* 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.
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL*3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88percent over two steps), which was used directly in next step.
Reference：
[1] Green Chemistry, 2018, vol. 20, # 13, p. 3038 - 3043
3
[ 29668-44-8 ]
[ 39270-39-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h; Stage #2: With water In ethanol
2,3-Dihydro-benzo [1, 4] dioxine-6-carbaldehyde [RN 29668-44-8] (3.04g, 18. 54mmol) was dissolved in ethanol (lOOmL) and cooled to 0°C. To the resulting solution was added sodium borohydride (1. 41g, 37. 07mmol). The resulting slurry was stirred at room temperature for 1 hour and then quenched with water (lOmL) before being concentrated to dryness under reduced pressure. The residue was partitioned between a 5percent aqueous solution of sodium hydrogen carbonate (20mL) and dichloromethane (2x50mL). The organic phases were combined and dried over magnesium sulfate then evaporated under reduced pressure to provide and oil which was purified on silica gel using a dichloromethane and methanol solvent gradient. This provided the desired product as a colourless oil (3. 00g, 97percent).
95%
at 0℃; for 0.5 h;
(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)methanol. To a solution of 2,3- dihydrobenzo[b][l,4]dioxine-6-carbaldehyde (TCI America Laboratory Chemicals B2019) (20 g, 0.12 mol) in MeOH (400 mL) at 0 0C was added NaBH4 (14 g, 0.36 mol) in portions. After stirring at 0 0C for 30 minutes, the mixture was neutralized to pH = 7 by addition of 2 M aqueous HCl. The MeOH was removed under reduced pressure, and the residue was extracted with DCM (2 x 200 mL). The combined organic layers were concentrated under reduced pressure to afford (2,3-dihydrobenzo[b][l,4]dioxin-6- yl)methanol (19 g, 95 percent).
Reference：
[1] Patent: WO2003/87098, 2003, A1, . Location in patent: Page/Page column 43
[2] Patent: WO2010/83246, 2010, A1, . Location in patent: Page/Page column 149-150
[3] Australian Journal of Chemistry, 1984, vol. 37, # 4, p. 893 - 901
[4] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 83, p. 11805 - 11808
[5] Tetrahedron, 2001, vol. 57, # 39, p. 8297 - 8303
[6] Journal of the American Chemical Society, 2002, vol. 124, # 34, p. 10071 - 10082
[7] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 125 - 136
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5971 - 5975
[9] Molecules, 2013, vol. 18, # 4, p. 3872 - 3893
[10] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5626 - 5632
4
[ 20825-87-0 ]
[ 39270-39-8 ]
Yield
Reaction Conditions
Operation in experiment
10.6 g
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 11 h; Inert atmosphere
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0° C. under N2. The mixture was stirred at room temperature for 11 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10percent, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g). 1H NMR (300 MHz, DMSO-d6) δ 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
2,3-Dihydro-benzo [1, 4] dioxine-6-carbaldehyde [RN 29668-44-8] (3.04g, 18. 54mmol) was dissolved in ethanol (lOOmL) and cooled to 0C. To the resulting solution was added sodium borohydride (1. 41g, 37. 07mmol). The resulting slurry was stirred at room temperature for 1 hour and then quenched with water (lOmL) before being concentrated to dryness under reduced pressure. The residue was partitioned between a 5% aqueous solution of sodium hydrogen carbonate (20mL) and dichloromethane (2x50mL). The organic phases were combined and dried over magnesium sulfate then evaporated under reduced pressure to provide and oil which was purified on silica gel using a dichloromethane and methanol solvent gradient. This provided the desired product as a colourless oil (3. 00g, 97%).
95%
With methanol; sodium tetrahydroborate; at 0℃; for 0.5h;
(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)methanol. To a solution of 2,3- dihydrobenzo[b][l,4]dioxine-6-carbaldehyde (TCI America Laboratory Chemicals B2019) (20 g, 0.12 mol) in MeOH (400 mL) at 0 0C was added NaBH4 (14 g, 0.36 mol) in portions. After stirring at 0 0C for 30 minutes, the mixture was neutralized to pH = 7 by addition of 2 M aqueous HCl. The MeOH was removed under reduced pressure, and the residue was extracted with DCM (2 x 200 mL). The combined organic layers were concentrated under reduced pressure to afford (2,3-dihydrobenzo[b][l,4]dioxin-6- yl)methanol (19 g, 95 %).
70%
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
To a stirred solution of 2,3-dihydrobenzo[b][1 ,4]dioxine-6-carbaldehyde (1.0 g, 6.09 mmol) in MeOH (10 mL) was added NaBH4 (0.28 g, 6.69 mmol) at 0? and the reaction mixture was stirred for 1 h at RT. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water (20 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2S04 and concentrated to afford the tittle compound. Yield: 70% (0.71 g, colourless gummy solid). 1H NMR (400 MHz, DMSO-cfe): d 6.79-6.73 (m, 3H), 5.04 (t, J = 5.6 Hz, 1 H), 4.36 (d, J = 5.6 Hz, 2H), 4.23 (s, 4H). LCMS: (Method A) No ionisation (M+H), Rt. 1.3 min, 95.7% (Max)
With sodium tetrahydroborate; In dichloromethane; at 20℃; for 0.5h;
General procedure: To a solution of various benzaldehydes 4aew (10 mmol) dissolved in methanol (50 mL) was added sodium borohydride (20 mmol) at room temperature, and the mixturewas stirred at the same temperature for 30 min and concentrated under reduced pressure. The residue was diluted with methylene chloride (500 mL) and washed with water, and dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the corresponding crude phenylmethanols 5a-w
With methanol; sodium tetrahydroborate; at 0℃; for 2.5h;
General procedure: To a stirring solution of 2,5-dimethoxyl benzaldehyde 1a (0.67 g, 4 mmol) dissolved in anhydrous methanol (30 mL) was added NaBH4 (0.84 g, 22 mmol) in batches at 0 ºC over a period of 0.5 h. The reaction mixture was stirred at the same temperature for 2 h. After removal of the methanol under reduced pressure, the residue was diluted with methylene chloride (30 mL), washed with distilled water (3 Chi 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 2a.
With sodium tetrahydroborate; In ethanol; at 20℃; for 2h;
Sodium borohydride (0.38 g, 10 mmol) was added to a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1.64 g, 10 mmol) in anhydrous ethanol (29 mL) and the reaction mixture was stirred at room temperature for 2 h while monitoring by TLC. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate and distilled water. The organic layer was then dried over anhydrous Na2SO4, concentrated and purified by recrystallization.
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 1h;
To a stirred solution of (2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)methanol, Step 1 : Example 30, (0.3 g, 1.81 mmol) in dry DCM (3 mL), was added thionyl chloride (0.4 mL, 5.42 mmol) slowly at 0 C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, and the resulting residue was co-distilled with DCM (3 x 10 mL) and dried under vacuum to give the tittle compound. Yield: 95% (0.31 g, colourless gummy solid). LCMS: (Method A) No ionisation (M+H), Rt. 1.8 min, 82.3% (Max).
88%
In thionyl chloride;
6-Chloromethyl-2,3-dihydro-benzo[1,4]dioxine A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL*3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
With thionyl chloride; at 20℃; for 0.166667h;
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
12 g
With thionyl chloride; at 20℃; for 0.166667h;
A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL*3). The combined organic layers were washed with NaHCO3 (sat solution), water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next step.
With thionyl chloride; at 20℃; for 0.166667h;
Step c : 6-Chloromethyl-2,3-dihydro-benzo[l,4]dioxine; A mixture of (2,3-dihydro-benzo[l,4]dioxin-6-yl)methanol (10.6 g) in SOCl2 (10 mL) was stirred at room temperature for 10 min and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated solution OfNaHCO3 , water and brine, dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-dihydro- benzo[l,4]dioxine (12 g, 88% over two steps), which was used directly in next step without <n="78"/>further purification.
With phosphorus tribromide; In dichloromethane; at 0℃; for 0.5h;
To a solution of (2,3- dihydrobenzo[b][l,4]dioxin-6-yl)methanol (2.77 g, 16.66 mmol) in CH2CI2 was added PBn (0.63 mL, 6.66 mmol) dropwise at 0 C. The mixture was stirred at 0 C for 0.5 h. Upon completion, the mixture was diluted with CH2CI2 and washed with saturated NaHCCL. The organic layer was concentrated under vacuum. Colorless oil (hexanes :ethyl acetate = 20:1, 3.22 g, 84% yield) was isolated with column chromatography. 1 H NMR (500 MHz, Chlorol'ornw/) d 6.92 (d, J = 3.1 Hz, 1H), 6.88 (dd, J = 8.4, 2.5 Hz, 1H), 6.82 (dt, J = 8.4, 2.4 Hz, 1H), 4.44 (d, J = 2.0 Hz, 2H), 4.28 - 4.21 (m, 4H). 13C NMR (126 MHz, Chloroform-^/) d 143.82, 143.46, 130.93, 122.28, 118.02, 117.55, 64.39, 64.27, 33.82
80%
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 24h;
To a solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methanol (1.0 g, 6.0 mmol) in dichloromethane (25 mL) was added carbontetrabromide (3.0 g, 9 mmol), and triphenylphosphine (2.35 g, 9.0 mmol). The reaction mixture was stirred at room temperature for 24 h and concentrated under reduced pressure. Purification by column chromatography (Silica gel, EtOAc/Hexanes) resulted in 1.1 g (80% Yield) of 6-(bromomethyl)-2,3- dihydrobenzo[b][l,4]dioxine. MS (EI) for C9H9BrO2 found 229 (MH+)
37%
With phosphorus tribromide; In diethyl ether; at -40 - 20℃;
6-(Bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine. To a solution of(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methanol (46 g, 0.28 mol) in Et2O (1 L) at - 40 0C was added PBr3 (84 g, 0.3 mol, Aldrich) dropwise. The resulting mixture was stirred for 16 hoursat room temperature. The reaction was quenched by careful addition of H2O (1 L). The organic phase was separated, washed with H2O (2 x 1 L), dried (Na2SO4), filtered, and concentrated in vacuo to give the initial product, which was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100: 1 to 20: 1) to afford 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (23 g, 37 %).
With phosphorus tribromide; In dichloromethane; at 0℃; for 0.5h;
General procedure: To a solution of phenylmethanols 5a-w (5 mmol) dissolved in methylene chloride (50 mL) in an ice-water bath was added phosphorus tribromide (5.5 mmol), and the mixture was stirred at the same temperature for 30 min. The mixture was washed with cool water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield (bromomethyl)benzenes 6aew as offwhite solids or light yellow oils
With phosphorus tribromide; In dichloromethane; at 0 - 5℃; for 0.75h;
General procedure: crude product 2a which was then dissolved in anhydrous methylene chloride (50 mL) and cooled to 0-5 ºC by ice bath. To this solution was added dropwise phosphorus tribromide (0.5 mL, 5 mmol) over a period of 15 min and stirred for 0.5 h at the same temperature, and then washed with saturated brine (3 Chi 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 3a.
With boron tribromide; In dichloromethane; at 20℃; for 8h;
Boron tribromide (2.6 g, 10 mmol) was slowly added to a solution of 1 (1.66 g, 10 mmol) in anhydrous dichloromethane (10 mL) and the mixture was stirred at room temperature for 8 h while monitoring by TLC. The mixture was then concentrated under reduced pressure and saturated sodium bicarbonate solution was added to pH 7. The product was obtained by precipitation.
To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 C. under N2. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g). 1H NMR (300 MHz, DMSO-d6) delta 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
With NaOH; LiAlH4; In tetrahydrofuran; water;
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 C. under N2. The mixture was stirred at room temperature for 1 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g). 1H NMR (300 MHz, DMSO-d6) delta 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
10.6 g
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 11h;Inert atmosphere;
(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 C. under N2. The mixture was stirred at room temperature for 11 h and then quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to obtain (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g). 1H NMR (300 MHz, DMSO-d6) delta 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
Step b: (2,3-Dihydro-benzofl,4Jdioxin-6-yl)-methanol; To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[l,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0 0C under N2 atmosphere. The mixture was stirred at room temperature for 1 h and then quenched carefully by addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to yield (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methanol (10.6 g) that was taken into the next step without further purification. 1H NMR (300 MHz, DMSO-d6) delta 6.73-6.78 (m, 3 H), 5.02 (t, J = 5.7 Hz, 1 H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17-4.20 (m, 4 H).
methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate[ No CAS ]
[ 39270-39-8 ]
(2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-yl-methoxy)phenyl]propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 5 - 20℃; for 18 - 24h;
2,3-Dihydro-1 ,4-benzodioxin-6-ylmethanol (0.25 g, 1.5 mmol), methyl (2S)-2-(1 ,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate (0.31 g, 1 mmol) and triphenylphosphine (0.26 g, 1 mmol) were dissolved in 5 ml of tetrahydrofuran (THF). The reaction mixture was cooled to 5 C. DIAD (0.61 g, 3 mmol) was then added and the reaction was stirred at room temperature for 18-24h. Subsequently, THF was evaporated to obtain the product, the title acid methyl ester.The crude product was dissolved in a THF/MeOH/H2O mixture (6:0.1 :1 , 2 ml). 1M LiOH (1.6 ml) was added and the reaction was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated. The purification was performed by chromatography. The yield was 50%. MS (ES) 446 (M+, 100%)
methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)propionate[ No CAS ]
[ 39270-39-8 ]
Methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethoxy)phenyl]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 5 - 20℃; for 18 - 24h;
Step A: Methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethoxy)phenyl]propionate 2,3-Dihydro-1,4-benzodioxin-6-ylmethanol (0.25 g, 1.5 mmol), methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)-propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (3 ml). After cooling to 5 C., DIAD (0.61 g, 3 mmol) was added to the reaction mixture. The reaction was then stirred at room temperature for 18-24 h. THF was evaporated to obtain crude title product.
methyl 2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)oxy]-3-(4-hydroxyphenyl)propionate[ No CAS ]
[ 39270-39-8 ]
methyl 2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)oxy]-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyloxy)phenyl]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 5 - 20℃; for 18 - 24h;
Step A: Methyl 2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)oxy]-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylomethyloxy)phenyl]propionate 2,3-Dihydro-1,4-benzodioxin-6-ylmethanol (0.25 g, 1.5 mmol), methyl 2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)oxy]-3-(4-hydroxyphenyl)propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (3 ml). After cooling the reaction mixture to 5 C., DIAD (0.61 g, 3 mmol) was added. The reaction was then stirred at room temperature for 18-24 h. THF was evaporated to obtain crude title product.
methanesulfonic acid 2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Alcohol (5a) (640mg, 3.855mmol), was dissolved in dichloromethane (20mL). This solution was cooled to 0C and triethylamine (0.70mL, 5. 012mmol) was added. This was followed by the dropwise addition of methane sulfonylchloride (0.36mL, 4.627mmol). The resulting mixture was stirred at room temperature for 2 hours and then partitioned between a 10% aqueous solution of sodium hydrogen carbonate (25mL) and dichloromethane (2x l OOmL). The organic phases were combined and dried over magnesium sulfate. They were then dried under reduced pressure to afford the desired product which was used without further purification (1. OOg, 60% w/w).
2-([(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)oxy]carbonyl}amino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
2,3-Dihydro-1 ,4-benzodioxin-6-ylmethanol (0.025g, 0.15mmol) was treated with a solution of methyl 2-isocyanatobenzoate (0.04g, 0.24mmol) and triethylamine EPO <DP n="25"/>(0.035ml, 0.25mmol) in THF (1ml). After stirring at ambient temperature for 18 hours the mixture was heated at 6O0C for 3 hours then cooled. The mixture was subsequently treated with a solution of lithium hydroxide (0.011g, 0.46mmol) in a mixture of of methanol (0.65ml) and water (0.65ml) then heated at 450C for 3 hours. The mixture was cooled, filtered and the filtrate acidified to about pH 4 using 2M aqueous hydrochloric acid. The precipitated material was filtered off and from this the product was obtained using reverse-phase HPLC. This gave the title compound as a white solid (0.0047g, 10%). NMR; deltaH (400MHz, d6-DMSO) 4.23(s, 4H), 5.04(s, 2H), 6.84-6.94(m, 3H), 7.11(t, 1 H, J=7.3Hz), 7.60(dt, 1H, J=1.5, 7.0Hz), 7.97(dd, 1 H, J=1.5, 8.0Hz)1 8.28(d, 1H1 J=8.3Hz), 10.77(s, 1 H)1 13.71(br s, 1H); m/z 347[MNH4+].
With thionyl chloride; triethylamine; In sodium-dried diethyl ether; toluene;
EXAMPLE 5 3-Benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea 1,4-Benzodioxan-6-ylmethanol (1.55 g, 9.34 mmol) and thionyl chloride (1.7 g, 14.29 mmol) were refluxed in sodium-dried diethyl ether (30 cm3) for 3 hours then the solvent and excess thionyl chloride evaporated. The residue was dissolved in toluene (20 cm3), thionyl chloride (1.7 g, 14.29 mmol) was added and the solution heated and stirred at 80 C. for 3 hours. Evaporation of the solvent gave a residue. 4-Benzoylureidopiperidine (2.0 g, 8.1 mmol) and triethylamine (1.09 g, 10 mmol) were added to the residue and refluxed in isopropyl alcohol overnight. The isopropyl alcohol was evaporated and the residue triturated with water. The water was decanted and the residue crystallized from isopropyl alcohol (1.64 g). The base was suspended in refluxing isopropyl alcohol, ethanolic HCl was added and the mixture filtered. The filtrate was cooled at 5 C. overnight and the title compound collected and dried as the hydrochloride, quarterhydrate (1.46 g), m.p. 231-235 C. Analysis: C22 H25 N3 O4.HCl.1/4H2 O requires: C, 60.55; H, 6.12; N, 9.63%. Found: C, 60.74; H, 6.27; N, 9.38%.
With thionyl chloride; triethylamine; In sodium-dried diethyl ether; toluene;
EXAMPLE 5 3-Benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]-urea 1,4-Benzodioxan-6-ylmethanol (1.55 g, 9.34 mmol) and thionyl chloride (1.7 g, 14.29 mmol) were refluxed in sodium-dried diethyl ether (30 cm3) for 3 hours then the solvent and excess thionyl chloride evaporated. The residue was dissolved in toluene (20 cm3), thionyl chloride (1.7 g, 14.29 mmol) was added and the solution heated and stirred at 80 C. for 3 hours. Evaporation of the solvent gave a residue. 4-Benzoylureidopiperidine (2.0 g, 8.1 mmol) and triethylamine (1.09 g, 10 mmol) were added to the residue and refluxed in isopropyl alcohol overnight. The isopropyl alcohol was evaporated and the residue triturated with water. The water was decanted and the residue crystallized from isopropyl alcohol (1.64 g). The base was suspended in refluxing isopropyl alcohol, ethanolica HCl was added and the mixture filtered. The filtrate was cooled at 5 C. overnight and the title compound collected and dried as the hydrochloride, quarterhydrate (1.46 g), m.p. 231-235 C. Analysis: C22 H25 N3 O4.HCl.1/4H2 O requires: C, 60.55; H, 6.12; N, 9.63%. Found: C, 60.74; H, 6.27; N, 9.38%.
EXAMPLE 1 A solution of 16.6 g of 1,4-benzodioxan-6-methanol in 20 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. 11.8 g of propargyl bromide are then added dropwise. The mixture is stirred for 3 hours at room temperature, cooled in an ice-bath, decomposed with 20 ml of ice-water, diluted with 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The ether extract is washed with water, dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using benzene as the elution agent. There is obtained 6-[(2-propynyloxy)methyl]-1,4-benzodioxan; nD24 = 1.5487.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 45℃; for 24h;
((S)- 1 -f5-Benzyl-7-cvano-3-(2,3-dihvdro-benzof1.41dioxin-6-ylmethvn-4 -oxo-4.5-dihydro- 3H-pyrrolor3,2-d1pyrimidin-6-yll-piperidin-3-yl}-carb amic acid tert-butyl esterTriphenyl phosphine (52.4mg, 0.20mmol) followed by diethyl azodicarboxylate (31 ?L, 0.20mmol) were added to a solution of [(S)-I -(5-benzyl-7-cyano-4-oxo-415-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester (75mg, 0.167mmol) and (2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-MeOH (27.7mg, 0.167mmol) in THF (2mL) and the mixture was stirred at room temperature for 18 hours then heated to 45 CC for 6 hours. The solvent was removed under a stream of nitrogen at 300C and the residue was partially purified by flash chromatography (Silica, gradient eiution using DCM to 30% ethyl acetate in DCM) and finally purified by reversed phase HPLC (5% to 95% MeCN in water + 0.1 % HCO2H at 5 mL/min) to give the title compound which was used directly in the next step.
7-[3-aminomethyl-4-(3',4'-ethylenedixoybenzyloxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naph-thyridine-3-carboxylic acid dimesylate[ No CAS ]
(2S,3S,4R,5S,6R)-2-(acetoxymethyl)-6-(((E)-4-(2-((2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methoxy)-2-oxoethyl)-3-ethylidene-5-(methoxycarbonyl)-3,4-dihydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
General procedure: To a solution of oleoside 11-methylester tetraacetate 3 or oleoside tetraacetate 5 (1 equiv.) in dichloromethane were added at 0C 1.2 equiv of trichlorobenzoyl chloride and 1.4 equiv triethylamine. After 2h stirring at room temperature, the mixture was cooled to 0C and a solution of alcohol/thiol/amine (1.5 equiv.) in dichloromethane and DMAP (1.4 equiv.) were added. After stirring for 2hat room temperature, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with dichloromethane and ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (cyclohexane/ethylacetate 1:1) led to the acetylated derivatives.
(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine; In dichloromethane; at 20℃;
General procedure: To a solution of benzyl or hetero-benzyl alcohols (2.0 mmol) in CH2Cl2 (6 mL) was added acetyl chloride (173 mg, 2.2 mmol) and Et3N (202 mg, 2.0 mmol). The reaction mixture was stirred at room temperature until completion (monitored by TLC), and then water (30 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was puried by flash chromatography (petroleum ether/ethyl acetate 300:1 to 50:1) to give the products 5a-5l and 5q-5t.
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