-7.82 (m, 1H), 7.19-7.15 (t, 1H), 7.08-7.04 (m, 2H), 4.81-4.80 (m, 1H), 4.52-4.50 (m, 1H), 4.33-4.29 (m, 1H), 4.14-4.10 (m, 1H), 4.03-4.00 (m, 1H), 3.88-3.86 (m, 1H), 1.60 (s, 6H). |
Tags: 285-69-8 synthesis path| 285-69-8 SDS| 285-69-8 COA| 285-69-8 purity| 285-69-8 application| 285-69-8 NMR| 285-69-8 COA| 285-69-8 structure
[ 86087-23-2 ]
(S)-(+)-3-Hydroxytetrahydrofuran
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[ 5306-85-4 ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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