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Structure of 949-69-9 * 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.
With hydroxylamine hydrochloride; potassium carbonate In ethanol at 20℃; for 16 h;
compound 1a (1.89 g, 10 mmol) was dissolved in 50 mL of absolute ethanol, and potassium carbonate (2.76 g, 20 mmol) and hydroxylamine hydrochloride (1.04 g, 15 mmol) were added successively and stirred at room temperature for 6 hours. After the mixture was concentrated, water was added. Then the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give white solids 1b (2.04 g, yield 100percent), MS: 205.0 [M+H]+.
72%
With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol at 0 - 20℃;
Step 1: Synthesis of l-benzylpiperidin-4-one oxime [141]To a clean and dried single necked round bottom flask was added hydroxyl amine hydrochloride (3.08 g, 0.04 mol), sodium bicarbonate (9.32 g, 0.1 1 mol), and ethanol (120 ml) at 0 °C. After 5 min compound [140] (7.0 g, 0.04 mol) was added dropwise at 0 °C. The reaction mixture was brought to RT in 2 h. TLC analysis showed complete consumption of starting material. The reaction was worked up by removing the ethanol by distillation followed by addition of water (50 ml), extracted into EtOAc (3 X 150 ml), combined the organic layer which were dried over sodium sulphate and concentrated to yield [141] as a white solid (5.5 g, 72 percent).ESIMS: 205 (M+ + 1)
72%
With hydroxylamine hydrochloride; sodium hydrogencarbonate In ethanol at 0 - 20℃; for 2 h;
Step l To a clean and dried single necked round bottom flask was added hydroxyl amine hydrochloride (3.08 g, 0.04 mol), sodium bicarbonate (9.32 g, 0. 1 1 mol), and ethanol (120 ml) at 0 °C. After 5 min compound [109] (7.0 g, 0.04 mol) was added dropwise at 0 °C. The reaction mixture was brought to RT in 2 h. TLC analysis showed complete consumption of starting material. ' The reaction was worked up by removing the ethanol by distillation followed by addition of water (50 ml), extracted into EtOAc (3 X 150: ml), combined the organic layer which were dried over sodium sulphate and concentrated to yield [110] as a white solid (5.5 g, 72 percent). ESIMS: 205 (M+ + 1 ) .
70.17%
With hydroxylamine hydrochloride; potassium carbonate In ethanol; water at 0 - 20℃;
28.35 g ( 1 equiv., 0.15 mol) of 1-benzylpiperidin-4-one was dissolved in 60 mL of EtOH and then cooled to 0 °C using an ice bath. A solution containing 20.85 g (2 equiv., 0.30 mol) of hydroxylamine hydrochloride dissolved in 75 mL of H2O was prepared and then added dropwise to the reaction mixture followed by dropwise addition of a solution containing 20.7 g (1 equiv., 0.15 mol) of K2CO3 dissolved in 75 mL of H2O. The reaction mixture was then brought to room temperature and stirred overnight. The EtOH was then removed via rotary evaporation and the reaction mixture was then cooled in an ice bath to allow the product to crystallize out of solution. The product was filtered and washed several times with H2O and recrystallized in EtOH. Yield: 27.78 g (70.17percent).
Reference：
[1] Patent: US2017/44187, 2017, A1, . Location in patent: Paragraph 0086; 0087
[2] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2827 - 2840
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 14, p. 4085 - 4090
[4] Tetrahedron, 1995, vol. 51, # 17, p. 5143 - 5156
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9089 - 9099
[6] Patent: WO2012/101654, 2012, A2, . Location in patent: Page/Page column 73
[7] Patent: WO2014/16849, 2014, A2, . Location in patent: Page/Page column 124
[8] Patent: WO2016/29218, 2016, A1, . Location in patent: Page/Page column 12-13
[9] Patent: US5580872, 1996, A,
[10] Patent: US4481360, 1984, A,
[11] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2837 - 2842
2
[ 3612-20-2 ]
[ 949-69-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium acetate In ethanol; water
Stage A 1-benzyl-4-hydroxyiminopiperidine 18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylamide hydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol are stirred for 8 hours. The mixture is concentrated, taken up in 100 ml of water and rendered basic and the resulting precipitate is filtered off. Yield: 98percent Melting point: 125°-127° C. Proton nuclear magnetic resonance spectrum (solvent CDCl3): 7.3 ppm, 5H, m; 3.55 ppm, 2H, s; 2.75 to 2.4 ppm, 6H, m; 2.35 ppm, 2H, m; 3 ppm, 1H exchangeable.
Reference：
[1] Patent: US5189045, 1993, A,
3
[ 20821-52-7 ]
[ 949-69-9 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 3165,3171
4
[ 949-69-9 ]
[ 55186-89-5 ]
Yield
Reaction Conditions
Operation in experiment
30%
Stage #1: With benzenesulfonyl chloride; sodium hydroxide In water; acetone; acetonitrile at 0℃; Reflux Stage #2: With sodium hydroxide In acetone at 20℃;
Step 2: Synthesis of l-benzyl-l,4-diazepan-5-one [142]To a clean and dried two necked round bottom flask [141] (2 g, 0.00976 mol) was dissolved in acetone (20 ml) and acetonitrile (20 ml). The reaction mixture was cooled to 0 °C, and then to it 15 percent aqueous NaOH ( 1.2 ml) was added drop wise, followed by the addition of benzene sulphonyl chloride (1.49 ml, 0.01 1 mol). The reaction mixture was refluxed overnight. TLC showed complete consumption of SM. The reaction mixture was diluted with acetone, and passed through celite and concentrated. Saturated NaHC03 (50 ml) was added to the solid followed by extraction with EtOAc (3 X 150 ml), removal of the solvent under reduced pressure. The residue was purified by column chromatograph on silica gel with MeOH:DCM (1percent) as an eluent to afford [142] as a white solid (600 mg, 30 percent).ESIMS: 205 (M+ + 1)
30%
With benzenesulfonyl chloride; sodium hydroxide In water; acetone; acetonitrile at 0℃; Reflux
Step 2 To a clean and dried two necked round bottom flask [110] (2 g, 9.76 mmol) was dissolved in acetone (20 ml) and acetonitrile (20 ml). The reaction mixture was cooled to 0 (>C, and then to it 15 percent aqueous NaOH ( 1.2 ml) was added drop wise, followed by the addition of benzene sulphonyl chloride ( 1.49 ml, 1 1 mmol). The reaction mixture was refluxed overnight. TLC showed complete consumption of SM. The reaction mixture was diluted with acetone, and passed through celite and concentrated. Saturated NaHCOj (50 ml) was added to the solid followed by extraction with EtOAc (3 X 150 ml), removal of the solvent under reduced pressure. The residue was purified by column chromatography on silica gel with MeOH: DCM ( 1 ) as an eluent to afford [111] as a white solid (600 mg, 30 ). , ESIMS: 205 (M+ + 1 )
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 16, p. 5832 - 5835
[2] Patent: WO2012/101654, 2012, A2, . Location in patent: Page/Page column 73
[3] Patent: WO2014/16849, 2014, A2, . Location in patent: Page/Page column 124
Compound 1b (2.04 g, 10 mmmol) was dissolved in 50 mL of anhydrous n-amyl alcohol and stirred at reflux, to which was added sodium (2.76 g, 120 mmol) in batches. The reaction was maintained for 2.5 hours. Then the reaction mixture was cooled, adjusted with 1M hydrochloric acid to PH 12 and extracted with water. The combined aqueous phase was adjusted with 1M sodium hydroxide to PH 8. Then the mixture was extracted by ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give colourless liquid 1c (1.71 g, yield 90%), MS: 191.0 [M+H]+.
64%
With i-Amyl alcohol; sodium; at 20 - 110℃;
A solution containing 6.12 g (1 equiv., 0.03 mol) of <strong>[949-69-9]1-benzylpiperidin-4-one oxime</strong> dissolved in 90 mL of iso-amyl alcohol was prepared and heated to approximately 1 10 C. 6.9 g (10 equiv., 0.3 mol) of Na metal was then added slowly to the reaction mixture. After addition of Na, the reaction mixture was allowed to cool to room temperature and stirred until the reaction mixture turned into a thick slurry. The slurry was dissolved in 50 mL of ethyl acetate and 25 mL of H2O. The organic layer was separated and washed with H2O (2 x 20 mL) followed by drying over anhydrous magnesium sulfate. The solvent was removed via rotary evaporation, resulting in a yellow oil. The crude product was purified via column chromatography utilizing silica gel and a DCM:MeOH solvent system in a ratio of 4: 1 with an additional 1% of Et3N. Yield: 3.7 g (64%).
EXAMPLE 16 1-benzyl-4-amino-piperidine 7.6 grs (0.2 mol) lithium aluminium hydride and 300 ml anhydrous ether were introduced into a 1 l. flask, provided with a mechanical agitator and a Soxhlet extractor. 20 grs (0.1 mol) <strong>[949-69-9]1-benzyl-4-piperidone oxime</strong> were placed in the Soxhlet cartridge, and the mixture was heated under reflux for 12 hours, at the end of which time the excess of LiAlH4 was destroyed. The ethereal extracts were dried and concentrated to dryness giving an oil that weighed 18 grs. On distillation in vacuo 17 grs of pure product was obtained. b.p. = 103-105 C. at 0.07 mmHg.
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; at 20℃; for 16.0h;
compound 1a (1.89 g, 10 mmol) was dissolved in 50 mL of absolute ethanol, and potassium carbonate (2.76 g, 20 mmol) and hydroxylamine hydrochloride (1.04 g, 15 mmol) were added successively and stirred at room temperature for 6 hours. After the mixture was concentrated, water was added. Then the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give white solids 1b (2.04 g, yield 100%), MS: 205.0 [M+H]+.
72%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; at 0 - 20℃;
Step 1: Synthesis of l-benzylpiperidin-4-one oxime [141]To a clean and dried single necked round bottom flask was added hydroxyl amine hydrochloride (3.08 g, 0.04 mol), sodium bicarbonate (9.32 g, 0.1 1 mol), and ethanol (120 ml) at 0 C. After 5 min compound [140] (7.0 g, 0.04 mol) was added dropwise at 0 C. The reaction mixture was brought to RT in 2 h. TLC analysis showed complete consumption of starting material. The reaction was worked up by removing the ethanol by distillation followed by addition of water (50 ml), extracted into EtOAc (3 X 150 ml), combined the organic layer which were dried over sodium sulphate and concentrated to yield [141] as a white solid (5.5 g, 72 %).ESIMS: 205 (M+ + 1)
72%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; at 0 - 20℃; for 2.0h;
Step l To a clean and dried single necked round bottom flask was added hydroxyl amine hydrochloride (3.08 g, 0.04 mol), sodium bicarbonate (9.32 g, 0. 1 1 mol), and ethanol (120 ml) at 0 C. After 5 min compound [109] (7.0 g, 0.04 mol) was added dropwise at 0 C. The reaction mixture was brought to RT in 2 h. TLC analysis showed complete consumption of starting material. ' The reaction was worked up by removing the ethanol by distillation followed by addition of water (50 ml), extracted into EtOAc (3 X 150: ml), combined the organic layer which were dried over sodium sulphate and concentrated to yield [110] as a white solid (5.5 g, 72 %). ESIMS: 205 (M+ + 1 ) .
70.17%
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 0 - 20℃;
28.35 g ( 1 equiv., 0.15 mol) of 1-benzylpiperidin-4-one was dissolved in 60 mL of EtOH and then cooled to 0 C using an ice bath. A solution containing 20.85 g (2 equiv., 0.30 mol) of hydroxylamine hydrochloride dissolved in 75 mL of H2O was prepared and then added dropwise to the reaction mixture followed by dropwise addition of a solution containing 20.7 g (1 equiv., 0.15 mol) of K2CO3 dissolved in 75 mL of H2O. The reaction mixture was then brought to room temperature and stirred overnight. The EtOH was then removed via rotary evaporation and the reaction mixture was then cooled in an ice bath to allow the product to crystallize out of solution. The product was filtered and washed several times with H2O and recrystallized in EtOH. Yield: 27.78 g (70.17%).
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water;
Step 262a. N-benzyl-4-(N-hydroxyimino)piperidine A 3.78 g (20 mmol) sample of N-benzyl-4-oxo-piperidine (Aldrich Chemical Co.) was dissolved in 50 mL of methanol. To this solution was added 4.16 g (60 mmol) of hydroxylamine hydrochloride and 5.2 g NaHCO3 (52 mmol) (Dissolved in 80 mL of water and added in 5 mL portions). The mixture was then stirred at room temperature for 18 hours. The mixture was filtered, and the solvent was removed from the filtrate on a rotary evaporator to give 3.05 g of the title product. mp 127-128 C.
With pyridine; hydroxylamine hydrochloride; In ethanol;
PART A 1-Benzyl-4-piperidinone-oxime Following a procedure of P. Brookes, et al., J. Chem. Soc., 3165 (1957), 1-benzyl-4-piperidinone (44.6 g, 0.234 mol) and hydroxylamine hydrochloride (14.0 g, 0.201 mol) are added to 140 ml of dry pyridine and the resulting mixture is heated to 100 C. in an oil bath for 3 hours. The resulting solid is cooled overnight, filtered and crystallized from 1 liter of ethanol. The product is collected as colorless needles, 38.17 g, in two groups with melting point of 225-237 C., decomposed depending upon the rate of heating.
Step 2: Synthesis of l-benzyl-l,4-diazepan-5-one [142]To a clean and dried two necked round bottom flask [141] (2 g, 0.00976 mol) was dissolved in acetone (20 ml) and acetonitrile (20 ml). The reaction mixture was cooled to 0 C, and then to it 15 % aqueous NaOH ( 1.2 ml) was added drop wise, followed by the addition of benzene sulphonyl chloride (1.49 ml, 0.01 1 mol). The reaction mixture was refluxed overnight. TLC showed complete consumption of SM. The reaction mixture was diluted with acetone, and passed through celite and concentrated. Saturated NaHC03 (50 ml) was added to the solid followed by extraction with EtOAc (3 X 150 ml), removal of the solvent under reduced pressure. The residue was purified by column chromatograph on silica gel with MeOH:DCM (1%) as an eluent to afford [142] as a white solid (600 mg, 30 %).ESIMS: 205 (M+ + 1)
30%
With benzenesulfonyl chloride; sodium hydroxide; In water; acetone; acetonitrile; at 0℃;Reflux;
Step 2 To a clean and dried two necked round bottom flask [110] (2 g, 9.76 mmol) was dissolved in acetone (20 ml) and acetonitrile (20 ml). The reaction mixture was cooled to 0 (>C, and then to it 15 % aqueous NaOH ( 1.2 ml) was added drop wise, followed by the addition of benzene sulphonyl chloride ( 1.49 ml, 1 1 mmol). The reaction mixture was refluxed overnight. TLC showed complete consumption of SM. The reaction mixture was diluted with acetone, and passed through celite and concentrated. Saturated NaHCOj (50 ml) was added to the solid followed by extraction with EtOAc (3 X 150 ml), removal of the solvent under reduced pressure. The residue was purified by column chromatography on silica gel with MeOH: DCM ( 1 ) as an eluent to afford [111] as a white solid (600 mg, 30 ). , ESIMS: 205 (M+ + 1 )
EXAMPLE 15 1-benzyl-4-piperidone-oxime 48 grs 1-benzyl-4-piperidone oxime hydrochloride(1) were placed in a liquid-liquid extraction apparatus, and dissolved in a solution of 8 grs NaOH in 100 ml water. After 7 hours of extraction with ether, 38 grs white solid were obtained. m.p. = 129-131 C. Yield = 93%. (1) P. Brookers, R. J.
With hydroxylamine hydrochloride; sodium hydroxide; In water; at 0 - 20℃; for 16.0h;
General procedure: dicyclopentylmethanone (1.436 ml, 8.63 mmol) was added into a water (10 ml) solution of hydroxylamine hydrochloride (1.2 g, 17.27 mmol) and sodium hydroxide (0.69 1 g, 17.27 mmol) at 0 C. The resulting mixture was stirred vigorously and was allowed to slowly warm to room temperature. After 16 h, the reaction mixture was extractedwith EtOAc (3x 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the title compound:
8
[ 949-69-9 ]
[ 74-86-2 ]
5-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine[ No CAS ]
Stage A 1-benzyl-4-hydroxyiminopiperidine 18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylamide hydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol are stirred for 8 hours. The mixture is concentrated, taken up in 100 ml of water and rendered basic and the resulting precipitate is filtered off. Yield: 98% Melting point: 125-127 C. Proton nuclear magnetic resonance spectrum (solvent CDCl3): 7.3 ppm, 5H, m; 3.55 ppm, 2H, s; 2.75 to 2.4 ppm, 6H, m; 2.35 ppm, 2H, m; 3 ppm, 1H exchangeable.
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