| 100% |
Stage #1: With sodium tetrahydroborate In methanol at 0 - 18℃; for 1 h;
Stage #2: With water In dichloromethane |
V) Synthesis of CP30347-8; 4,4-Ethylenedioxycyclohexan-l-ol (41); Following protocols reported by Kitano et al.,s a magnetically stirred solution of 1,4- cyclohexanedione monoethylene acetal 40 (5.00 g, 32.0 mmol) in MeOH (30 mL), maintained at 0 0C, was treated with sodium borohydride (1.57 g, 41.5 mmol). After 0.5 h, the reaction mixture was warmed to 18 °C and stirred at this temperature for an additional 0.5 h. The solvent was then removed under reduced pressure and the ensuing residue partitioned between H2O (30 mL) and CH2Cl2 (30 mL). The separated aqueous phase was extracted with CH2Cl2 (1 x 20 mL) and the combined organic fractions were then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 41 (5.06 g, quant.) as a colourless oil. <n="84"/>1H NMR (300 MHz) δ 3.96-3.88 (complex m, 4H), 3.77 (m, IH), 1.90-1.75 (complex m, 5H), 1.68-1.50 (complex m, 4H). |
| 100% |
at 0 - 20℃; for 3 h; |
The reduction of the free keto group in 3 followed by the methylation of the resulting alcohol affords methoxy derivative 5. |
| 99% |
With methanol; sodium tetrahydroborate In tetrahydrofuran at 0℃; for 3 h; Inert atmosphere |
Into a 2-L 3-necked round-bottom flunder nitrogen, was placed 153.1 (100 g, 640.29 mmol, 1.00 equiv), THF (0.8 L), MeOH (0.16 L) and NaBH4 (12.18 g, 321.97 mmol, 0.50 equiv). The reaction was stirred for 3 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of 1 L of H4C1 (aq). The resulting mixture was concentrated under vacuum, and then extracted with 3 x 2 L of EtOAc . Organic layers were combined and washed with 3 x 500 mL of Brine. The crude was purified by column chromatography to provide 100 g (99.0 percent) of 153.2 as light yellow oil. |
| 96% |
With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; Inert atmosphere |
Synthesis of compound 7 (1,4-dioxaspiro[4.5]denan-8-ol)In a dry 250 ml flask 2.5 g (68.5 mmole, 1 eq.) LiAlH4 was suspended in 20 ml dry diethyl ether. The flask was placed under inert N2-atmosphere and cooled to 0° C. 10.4 g (66.6 mmole, 1 eq.) 1,4-dioxaspiro[4.5]decan-8-one 6 was dissolved in 100 ml dry diethyl ether and slowly added to the suspension. The reaction mixture was stirred for 30 minutes at room temperature. Water, diluted with THF, was added in order to remove the excess LiAlH4. The reaction mixture was filtrated over MgSO4 and the volatile components were removed by evaporation. |
| 96% |
at 20℃; for 3 h; |
l,4-Dioxaspiro[4.5]decan-8-ol (14-1): Sodium borohydride (0.8 g, 21 mmol, 1.05 equiv) was added at 0 to 10 °C in portions to a solution ofl ,4-dioxaspiro[4.5]decan-8-one (SM14) (3.1 g, 20 mmol, 1.0 equiv) was dissolved in methanol (50 mL). The mixture was stirred at room temperature for 3 h and concentrated under reduced pressure to remove most of solvent. Water (50 mL) was added and the mixture and stirred for 30 minutes. The mixture was extracted with ethyl acetate (3 x 50 mL)and the combined organic layers were washed with sequentially with IN HC1 (30 mL), water and saturated brine . The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 14-1 (3.0 g, 96percent yield) as a colorless oil which was used subsequently . |
| 96% |
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide; water In ethanol |
Description 1; . 1,4-dioxaspiro[4.5]decan-8-ol (D1) <n="52"/>1 ,4-Dioxaspiro[4.5]decan-8-one (256 mmol, 40 g) was dissolved in EtOH (500 ml) and treated with NaBH4 (1.2eq., 307.2 mmol, 11.6 g), at O 0C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (200 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane. The organic extracts were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, (38.7 g, 96percent) as colourless oil. 1H NMR δ(d6-DMSO, 400 MHz) 1.446 (4H, m), 1.661 (4H, m), 3.537 (1 H, broad), 3.828 (4H, m), 4.529 (1 H, d). |
| 95% |
With sodium tetrahydroborate In methanol for 0.5 h; |
1 ,4-Dioxaspiro[4.5]decan-8-one (60 g, 384 mmol) was dissolved in methanol (600 mL) under Argon, then sodium borohydride (15.99 g, 423 mmol) was added portionwise (the addition was exothermic and a huge gas evolution was observed). The resulting mixture was stirred for 30 min. The reaction was quenched with water (200 mL) and stirred for 10 min. Solvent was removed under reduced pressure and the residue taken-up with DCM (600 mL) and water (300 mL). Phases were separated then the aqueous phase extracted with DCM (1 x 600 mL). Combined organic phases were dried on Na2SO4 and concentrated under vacuum to obtain title material (58 g; 95percent) as colourless oil.1H NMR δ (CDCI3, 400 MHz): 1.64 (4H, m), 1.87 (4H, m), 3.83 (1 H, m), 3.97 (4H, dt). |
| 95.2% |
Stage #1: With sodium tetrahydroborate In methanol at 0℃; for 1.5 h;
Stage #2: With hydrogenchloride In methanol; water |
To a solution of 1,4-cyclohexanedione monoethylene acetal (3.41 g, 21.8 mmol) in 50 ml methanol cooled to 0° C. was added sodium borohydride (0.826 g, 21.8 mmol) in portions. The reaction was stirred for an additional 1.5 hr before being brought to pH 7 by the addition of 1 N HCl. The mixture was partitioned between ethyl acetate and brine. The aqueous layer was concentrated to the point that a precipitate began to form and this layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. This crude alcohol (3.28 g, 95.2percent) was used without further purification. 1H NMR (CDCl3) δ: 1.54-1.87 (8H, m, 4.x.-CH2-), 3.77 (1H, m, -CH-), 3.91 (4H, t, 2.x.O-CH2-). |
| 94% |
With sodium tetrahydroborate In methanol at 0℃; for 3 h; |
NaBH4 (2.42 g, 64 mmol) was added portionwise to a cold (0 0C) solution of 1 ,4- dioxaspiro[4.5]decan-8-one (5.00 g, 32 mmol) in MeOH (30 ml_). The solution was stirred at 0 0C for 3 hours, concentrated under reduced pressure and 5percent aqueous NaOH was added. The solution was extracted with 2-propanol/CHCI3 (1 :4, 2x100 ml_). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as an oil (4.74 g, 94 percent yield).1H NMR (300 MHz, CDCI3) 4.02-3.92 (4H, m), 3.85-3.77 (1 H, m), 1.94-1.80 (4H, m), 1.73- 1.56 (4H, m). |
| 94% |
at 20℃; for 2 h; |
Commercially available 1,4-cyclohexadione monoethylene acetal (5 g, 32 mmol) was dissolved in methanol (65 mL) and the mixture was placed in a cold-water bath. Sodium borohydride (1.9 g, 50 mmol) was added in small portions (exotherm). After the addition was completed, the mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was dissolved in ethyl acetate (150 mL), water (40 mL) and 1 M NaOH (10 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (4.x.75 mL). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed to afford the title compound as a colorless liquid (4.8 g, 94percent).1H-NMR (400 MHz, CDCl3): δ=1.53-1.70 (m, 4H), 1.78-1.95 (m, 4H), 3.77-3.83 (m, 1H), 3.94-3.97 (m, 4H) |
| 94% |
at 20℃; for 1 h; Inert atmosphere; Cooling with ice |
In a 250 ml three-mouth bottle by adding 15.8g (0.1mol) of 1,4-cyclohexanedione monoethylene ketal, 100 ml of anhydrous methanol, under nitrogen protection and ice bath stirring condition for 10 min, then added 1g (1.1mol) of NaBH4, this reaction stirred under room temperature for 60 min, raw material by thin layer chromatography (TLC) to determine a basic after the reaction is complete, add 30 ml of water to stop the reaction, with 30 ml dichloromethane sub-2 time extraction, from the separatory funnel for methylene chloride level, with 20 ml water 2 times of cleaning, the resulting organic phase is dried with anhydrous sodium sulfate sleepovers, pulls out worry, desolution of the oily liquid to obtain yellow product 14.8g, the yield is 94percent. |
| 93% |
With sodium hydroxide In methanol; sodium tetrahydroborate; isopropyl alcohol |
1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)
1,4-dioxaspiro[4.5]decan-8-one (150 g, 0.96 mol) was stirred with MeOH (1200 mL) under N2 until dissolution occurred.
The reaction mixture was cooled to -5° C. in a drykold/acetone bath and treated portionwise with NaBH4 (72.6g, 1.82 mol) over 2 hrs. (T<10° C.).
On complete addition, the mixture was cooled to -10° C. and then left to warm to room temperature and stirred overnight at room temperature.
The resulting mixture was evaporated and treated with ice-cold 5N NaOH (400 mL) and extracted with CH2Cl2 (2*500 mL) followed by extraction with 4:1 dichloromethane:isopropanol (2*250 mL).
The combined extracts were washed with brine (2*200 mL), dried overnight (Na2SO4) and evaporated to give a colourless oil.
This was further dried in vacuo (to remove residual isopropanol) to give 1,4-dioxaspiro[4.5]decan-8-ol 141.8 g, 93percent yield. 1H NMR: CDCl3 (250 MHz): 3.91 (4H, m), 3.81 (1H, m), 1.21-1.88 (8H, m, aliphatic H's).
|
| 93% |
With sodium hydroxide In methanol; sodium tetrahydroborate |
1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)
1,4-dioxaspiro[4.5]decan-8-one (150 g, 0.96mol) was stirred with MeOH (1200 mL) under N2 until dissolution occurred.
Cooled to -5° C. in a drykold/acetone bath and treated portionwise with NaBH4 (72.6 g, 1.82 mol) over 2hrs. (T<10° C.).
On complete addition, the mixture was cooled to -10° C. and then left to warm to room temperature.
Stirred overnight at room temperature.
The resulting mixture was evaporated and treated with ice-cold 5N NaOH (400 mL) and extracted with CH2Cl2 (2*500 mL) followed by extraction with 4:1 dichloromethane:isopropanol (2*250 mL).
The combined extracts were washed with brine (2*200 mL), dried overnight (Na2SO4) and evaporated to give a colourless oil.
This was further dried in vacuo to give 1,4-dioxaspiro[4.5]decan-8-ol (141.8 g, 93percent yield.)1H NMR: CDCl3 (250 MHz) 3.91 (4H, m), 3.81 (1H, m), 1.21-1.88 (8H, m, aliphatic H's).
|
| 93% |
With sodium hydroxide In methanol; sodium tetrahydroborate; isopropyl alcohol |
1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)
1,4-dioxaspiro[4.5]decan-8-one (150 g, 0.96 mol) was stirred with MeOH (1200 mL) under N2 until dissolution occurred.
The reaction mixture was cooled to -5° C. in a drykold/acetone bath and treated portionwise with NaBH4 (72.6 g, 1.82 mol) over 2 hrs. (T<10° C.).
On complete addition, the mixture was cooled to -10° C. and then left to warm to room temperature and stirred overnight at room temperature.
The resulting mixture was evaporated and treated with ice-cold 5N NaOH (400 mL) and extracted with CH2Cl2 (2*500 mL) followed by extraction with 4:1 dichloromethane:isopropanol (2*250 mL).
The combined extracts were washed with brine (2*200 mL), dried overnight (Na2SO4) and evaporated to give a colourless oil.
This was further dried in vacuo (to remove residual isopropanol) to give 1,4-dioxaspiro[4.5]decan-8-ol 141.8 g, 93percent yield. 1H NMR: CDCl3 (250 MHz): 3.91 (4H, m), 3.81 (1H, m), 1.21-1.88 (8H, m, aliphatic H's).
|
| 93% |
With sodium hydroxide In methanol; sodium tetrahydroborate |
1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)
1,4-dioxaspiro[4.5]decan-8-one (150 g, 0.96 mol) was stirred with MeOH (1200 mL) under N2 until dissolution occurred.
Cooled to -5° C. in a drykold/acetone bath and treated portionwise with NaBH4 (72.6 g, 1.82 mol) over 2hrs. (T<10° C.).
On complete addition, the mixture was cooled to -10° C. and then left to warm to room temperature.
Stirred overnight at room temperature.
The resulting mixture was evaporated and treated with ice-cold 5N NaOH (400 mL) and extracted with CH2Cl2 (2*500 mL) followed by extraction with 4:1 dichloromethane:isopropanol (2*250 mL).
The combined extracts were washed with brine (2*200 mL), dried overnight (Na2SO4) and evaporated to give a colourless oil.
This was further dried in vacuo to give 1,4-dioxaspiro[4.5]decan-8-ol (141.8 g, 93percent yield.)1H NMR: CDCl3 (250 MHz) 3.91 (4H, m), 3.81 (1H, m), 1.21-1.88 (8H, m, aliphatic H's).
|
| 93% |
at 0 - 20℃; for 3 h; |
Step 1.
Preparation of 1,4-dioxaspiro[4.5]decan-8-ol.
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (15.0 g, 96 mmol) in MeOH (240 mL) was added NaBH4 (4.00 g, 106 mmol) in small portions at 0° C.
After being stirred for 3 hours at room temperature, the reaction mixture was concentrated in vacuo and brine was added.
The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered and passed through a short pad of silica gel and concentrated in vacuo to give the desired product (14.2 g, 93percent) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 1.54-1.67 (4H, m), 1.79-1.91 (5H, m), 3.77-3.83 (1H, m), 3.91-3.98 (4H, m). |
| 92% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h; |
To a solution of 1,4-dioxa-spiro [4.5] decan-8-one (16) (Aldrich, 10.0 g, 64.0 mmol) in anhydrous methanol (250 mL) at 0 C was added solid sodium borohydride (4.6 g, 121 mmol). The reaction mixture was allowed to warm to rt over 1 h, whereupon TLC analysis indicated complete reaction. Water (60 mL) was added, and the methanol was removed under reduced pressure. The aqueous residue was partitioned between ethyl acetate (200 mL) and saturated aqueous brine (50 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate (200 mL). The combined organic layers were dried (Mg04), filtered and concentrated under reduced pressure to afford the crude alcohol 17 (9.3 g, 92percent) : Rf = 0.2 (CH2CI2) ; H NMR (300 MHz, CDCI3) (5 3. 95 (s, 4H), 3.85-3. 75 (m, 1 H), 2.00-1. 75 (m, 4H), 1.75-1. 50 (m, 4H). |
| 92% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h; |
To a solution of 1,4-dioxa-spiro [4.5] decan-8-one (Aldrich, 10.0 g, 64.0 mmol) in anhydrous methanol (250 mL) at 0 °C was added solid sodium borohydride (4.6 g, 121 mmol). The reaction mixture was then allowed to warm to room temperature over 1 h, whereupon TLC analysis indicated complete reaction. Water (60 mL) was added, and the methanol was removed under reduced pressure. The aqueous residue was partitioned between ethyl acetate (200 mL) and saturated aqueous brine (50 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate (200 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford the crude alcohol 2 (9.3 g, 92percent): Rf = 0.2 (CH2CI2) ; 1H NMR (300 MHz, CDC13) 6 3.95 (s, 4H), 3.85-3. 75 (m, 1 H), 2.00-1. 75 (m, 4H), 1.75-1. 50 (m, 4H). |
| 92% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h; |
To a solution of 1,4-dioxa-spiro [4.5] decan-8-one (Aldrich, 10.0 g, 64.0 mmol) in anhydrous methanol (250 mL) at 0°C was added solid sodium borohydride (4.6 g, 121 mmol). The reaction mixture was then allowed to warm to room temperature over 1 h, whereupon TLC analysis indicated complete reaction. Water (60 mL) was added, and the methanol was removed under reduced pressure. The aqueous residue was partitioned between ethyl acetate (200 mL) and saturated aqueous brine (50 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate (200 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated under reduced pressure yielding the crude alcohol 2 (9.3 g, 92percent): Rf = 0.2 (CH2CI2) ; H NMR (300 MHz, CDCI3) ; 6 3.95 (s, 4H), 3.85-3. 75 (m, 1 H), 2.00-1. 75 (m, 4H), 1.75-1. 50 (m, 4H). |
| 92% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h; |
1,4-dioxa-spiro [4. 5] decan-8-ol (66) from 1,4-dioxa-spiro [4. 5] decan-8-one (65) To a solution of 1,4-dioxa-spiro [4.5] decan-8-one (65) (Aldrich, 10.0 g, 64.0 mmol) in anhydrous methanol (250 mL) at 0 C was added solid sodium borohydride (4.6 g, 121 mmol). The reaction mixture was allowed to warm to rt over 1 h, whereupon TLC analysis indicated complete reaction. Water (60 mL) was added, and the methanol was removed under reduced pressure. The aqueous residue was partitioned between ethyl acetate (200 mL) and saturated aqueous brine (50 mL). The layers were separated, and the aqueous extracted with addition ethyl acetate (200 mL). The combined organic layers were dried (MgS04), filtered and concentrated under reduced pressure to afford the crude alcohol 66 (9.3 g, 92percent): Rf = 0.2 (CH2CI2) ; H NMR (300 MHz, CDCI3) 63. 95 (s, 4H), 3.85-3. 75 (m, 1 H), 2.00-1. 75 (m, 4H), 1.75-1. 50 (m, 4H). |
| 90% |
at 0 - 20℃; for 2.25 h; |
Sodium borohydride (370 mg, 9.6 mmol) was added portion wise to a stirred solution of 1,4- dioxa-spiro[4.5]decan-8-one (1.0 g, 6.4 mmol) in methanol (10 mL) over a period of 15 mm at 0 °C. Reaction mass was warmed to room temperature and stirred for 2h. Methanol was evaporated and the residue diluted with water. Extracted with ethyl acetate, the organic layerdried over anhydrous sodium sulfate and evaporated to afford 0.9 g (90percent) of 1, 4-dioxa- spiro[4.5]decan-8-ol as a brown oil. [TLC system: 3:7 Ethyl acetate Pet ether; Rrvalue: 0.15] |
| 87% |
at 10 - 20℃; for 0.5 h; |
To a solution of l,4-dioxaspiro[4.5]decan-8-one (244 g, 1.56 mol, 1.0 eq.) in MeOH (5 L) was slowly added NaBH4 (59 g, 1.56 mol, 1.0 eq.) keeping the internal temperature <10 °C using an ice bath. The ice bath was removed and the mixture was stirred for 30 min at room temperature. The solvent was then removed under reduced pressure and the resulting solid was dissolved in 50percent diethyl ether in EtOAc (5 L), washed with saturated aqueous NH4CI (800 mL X 3), brine (800 mL), dried over Na2S04, filtered, and evaporated to give 215 g (87percent yield) of l,4-dioxaspiro[4.5]decan-8-ol. GC-MS: 159 (M+l).. |
| 84% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 3 h; |
1.28 g of Sodium borohydride (33.9 mmol, 1.06 eq) were added to a 0 °C cold solution of 5.00 g of 1,4-dioxaspiro[4.5]decan-8-one, S16, (32.0 mmol, 1.0 eq) in 75 mL of abs. methanol. The mixture was stirred for 3 hours at room temperature. After neutralization with 1 M hydrochlorid acid the solution was extracted with dichoromethane (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure giving 4.25 g (84percent) of a colorless oil. |
| 84% |
With sodium borohydrid In ethanol; water |
1.
1,4-Dioxaspiro[4.5]decan-8-ol
A stirred, cooled (5° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 0.128 mol) in ethanol (250 ml) was treated with sodium borohydride (7.3 g, 0.192 mol) in portions over 20 minutes.
The reaction mixture was stirred at 5° C. for 1 hour then at room temperature for 1 hour.
Water (20 ml) was added and the mixture was stirred vigorously for 10 minutes then concentrated in vacuo.
The residue was partitioned between water (100 ml) and ethyl acetate (100 ml).
The organic layer was separated and the aqueous re-extracted with ethyl acetate (100 ml).
The combined organics were dried (sodium sulphate) then evaporated to give the title alcohol as a colourless oil (17.1 g, 84percent). MS ES+, m/z=159 for (M+H)+; δ(360 MHz, CDCl3) 1.52-1.71 (4H, m), 1.78-1.92 (4H, m), 3.76-3.83 (1H, m), 3.91-3.94 (4H, m).
|
| 83% |
With sodium tetrahydroborate In methanol at 20℃; for 16 h; Inert atmosphere |
Into a 500 ml 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.06 mmol, 1.00 equiv.), methanol (200 ml). Then NaBH4 (3.9 g, 105.91 mmol, 0.83 equiv.) was added at 0 °C. The resulting solution was stuffed at room temperature for 16 h. The reaction was then quenched by the addition of 100 ml of NH4C1 (sat. aq.). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 ml of H20. The resulting solution was extracted with 3x200 ml of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 16.84 g of the title compound as a colorless oil (83percent). ‘H NMR (300 MHz, CDC13) & 4.0 1-3.89 (m, 4H), 3.88-3.76 (m, 1H), 1.95-1.74 (m, 4H), 1.74-1.52 (m, 4H). |
| 82% |
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h; |
1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml_) and treated with NaBH4 (1.2 eq., 76.8 mmol, 2.9 g), at 0 0C portionwise and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml_, 2N aqueous solution). The aqueous solution was extracted with dichloromethane (2 x). The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82percent, as a colourless oil.1H NMR δ ( DMSO-d6, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1 H, d broad), 3.82 (4H, m), 4.48 (1 H, d). |
| 82% |
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide In ethanol; water |
1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and treated with NaBH4 (1.2eq., 76.8 mmol, 2.9 g), at O0C portionwise and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane (2x). The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82percent, as a colourless oil.1H NMR δ (d6DMSO, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1 H, d broad), 3.82 (4H, m), 4.48 (1 H, d). |
| 82% |
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide; water In ethanol |
Description s. 1 ,4-Dioxaspiro[4.5]decan-8-ol (D8); .1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and treated portionwise with NaBH4 (1.2eq., 76.8 mmol, 2.9 g), at O0C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane. The organic extracts were combined, dried over Na2SC>4, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82percent, as a colourless oil. 1H NMR δ (d6DMSO, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1 H, d broad), 3.82 (4H, m), 4.48 (1 H, d). |
| 82% |
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide; water In ethanol |
Description 3. 1,4-Dioxaspiro[4.5]decan-8-ol (D3); 1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and treated with NaBH4 (1.2eq., 76.8 mmol, 2.9 g), at O0C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane (2x). The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82percent, as a colourless oil.1HNMR q (d6DMSO, 400 MHz) 1.443 (4H, m), 1.645 (4H, m), 3.549 (1 H, d broad), 3.827 (4H, m), 4.480 (1 H, d). |
| 82% |
Stage #1: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide; water In ethanol |
Description 4. 1,4-Dioxaspiro[4.5]decan-8-ol (D4); 1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and treated with NaBH4 (1.2eq., 76.8 mmol, 2.9 g), at O0C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane (2x). The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82percent, as a colourless oil. 1HNMR D (d6DMSO, 400 MHz): 1.44 (4H, m), 1.65 (4H, m), 3.55 (1 H, d broad), 3.83 (4H, m), 4.48 (1 H, d). |
| 63% |
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2 h; |
At RT, l,4-dioxaspiro[4.5]decan-8-one (5.00 g, 32.01 mmol, 1.00 equiv) was dissolved in THF (50 mL). This was followed by the addition of LiAlH4 (1.22 g, 32.14 mmol, 1.00 equiv) in portions at 0 °C over 5 min period. The mixture was then stirred for 2 h at 0 °C. The reaction was then quenched by the addition of 10 mL water. The pH value of this mixture was adjusted to 1.0 with HC1 solution (2 M), which was extracted with 3 x 100 mL ethyl acetate. The organic phases were combined and washed with 2 x 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield l,4-dioxaspiro[4.5]decan-8-ol as colorless oil (3.2 g, 63percent). |
| 61% |
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 0.0833333 h;
Stage #2: With hydrogenchloride In methanol; water at 0℃; |
Example 117 cis-2-methyl-3-(4-[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone and trans-2-methyl-3-(4-[4-(1-pyrrolidinyl)cyclohexyl]oxy}phenyl)-4(3H)-quinazolinone (1) Manufacture of 1,4-dioxaspiro[4.5]decan-8-ol 1,4-dioxaspiro[4.5]decan-8-one (1.0 g, 6.40 mmol) was dissolved in methanol (10 mL), sodium borohydride (242 mg, 6.40 mmol) was slowly added, and stirred at room temperature for 5 minutes. The mixture was cooled on an ice bath, 10percent hydrochloric acid aqueous solution and sodium chloride were added, and the mixture extracted with ethyl acetate. The organic phase was washed with saturated brine, and dried by anhydrous sodium sulfate. The sodium sulfate was filtered off, and the product concentrated under reduced pressure to obtain the target compound (614 mg, 61percent) as a light yellow oily substance. |
| 59% |
With sodium tetrahydroborate In methanol at 0 - 20℃; for 2 h; |
To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32.0 mmol, Lobochem) in dry MeOH (50 mL) was added Sodium borohydride (1 .8 g, 48.0 mmol) portion wise at 0 00. The reaction mixture was stirred at RT for 2h. Reaction completion was monitored by TLC. Reaction mixture was quenched with ice. The reaction mixture was concentrated completely and extracted with dichloromethane, washed with water (2 x 30 mL) andbrine solution (2 x 20 mL). Combined organic layers were dried over anhydrous Na2504, filtered, concentrated and the crude mass obtained as brown liquid was used as such for next step without further purification (3 g, 59percent). 1H NMR (400 MHz, DMSO-d6: 6 4.47 (d, J = 4.0 Hz, 1 H), 3.85-3.80 (m, 4H), 3.55 (s, 1 H), 1.66-1.64 (m, 4H), 1.48-1.42 (m, 4H). |
| 750 mg |
With sodium tetrahydroborate In methanol at 30℃; for 1 h; |
To a solution of 1 ,4-dioxaspiro[4.5]decan-8-one (1 .0 g) in methanol (3 mL) was added NaBH4 (0.2 g). The mixture was stirred at 30°C for 1 hour, and then poured into H20 (20 mL). The mixture was extracted with EA (10 mL). The organic layer was washed with brine, driedover Na2SO4, and concentrated to afford 1 ,4-dioxaspiro[4.5]decan-8-ol (750 mg). |
| 57 g |
at 0 - 25℃; Inert atmosphere |
To a mixture of l,4-dioxaspiro[4.5]decan-8-one (60 g, 384 mmol) in MeOH (750 mL) was added NaBH4 (43.6 g, 1.15 mol) slowly at about 0° C under N2 atmosphere. The reaction was stirred at about 25 °C for about 2. The reaction mixture was cooled to about 0° C and water was added to quench the reaction. The reaction was concentrated to remove the MeOH and the residue was extracted with EtOAc (3 x200 mL). The organics were combined, dried over MgS04 filtered and concentrated to give the intermediate, 1,4- dioxaspiro[4.5]decan-8-ol (57 g). |
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