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Chemical Structure| 381209-09-2
Chemical Structure| 381209-09-2
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Product Details of [ 381209-09-2 ]

CAS No. :381209-09-2 MDL No. :MFCD23104331
Formula : C13H24O2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 212.33 Pubchem ID :-
Synonyms :

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* 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.

  • Downstream synthetic route of [ 381209-09-2 ]

[ 381209-09-2 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 3814-34-4 ]
  • [ 98-89-5 ]
  • [ 381209-09-2 ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: Cyclohexanecarboxylic acid With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.33333h; Stage #2: With n-butyllithium; diethylamine In tetrahydrofuran; hexane at 20℃; for 4h; Stage #3: 2-ethyl-1-bromobutane With hydrogenchloride; n-butyllithium more than 3 stages; 10 At 0°C, cyclohexanecarboxylic acid (2.0 g, 15.6 mmol) in THF (15 mL) was added dropwise over 30 min under an argon atmosphere to a stirred suspension of 60% sodium hydride in oil (811 mg, 20.3 mmol). After another 10 min at 0°C, the suspension was stirred at RT for 40 min. DEA (114 mg, 1.56 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (11.7 mL, 18.7 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1 h. 1-Bromo-2-ethylbutane (3.35 g, 20.3 mmol) in THF (10 mL) was added dropwise to the orange and slightly turbid reaction mixture at 0°C over 10 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 18 h at ambient temperature. GC analysis indicated the presence of 11% unreacted starting material. An additional portion of 1.6 M BuLi in hexane (1.95 mL, 3.12 mmol) was added over 1 h to the reaction mixture and stirring at RT was continued for 1 h. At 5°C, ice-cold H2O (15 mL) was cautiously dropped to the reaction mixture under stirring. Then heptane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with heptane (2x60 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to
Stage #1: Cyclohexanecarboxylic acid With lithium diisopropyl amide In tetrahydrofuran at 20℃; for 1.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran at 20℃;
  • 2
  • [ 381209-09-2 ]
  • [ 211513-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 38 percent / oxalyl chloride / CH2Cl2 / 1 h / 20 °C 2: pyridine / 100 °C 3: Ph3P; H2O / dioxane / 1 h / 50 °C 4: 97 percent / pyridine / 1 h / 20 °C
  • 3
  • [ 38225-32-0 ]
  • [ 3814-34-4 ]
  • [ 98-89-5 ]
  • [ 381209-09-2 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; cyclohexane; water 2.i Synthesis of bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl disulfide (formula (I); R=1-(2-ethylbutyl)cyclohexyl, X1, X2, X3, X4=a hydrogen atom, Y=carbonyl, Z=2-[1-(2-ethylbutyl)-cyclohexanecarbonylamino]phenylthio) i) A suspension of 60% sodium hydride (980 mg) in tetrahydrofuran (80 ml) was stirred at room temperature and a tetrahydrofuran solution (10 ml) containing cyclohexanecarboxylic acid (3.00 g) was added dropwise thereto. After completion of addition, a mixture was stirred for 1 hour and cooled to 0° C., followed by adding a cyclohexane solution (18.7 ml) containing 1.5 M lithium isopropylamide dropwise thereto. Then, after stirring at room temperature for 1.5 hours and cooling to 0° C., a tetrahydrofuran solution (10 ml) containing 1-bromo-2-ethylbutane (4.64 g) was added dropwise thereto. The solution was gradually warmed to room temperature and stirred overnight. Water and a 10% hydrochloride solution were added to this reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After drying, the resulting solution was concentrated to obtain 1-(2-ethylbutyl)cyclohexanecarboxylic acid (3.17 g, yield: 64%).
  • 4
  • [ 136-01-6 ]
  • [ 3814-34-4 ]
  • [ 381209-09-2 ]
  • [ 98-89-5 ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; diethylamine In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane With n-butyllithium In tetrahydrofuran; hexane at 10 - 20℃; for 21.5h; Stage #3: With hydrogenchloride In water 7 CHCA Na salt (6.0 g, 40 mmol) was suspended under argon in THF (75 mL). DEA (292 mg, 4 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (30 mL, 48 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (8.58 g, 52 mmol) in THF (26 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 17 h at ambient temperature. GC analysis indicated the presence of 12% unreacted starting material. An additional portion of 1.6 M BuLi in hexane (6.2 mL, 10 mmol) was added over 1 h to the reaction mixture and stirring at RT was continued for another 2 h. At 5°C, ice-cold H2O (50 mL) was added cautiously under stirring. Then heptane and H2O was added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with heptane. The aqueous phase was separated and extracted again with heptane. The organic phases were washed with H2O. The aqueous phases were combined, adjusted to pH 1-2 with aqueous HCl and extracted twice with DCM. The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 6.86 g crude product with a content of 93.6% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 3.7% cyclohexanecarboxylic acid. The crude product was dissolved in TBME (60 mL) and extracted with 7% aqueous sodium bicarbonate (2x40 mL). The aqueous phases were extracted with TBME (60 mL). The organic phases were washed with dilute brine, combined, dried over sodium sulfate and concentrated in vacuo to afford 6.62 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 99.4% according to GC with internal standard. Only 0.2% cyclohexanecarboxylic acid (from starting material) was detected by GC analysis. 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J = 7.3, 6H), 1.15-1.65 (m, 15H), 2.05-2.15 (m, 2H), 11.9 (br s, 1H).
73% Stage #1: cyclohexanecarboxylic acid Na-salt With morpholine; n-butyllithium In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 10 - 20℃; for 19.5h; Stage #3: With hydrogenchloride In water 22 CHCA Na salt (3.0 g, 20 mmol) was suspended under argon in THF (37.5 mL). Morpholine (174 mg, 2 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (15 mL, 24 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (4.29 g, 26 mmol) in THF (13 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 18 h at ambient temperature. The reaction mixture was worked up in analogous manner as described in Example 7 to give 4.16 g crude product with a content of 20.5% cyclohexanecarboxylic acid and 74.5% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 73%.
72% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 20℃; for 3.5 - 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 0 - 23℃; for 16.5 - 19.17h; Stage #3: With hydrogenchloride In water 3; 4 CHCA Na salt (2.34 g, 15.6 mmol) was suspended under argon in THF (30 mL). Diisopropylamine (158 mg, 1.56 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (11.2 mL, 17.9 mmol) over 2 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (3.35 g, 20.3 mmol) in THF (10 mL) was added dropwise to the orange and slightly turbid reaction mixture at ~0°C over 10 min. After 1 h the cooling bath was removed and the white suspension was stirred 18 h at ambient temperature. At 5°C, ice-cold H2O (15 mL) was cautiously dropped to the reaction mixture under stirring. Then hexane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with hexane (2x60 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to ~pH2 with aqueous HCl and extracted with DCM (2x100 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 2.7 g crude product with a content of 4.7% cyclohexanecarboxylic acid and 87.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 72%.; CHCA Na salt (2.34 g, 15.6 mmol) was suspended under argon in THF (30 mL). Diisopropylamine (158 mg, 1.56 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (11.2 mL, 17.9 mmol) over 2 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (3.35 g, 20.3 mmol) in THF (10 mL) was added dropwise to the orange and slightly turbid reaction mixture at ~0°C over 10 min. After 1 h the cooling bath was removed and the white suspension was stirred 18 h at ambient temperature. At 5°C, ice-cold H2O (15 mL) was cautiously dropped to the reaction mixture under stirring. Then hexane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with hexane (2x60 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to ~pH2 with aqueous HCl and extracted with DCM (2x100 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 2.7 g crude product with a content of 4.7% cyclohexanecarboxylic acid and 87.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 72%.
71% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; diethylamine In tetrahydrofuran; tert-butylbenzene; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane; tert-bytylbenzene at 10 - 20℃; for 21.5h; Stage #3: With hydrogenchloride In water 9 CHCA Na salt (6.0 g, 40 mmol) was suspended under argon in a mixture of THF (60 mL) and tert-butylbenzene (15 mL). DEA (292 mg, 4 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (30 mL, 48 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (8.58 g, 52 mmol) in THF (26 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10-15°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 20 h at ambient temperature. At 5°C, ice-cold H2O (30 mL) was added cautiously under stirring. Then heptane and H2O was added and the mixture was concentrated in vacuo until most of the THF was removed. The aqueous residue was extracted with heptane (80 mL). The aqueous phase was separated and extracted again with heptane (120 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to pH 1-2 with aqueous HCl and extracted with DCM (2x150 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 7.1 g crude product with a content of 82.6% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 9% cyclohexanecarboxylic acid. The crude product was dissolved in TBME (70 mL) and extracted with 7% aqueous sodium bicarbonate (2x70 mL). The aqueous phases were extracted with TBME (70 mL). The organic phases were washed with dilute brine (80 mL), combined, dried over sodium sulfate and concentrated in vacuo to afford 6.36 g (71%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 95.3% according to GC with internal standard. Only a very small amount of cyclohexanecarboxylic acid (~0.1%) was detected in this product.
70% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 20℃; for 3h; Stage #2: 2-ethyl-1-bromobutane With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 23.17h; Stage #3: With hydrogenchloride In water 2 CHCA Na salt (2.34 g, 15.6 mmol) was suspended under argon in THF (30 mL). Diisopropylamine (474 mg, 4.68 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (13.6 mL, 21.8 mmol) over 1.5 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (3.35 g, 20.3 mmol) in THF (10 mL) was added dropwise to the orange and slightly turbid reaction mixture at ~0°C over 10 min. After 1 h the cooling bath was removed and the white suspension was stirred 18 h at ambient temperature. GC analysis indicated the presence of 7% unreacted starting material. An additional portion of 1.6 M BuLi in hexane (2.9 mL, 4.6 mmol) was added over 1 h to the reaction mixture and stirring at room temperature was continued for another 3 h. At 5°C, ice-cold H2O (15 mL) was cautiously dropped to the reaction mixture under stirring. Then hexane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with hexane (2x60 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to ~pH 2 with aqueous HCl and extracted with DCM (2x100 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 2.75 g crude product with a content of 5.4% cyclohexanecarboxylic acid and 83.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 70%.
61% Stage #1: cyclohexanecarboxylic acid Na-salt With 4-methylpiperidin; n-butyllithium In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 10 - 20℃; for 19.5h; Stage #3: With hydrogenchloride In water 24 CHCA Na salt (3.0 g, 20 mmol) was suspended under argon in THF (37.5 mL). 4-Methylpiperidine (198 mg, 2 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (15 mL, 24 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (4.29 g, 26 mmol) in THF (13 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 18 h at ambient temperature. The reaction mixture was worked up in analogous manner as described in Example 7 to give 3.73 g crude product with a content of 28.8% cyclohexanecarboxylic acid and 69.6% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 61%.
60% Stage #1: cyclohexanecarboxylic acid Na-salt With pyrrolidine; n-butyllithium In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 10 - 20℃; for 19.5h; Stage #3: With hydrogenchloride In water 23 CHCA Na salt (3.0 g, 20 mmol) was suspended under argon in THF (37.5 mL). Pyrrolidine (142 mg, 2 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (15 mL, 24 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (4.29 g, 26 mmol) in THF (13 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 18 h at ambient temperature. The reaction mixture was worked up in analogous manner as described in Example 7 to give 3.92 g crude product with a content of 30% cyclohexanecarboxylic acid and 65.1% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 60%.
60% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; N-cyclohexyl-cyclohexanamine In tetrahydrofuran; hexane at 20℃; for 3h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 0 - 20℃; for 19.17h; Stage #3: With hydrogenchloride In water 6 CHCA Na salt (2.34 g, 15.6 mmol) was suspended under argon in THF (30 mL). Dicyclohexylamine (849 mg, 4.68 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (13.6 mL, 21.8 mmol) over 1.5 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (3.35 g, 20.3 mmol) in THF (10 mL) was added dropwise to the orange and slightly turbid reaction mixture at ~0°C over 10 min. After 1 h the cooling bath was removed and the white suspension was stirred 18 h at ambient temperature. GC analysis indicated the presence of 7% unreacted starting material. At 5°C, ice-cold H2O (15 mL) was cautiously dropped to the reaction mixture under stirring. Then hexane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with hexane (2x60 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to ~pH 2 with aqueous HCl and extracted with DCM (2x100 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 2.3 g crude product with a content of 6.9% cyclohexanecarboxylic acid and 87.0% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 60%.
52% Stage #1: cyclohexanecarboxylic acid Na-salt With n-butyllithium; diethylamine In tetrahydrofuran; hexane at 20 - 35℃; for 3 - 6h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 8 - 37℃; for 18.5 - 21h; Stage #3: With hydrogenchloride In water at 0 - 15℃; 8; 13- 20 Example 8: Alkylation of CHCA Na salt in the presence of DEA (0.1 eq) without supplementary BuLi addition CHCA Na salt (24.0 g, 160 mmol) was suspended under argon in THF (300 mL). DEA (1.17 g, 16 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (120 mL, 192 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (34.29 g, 208 mmol) in THF (102 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 19 h at ambient temperature. GC analysis indicated the presence of 13% unreacted starting material. In contrast to the procedure described in Example 7 no supplementary BuLi was added at this point. The reaction mixture was worked up in analogous manner as described in Example 7 to give 28.98 g crude product with a content of 85.2% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 13.1% starting material. The crude product was dissolved in TBME (100 mL) and extracted with 7% aqueous sodium bicarbonate (2x120 mL). The aqueous phases were extracted with TBME (120 mL). The organic phases were washed with dilute brine (120 mL), combined, dried over sodium sulfate and concentrated in vacuo to afford 25.17 g (73%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 98.2% according to GC with internal standard. The content of cyclohexanecarboxylic acid was found to be 0.3%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 4 h at 20-25°C. After complete BuLi addition the reaction mixture was cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was warmed to 35°C within 30 min and stirred for 19 h at 33-37°C. GC analysis indicated the presence of 10.8% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 10-20 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed twice with hexanes (240 and 120 mL) and acidified by addition of HCl 37% (35 mL) at 0-15°C. The acidic aqueous solution was extracted with toluene (240 mL) and the organic phase was washed with H2O (240 mL). The toluene solution with the crude product was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate (set to pH=9 by addition of 28% NaOH) and once with HCl 0.5N (50 mL). The organic phase was concentrated in vacuo to afford 51.8 g (78.8% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 96.9% according to GC with internal standard. The content of toluene was found to be 3.7% and of cyclohexanecarboxylic acid was found to be <0.1%.; Alkylation of CHCA Na salt as in Example 13 but with aging time of dianion solution (90 min) and with alkylation temperature of 20-25°C CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 4 h at 20-25°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 20-25°C, then cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for additional 60 min at 10-12°C and then warmed to 20-25°C within 30 min and stirred for 16.5 h at 20-25°C. GC analysis indicated the presence of 7.7% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 10-20 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed twice with hexanes (240 and 120 mL) and acidified by addition of HCl 37% (33 mL) at 0-15°C. The acidic aqueous solution was extracted with toluene (240 mL) and the organic phase was washed with H2O (240 mL). The toluene solution with the crude product (89.0% area 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 9.5 % area cyclohexanecarboxylic acid) was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate (set to pH=9 by addition of 28% NaOH) and once with HCl 0.5N (50 mL). The organic phase was concentrated in vacuo to afford 50.2 g (76.0% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 94.5% according to GC with internal standard. The content of toluene was found to be 3.4% and of cyclohexanecarboxylic acid was found to be <0.1%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 90 min at 20-25°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 20-25°C, then cooled to 10°C and 1-bromo-2-ethylbutane (65.0 g, 390 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was warmed to 20-25°C within 30 min and stirred for 20 h at 20-25°C. GC analysis indicated the presence of 9.3% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 5 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed with hexanes (240 mL) and acidified by addition of HCl 37% (38 mL) at 10-15°C. The acidic aqueous solution was extracted with toluene (240 mL). The organic phase was washed with H2O (240 mL) and concentrated in vacuo. The residue was dissolved in toluene (220 mL) and the solution with the crude product was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate and once with HCl 0.29N (140 mL). The organic phase was concentrated in vacuo to afford 42.0 g (61.7.0% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 92.3% according to GC with internal standard. The content of toluene was found to be 4.5% and of cyclohexanecarboxylic acid was found to be <0.1%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (4.4 g, 60 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 3 h at 20-25°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 20-25°C, then cooled to 10°C and 1-bromo-2-ethylbutane (65.0 g, 390 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for 1 h at 8-12°C, then warmed to 20-25°C within 30 min and stirred for 19 h at 20-25°C. GC analysis indicated the presence of 13.7% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 5 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed with hexanes (240 mL) and acidified by addition of HCl 37% (38 mL) at 10-15°C. The acidic aqueous solution was extracted with toluene (240 mL). The organic phase was washed with H2O (240 mL) and concentrated in vacuo. The residue was dissolved in toluene (220 mL) and the solution with the crude product was extracted 2 times (150 mL each) with 7% aqueous sodium bicarbonate and once with 5% NaCl (55 mL). The organic phase was concentrated in vacuo to afford 45.2 g (65.6% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 88.5% according to GC with internal standard. The content of toluene was found to be 5.3% and of cyclohexanecarboxylic acid was found to be 4.3%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (206 mL, 330 mmol) over 3 h at 20-25°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 20-25°C, then cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for 1 h at 8-12°C, then warmed to 20-25°C within 30 min and stirred for 19 h at 20-25°C. GC analysis indicated the presence of 18.4% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 5 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed with TBME (240 mL) resulting in a 3 layer system. The lower 2 layers were acidified by addition of HCl 37% (38 mL) at 10-15°C. The acidic aqueous solution was extracted with toluene (240 mL). The organic phase was washed with H2O (240 mL) and concentrated in vacuo. The residue (50.4g), which contained 66.4% of 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 27.3 % of cyclohexanecarboxylic acid was divided in 2 equal parts. 25.2 g of the crude residue were dissolved in toluene (110 mL). Then, the toluene solution was extracted 3 times (75 mL each) with 7% aqueous sodium bicarbonate and once with H20 (50 mL). The organic phase was concentrated in vacuo to afford 17.5 g (52.0% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 93.9% according to GC with internal standard. The content of toluene was found to be 3.8% and of cyclohexanecarboxylic acid was found to be 0.33%. The second part of the crude residue (25.2g) was dissolved in 110 mL toluene. Then, the toluene solution was extracted twice (75 mL each) with 7% aqueous sodium phosphate (set to pH=8.5 with H3PO4). The organic phase was concentrated in vacuo to afford 20.0 g (52.8% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 83.5% according to GC with internal standard. The content of toluene was found to be 3.0% and of cyclohexanecarboxylic acid was found to be 10.6%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 3.5 h at 35°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 35°C, then cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for 1 h at 8-12°C, then warmed to 20-25°C within 30 min and stirred for 19 h at 20-25°C. GC analysis indicated the presence of 12.7% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 5 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed with hexanes (240 mL and 120 mL) and acidified by addition of HCl 37% (38 mL) at 10-15°C. The acidic aqueous solution was extracted with toluene (240 mL). The organic phase was washed with H2O (240 mL). The toluene solution with the crude product (83.7% area 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 15.2 % area cyclohexanecarboxylic acid) was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate (set to pH=9 by addition of 28% NaOH) and once with IN HCl (100 mL). The organic phase was concentrated in vacuo to afford 46.5 g (69.6% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 95.3% according to GC with internal standard. The content of toluene was found to be 3.9% and of cyclohexanecarboxylic acid was found to be <0.10%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (225 mL, 360 mmol) over 3 h at 30°C. After complete BuLi addition the reaction mixture was stirred for further 3 h at 30°C, then cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for 1 h at 8-12°C, then warmed to 20-25°C within 30 min and stirred for 17 h at 20-25°C. GC analysis indicated the presence of 17.4% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 5 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed with hexanes (240 mL and 120 mL) and acidified by addition of HCl 37% (38 mL) at 10-15°C. The acidic aqueous solution was extracted with toluene (240 mL). The organic phase was washed with H2O (240 mL). The toluene solution with the crude product (77.8% area 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 21.5 % area cyclohexanecarboxylic acid) was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate (set to pH=9 by addition of 28% NaOH) and once with IN HCl (50 mL). The organic phase was concentrated in vacuo to afford 41.4 g (62.3% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxyfic acid with a content of 95.8% according to GC with internal standard. The content of toluene was found to be 3.0% and of cyclohexanecarboxylic acid was found to be <0. 10%.; CHCA Na salt (45.0 g, 300 mmol) was suspended under argon in THF (420 mL). DEA (2.2 g, 30 mmol) was added to the stirred mixture followed by addition of 2.5 M BuLi in hexane (144 mL, 360 mmol) over 3 h at 20-25°C. After complete BuLi addition the reaction mixture was stirred for further 90 min at 20-25°C, then cooled to 10°C and 1-bromo-2-ethylbutane (60.0 g, 360 mmol) was added at 8-12°C over 30 min. After complete addition the reaction mixture was stirred for additional 60 min at 10-12°C and then warmed to 20-25°C within 30 min and stirred for 18.5 h at 20-25°C. GC analysis indicated the presence of 19.9% area unreacted starting material (cyclohexanecarboxylic acid). The reaction mixture was cooled to 0-5°C and H2O (400 mL) was added within 10-20 min at 0-15°C. Volatile components (THF, hexanes,etc) were distilled at 45°C/400-100 mbar. The remaining basic aqueous solution was washed twice with hexanes (240 and 120 mL) and acidified by addition of HCl 37% (38 mL) at 0-15°C. The acidic aqueous solution was extracted with toluene (240 mL) and the organic phase was washed with H2O (240 mL). The toluene solution with the crude product (73.7% area 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 25.7 % area cyclohexanecarboxylic acid) was extracted 3 times (150 mL each) with 7% aqueous sodium bicarbonate (set to pH=9 by addition of 28% NaOH) and once with HCl 0.5N (50 mL). The organic phase was concentrated in vacuo to afford 35.4 g (54.6% yield) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid with a content of 98.4% according to GC with internal standard. The content of toluene was found to be 1.7% and of cyclohexanecarboxylic acid was found to be 0.11%.
51% Stage #1: cyclohexanecarboxylic acid Na-salt With phenyllithium; diethylamine In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 10 - 20℃; for 19.5h; Stage #3: With hydrogenchloride In water 25 CHCA Na salt (3.0 g, 20 mmol) was suspended under argon in THF (37 mL). DEA (146 mg, 2 mmol) was added to the stirred mixture followed by addition of 1.9 M PhLi in hexane (12.6 mL, 24 mmol) over 3 h using a syringe pump. After complete PhLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (4.29 g, 26 mmol) in THF (13 mL) was added dropwise to the slightly turbid reaction mixture at 10°C over 30 min. After 1 h the cooling bath was removed and the reaction mixture was stirred 18 h at ambient temperature. The reaction mixture was worked up in analogous manner as described in Example 7 to give 3.59 g crude product with a content of 36.4% cyclohexanecarboxylic acid and 60.7% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 51%.

  • 5
  • [ 16090-10-1 ]
  • [ 3814-34-4 ]
  • [ 381209-09-2 ]
  • [ 98-89-5 ]
YieldReaction ConditionsOperation in experiment
49% Stage #1: cyclohexanecarboxylic acid Li-salt With n-butyllithium; diethylamine In tetrahydrofuran; hexane at 20℃; for 4.5h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran; hexane at 10 - 20℃; for 19.5h; Stage #3: With hydrogenchloride In water 12 Cyclohexanecarboxylic acid lithium salt (6.0 g, 44.7 mmol, preparation see Example 11) was suspended under argon in THF (75 mL). DEA (327 mg, 4.47 mmol) was added to the stirred mixture followed by addition of 1.6 M BuLi in hexane (33.6 mL, 53.7 mmol) over 3 h using a syringe pump. After complete BuLi addition stirring at RT was continued for 1.5 h. 1-Bromo-2-ethylbutane (9.6 g, 58.2 mmol) in THF (26 mL) was added dropwise to the orange and slightly turbid reaction mixture at 10-15°C over 30 min. After 1 h the cooling bath was removed and the white suspension was stirred 18 h at ambient temperature. At 5°C, ice-cold H2O (30 mL) was cautiously dropped to the reaction mixture under stirring. Then hexane and H2O were added and the mixture was concentrated in vacuo until most of the THF was removed. The residue was extracted with hexane (80 + 120 mL). The organic phases were washed with H2O. The aqueous phases were combined, adjusted to ~pH 2 with aqueous HCl and extracted with DCM (2x150 mL). The dichloromethane phases were washed with dilute brine, dried over sodium sulfate and concentrated in vacuo to give 6.75 g crude product with a content of 27.7% cyclohexanecarboxylic acid and 68.3% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid corresponding to a yield of 49%.
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