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Structure of 69947-09-7 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 29, p. 5589 - 5592
[2] Synthesis, 1992, # 11, p. 1080 - 1082
[3] Tetrahedron, 2002, vol. 58, # 8, p. 1557 - 1563
[4] Journal of Organic Chemistry, 2002, vol. 67, # 7, p. 2197 - 2205
[5] Patent: US2005/261327, 2005, A1, . Location in patent: Page/Page column 17; 26
2
[ 69947-09-7 ]
[ 34916-10-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogenchloride; boric acid In tetrahydrofuran; water at 60℃; for 2 h;
Add 1,4-dioxaspiro[4,5]nonane-8-carbonitrile 200.6 g (1.2 mol), boric acid 72 g (1.2 mol), water 2000 mL (10 V), hydrochloric acid in a 5000 mL three-necked flask. 1000 mL (5 V), tetrahydrofuran 500 mL (2.5 V), heated to 60 ° C,The reaction was carried out for two hours, sampled, and sent to the GC for detection. The remaining amount of the raw material was <2percent, and the reaction was completed.Decrease to room temperature, add dichloromethane, extract three times, combine the dichloromethane layer, distill off the dichloromethane under reduced pressure, and rectify the product under the condition of 100 ° C 2 mmHg.4-cyanocyclohexanone 140.4 g, GC purity 98percent, yield 95percent.
75%
With ammonium cerium(IV) nitrate In water; acetonitrile at 70℃; for 0.75 h;
4-OxocyclohexanecarbonitriIeA solution of ammonium cerium (IV) nitrate (3.70 g, 6.75 mmol) in water (100 mL) was added to a solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (11.3 g, 67.5 mmol) in MeCN (200 mL) and water (100 mL) at 700C. The reaction mixture was stirred for 45 minutes at 7O0C and cooled to ambient temperature where 100 mL of water were added. The product was extracted with ether (4 x 200 mL). The combined organics were EPO <DP n="10"/>washed with brine and dried over MgSO4. The product was purified by flash chromatography on silica gel using EtOAc 50percent in hexane as eluent to afford the title compound as a colorless liquid. Yield: 6.30 g (75percent). 1H NMR (400 MHz, CHLOROFORM-D): δ 2.07 - 2.31 (m, 4 H), 2.34 - 2.53 (m, 2 H), 2.54 - 2.72 (m, 2 H), 2.95 - 3.14 (m, I H).
68%
With hydrogenchloride In water at 20℃; for 2 h;
Step 2: A mixture of compound 116-1 (3 g, 18 mmol) in conc. hydrochloric acid / H2O (v/v = 1:1, 20 mL) wasstirred at room temperature for 2h. The reaction mixture was adjusted to pH = 8 with NaOH, and extracted with EtOAc.The combined extraction liquid was washed with brines, dried over sodium sulfate and concentrated to dry, finally purifiedby column chromatography (PE:EtOAc = 1:1) to deliver compound 116-3 (1.5 g, yield 68percent) as colorless oil.
Reference：
[1] Patent: CN108329234, 2018, A, . Location in patent: Paragraph 0018-0022
[2] Patent: WO2007/13848, 2007, A1, . Location in patent: Page/Page column 8-9
[3] Patent: EP3124482, 2017, A1, . Location in patent: Paragraph 0211; 0213
[4] Patent: WO2007/50612, 2007, A1, . Location in patent: Page/Page column 116-117
[5] Patent: WO2009/156100, 2009, A1, . Location in patent: Page/Page column 156
3
[ 69947-09-7 ]
[ 24056-34-6 ]
Reference：
[1] Patent: WO2009/156100, 2009, A1,
4
[ 4746-97-8 ]
[ 38622-91-2 ]
[ 69947-09-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 0 - 20℃;
The present invention will now be described in detail with reference to the foregoing,As shown above,In the present technical solution,The p-toluenesulfonyl methyl isocyanide of formula 1, and(1,4-dioxaspiro [4,5] decan-8-one)The contacting of the compounds shown is carried out in ethylene glycol dimethyl ether,And the molar ratio of p-toluenesulfonylmethyl isonitrile to the compound of formula 1 is 1: 1,The reaction temperature of the reaction system is 0-5 degrees Celsius,P-Methylphenylsulfonylmethylisonitrile (320 g, 1 mole)And compound 1 (156 g, 1 mole) were dissolved in ethylene glycol dimethyl ether (2000 ml)And the reaction system is cooled to 0-5 degrees;Potassium t-butoxide (224 g, 2 mol) was added in portions,Keep the system temperature does not exceed 5 degrees,After the addition was complete the system was slowly raised to room temperature with stirring,To the raw material reaction is complete;Saturated sodium chloride solution (3000 ml) was added,Extraction with methyl tert-butyl ether (500 ml * 2)Combine organic phase,dry,Spin dry,Distilled (100 ° C, 5 mm Hg) to give compound 2 (142 g, 85percent) as a colorless oil,
71%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; ethanol at -13 - 5℃; for 0.666667 h;
To a solution of Compound 58 (10.0 g, 64.0 mmol) in a mixture of 1,2-dimethoxyethane (218 ml)-ethanol (6.5 mL) was added p-toluenesulfonyl methyl isocyanide (16.3 g, 83.0 mmol), and the obtained reaction mixture was cooled to −13° C. Potassium t-butoxide (17.2 g, 154 mmol) was added thereto at 5° C. or less over 40 minutes. The reaction liquid was stirred under ice-cooling for one hour, and further stirred at room temperature for one hour, and the solvent was removed by distillation under reduced pressure. The residue was diluted with ethyl acetate, and then washed with water, and the solvent was removed by distillation under reduced pressure, followed by purification by silica gel chromatography to obtain Compound 67 (7.63 g, 45.6 mmol, 71percent) as a colorless oily substance. Compound 67: 1H-NMR (CDCl3) δ: 1.57-1.67 (2H, m), 1.79-2.03 (5H, m), 2.66 (1H, s), 3.95 (4H, s).
69%
Stage #1: With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol at 0 - 20℃; for 2 h; Stage #2: With water In 1,2-dimethoxyethane; <i>tert</i>-butyl alcohol
l,4-Dioxaspiro[4.5]decane-8-carbonitrileA solution of t-BuOK (22.8 g, 0.203 mol) in a 1: 1 mixture of t-BuOH and 1,2- dimethoxyethane (200 niL) was added to a solution of 1,4-cyclohexanedione monoethylene ketal (15.5 g, 0.099 mol) and tosylmethyl isocyanide (20.3 g, 0.104 mol) in dimethoxyethane (200 mL) at 00C. The reaction mixture was stirred for one hour at 00C, allowed to warm to ambient temperature and stirred for one extra hour. The reaction mixture was poured in water (500 mL). The product was extracted with hexane (3 x 200 mL) and ether (3 x 200 mL). The combined organics were dried with anhydrous Na2SO4 and the solvent was concentrated. The product was purified by flash chromatography on silica gel using EtOAc 40percent in hexane as eluent to afford the title compound as a colorless liquid. Yield: 11.5 g (69percent). 1H NMR (400 MHz, METHANOL-D4): δ 1.55 - 1.69 (m, 2 H), 1.70 - 1.80 (m, 2 H), 1.78 - 1.90 (m, 2 H), 1.90 - 2.05 (m, 2 H), 2.71 - 2.89 (m, 1 H), 3.86 - 3.98 (m, 4 H).
Reference：
[1] Patent: CN106467477, 2017, A, . Location in patent: Paragraph 0025; 0026; 0027
[2] Synthesis, 1992, # 11, p. 1080 - 1082
[3] Tetrahedron Letters, 2000, vol. 41, # 29, p. 5589 - 5592
[4] Tetrahedron, 2002, vol. 58, # 8, p. 1557 - 1563
[5] Patent: US9567330, 2017, B2, . Location in patent: Page/Page column 67
[6] Patent: WO2007/13848, 2007, A1, . Location in patent: Page/Page column 8
5
[ 4746-97-8 ]
[ 19158-51-1 ]
[ 69947-09-7 ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 0℃; for 2 h;
Step 1: t-BuOK (18.5 g, 165.2 mmol) was added into a solution of compound 116-1 (10 g, 64 mmol) and TosMIC(17.6 g, 90.27 mmol) in DME (10 mL) at 0 °C. The reaction mixture was stirred at 0°C for 2h. After the reaction wascomplete, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combinedextraction liquid was washed with brines, dried over sodium sulfate and concentrated to dry, finally purified by columnchromatography (PE:EtOAc = 1:1) to deliver 2 (6.7 g, yield 50percent) as colorless oil.
With potassium tert-butylate; In 1,2-dimethoxyethane; at 0 - 20℃;
The present invention will now be described in detail with reference to the foregoing,As shown above,In the present technical solution,The p-toluenesulfonyl methyl isocyanide of formula 1, and(1,4-dioxaspiro [4,5] decan-8-one)The contacting of the compounds shown is carried out in ethylene glycol dimethyl ether,And the molar ratio of p-toluenesulfonylmethyl isonitrile to the compound of formula 1 is 1: 1,The reaction temperature of the reaction system is 0-5 degrees Celsius,P-Methylphenylsulfonylmethylisonitrile (320 g, 1 mole)And compound 1 (156 g, 1 mole) were dissolved in ethylene glycol dimethyl ether (2000 ml)And the reaction system is cooled to 0-5 degrees;Potassium t-butoxide (224 g, 2 mol) was added in portions,Keep the system temperature does not exceed 5 degrees,After the addition was complete the system was slowly raised to room temperature with stirring,To the raw material reaction is complete;Saturated sodium chloride solution (3000 ml) was added,Extraction with methyl tert-butyl ether (500 ml * 2)Combine organic phase,dry,Spin dry,Distilled (100 C, 5 mm Hg) to give compound 2 (142 g, 85%) as a colorless oil,
71%
With potassium tert-butylate; In 1,2-dimethoxyethane; ethanol; at -13 - 5℃; for 0.666667h;
To a solution of Compound 58 (10.0 g, 64.0 mmol) in a mixture of 1,2-dimethoxyethane (218 ml)-ethanol (6.5 mL) was added p-toluenesulfonyl methyl isocyanide (16.3 g, 83.0 mmol), and the obtained reaction mixture was cooled to -13 C. Potassium t-butoxide (17.2 g, 154 mmol) was added thereto at 5 C. or less over 40 minutes. The reaction liquid was stirred under ice-cooling for one hour, and further stirred at room temperature for one hour, and the solvent was removed by distillation under reduced pressure. The residue was diluted with ethyl acetate, and then washed with water, and the solvent was removed by distillation under reduced pressure, followed by purification by silica gel chromatography to obtain Compound 67 (7.63 g, 45.6 mmol, 71%) as a colorless oily substance. Compound 67: 1H-NMR (CDCl3) delta: 1.57-1.67 (2H, m), 1.79-2.03 (5H, m), 2.66 (1H, s), 3.95 (4H, s).
69%
l,4-Dioxaspiro[4.5]decane-8-carbonitrileA solution of t-BuOK (22.8 g, 0.203 mol) in a 1: 1 mixture of t-BuOH and 1,2- dimethoxyethane (200 niL) was added to a solution of 1,4-cyclohexanedione monoethylene ketal (15.5 g, 0.099 mol) and tosylmethyl isocyanide (20.3 g, 0.104 mol) in dimethoxyethane (200 mL) at 00C. The reaction mixture was stirred for one hour at 00C, allowed to warm to ambient temperature and stirred for one extra hour. The reaction mixture was poured in water (500 mL). The product was extracted with hexane (3 x 200 mL) and ether (3 x 200 mL). The combined organics were dried with anhydrous Na2SO4 and the solvent was concentrated. The product was purified by flash chromatography on silica gel using EtOAc 40% in hexane as eluent to afford the title compound as a colorless liquid. Yield: 11.5 g (69%). 1H NMR (400 MHz, METHANOL-D4): delta 1.55 - 1.69 (m, 2 H), 1.70 - 1.80 (m, 2 H), 1.78 - 1.90 (m, 2 H), 1.90 - 2.05 (m, 2 H), 2.71 - 2.89 (m, 1 H), 3.86 - 3.98 (m, 4 H).
With potassium tert-butylate; In 1,2-dimethoxyethane; tert-butyl alcohol; at 0 - 20℃; for 13h;
A solution of t-BuOK (147 g, 1.31 mol) in t-BuOH and DME (2.0 L, 1:1 v/v) was added dropwise to a 0-5 C. solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640 mmol) and TosMIC (131 g, 672 mmol) in DME (2.0 L), and the resulting mixture was stirred at 0-5 C. for 1 h before it was allowed to warm to rt over 12 h. After this time, the mixture was poured into water and then extracted three timed with MTBE. The organic layers were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated to afford the title compound, which was used in the next step without further purification.
With potassium tert-butylate; In 1,2-dimethoxyethane; tert-butyl alcohol; at 0 - 20℃; for 13h;
A solution of t-BuOK (147 g, 1.31 mol) in t-BuOH and DME (2.0 L, 1:1 v/v) was added dropwise to a 0-5 C. solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640 mmol) and TosMIC (131 g, 672 mmol) in DME (2.0 L), and the resulting mixture was stirred at 0-5 C. for 1 h before it was allowed to warm to rt over 12 h. After this time, the mixture was poured into water and then extracted three timed with MTBE. The organic layers were combined, washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated to afford the title compound, which was used in the next step without further purification.
Lithium aluminum hydride (9.42 mL of a 1M solution in THF) was cooled to 0° C. 1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.05 g, 6.28 mmol) dissolved in THF (4 mL) was then added over to the lithium aluminum hydride solution slowly via cannula. The reaction mixture was then heated to reflux for two hours and left to stand at room temperature overnight. The reaction was quenched with the sequential addition of water (0.36 mL), aqueous 15percent NaOH (0.36 mL), and water (1.06 mL). The resulting suspension was filtered, washing the solids with THF (3.x.30 mL). Concentration of the filtrate gave 1-(1,4-dioxaspiro[4.5]dec-8-yl)methanamine, 28, which was used without further purification. LCMS (ES) m/z 172.3 (M+H)+.
With potassium tert-butylate; In 1,2-dimethoxyethane; ethanol; at 0 - 20℃;
P-toluenesulfonylacetonitrile (6.25 g, 32.01 mmol) and 11 (5 g, 32.01 mmol) were dissolved in DME (160 mL) and EtOH (2 mL) and cooled to 0 C. Potassium t-butoxide (7.18 g, 64.03 mmol) was added. The reaction mixture stirred at 0 C. for thirty minutes and was warmed to room temperature. Upon completion, the reaction mixture was concentrated in vacuo. Water (40 mL) and NaCl were added to the residue, and a precipitate formed. After filtering through celite, the filtrate was extracted with Ether (5×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. Short-path distillation (105 to 115 C.) gave 1,4-dioxaspiro[4.5]decane-8-carbonitrile.
With potassium tert-butylate; In 1,2-dimethoxyethane; ethanol; at 0 - 40℃; for 28h;
General procedure: Example 4A 1-oxaspiro[4.5]decane-8-carbonitrile Potassium t-butoxide (1.68 g) was added portionwise to a mixture of 1-oxaspiro[4.5]decan-8-one (0.96 g) and TosMIC reagent (p-toluenesulfonylmethyl isocyanide, 1.46 g) in 1,2-dimethoxyethane (30 mL) and ethanol (0.5 mL) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours, then heated to 40 C. for 24 hours. The reaction mixture was cooled, diluted with ether (600 mL), washed twice with water and brine, and concentrated. The crude product was chromatographed on silica gel with 1-20% ethyl acetate/hexanes to afford the title compound.
33
[ 69947-09-7 ]
[ 7051-34-5 ]
[ 916159-85-8 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at -10 - 20℃; for 18h;
To a stirred solution of <strong>[69947-09-7]1,4-dioxaspiro[4.5]decane-8-carbonitrile</strong> (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at -10 C. was added KHMDS (0.5M solution in toluene; 263.15 ml; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR delta (ppm)(CDCl3): 3.99-3.89 (4 H, m), 2.08 (2 H, d, J=13.5 Hz), 1.96-1.72 (9 H, m), 0.96-0.82 (1 H, m), 0.59-0.53 (2 H, m), 0.17 (2 H, q, J=5.1 Hz).
With hydrogenchloride; boric acid; In tetrahydrofuran; water; at 60℃; for 2h;
Add 1,4-dioxaspiro[4,5]nonane-8-carbonitrile 200.6 g (1.2 mol), boric acid 72 g (1.2 mol), water 2000 mL (10 V), hydrochloric acid in a 5000 mL three-necked flask. 1000 mL (5 V), tetrahydrofuran 500 mL (2.5 V), heated to 60 C,The reaction was carried out for two hours, sampled, and sent to the GC for detection. The remaining amount of the raw material was <2%, and the reaction was completed.Decrease to room temperature, add dichloromethane, extract three times, combine the dichloromethane layer, distill off the dichloromethane under reduced pressure, and rectify the product under the condition of 100 C 2 mmHg.4-cyanocyclohexanone 140.4 g, GC purity 98%, yield 95%.
87%
With trifluoroacetic acid; In dichloromethane; at 20℃; for 16h;
A solution of R-06i-2 (7.00 g, 41.87 mmol) in TFA (50 mL) and DCM (50 mL) was stirred at 20 C for 16 hours. Then, the mixture was concentrated to give the crude product. The crude product was purify by column chromatography (Si02, Petroleum ether/Ethyl acetate = 10/1 to 5/1 ) to obtain R-06i-3 (4.50 g, 87%) as yellow oil. This compound was used in the next step without further characterization.
75%
With ammonium cerium(IV) nitrate; In water; acetonitrile; at 70℃; for 0.75h;
4-OxocyclohexanecarbonitriIeA solution of ammonium cerium (IV) nitrate (3.70 g, 6.75 mmol) in water (100 mL) was added to a solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (11.3 g, 67.5 mmol) in MeCN (200 mL) and water (100 mL) at 700C. The reaction mixture was stirred for 45 minutes at 7O0C and cooled to ambient temperature where 100 mL of water were added. The product was extracted with ether (4 x 200 mL). The combined organics were EPO <DP n="10"/>washed with brine and dried over MgSO4. The product was purified by flash chromatography on silica gel using EtOAc 50% in hexane as eluent to afford the title compound as a colorless liquid. Yield: 6.30 g (75%). 1H NMR (400 MHz, CHLOROFORM-D): delta 2.07 - 2.31 (m, 4 H), 2.34 - 2.53 (m, 2 H), 2.54 - 2.72 (m, 2 H), 2.95 - 3.14 (m, I H).
68%
With hydrogenchloride; In water; at 20℃; for 2h;
Step 2: A mixture of compound 116-1 (3 g, 18 mmol) in conc. hydrochloric acid / H2O (v/v = 1:1, 20 mL) wasstirred at room temperature for 2h. The reaction mixture was adjusted to pH = 8 with NaOH, and extracted with EtOAc.The combined extraction liquid was washed with brines, dried over sodium sulfate and concentrated to dry, finally purifiedby column chromatography (PE:EtOAc = 1:1) to deliver compound 116-3 (1.5 g, yield 68%) as colorless oil.
With hydrogenchloride; water; In acetone;Heating / reflux;
STEP A: 4-Oxo-cycohexanecarbonitrileA solution of l,4-dioxasrhoiro[4,5]decane-8-carbonitrile (15.86 g, 94.8 mmol) (prepared according to the procedure in Lucija Peterlin-Masic, Andreja Jurca, Petra Marrinko, Anita Jancar and Danijel Kikelj, Tetrahedron 2002, 55, 1557-1563), in a mixture of aqueous hydrochloric acid (2 N, 60 mL) and acetone (100 mL) was refluxed overnight. The acetone <n="118"/>was removed by evaporation. The aqueous phase was extracted with ethyl acetate three times. The combined organic extracts were washed with water one time and then dried over magnesium sulfate. The solution was filtered and concentrated to yield 4-oxo- cycohexanecarbonitrile as a colorless oil, which was used in the next reaction without purification.
A solution of 10.0 g (59.8 mmol) of 4-cyanocyclohexanone cyclic ethylene acetal in a mixture of 80 ml_ of acetic acid and 20 ml_ of water was heated in the microwave oven at 130 0C for 20 min. The mixture was cooled to room temperature and slowly poured onto 2.2 L of cold saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with dichloromethane, the organic phase was dried over magnesium sulphate, filtered, 100 ml_ of ethanol were added and the dichloromethane was removed in vacuo. To the solution were then added 2.0 g (52.9 mmol) of sodium borohydride and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and extracted twice with dichloromethane. The combined organic layer was concentrated in vacuo to give 6.4 g of 4-hydroxy- cyclohexanecarbonitrile as a mixture of cis/trans isomers in a purity sufficient for further conversion. Rt= 0.14 min (Method 18). Detected mass: 126.1 (M+H+).
To a 2M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (18 ml_, 35.9 mmol, 1.5 eq.) at -78 0C was added dropwise a solution of 1 ,4-dioxa- spiro[4.5]decane-8-carbonitrile (commercially available or via literature procedure described for example in Becker et al. Synthesis 1992, 11 , 1080-1082; 4.0 g, 23.9 mmol) in tetrahydrofuran (40 mL). After stirring for 30 min at -78 0C, 4-iodotetrahydro- 2H-pyran (5.1 g, 23.9 mmol, 1 eq.) was added carefully. The reaction mixture was allowed to warm to room temperature over night before being quenched by slow addition of ethanol (10 mL) and water (20 mL) subsequently. The resulting suspension was filtered through celite and extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo and purified by flash chromatography (SiO2, 0percent --> 30percent methanol in dichloromethane) to give 2.80 g of 8- (tetrahydropyran-4-yl)-1 ,4-dioxa-spiro[4.5]decane-8-carbonitrile (5). Rt = 1.03 min (Method B). Detected mass: 252.3 (M+H+).
Under argon, phenylmagnesium bromide (3M) in diethyl ether (6.7 ml_, 20 mmol) was added to a solution of 1 ,4-dioxa-spiro[4.5]decane-8-carbonitrile (3.34 g, 20 mmol) in <n="137"/>diethyl ether (60 ml_). The mixture was stirred for 30 minutes. Titanium (IV) isopropoxide (5.7 g, 20 mmol) was then added. After stirring for 5 min, methyl lithium (1.6 M in diethyl ether, 31.2 ml_, 50 mmol) was added and the reaction was heated under reflux for 10 hours. After cooling in ice/water the brown mixture was treated cautiously with 2M NaOH solution (30 ml_) dropwise (exothermic). The mixture was extracted with t-butyl methyl ether and dried over sodium sulphate. After filtration the organic phase was evaporated to give 5 g of a pale yellow oil, which was used in the next step without further purification. R1 = 2.10 min (Method 2). Detected mass: 261.2 (M+H+).
In tetrahydrofuran; for 18h;Inert atmosphere; Reflux;
Under argon, 4-methoxy-phenylmagnesium bromide (0.5M in THF, 24 ml_, 12 mmol) was added to a solution of 1 ,4-dioxa-spiro[4.5]decane-8-carbonitrile (1.0 g, 6 mmol) in THF (100 ml_). The mixture was stirred under reflux for 16 hours. The reaction mixture was then cooled to 0 C. Saturated sodium sulphate solution was added dropwise until no more precipitate formed. The precipitate was removed by filtration and washed with THF. The combined organic phases were stirred with sodium borohydride (452 mg, 12 mmol) overnight at 25 0C. The reaction mixture was then diluted with t-butyl methyl ether (100 mL) and treated with 0.05M aqueous hydrochloric acid (three times with 100 ml_). The combined aqueous phases were adjusted to alkaline pH with a 6M aqueous sodium hydroxide solution with cooling, before extraction with dichloromethane gave a solution of the desired product which was used directly in the next stage. Rt = 0.74 min (Method 5). Detected mass: 278.2 (M+H+).
A suspension of commercial anhydrous cerium chloride (ABCR, 8.8 g) in anhydrous THF (62 mL) was heated for 4h at 6O0C under vigourous stirring. The slurry was cooled to room temperature and treated with 3g of 4-cyanocyclohexanone cyclic ethylene acetal. After cooling to -200C, 35 mL of a 1.5 M solution of MeLi LiBr in diethyl ether were added dropwise. The mixture was allowed to stir for 1h at -10 0C, then 20 mL of THF were added and the reaction was quenched by addition of concentrated <n="85"/>NH4OH (10 ml_) over 10 min. The mixture was allowed to warm to room temperature, stirred for 30 min, diluted with methyl tert. butyl ether and then filtered. The filter cake was rinsed several times with methyl tert. butyl ether. The combined filtrates were then concentrated in vacuo. The crude product was dissolved in dichloromethane and extracted twice with 0.1 N HCI. The combined HCI layers were washed with dichloromethane, cooled and the pH was adjusted to 12 by addition of 5 N sodium hydroxide solution. The aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, washed with brine, and dried over sodium sulphate. 1.82 g of triethylamine and 2.74 g of di-tert.-butyl dicarbonate were added. The mixture was stirred for two days at room temperature, washed with 1 N sodium hydroxide solution, twice with 0.1 N hydrochloric acid and water, and once with brine, dried over sodium sulphate and evaporated to dryness to give 3.0 g of crude product. The crude product was dissolved in 100 ml_ of acetone and 10 ml_ of 1 N HCI were added and stirred at room temperature. Additional HCI was added and stirring was continued until conversion was complete. Sodium hydroxide solution and methyl-tert.- butyl ether was added, the aqueous layer was separated and extracted with methyl- tert.-butyl ether. The combined ether layers were dried over sodium sulphate and evaporated to dryness to give 2.4 g of (20). Rt= 3.08 min (Method 1). Detected mass: 256.2 (M+H+).
A suspension of commercial anhydrous cerium chloride (ABCR, 8.8 g) in anhydrous THF (62 mL) was heated for 4h at 6O0C under vigourous stirring. The slurry was cooled to room temperature and treated with 3g of 4-cyanocyclohexanone cyclic ethylene acetal. After cooling to -200C, 35 mL of a 1.5 M solution of MeLi LiBr in diethyl ether were added dropwise. The mixture was allowed to stir for 1h at -10 0C, then 20 mL of THF were added and the reaction was quenched by addition of concentrated <n="85"/>NH4OH (10 ml_) over 10 min. The mixture was allowed to warm to room temperature, stirred for 30 min, diluted with methyl tert. butyl ether and then filtered. The filter cake was rinsed several times with methyl tert. butyl ether. The combined filtrates were then concentrated in vacuo. The crude product was dissolved in dichloromethane and extracted twice with 0.1 N HCI. The combined HCI layers were washed with dichloromethane, cooled and the pH was adjusted to 12 by addition of 5 N sodium hydroxide solution. The aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, washed with brine, and dried over sodium sulphate. 1.82 g of triethylamine and 2.74 g of di-tert.-butyl dicarbonate were added. The mixture was stirred for two days at room temperature, washed with 1 N sodium hydroxide solution, twice with 0.1 N hydrochloric acid and water, and once with brine, dried over sodium sulphate and evaporated to dryness to give 3.0 g of crude product. The crude product was dissolved in 100 ml_ of acetone and 10 ml_ of 1 N HCI were added and stirred at room temperature. Additional HCI was added and stirring was continued until conversion was complete. Sodium hydroxide solution and methyl-tert.- butyl ether was added, the aqueous layer was separated and extracted with methyl- tert.-butyl ether. The combined ether layers were dried over sodium sulphate and evaporated to dryness to give 2.4 g of (20). Rt= 3.08 min (Method 1). Detected mass: 256.2 (M+H+).
Step A: 5-Chloro-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-[1,2,4]thiadiazole To a stirred suspension of NH4Cl (0.29 g, 5.4 mmol) in dry toluene (2 mL) at 5 C. was slowly added a solution of trimethylaluminium in toluene (Aldrich, 2M, 2.5 mL, 5 mmol) under Ar. After the addition, the mixture was warmed to rt and stirred for 2 h until gas evolution had ceased. Then a solution of the intermediate <strong>[69947-09-7]1,4-dioxa-spiro[4.5]decane-8-carbonitrile</strong> (0.50 g, 3 mmol, prepared according to the procedure from Tremblay, Maxime, PCT Int. Appl. (2007)) in toluene (1 mL) was added and the mixture was heated to 80 C. for 18 h. The reaction mixture was slowly poured into a slurry of silica gel (1.5 g) in CHCl3 (5 mL) and stirred for 5 min. The silical gel was filtered and washed with methanol. The filtrate was condensed to 1/3 volume and filtered again. The filtrate was evaporated to dryness to give the crude intermediate as an HCl salt, which was dissolved in a NaOH solution (5N, 3.48 mL, 17.4 mmol) and cooled to 0 C., followed by addition of a solution of perchloromethyl mercaptan (Aldrich, 0.39 mL, 3.6 mmol). The mixture was vigorously stirred at rt overnight. Aqueous workup and purification by column chromatography (eluent: EtOAc/hexanes, 1:6) gave the product. 1H NMR (400 MHz, CDCl3): delta 3.95-3.97 (4H, m), 2.98-3.03 (1H, m), 2.08-2.14 (2H, m), 1.98-2.04 (2H, m), 1.83-1.88 (2H, m), 1.53-1.70 (2H, m).
With hydroxylamine; In ethanol; water; at 80℃; for 6h;Sealed tube;
Step A: N-Hydroxy-1,4-dioxa-spiro[4.5]decane-8-carboxamidine A mixture of <strong>[69947-09-7]1,4-dioxa-spiro[4.5]decane-8-carbonitrile</strong> (0.40 g, 2.4 mmol, prepared according to the procedure from Tremblay, Maxime, PCT Int. Appl. (2007), WO 2007013848) and hydroxylamine (Aldrich, 50% in H2O, 0.7 mL, 9.6 mmol) in ethanol (1.5 mL) in a sealed tube was heated to 80 C. for 6 h. After removal of organic solvent by evaporation, the residue was dissolved in water, extracted with EtOAc and dried over Na2SO4. Filtration and evaporation to dryness gave the product as a white solid. 1H NMR (400 MHz, CDCl3): delta 4.5 (2H, br s), 3.92-3.97 (4H, m), 2.13-2.20 (1H, m), 1.57-1.90 (8H, m).
Step 2: To a solution of l,4-dioxaspiro[4.5]decane-8-carbonitrile (3 g, 17.9 mmol) in anhydrous toluene (95 ml) at 0C, was added sodium bis(trimethylsilyl)amide (1M in toluene, 21.5 ml, 21.5 mmol). The resulting orange solution was maintained at 0C for 1 h, before introducing a solution of 2-chlorotriazole (2.14 g, 17.9 mmol) in anhydrous toluene (10 ml) via cannulation. The residual dark brown solution was allowed to slowly warm to 23C over 16 h. The reaction was diluted with saturated aqueous NH4C1 (100 ml) and extracted with EtOAc (2x80 ml). The combined organic layers were washed with brine (100 ml), dried over NajSO^ filtered and concentrated in vacuo. The crude oil was purified via flash column chromatography (Si02: 100% Hex to 80:20 Hex:EtOAc) to provide 8-(l,3-thiazol-2-yl)-l54-dioxaspiro[4.5]decane-8- carbonitrile (1.78 g, 6.74 mmol, 37.5% yield) as a fluffy, off-white solid. MS ESI: [M+H]+ m/z 251.1. 'H NM (500 MHz, CDC13): delta 7.79 (d, 1H, J= 3.2 Hz), 7.35 (d, 1H, J= 3.5 Hz), 4.01-3.95 (m, 4H), 2.44-2.31 (m, 4H), 2.09-2.03 (m, 2H), 1.89-1.86 (m, 2H).
Methyl-4-oxo-cyclohexanecarbonitrile To a 0 C. solution of <strong>[69947-09-7]1,4-dioxaspiro[4.5]decane-8-carbonitrile</strong> (1 THF (1.25 equiv.) dropwise. The resulting solution equiv.) in THF (0.5 M) was added 1 M lithium bis(trimethylsilyl)amide in was stirred for 1 h at 0 C. before iodomethane (1.5 eq) was added. After 1 h stirring at 0 C., the reaction was stirred at room temperature for 15 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phases were combined and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was stirred with hydrochloric acid (2 equiv.) in acetone (0.3 M) at 25 C. for 5 h. The reaction mixture was cooled to 0 C. and the pH was adjusted to 8 with 3N sodium hydroxide. The mixture was extracted with ether. The organic portions were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel column chromatography to afford 1-methyl-4-oxo-cyclohexanecarbonitrile as a white solid (56% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm: 2.41-2.48 (m, 2H), 2.23-2.34 (m, 2H), 2.09-2.23 (m, 2H), 1.86 (td, J=13.18, 4.49 Hz, 2H), 1.37-1.47 (m, 3H). MS (ESI) m/z=138.3 [M+H]+.
1-((isocyanomethyl)sulfonyl)-2-methylbenzene[ No CAS ]
[ 69947-09-7 ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In 1,2-dimethoxyethane; ethanol; water; at -10 - 20℃; for 16h;
1,4-Dioxaspiro[4.5]decane-8-carbonitrile To a -10 C. solution of 1,4 dioxaspiro[4.5]decan-8-one (1 equiv.), ethanol (1.78 equiv.) and toluenesulfonylmethyl isocyanide (1.3 equiv.) in DME (0.3 M) was added potassium 2-methylpropan-2-olate (2.3 equiv.) portion wise. The reaction was stirred at -10 C. for 1 h, and 15 h at room temperature. The reaction mixture was concentrated to a beige solid, dissolved in water and extracted with ether. The combined extracts were washed with brine and dried. Concentration under reduced pressure gave an orange oil. This material was purified by distillation [(103 C. (oil bath 150 C.) at about 2-3 mbar] to give 1,4-dioxaspiro[4.5]decan-8-one as a colorless oil (87% yield). 1H NMR (400 MHz, CDCl3) delta ppm: 3.88-4.02 (m, 4H), 2.56-2.74 (m, 1H), 1.79-2.05 (m, 6H), 1.50-1.71 (m, 2H).
(1R,4s)-4-(8-((2,4-dichloro-6-fluorophenyl)amino)-2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-4-carboxamide[ No CAS ]
(1S,4s)-4-(8-((2,6-dichloro-4-cyanophenyl)amino)-2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide[ No CAS ]
(1S,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide[ No CAS ]
With potassium hydroxide; In ethanol; water; for 7.5h;Reflux;
To a solution of Compound 67 (7.63 g, 45.6 mmol) in a mixture of ethanol (57 ml)-water (14 mL) was added caustic potash (9.04 g, 137 mmol), and the obtained reaction mixture was refluxed for 1.5 hours by heating. Then, caustic potash (4.52 g, 68.4 mmol) was added thereto, and the obtained reaction mixture was refluxed for another 6 hours by heating. After cooling to room temperature, the solvent was removed by distillation under reduced pressure, followed by dilution with water (25 mL). The aqueous layer was then washed with diethyl ether (30 mL), and concentrated hydrochloric acid was added thereto under ice-cooling to obtain pH 4. After extraction with ethyl acetate, the solvent was removed by distillation under reduced pressure to obtain Compound 68 (8.36 g, 44.9 mmol, 98.4%) as a brown oily substance. The substance was used for the following step without purification
With potassium tert-butylate; In 1,2-dimethoxyethane; at 0℃; for 2h;
Step 1: t-BuOK (18.5 g, 165.2 mmol) was added into a solution of compound 116-1 (10 g, 64 mmol) and TosMIC(17.6 g, 90.27 mmol) in DME (10 mL) at 0 C. The reaction mixture was stirred at 0C for 2h. After the reaction wascomplete, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combinedextraction liquid was washed with brines, dried over sodium sulfate and concentrated to dry, finally purified by columnchromatography (PE:EtOAc = 1:1) to deliver 2 (6.7 g, yield 50%) as colorless oil.
The solution of the compound represented by the formula 2 (1,4-dioxaspiro [4,5] -8-cyanocyclohexane) in tetrahydrofuran is reacted with lithium diisopropylamine to a solution of the compound represented by formula 2 in tetrahydrofuran Was added dropwise diisopropylamine lithium,And the molar ratio of the compound represented by formula 2 to lithium diisopropylamine is 1: 1.2,The reaction temperature of the reaction system is -70 C,At -78 ,To a solution of compound 2 (167.2 g, 1 mol) in tetrahydrofuran (1672 mL) was added lithium diisopropylamine (600 mL, 1.2 mol)-70 below the insulation for 1h;To the reaction system was added bromocyclopropane (132 g, 1.1 mol)Of tetrahydrofuran (660 mL),-70 below the insulation 2h,Saturated ammonium chloride solution quenched,Extraction with methyl tert-butyl ether (500 mL * 3)The organic phase was washed with saturated sodium chloride (500 mL)Dried over anhydrous sodium sulfate,concentrate,The residue was purified by column chromatography to give compound 3 (72.5 g, 35%) as a colorless oil
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