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CAS No. : | 22633-44-9 | MDL No. : | MFCD09800598 |
Formula : | C5H9BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SESXZSLSTRITGO-UHFFFAOYSA-N |
M.W : | 181.03 | Pubchem ID : | 529264 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.89 |
TPSA : | 29.46 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.38 cm/s |
Log Po/w (iLOGP) : | 1.5 |
Log Po/w (XLOGP3) : | 0.04 |
Log Po/w (WLOGP) : | 0.39 |
Log Po/w (MLOGP) : | 0.39 |
Log Po/w (SILICOS-IT) : | 1.65 |
Consensus Log Po/w : | 0.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.86 |
Solubility : | 25.2 mg/ml ; 0.139 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.21 |
Solubility : | 111.0 mg/ml ; 0.615 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.52 |
Solubility : | 5.4 mg/ml ; 0.0299 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.36 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
52% | With sodium ethanolate In ethanol; dichloromethane | A. Preparation of 3-Bromomethyl-3-hydroxymethyloxetane Sodium ethoxide in ethanol (21percent, 185.74 g, 0.573 mol) was added over a period of 10 min to a solution of 2,2-bis-(bromomethyl)propane-1,3-diol (150 g, 0.573 mol) in 650 mL of ethanol. This solution was refluxed for 2 h, stirred at ambient temperature for 16 h, filtered and then evaporated to give an oil containing solids. The resulting residue was dissolved in 200 mL of methylene chloride, filtered and evaporated to give 98 g of crude oxetane. An analytical sample was purified by distillation at 113° C. and 3-mm pressure. 52.95 g, representing a 52percent yield, of 3-bromomethyl-3-hydroxymethyl oxetane were obtained. NMR: 1 H NMR 3.75 (s, 2H), 3.88 (d, J=4.9 Hz, 2H), 4.45 (s, 4H); 13 C NMR 36.336 (t, J=152.78 Hz), 45.0935 (s), 63.995 (t, J=143.3 Hz), 77.216 (t, J=152.78 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol;Heating / reflux; | Example 45: synthesis of 6,6-dioxo-2-oxa-6lambda6-thia-spiro|"3.5]nonan-8-one (458); Step 1; A mixture of 2,2-bis(bromomethyl)propane-l,3-diol (25 g, 95 mmol) and potassium hydroxide (6.1 g, 92 mmol) in ethanol (250 mL) was stirred at room temperature during 2h. The reaction mixture was then filtered over decalite and concentrated to dryness to give a yellowish oil, which was used in the next step without further purification.To the previous intermediate <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> dissolved in EtOH (175 mL) was added cyanosodium (5.39 g, 1.15 eq). The reaction mixture was <n="159"/>refluxed overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give 3.8 g (31% overall yield) of the desired product 2-(3 -(hydroxymethyl)oxetan-3 -yl)acetonitrile (455) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium ethanolate; In ethanol; at 20℃; for 4h; | A solution of 1 (10 gm, 0.038 mol) in ethanol (50 ml) was added to a freshly prepared solution of sodium ethoxide (2.5 gm, 0.038 mol) in ethanol (25 ml) at RT. The mixture was stirred at RT for 4 hr. After completion of reaction as shown by TLC, salts were filtered. The insoluble salts were washed with cold ethanol (25 ml) and the combined ethanolic filtrate concentrated under reduced pressure to obtain a colourless liquid as residue. Yield : 4.5 gm (65%). [Found : C, 33.01, H, 5.10 C5H9BrO2 requires C, 33.17, H, 5.00%]. |
52% | With sodium ethanolate; In ethanol; dichloromethane; | A. Preparation of 3-Bromomethyl-3-hydroxymethyloxetane Sodium ethoxide in ethanol (21%, 185.74 g, 0.573 mol) was added over a period of 10 min to a solution of 2,2-bis-(bromomethyl)propane-1,3-diol (150 g, 0.573 mol) in 650 mL of ethanol. This solution was refluxed for 2 h, stirred at ambient temperature for 16 h, filtered and then evaporated to give an oil containing solids. The resulting residue was dissolved in 200 mL of methylene chloride, filtered and evaporated to give 98 g of crude oxetane. An analytical sample was purified by distillation at 113 C. and 3-mm pressure. 52.95 g, representing a 52% yield, of 3-bromomethyl-3-hydroxymethyl oxetane were obtained. NMR: 1 H NMR 3.75 (s, 2H), 3.88 (d, J=4.9 Hz, 2H), 4.45 (s, 4H); 13 C NMR 36.336 (t, J=152.78 Hz), 45.0935 (s), 63.995 (t, J=143.3 Hz), 77.216 (t, J=152.78 Hz). |
With sodium hydroxide; In diethyl ether; ethanol; | (i) 60.0 g of 2,2-bis(bromomethyl)-1,3-propanediol was dissolved in 200 ml of ethanol and 10.1 g of 98% sodium hydroxide was added. The reaction mixture was stirred for 3 hours at reflux temperature, the solvent was evaporated under reduced pressure, the residue was taken up in diethyl ether and the solid material (sodium bromide) was removed by filtration. The resulting ethereal solution was evaporated to dryness. The residue was distilled under reduced pressure to yield 3-(bromomethyl)-3-(hydroxymethyl)oxetane (1A) as a clear, colorless oil, b.p.: 101-110 C. at 1 Torr. |
With sodium hydroxide; In water; at 25 - 53℃; for 4h;Large scale; | First, step R1 was performed, and 810 kg of pure water and 54.0 kg of sodium hydroxide were charged into a reaction tank of 2000 L, stirred until clear and cooled to an internal temperature of less than 25C. 270 kg of Compound 5 was added to the reactor, heated to an internal temperature of 48-53[deg.] C. and stirred at 48-53[deg.] C. for 4 hours to obtain a reaction liquid of Step R1. The reaction solution of step R1 was cooled to an internal temperature of 10-15C to obtain a crude solution of compound 6. Further, step R2 is performed, To a crude solution of compound 6 was added 270 L of acetonitrile and 25.8 kg of tetramethylpiperidine nitrous oxide, Stir at 10-15C for 0.5 hours, 189 kg of potassium phosphate and 1701 kg of aqueous solution of sodium hypochlorite (concentration 8.4%) were added at 10-20C and the pH was maintained at 10-13, Stirring at 10-20C for 2 hours gives the reaction solution of step R2. The reaction solution of step R2 was extracted twice with 540 L of ethyl acetate. The pH of the extracted aqueous phase was adjusted to 6-8 with 24 kg of hydrochloric acid (18% concentration). Then 1.51 kg sodium bisulfite solution (concentration 0.6%) was added. Then use 24kg of hydrochloric acid (concentration is 18%) The extracted aqueous phase was adjusted to pH 3-4 and then extracted three times with 540 L of dichloromethane. The pH of the extracted aqueous phase was further adjusted to 1-2 with 24 kg of hydrochloric acid (18% concentration) and then extracted three times with 540 L of ethyl acetate. The organic phase was combined and the internal temperature of the organic phase was maintained at 45-55C to carry out the concentration step. The organic phase remaining after concentration was added to a new reactor, then 135 L of n-hexane and 30 l of ethyl acetate were added and stirred at room temperature for 12 hours, filtered to obtain a cake and washed with n-hexane. The washed cake was vacuum-dried at 45C for 16 hours to obtain 70.5 kg of compound 7. (purity: 99.4%, moisture: 0.04%, content: 95.3%, total yield of steps R1 and R2: 35%). | |
With potassium hydroxide; In methanol; at 60℃; for 16h; | KOH (1.07 g, 19.08 mmol) was added slowly to a solution of 2,2-bis(bromomethyl)-propane-1,3-diol (5 g, 19.08 mmol) in MeOH (50 mL). The mixture was stirred at 60C for 16 hours. On completion, excess solvent was evaporated under vacuum and theresidue was diluted with water (100 mL) and extracted twice with diethyl ether (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated and the residue was purified by silica gel (100-200 mesh) column chromatography (5Q% EtOAc in Pet ether as eluent) to afford the title compound as pale yellow liquid.H NMR (300MHz, DMSO-d6): O 5.07 (t, J = 5.5 Hz, 1H), 4.37 - 4.20 (m, 4H), 3.83 (s,2H), 3.66 (d, J = 5.5 Hz, 2H). | |
With potassium hydroxide; In ethanol; at 20℃; for 2h; | Example 45: synthesis of 6,6-dioxo-2-oxa-6lambda6-thia-spiro|"3.5]nonan-8-one (458); Step 1; A mixture of 2,2-bis(bromomethyl)propane-l,3-diol (25 g, 95 mmol) and potassium hydroxide (6.1 g, 92 mmol) in ethanol (250 mL) was stirred at room temperature during 2h. The reaction mixture was then filtered over decalite and concentrated to dryness to give a yellowish oil, which was used in the next step without further purification.To the previous intermediate (3-(bromomethyl)oxetan-3-yl)methanol dissolved in EtOH (175 mL) was added cyanosodium (5.39 g, 1.15 eq). The reaction mixture was <n="159"/>refluxed overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give 3.8 g (31% overall yield) of the desired product 2-(3 -(hydroxymethyl)oxetan-3 -yl)acetonitrile (455) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | A. Preparation Of 3-Bromomethyl-3-hydroxymethyloxetane Sodium ethoxide in ethanol (21%, 185.74 g, 0.573 mol) was added over a period of 10 min to a solution of 2,2-bis-(bromomethyl)propane-l,3-diol (150 g, 0.573 mol) in 650 mL of ethanol. This solution was refluxed for 2 h, stirred at ambient temperature for 16 h, filtered and then evaporated to give an oil containing solids. The resulting residue was dissolved in 200 mL of methylene chloride, filtered and evaporated to give 98 g of crude oxetane. An analytical sample was purified by distillation at 113 C. and 3-mm pressure. 52.95 g, representing a 52 % yield, of 3-bromomethyl-3-hydroxymethyl oxetane were obtained. NMR: 1 H NMR 3.75 (s, 2 H), 3.88 (d, J=4.9 Hz, 2 H), 4.45 (s, 4 H); 13 C NMR 36.336 (t, J=152.78 Hz), 45.0935 (s), 63.995 (t, J =143.3 Hz), 77.216 (t, J=152.78 Hz). | |
EXAMPLE 1 [3-(Bromomethyl)oxetan-3-yl]methanol A solution of 25 g (94 mmol) of 2,2-bis(bromomethyl)-1,3-propanediol (pentaerythritol dibromide) in 250 ml of ethanol was stirred with 6.1 g (94 mmol) of potassium hydroxide (86 percent, pellets) for 2 hours at room temperature. Then, the potassium bromide that had developed, was filtered off and the filtrate was concentrated by evaporation in a vacuum. The thus-obtained yellowish oil was usable for the following stage without further purification. The yield (crude product) was 18.1 g (100 percent). The boiling point of the product was 86 C./0.2 torr Other data concerning the product was: 1 H-NMR (CDCl3, 300 MHz): delta4.49, 4.47 (AB system, JAB =7.5 Hz, 4 H, ring-H); 3.96 (s, 2 H, CH2 OH); 3.78 (s, 2 H, CH2 Br); 3.50 (s, 1 H, OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In water; ethyl acetate; acetone; | B. Preparation of 3-Azidomethyl-3-hydroxymethyloxetane A mixture of sodium azide (9.5 g, 0.14 mol), <strong>[22633-44-9]3-bromomethyl-3-hydroxymethyloxetane</strong> (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1 H NMR 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); NMR 44.283, 53,852, 64,073, 76.227. |
1.92 g (49%) | With tetrabutylammomium bromide; In water; | EXAMPLE IV This example illustrates the preparation and properties of 3-azidomethyl-3hydroxymethyloxetane. A solution of sodium azide (2.07 g, 0.0317 mol), <strong>[22633-44-9]3-bromomethyl-3-hydroxymethyloxetane</strong> (5.0 g, 0.028 mol) and tetra-n-butylammonium bromide (0.0978 g, 0.3 mmol) in water (14 mL) was heated for 3 h at 104-107 C. The solution was cooled and was extracted with ethyl ether (5*20 mL). The combined extracts were evaporated to give 1.92 g (49%) of 3-azidomethyl-3-hydroxymethyloxetane, essentially pure by glc analysis, as an oil. NMR: 1 H NMR: 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); 13 C NMR: 44.283, 53.852, 64.073, 76.227. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In water; ethyl acetate; acetone; | B. Preparation of 3-Azidomethyl-3-hydroxymethyloxctane A mixture of sodium azide (9.5 g, 0.14 mol), <strong>[22633-44-9]3-bromomethyl-3-hydroxymethyloxetane</strong> (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1 H NMR 3.70 (s, 2 H), 3.84 (d, J=4.9 Hz, 2 H), 4.44 (s, 4 H); 13 C NMR 44.283, 53,852, 64,073, 76.227. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | EXAMPLE 2 [3-(Hydroxymethyl)-oxetan-3-yl]acetonitrile (II) A solution of 42 g (0.23 mol) of [3-(bromomethyl)oxetan-3-yl] methanol (produced according to Example 1) in 420 ml of ethanol was refluxed with 13 g (0.265 mol) of sodium cyanide for 18 hours. After cooling to room temperature, the precipitated sodium bromide was filtered off and the filtrate concentrated by evaporation. The residue was distilled at 0.4 torr. The yield of product as a colorless oil was 16 g (54 percent). The boiling point of the product was 107 C./0.4 torr. Other data concerning the product was: 1 H-NMR (CDCl3, 300 MHz): delta4.43 (s, 4 H, ring-H); 3.97 (s, 2 H, CH2 OH); 2.85 (s, 2 H, CH2 CN); 2.50 (s, 1 H, OH). IR(Film): v=2247 cm-1 (C N) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium bromide; In ammonium hydroxide; | EXAMPLE 2 Preparation of 3,3-bis(hydroxymethyl)azetidine (2) 7.5 g of 1A was taken up in 100 ml of 25% (w/w) aqueous ammonia and the mixture was stirred for 16 hours in an autoclave at 80 C. After evaporation of the aqueous ammonia, 10 ml of 48% (w/w) aqueous hydrobromic acid was added to the residue and the resulting solution was stirred at 60 C. After 2 hours the aqueous hydrobromic acid was evaporated, 75 ml of 25% (w/w) aqueous ammonia was added to the residue, and the resulting solution was stirred at 60 C. After 2 hours the aqueous ammonia was evaporated. The white, solid residue was freed from ammonium bromide by purification over "Dowex" 50W-X8 (H+) (registered Trademark) ion exchange resin, to yield crystalline 3,3-bis(hydroxymethyl)azetidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In dichloromethane; | Method E, Step 1 Compound C1 will be converted to E1 using SOCI2 in DCM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | General procedure: To a stirred solution of glycerol (4.01 mL, 55 mmol) and imidazole (18.7 g, 275 mmol) in DMF (150 mL) at 0C was added tert-butyldimethylsilyl chloride (17.2 g, 1 13 mmol) in DMF (33 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Water (500 mL) was added to the reaction mixture and the resulting mixture extracted with heptane (500 mL x 3). The combined organic layers were washed with water (300 mL), dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of heptane:EtOAc 100:0 to 80:20 to afford the title compound as a colourless oil in 68% yield, 11 .9 g. 1H NMR (400 MHz, DMSO-d6) delta; 0.03 (s, 12H), 0.86 (s, 18H), 3.40-3.59 (m, 5H), 4.58 (d, 1 H). The title compound was prepared according to the method described for Preparation 124 using <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> to afford the title compound as a colourless oil in 100% yield, 2.45 g. 1H NMR (400 MHz, CDCl3): delta ppm 0.09 (s, 6H), 0.90 (s, 9H), 3.74 (s, 2H), 3.90 (s, 2H), 4.41 (br s, 4H) |
With 1H-imidazole; In dichloromethane; | Method C, Step 1Commercially available C1 will be treated with TBSCI and imidazole in DCM to give C2 after purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In acetone; for 20h; | General procedure: A mixture of 2 (0.02 mol), K2CO3 (0.04 mol) and the respective phenols 3(a-d) (0.02 mo) was refluxed for 20 hr. On completion of the reaction, which was monitored by TLC, the mixture was cooled to RT and salts were filtered. The insoluble salts were washed with acetone (20 ml) and the acetone filtrate was concentrated under reduced pressure to obtain a crude residue. The latter was dissolved in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography using EtOAc/Hexane as eluent to obtain the pure 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetonitrile; at 60℃; for 16h;Inert atmosphere; | Example 234: N-(l-((3-((Dimethylamino)methyl)oxetan-3-yl)methyl)-1H-pyrazol-4-yl)-1-(3- morpholinobenzyl)-1H-pyrazol -d]pyrimidin-6-amineStep (i)4-nitro-1H-pyrazole (0.5g, 4.42mmol) and K2CO3 (1.22g, 8.84mmol) were suspended in acetonitrile (30mL) in a 2-necked flask under Nitrogen and (3-(bromomethyl)oxetan-3- yl)methanol (1.36g, 7.52mmol) was added dropwise. The reaction was heated at 60C for 16h and the solution was concentrated to about 1/3 of the volume under vacuum and then partitioned between DCM (50mL) and water (50mL). The organics were dried over Na2S04, filtered and the solvent evaporated to give (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3- yl)methanol as a transparent oil (0.94g, quantitative yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | To a stirring solution of (3-Bromomethyl-oxetan-3-yl)-methanol (200 mg, 1.104 mmol) in tetrahydrofuran (15 mL) at 0 C, was added sodium hydride (63 mg, 2.65 mmol) and stirred for 15 min. To this methyl iodide (629 mg, 4.419 mmol) was added to the above reaction mixture and the resultant reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 3- (bromomethyl)-3-(methoxymethyl)oxetane as a liquid (120 mg, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3- dihydro-lH-inden-l-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)- methanol (135.7 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 38%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.23 mmol) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (267 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 30 mg of (3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)oxetan-3- yl)methanol_ as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro- lH- inden-l-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate ( 111 mg, 0.80 mmol) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (97 mg, 0.536 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%) . UPLC-MS (M + l) : 399.18 ; UPLC-MS RT (min) : 2.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-l(3H)- one (80 mg, 0.266 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.798 mmol) and (3-Bromomethyl-oxetan-3-yl)-methanol (96 mg, 0.532 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (30 mg, 28%).UPLC-MS (M + l) : 401.16; UPLC-MS RT (min) : 2.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.6% | With potassium carbonate; In acetonitrile; at 80℃; for 4h; | To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-lH-inden-l- one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (115 mg, 0.843 mmol) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (153 mg, 0.843 mmol) 20 and the resultant reaction mixture was heated to 80 C for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 27.6%).UPLC-MS (M + l) : 385.17 ; UPLC-MS RT (min) : 2.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.9% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-lH-inden-l- one (80 mg, 0.281 mmol) in acetonitrile (5 ml.) was added potassium carbonate (155 mg, 1.124 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (82 mg, 0.422 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 17.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.2% | With potassium carbonate; In acetonitrile; at 80℃; for 4h; | To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-l-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> ( 151 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80 C for 4 h . The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was pu rified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 23.2%).UPLC-MS (M + l) : 387.18 ; UPLC-MS RT (min) : 2.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3- dihydro-lH-inden-l-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)- methanol (68 mg, 0.375 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19%).UPLC-MS (M + l) : 421.15 ; UPLC-MS RT (min) : 2.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4- methoxyphenyl)isobenzofuran-l(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and (3-bromomethyl-oxetan-3- yl)-methanol (89 mg, 0.493 mmol) and the resultant reaction mixture was heated to 80 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 19%).UPLC-MS (M + l) : 423.12 ; UPLC-MS RT (min) : 2.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2% | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | To a stirring solution of 4-(3-(cydopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3- dihydro-lH-inden-l-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and (3-bromomethyl-oxetan-3-yl)- methanol (134 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70 C for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).UPLC-MS (M + l) : 425.18 ; UPLC-MS RT (min) : 2.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2% | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4- methoxyphenyl)isobenzofuran-l(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL), was added potassium carbonate (102 mg, 0.745 mmol) and (3-bromomethyl-oxetan-3- yl)-methanol (134 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70 C for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).UPLC-MS (M + l) : 427.18 ; UPLC-MS RT (min) : 2.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In water; ethyl acetate; acetonitrile; | [3-(2-Chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol600 mg of <strong>[35852-58-5]3-chloro-4-hydroxybenzotrifluoride</strong> and 829 mg of 3-bromomethyl-3-oxetanemethanol were dissolved in 20 ml of acetonitrile, and 1.49 g of cesium carbonate were added.The reaction mixture was heated to 110° C. and stirred at this temperature for three hours. 50 ml of water and 50 ml of ethyl acetate were added to the cooled reaction mixture.The organic phase was removed, dried over MgSO4 and then concentrated under reduced pressure.The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100percent n-heptane=>100percent ethyl acetate.This gave 990 mg of [3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol.C12H12ClF3O3. (296.68), LCMS (ESI-neg): 341.0 (M+HCOO-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.9% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 42h;Inert atmosphere; | 100 mg of 2-[1-(4-beta?Gamma?omicronchinu-2,6-(.??IotaupsilonomicronGammatheta ThetaetazetanuIota)-1Eta-?etaepsilon?3zetaomicronIota-3-nuIota]-4-(rhonupiepsilonIota?eta-4-ylamino)pyrimidin-5-ol (3-1 , 0.21 mmol, 1. eq.) were dissolved in 1 ,6 ml of DMF under a nitrogen atmosphere, then 87 mg of potassium carbonate (0.63 mmol, 3 eq.) and 40 mg of <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> (0.21 mmol, 1 eq.) were added. The resulting mixture was stirred at room temperature for 18 hours. 6,0mg of <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> (0,032 mmol, 0,15 eq.) were added and stirred again for 24 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/ isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloro-methane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 75 mg (0.13 mmol, 61 ,9%) of the analytically pure target compound.1H-NMR (400 MHz, DMSO-de): delta [ppm]= 1.26 (t, 3H), 3.83 (d, 2H), 4.01 (q, 2H), 4.39 - 4.50 (m, 6H), 5.06 (t, 1 H), 5.65 (s, 2H), 6.72 - 6.81 (m, 2H), 7.23 (t, 1 H), 7.46 (ddd, 1H), 7.82 (d, 1 H), 8.01 - 8.09 (m, 2H), 8.38 - 8.46 (m, 4H), 8.90 (s, 1 H).LC-MS:retention time: 1.00 minMS ES+: 574.82 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 54 Ethyl 2-(3-(4-((4'-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-2',6'-dimethyl-[1 ,r- biphenyl]-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 54) To a stirred solution of ethyl 2-(3-(4-((4'-hydroxy-2',6'-dimethyl-[1 ,1 '-biphenyl]- 3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Step 1 c of Example 39, 105 mg, 0.235 mM) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (42.6 mg, 0.235 mM) dissolved in DMF (5 ml), cesium carbonate (91 mg, 0.470 mM) was added. The reaction mixture was stirred at 60 QC for 2h. The reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography to afford the title compound ethyl 2-(3-(4-((4'-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-2',6'- dimethyl-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (120 mg). Yield: 91 %; 1 H NMR (DMSO-d6, 300 MHz): delta 7.47-7.41 (m, 2H), 7.14-7.04 (m, 4H), 6.96 (d, J=8.4 Hz, 2H), 6.74 (s, 2H), 5.14 (s, 2H), 4.98 (bs, 1 H), 4.74 (s, 4H), 4.41 (s, 4H), 4.13 (s, 2H), 3.92-3.83 (m, 2H), 3.71 -3.69 (m, 2H), 3.07 (s, 2H), 1 .91 (s, 6H), 1 .02 (t, J=6.9 Hz, 3H); MS: m/z 547.1 (M+1 ), 569.1 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 65 Ethyl 2-(3-(4-((2'-chloro-4'-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-[1 , 1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 65) To a stirred solution of ethyl 2-(3-(4-((2'-chloro-4'-hydroxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Example 60, 102 mg, 0.225 mM) and <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (53.0 mg, 0.293 mM) in DMF (5 ml), cesium carbonate (147 mg, 0.450 mM) was added and stirred at 60 C for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Organic layer was washed with brine, dried and concentrated. The crude compound was purified by column chromatography to obtain ethyl 2-(3-(4-((2'-chloro-4'-((3- (hydroxymethyl)oxetan-3-yl)methoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)oxetan-3- yl)acetate (45 mg, 0.081 mM) as colorless liquid. Yield: 36 %; 1 H NMR (300 MHz, CDCI3) delta: 7.49-7.41 (m, 4H), 7.31 (d, J = 8.4 Hz, 1 H), 7.14-7.04 (m, 3H), 6.96-6.92 (m, 3H), 5.1 1 (s, 2H), 5.01 (d, J = 6.4 Hz, 2H), 4.87 (d, J = 6.4 Hz, 2H), 4.61 (s, 4H), 4.30 (s, 2 H), 4.15 (s, 2 H), 3.98 (q, J = 6.4 Hz, 2H), 3.1 1 (s, 2H), 1 .02 (t, J = 6.9 Hz, 3H); MS: (m/z) 553 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 130℃; for 2h;Sealed tube; | Step 1 : 3-Bromomethyl-3-oxetanemethanol (Apollo-Inter) (400 mg, 2.21 mmol) is charged in a pressure vessel and 2.0 M methylamine in THF is added (7.7 mL, 15 mmol, 7.0 eq). The vessel is sealed and heated at 130 C for 2 h. The mixture is cooled to RT and filtered. The filtrate is concentrated under reduced pressure to provide intermediate 101 OA. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Dissolve 4-hydroxybenzophenone in anhydrous THF and treat it with equimolar quantity of sodium hydride at 0 C for 2h. Stir and warm the suspension to 50 C and treat it with an equimolar quantity of 3-Bromomethyl-3-hydroxymethyloxetane (readily prepared in one step by method described in US5489700 or Tet. Lett. 2011, 52, p. 565 - 567 from commercially available 2,2-bis-(bromomethyl)propane-l,3-diol). Stir overnight at 50 C, filter the reaction mixture, evaporate the filtrate to dryness and purify the residue by column chromatography to provide (4-[3-(hydroxymethyl)oxetan-3-yl]methoxy}phenyl)(phenyl)methanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium fluoride; In diethylene glycol; at 150℃; for 3h; | Step 1 (3-Fluoromethyloxetan-3-yl)methanol A mixture of 21.5 g (0.119 mol, 1 eq) of <strong>[22633-44-9]3-bromomethyl-3-hydroxymethyloxetane</strong> and 27.7 g (0.476 mol, 4 eq) of potassium fluoride in 60 ml of diethylene glycol was heated at 150 C. for 3 hours. The reaction medium was diluted with 120 ml of water and extracted with diethyl ether (18*30 ml) and then with ethyl acetate (8*50 ml). The organic phases were combined, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (column SuperFlash SF40-240 g) eluted with 30/70 heptane/ethyl acetate (elimination of the diethylene glycol). 10.55 g of (3-fluoromethyloxetan-3-yl)methanol were recovered in the form of a colorless oil. Yield=74%. TLC SiO2/Heptane:EtOAc (20/80), developing with KMnO4. |
55% | With cesium fluoride; at 150℃; for 2h; | Cesium fluoride (5.03 g, 33.14 mmol) was added to a flask containing <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (2.00 g, 11.05 mmol) in ethylene glycol (6 mL) and the reaction was heated to 150 C. for 2 hours. After cooling, the reaction was diluted with EtOAc (30 mL) and water (30 mL). The aqueous was extracted with diethyl ether (3*30 mL) and ethyl acetate (3*30 mL). The combined organics were dried over MgSO4, filtered and evaporated, then the crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Product containing fractions were evaporated to dryness to afford (3-(fluoromethyl)oxetan-3-yl)methanol (0.734 g, 55%) as a colourless liquid. 1H NMR (500 MHz, CDCl3, 27 C.) 3.92 (2H, s), 4.52 (4H, t), 4.59-4.89 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; at 80℃; for 4.0h; | A mixture of <strong>[320-49-0]4-bromo-3-(trifluoromethyl)phenol</strong> (commercial source, 0.2 g, 0.83 mmol), (3-(bromomethyl)oxetan-3-yl)methanol (commercial source, 0.18 g, 0.994 mmol) and potassium carbonate (0.1 15 g, 0.994 mmol) was stirred in dry acetonitrile (4 ml) at 80 C for 4 h. The reaction mixture was diluted with EtOAc (20 ml). The solids were filtered, washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography (0.27 g) as semi solid. Yield: 95%; 1 H NMR (300 MHz, CDCI3) delta (ppm): 7.63 (d, J = 5.1 Hz, 1 H), 7.29 (s, 1 H), 7.0 (dd, J = 5.4 Hz, 1 H), 4.620 (m, 4H), 4.274 (s, 2H), 4.065 (d, J = 2.7 Hz, 2H); MS: m/z 341 .2 [M+], 340.7 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared in an analogous manner as the Compound 41 of Example 41 involving reaction of Methyl 2-((3-(4-((2'-chloro-4'-hydroxy-[1 ,1 '- biphenyl]-3-yl)methoxy) phenyl)oxetan-3-yl)oxy)acetate (compound of Step 1 of Example 41 ) with <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong>. 1 H NMR (CDCI3, 300 MHz): delta 7.45-7.49 (m, 3H), 7.36-7.41 (m, 3H),7.27-7.31 (m, 1 H), 7.06-7.09 (m, 3H), 6.94-7.03 (m, 1 H), 5.15 (s, 2H), 4.99 (d, J = 6.6 Hz, 2H), 4.86 (d, J = 6.9 Hz, 2H), 4.61 ( m, 4H), 4.30 (s, 2H), 4.06-4.08 (m, 2H), 3.85 (s, 2H), 3.72 (s, 3H); MS: m/z 576.8 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared in an analogous manner as the Compound 1 ' of Example 50 involving reaction of methyl 2-((3-(4-((4'-hydroxy-2',6'-dimethyl- [1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)oxetan-3-yl)oxy)acetate (compound of Step 2 of Example 51 ) with <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong>.1 H NMR (CDCI3, 300 MHz): delta 7.42-7.48 (m, 2H), 7.34-7.40 (m, 2H), 7.19 (s, 2H), 7.09-7.12 (m, 1 H), 7.00-7.03 (m, 2H), 6.72 (s, 2H), 5.15 (s, 2H), 4.99 ( d, J= 6.9 Hz, 2H), 4.85 (d, J = 6.9 Hz, 2H), 4.61 (s, 4H), 4.29 (s, 2H), 4.07 (s, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 2.01 (s, 6H); MS: m/z 571.3 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃; for 2h; | To a stirred solution of <strong>[22633-44-9](3-(bromomethyl)oxetan-3-yl)methanol</strong> (800 mg, 4.42 mmol) and ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 1044 mg, 4.42 mmol) in dry DMF (10 ml) was added Cs2CO3 (1705 mg, 8.84 mmol) and the reaction mixture was allowed to stir at RT for 2 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to obtain the title compound (945 mg) as off-white solid.Yield: 60.8 %; 1H NMR (300 MHz, CDC13): 7.17 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.1 Hz, 2H), 4.99 (t, J = 5.1 Hz, 1H), 4.76 (s, 4H), 4.40 (s, 4H), 4.12 (s, 2H), 3.91 (q, J = 6.9 Hz, 2H), 3.70 (d, J = 5.1 Hz, 2H), 3.09 (s, 2H), 1.05 (t, J = 7.2 Hz, 3H); MS (mlz): 359.0 (M + Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium phosphate; sodium hypochlorite solution; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In water; acetonitrile; at 10 - 20℃; for 2.5h;pH 10 - 13;Large scale; | First, step R1 was performed, and 810 kg of pure water and 54.0 kg of sodium hydroxide were charged into a reaction tank of 2000 L, stirred until clear and cooled to an internal temperature of less than 25C. 270 kg of Compound 5 was added to the reactor, heated to an internal temperature of 48-53[deg.] C. and stirred at 48-53[deg.] C. for 4 hours to obtain a reaction liquid of Step R1. The reaction solution of step R1 was cooled to an internal temperature of 10-15C to obtain a crude solution of compound 6. Further, step R2 is performed, To a crude solution of compound 6 was added 270 L of acetonitrile and 25.8 kg of tetramethylpiperidine nitrous oxide, Stir at 10-15C for 0.5 hours, 189 kg of potassium phosphate and 1701 kg of aqueous solution of sodium hypochlorite (concentration 8.4%) were added at 10-20C and the pH was maintained at 10-13, Stirring at 10-20C for 2 hours gives the reaction solution of step R2. The reaction solution of step R2 was extracted twice with 540 L of ethyl acetate. The pH of the extracted aqueous phase was adjusted to 6-8 with 24 kg of hydrochloric acid (18% concentration). Then 1.51 kg sodium bisulfite solution (concentration 0.6%) was added. Then use 24kg of hydrochloric acid (concentration is 18%) The extracted aqueous phase was adjusted to pH 3-4 and then extracted three times with 540 L of dichloromethane. The pH of the extracted aqueous phase was further adjusted to 1-2 with 24 kg of hydrochloric acid (18% concentration) and then extracted three times with 540 L of ethyl acetate. The organic phase was combined and the internal temperature of the organic phase was maintained at 45-55C to carry out the concentration step. The organic phase remaining after concentration was added to a new reactor, then 135 L of n-hexane and 30 l of ethyl acetate were added and stirred at room temperature for 12 hours, filtered to obtain a cake and washed with n-hexane. The washed cake was vacuum-dried at 45C for 16 hours to obtain 70.5 kg of compound 7. (purity: 99.4%, moisture: 0.04%, content: 95.3%, total yield of steps R1 and R2: 35%). |
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; water; In acetonitrile; at 10 - 20℃; | To a 100 ml flask was charged <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> (17.3 g, 9.6 mmol) followed with 25 ml water and 5.3 mL of acetonitrile and TEMPO (153 mg, 0.96 mmol). The mixture was cooled to 10 C. 15.3 g sodium hypochloride (14 %) was added over 10 mm with the inner temperature maintained between 15C and 20C. The reaction was stirred at roomtemperature till <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> was consumed as monitored by HPLC. The resulted mixture was adjusted to pH 8-9 and extracted with 20 mL EtOAc twice. The aqueous layer was adjusted to pH 1-2 with SN aqueous H2S04 solution and extracted with dichloromethane. After removal of dichloromethane, 3 -(bromomethyl)oxetane-3-carboxylic acid was obtained. MS obsd. (ESIj [(M+H)i 194. 1H NMR (400 MHz, METHANOL-d4) d ppm,9.40 - 9.90 (s, 1 H), 5.00 - 5.02 (d, 1=6.8 Hz, 2 H), 4.56 - 4.57 (d, 1=6.8 Hz, 2 H), 3.97 (s, 2 H) | |
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In water; acetonitrile; at 10 - 20℃; | To a 100 ml flask was charged [3-(bromomethyl) oxetan-3-yl]methanol (17.3 g, 9.6 mmol) followed with 25 ml water and 5.3 mL of acetonitrile and TEMPO (153 mg, 0.96 mmol). The mixture was cooled to 100 C. 15.3 g sodium hypochloride (14%) was added over 10 mm with the inner temperature maintained between 15 C. and 20 C. The reaction was stirred at room temperature till [3-(bro- momethyl)oxetan-3-yl]methanol was consumed as monitored by HPLC. The resulted mixture was adjusted to pH 8-9 and extracted with 20 mL EtOAc twice. The aqueous layer was adjusted to pH 1-2 with SN aqueous H2 SO4 solution and extracted with dichloromethane. After removal of dichloromethane, 3 -(bromomethyl)oxetane-3-carboxylic acid was obtained. MS obsd. (ESI) [(M+H)] 194. 1H NMR (400 MHz, METHANOL-d4)d ppm, 9.40-9.90(s, 1H), 5.00-5.02 (d, J=6.8 Hz, 2H), 4.56-4.57 (d, J=6.8 Hz, 2H), 3.97 (s,2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate; N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 55 - 80℃; for 48h; | General procedure: A mixture of 7a (0.2 mmol), an appropriate bromide or methanesulfonate (0.4 mmol), K2CO3 (0.6 mmol), DIEA (0.4 mmol) and KI (0.04 mmol) in 4 mL DMF was heated at 55 o C-80 o C for 2 days until the completion of the reaction. The mixture was treated with EtOAc (100 mL), washed with brine and then dried over with Na2SO4, filtered, and evaporated. The crude product was purified by chromatograph (CHCl3/MeOH) to give the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N-ethyl-N,N-diisopropylamine; In acetonitrile; for 12h;Reflux; | Compound 8 (772mg, 4.14mmol), and Compound 9 (500mg, 2.76mmol) with 20mL dry acetonitrile was dissolved, then add DIPEA0.5mL, then added to the dried potassium carbonate (1.1g, 8.28mmol), reflux 12h, TLC after the reaction was complete, filtration, the filtrate was collected, spin dry column chromatography to give intermediate 10. | |
With potassium carbonate; potassium iodide; at 75℃; for 4h; | A solution of the compound 3-bromomethyl-3-hydroxymethyl-1-oxetane, 1-tert-butoxycarbonylheptazine (1.5 eq), potassium carbonate (2 eq) and potassium iodide (0.2 eq) , Heated to 75 C for 4 h. After the reaction was complete, the potassium carbonate was filtered off, and the filtrate was spin-dried on a column, CH2CI2: Mu0HH = 50: 1To give compound 18-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 80℃; for 20h; | 1.67mmol compound 1-4 dissolved in 15 ml acetonitrile, adding 1.4eq of the <strong>[22633-44-9]3-bromomethyl-3-hydroxymethyloxetane</strong> and 4eq anhydrous potassium carbonate, 80 C reaction 20h. moisture content level by adding ethyl acetate and, removing the aqueous layer, organic layer saturated salt water washing, after drying by anhydrous sodium sulfate column get compound 1-5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; | The compound 1-1 and (3- (bromomethyl) oxetan-3-yl) methanol (2 eq) were dissolved in acetonitrile, (3 eq) diisopropylethylamine (DIPEA) was added, heated to 90 C reflux overnight. After completion of the reaction, the reaction solution was cooled, slowly poured into ice water, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate and mixed with the column. CH2CI2: Mu0H (volume ratio) = 20 : 1 Compound S1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetonitrile; at 75℃; for 4h; | Compound 1-2, 3-fluoropropidine hydrochloride (1.5 eq), potassium carbonate (2 eq) and potassium iodide (0.2 eq) were dissolved in acetonitrile and heated to 75 C for 4 h. After the reaction was complete, the potassium carbonate was filtered off, and the filtrate was spin-dried on a column, and the developing solvent was CH2CI2: MuOmicronEta (volume ratio) = 50: 1To give compound 19-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetonitrile; at 75℃; for 4h; | Compound 1-2, 3, 3-difluorobutidine hydrochloride (1.5 eq), potassium carbonate (2 eq) and potassium iodide (0.2 eq) were dissolved in acetonitrile and heated to 75 C for 4 h. After the reaction was complete, the potassium carbonate was filtered off, and the filtrate was spin-dried and the column was stirred. The developing solvent was CH2C12: Mu0HH (volume ratio) = 50: 1To give compound 20-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h; | A mixture of 6-hydroxy-4-(6-(4-((6-methoxypyridin-3 -yl)methyl)piperazin- 1-yl)pyridin-3 -yl)pyrazolo[ 1,5 -a]pyridine-3 -carbonitrile 2,2,2-trifluoroacetate (Intermediate P24:39 mg, 0.088 mmol), <strong>[22633-44-9][3-(bromomethyl)oxetan-3-yl]methanol</strong> (48.0 mg, 0.265 mmol) and K2C03(s)(61.0 mg, 0.442 mmol) in DMF (883 tL) was stirred 1 hour at 90 C. After cooling to ambienttemperature, the reaction mixture was purified directly by silica chromatography (using a stepwisegradient of 0-100% EtOAc in hexanes followed by EtOAc with 10% MeOH as eluents) to cleanlyprovide the title compound (21 mg, 44% yield). MS (apci) m/z = 542.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 80℃; for 16h; | [3-(Bromomethyl)oxetan-3-yl]methanol (0.39 g, 2.2 mmol) and Cs2CO3 (1.3 g, 4.01 mmol) were added to a solution of 3-ethylspiro[1,5,6,8-tetrahydropyrazolo[4,3- c]azepine-7,4?-tetrahydropyran]-4-one (0.5 g, 2.008 mmol) in MeCN (10 mL). The mixture was stirred at 80 C for 16 hours. On completion, excess solvent wasevaporated under vacuum and the residue was dissolved in DCM and filtered throughcelite. The filtrate was concentrated and the residue was purified by prep HPLC(separations of isomers), to afford the title compound as colorless solid.1H NMR (300MHz, DMSO-d6): c5 7.43 (br t, J = 5.6 Hz, 1H), 5.06 (br s, 1H), 4.55 (d, J= 6.2 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 4.21 (s, 2H), 3.68 - 3.49 (m, 4H), 3.42 (br s,2H), 3.01 (br d, J = 5.4 Hz, 2H), 2.81 - 2.66 (m, 4H), 1.42 (br t, J = 5.2 Hz, 4H),1.09 (t, J = 7.4 Hz, 3H).HPLC-Retention time (XE Metode 7 CM): 1.62 minutes.Detected ?M+1?-mass: 350.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetone; for 20h; | General procedure: A mixture of 2 (0.02 mol), K2CO3 (0.04 mol) and the respective phenols 3(a-d) (0.02 mo) was refluxed for 20 hr. On completion of the reaction, which was monitored by TLC, the mixture was cooled to RT and salts were filtered. The insoluble salts were washed with acetone (20 ml) and the acetone filtrate was concentrated under reduced pressure to obtain a crude residue. The latter was dissolved in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography using EtOAc/Hexane as eluent to obtain the pure 4. 4a (i.e. 4, R=H); Yield : 4.5 gm (80%); Colourless thick liquid. [Found : C, 67.91, H, 7.07 C11H14O3 requires C, 68.02, H, 7.27%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In acetone; for 20h; | General procedure: A mixture of 2 (0.02 mol), K2CO3 (0.04 mol) and the respective phenols 3(a-d) (0.02 mo) was refluxed for 20 hr. On completion of the reaction, which was monitored by TLC, the mixture was cooled to RT and salts were filtered. The insoluble salts were washed with acetone (20 ml) and the acetone filtrate was concentrated under reduced pressure to obtain a crude residue. The latter was dissolved in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography using EtOAc/Hexane as eluent to obtain the pure 4. |
4-Bromophenol (100 mg, 0.58 mmol) was dissolved in anhydrous DMF (8 ml_) at 0 C under N2. NaH (60% dispersion in mineral oil, 25 mg, 0.64 mmol) was added portion wise and the solution stirred for 15 min. 3-(Bromomethyl)oxetan-3-ylmethanol (105 mg, 0.58 mmol) was added dropwise as a solution in DMF (2 ml_). The solution was stirred at 0 C and allowed to warm to RT over 4 h. Excess NaH was quenched with H2O (2 ml_) and volatiles removed by rotary evaporator. The resulting residue was suspended in H2O (15 ml_) and extracted with DCM (3 x 10 ml_), combined organic fractions were dried by phase separator and residual DMF removed by high vacuum overnight. The product A10 was taken forward as a crude clear oil (155 mg, quant); LC-MS. Rt 2.92 min, AnalpH2_MeOH_4min(1 ); (ESI+) m/z 273.2, 275.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In acetone; for 20h; | General procedure: A mixture of 2 (0.02 mol), K2CO3 (0.04 mol) and the respective phenols 3(a-d) (0.02 mo) was refluxed for 20 hr. On completion of the reaction, which was monitored by TLC, the mixture was cooled to RT and salts were filtered. The insoluble salts were washed with acetone (20 ml) and the acetone filtrate was concentrated under reduced pressure to obtain a crude residue. The latter was dissolved in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography using EtOAc/Hexane as eluent to obtain the pure 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3c:Anhydrous cesium carbonate (4.5 g, 56.8 mmol) is added to a solution of 3b (13.8 g, 37.8 mmol) in 150 ml DMF. The reaction is stirred at room temperature for 10 minutes,Then (3-bromoethyl-oxetan-3-yl) -methanol (10.6 g, 56.8 mmol) is added.The reaction mixture is heated to 70 C. and stirred for 5 hours.After cooling to room temperature, the reaction mixture is added to 100 ml of water,Carefully neutralize with 2 M HCl. The aqueous phase is extracted with a solvent mixture of ethyl acetate / THF. Combine the organic phase into one,Wash with saturated aqueous NaCl solution and dry over sodium sulfate.After removal of the solvent, the crude product is purified by column chromatography on silica gel using DCM as eluent.The desired product 3c,A mixture with difunctionalized by-products is obtained (10.5 g),This is used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.9 g | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5h; | 1b: 1a (5.7 g, 20.6 mmol) and (3-bromoethyl-oxetan-3-yl) -methanol (5.77 g, 30.9 mmol) in 90 ml of DMF,Add anhydrous cesium carbonate (10.1 g, 30.9 mmol). The reaction mixture is stirred at 70 C. for 5 hours.After cooling to room temperature, the reaction mixture is added to 100 ml of water,Carefully neutralize with 2 M HCl. The aqueous phase is extracted with ethyl acetate. Combine the organic phases and wash with saturated aqueous NaCl solution,Dry with sodium sulfate. After removing the solventThe solid residue is recrystallized with a solvent mixture of toluene / heptane / ethyl acetate,1b was obtained as gray crystals (5.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With caesium carbonate; In acetonitrile; at 85℃; for 2h;Inert atmosphere; | To a solution of Ex 3 hydrochloride (200 mg, 0.49 mmol) and (3-(bromo-methyl)oxetanyl-3-yl)methanol (88 uL, 0.49 mmol) in MeCN (10 mL) is added CS2CO3 (316 mg, 0.97 mmol). The reaction mixture is stirred at 85C for 2 h (reaction monitored by LCMS). Water is added (20 mL) and the mixture is then extracted with EtOAc (2 x 50 mL). The organic extracts are washed with brine (10 mL), are dried over MgSCL, filtered and evaporated. The residue is purified by prep. HPLC (Prep-HPLC-1 conditions) to give the title compound Ex 11-89 (157 mg, 68% yield) as a beige solid. LCMS-1: tR = 0.75 min, [M+1]+ 476.37. |
Tags: 22633-44-9 synthesis path| 22633-44-9 SDS| 22633-44-9 COA| 22633-44-9 purity| 22633-44-9 application| 22633-44-9 NMR| 22633-44-9 COA| 22633-44-9 structure
[ 78385-26-9 ]
3-(Bromomethyl)-3-methyloxetane
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[ 165253-29-2 ]
3-(Bromomethyl)tetrahydrofuran
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[ 1522-92-5 ]
3-Bromo-2,2-bis(bromomethyl)propanol
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[ 78385-26-9 ]
3-(Bromomethyl)-3-methyloxetane
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[ 165253-29-2 ]
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[ 78385-26-9 ]
3-(Bromomethyl)-3-methyloxetane
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