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Product Details of [ 3612-20-2 ]

CAS No. :3612-20-2 MDL No. :MFCD00006192
Formula : C12H15NO Boiling Point : -
Linear Structure Formula :C5H8ONCH2C6H5 InChI Key :-
M.W : 189.25 Pubchem ID :-
Synonyms :
N-Benzyl-4-piperidone;NSC 77933
Chemical Name :1-Benzylpiperidin-4-one

Calculated chemistry of [ 3612-20-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.42
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 60.34
TPSA : 20.31 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.6 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.19
Log Po/w (XLOGP3) : 1.21
Log Po/w (WLOGP) : 1.32
Log Po/w (MLOGP) : 1.65
Log Po/w (SILICOS-IT) : 2.59
Consensus Log Po/w : 1.79

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.96
Solubility : 2.07 mg/ml ; 0.0109 mol/l
Class : Very soluble
Log S (Ali) : -1.23
Solubility : 11.1 mg/ml ; 0.0584 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.42
Solubility : 0.0725 mg/ml ; 0.000383 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.02

Safety of [ 3612-20-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3612-20-2 ]

* 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.

  • Upstream synthesis route of [ 3612-20-2 ]
  • Downstream synthetic route of [ 3612-20-2 ]

[ 3612-20-2 ] Synthesis Path-Upstream   1~75

  • 1
  • [ 3612-20-2 ]
  • [ 615-53-2 ]
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YieldReaction ConditionsOperation in experiment
31% With barium(II) oxide In methanol at -15℃; N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) at -15°C over a period of 30 minutes while maintaining the temperature at -5°C or lower. During the addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions. The resulting mixture was stirred overnight at -15°C and then filtered, and the filtrate was distilled under reduced pressure to remove the solvent and diethyl ether was added to the residue. The insoluble material was filtered off and a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31percent).1H-NMR (CDCl3) δ; 1.84 (2H, m), 2.54 (2H, m), 2.60 (2H, m), 2.73 (4H, s), 3.65 (2H, s), 7.25 (5H, m).
31% With barium(II) oxide In methanol at -15 - -5℃; (a)
Synthesis of 1-benzyl-4-azepanone
To a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) was added dropwise N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) over a period of 30 minutes so that the temperature might be maintained at -5°C or lower.
During the dropwise addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions.
The resulting mixture was stirred overnight at -15°C and then filtered, and the resulting filtrate was distilled under reduced pressure to remove the solvent, followed by adding diethyl ether to the residue.
After the insoluble material was filtered off, a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether.
The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31percent).
1H-NMR (CDCl3) δ;1.84 (2H, m), 2.54 (2H, m), 2.60 (2H, m), 2.73 (4H, s), 3.65 (2H, s), 7.25 (5H, m).
Example 100 Synthesis of tert-butyl 4-[4-(aminocarbonyl)-3-methoxyphenyl]amino}azepane-1-carboxylate(a) Synthesis of 1-benzyl-4-azepanone N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) at -15°C over a period of 30 minutes while maintaining the temperature at -5°C or lower. During the addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions. The resulting mixture was stirred overnight at -15°C and then filtered, and the filtrate was distilled under reduced pressure to remove the solvent and diethyl ether was added to the residue. The insoluble material was filtered off and a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31percent).
Reference: [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 93
[2] Patent: EP1500643, 2005, A1, . Location in patent: Page 27; 47
[3] Bulletin of the Chemical Society of Japan, 1958, vol. 31, p. 418,420
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  • [ 1208-75-9 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 38, p. 11889 - 11893
  • 3
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  • [ 5355-68-0 ]
Reference: [1] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 208 - 215
  • 4
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  • [ 72544-16-2 ]
Reference: [1] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 208 - 215
  • 5
  • [ 3612-20-2 ]
  • [ 59184-90-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 11, p. 3065 - 3067
[2] Synthetic Communications, 2003, vol. 33, # 13, p. 2329 - 2338
[3] Patent: WO2013/107336, 2013, A1,
[4] Patent: US2015/80380, 2015, A1,
  • 6
  • [ 3612-20-2 ]
  • [ 867-13-0 ]
  • [ 59184-90-6 ]
Reference: [1] Archiv der Pharmazie, 1984, vol. 317, # 12, p. 1010 - 1017
  • 7
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  • [ 19125-34-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3721 - 3738
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  • [ 40807-61-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 695 - 700
  • 9
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  • [ 16502-01-5 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 29, p. 5507 - 5514
  • 10
  • [ 3612-20-2 ]
  • [ 949-69-9 ]
YieldReaction ConditionsOperation in experiment
100% 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
  • 11
  • [ 3612-20-2 ]
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YieldReaction ConditionsOperation 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,
  • 12
  • [ 3612-20-2 ]
  • [ 55186-89-5 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: at 0 - 5℃; for 27 h;
Stage #2: With sodium hydroxide In water
[Referential Example 119]; 1-Benzylhexahydro-1H-1,4-diazepin-5-one ; [] Concentrated sulfuric acid (25 mL) was added to 1-benzyl-4-piperidone (10.14 g) in acetic acid (50 mL) at room temperature, and sodium azide (3.880 g) was added thereto at 0°C over a period of 2 hours, followed by stirring at 5°C for 25 hours. The reaction mixture was alkalinized through addition of aqueous sodium hydroxide, followed by partitioning by use of chloroform. The aqueous layer was extracted with chloroform. The organic layers were combined, and washed with saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and then the residue was purified through silica gel column chromatography (chloroform - methanol), to thereby give the title compound as a solid (5.081 g, 47percent).1H-NMR(400MHz,CDCl3)δ: 2.50-2.70(6H,m), 3.20-3.35(2H,m), 3.60(2H,s), 6.07(1H,br), 7.20-7.40(5H,m). MS(ESI)m/z: 205(M+H)+.
Reference: [1] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 72
[2] Tetrahedron Letters, 1991, vol. 32, # 22, p. 2469 - 2470
[3] Patent: WO2012/101654, 2012, A2,
[4] Patent: WO2014/16849, 2014, A2,
  • 13
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  • [ 616-38-6 ]
  • [ 57611-47-9 ]
Reference: [1] Heterocycles, 1987, vol. 26, # 8, p. 2165 - 2174
  • 14
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  • [ 5004-07-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 491 - 494
  • 15
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  • [ 2942-58-7 ]
  • [ 62718-31-4 ]
Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1927 - 1939
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  • [ 62718-31-4 ]
Reference: [1] Tetrahedron Letters, 1989, vol. 30, # 28, p. 3681 - 3684
[2] Journal of Organic Chemistry, 1991, vol. 56, # 5, p. 1827 - 1832
  • 17
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  • [ 61085-60-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7720 - 7732
[2] Journal of Organic Chemistry, 1992, vol. 57, # 14, p. 4037 - 4038
[3] Journal of Organic Chemistry, 1990, vol. 55, # 13, p. 4207 - 4209
[4] Patent: US8742111, 2014, B1,
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  • [ 62-53-3 ]
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Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 36, p. 11614 - 11617
  • 19
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  • [ 39143-25-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3972 - 3983
[2] Patent: US5270317, 1993, A,
[3] Patent: WO2012/101013, 2012, A1,
[4] Patent: US2013/23502, 2013, A1,
[5] Patent: WO2016/78771, 2016, A1,
  • 20
  • [ 67-56-1 ]
  • [ 3612-20-2 ]
  • [ 7677-24-9 ]
  • [ 60437-30-1 ]
Reference: [1] Patent: EP1221441, 2002, A2, . Location in patent: Page 201-202
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  • [ 60437-30-1 ]
Reference: [1] Patent: WO2013/106717, 2013, A1,
[2] Patent: US9156825, 2015, B2,
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  • [ 62-53-3 ]
  • [ 1155-56-2 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With acetic acid In dichloromethane at 20℃; for 2 h;
Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 1 h;
Preparation of 1 -benzyl-N-phenylpiperidin-4-amine (Compound 7-2) [00238j To a solution of aniline (Compound 7-1, 3.72 g, 40 mmol) indichloromethane (50 mL), was added 1-benzylpiperidin-4-one (7.94 g, 42 mmol) and acetic acid (240 mg, 4 mmol). After stirred at room temperature for 2 h, sodium triacetoxyborohydride (12.72 g, 60 mmol) was added. The reaction mixture was stirred for another 1 h, then diluted with water (50 mL), neutralized to pH 7 with sodium bicarbonate, extracted with dichloromethane (100 ml x 2). The combined organic layer was washed with brine (100 ml x 2), dried over anhydrous sodium sulfate and concentrated to give 1-benzyl-N-phenylpiperidin-4-amine (Compound 7-2, 9.49 g, yield: 89percent) as a white solid. MS (ES): mlz: 267[M+H].
84% With acetic acid; zinc In water at 20 - 70℃; for 36 h; To a mixture of N-benzylpiperidin-4-one 1 (0.01 mol, 1.89 g), aniline (0.01 mol), and activated zinc (0.04 mol), 90percent aqueous acetic acid (0.16 mol) was added in portions. The mixture was stirred at room temperature for 24 h and at 70°C on a water bath for an additional 12 h. After the reaction completion, the mixture was diluted with methanol and filtered. The filtrate was concentrated in a vacuum and then neutralized with a 30percent ammonium hydroxide solution to pH 10. The crude product was collected by filtration and recrystallized with petroleum ether to obtain the pure product in 84percent yield (2.2 g). IR (KBr), ν, cm–1: 3440 (N–H stretching), 3255, 3020, 2936, 2842,1615, 1526, 1490, 1372, 1318,1255, 1087, 977, 862, 751, 690. 1H NMR [400 MHz,CDCl3, δ (ppm)]: 1.50 (dq, 2H), 2.10 (br.d, 2H), 2.30(br.t, 2H), 2.60 (s, 2H), 2.90 (br.d, 2H), 3.35 (m, 1H),3.50 (br.s, 1H), 7.10–7.40 (m, Ar–H). Mass spectrum(m/z): 267 [M + 1].
64%
Stage #1: With sodium tris(acetoxy)borohydride In chloroform; ethyl acetate at 20℃; for 0.666667 h;
Stage #2: With water; sodium hydrogencarbonate In chloroform; ethyl acetate
Step 1
Sodium triacetoxyhydroborate (1.1 g, 5.3 mmol) was added to a solution of 1-benzyl-4-piperidone (1.0 g, 5.3 mmol) and aniline (0.5 g, 5.3 mmol) in a mixture of chloroform/ethyl acetate (10 mL/5 mL) by portions, and the mixture was stirred at room temperature for 40 minutes.
To the reaction mixture was added an aqueous saturated sodium bicarbonate solution (50 ml), the mixture was extracted with ethyl acetate (3x50 ml), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain (1-benzyl-4-piperidinyl)phenylamine (0.9 g, 64percent).
1H-NMR (CDCl3) δ: 1.49 (2H, m), 2.04 (2H, m), 2.17 (2H, dt, J = 2.3 Hz, 10.8 Hz), 2.86 (2H, br d, J = 12.0 Hz), 3.30 (1H, m), 3.54 (2H, s), 6.50-7.35 (10H, m).
4.40 g With sodium tetrahydroborate; acetic acid In 1,2-dichloro-ethane at 20℃; for 24 h; Inert atmosphere Sodium borohydride (0.90 g, 23.9 mmol) was suspended in 20 mL of 1,2-dichloroethaneunder a nitrogen atmosphere and cooled in an ice water bath. Acetic acid (4.30 g,71.6 mmol) was added dropwise with an addition funnel. It was rinsed with 10 mL of 1,2-dichloroethane. The mixture was removed from the ice water bath and stirred atroom temperature for 16 h. A solution of 1-benzyl-4-piperidone (3.00 g, 15.9 mmol),aniline (2.62 g, 17.4 mmol), acetic acid (0.96 g, 15.9 mmol), and 12 mL of 1,2-dichloroethane was added dropwise with an addition funnel. It was rinsed with 10 mLof 1, 2 dichloroethane. The mixture was stirred for 24 h at room temperature. Thereaction mixture was poured over 100 mL of a 2 M aqueous sodium hydroxide solutionand extracted with chloroform (3 £ 100 mL). The combined organic extractswere dried with sodium sulfate, filtered, and the volatiles were evaporated providing4.40 grams of the reductive amination product. The residue was taken up in 120 mL1,2-dichloroethane and propionyl chloride (7.36 g, 79.5 mmol) was added with asyringe. The mixture was heated to reflux under a nitrogen atmosphere for 20 h. Thereaction mixture was allowed to cool to room temperature and the volatiles wereevaporated. The residue was taken up with 100 mL of saturated aqueous sodiumbicarbonate and 100 mL of chloroform. The organic layer was separated. The aqueouslayer was washed with chloroform (2 £ 100 mL). The combined organic extractswere dried with sodium sulfate, filtered, and the volatiles were evaporated providing5.70 g of a tan oil. The residue was dissolved in 15 mL of isopropanol and the solutionwas gently warmed. Oxalic acid (2.21 g, 17.5 mmol) in 5 mL of water was addedwith an addition funnel. It was rinsed with 2 mL of water followed by 3 mL of isopropanol.The mixture was allowed to cool to room temperature and was placed in are frigerator for 24 h.

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[4] ACS Chemical Neuroscience, 2018,
  • 24
  • [ 3612-20-2 ]
  • [ 151-50-8 ]
  • [ 62-53-3 ]
  • [ 968-86-5 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With acetic acid In dichloromethane at 5 - 50℃; for 21.5 h;
Stage #2: With sodium hydroxide In dichloromethane; water at 0 - 20℃; for 1 h;
Example 1; Synthesis of l-BenzyI-4-phenylaininopiperidine-4-carbonitrile:; A 22.0 L, 4-necked jacketed R.B flask was charged with l-benzyl-4-piperidone (99percent), 170.1 g (0.9 mol); aniline, 334.8 g (3.6 mol); KCN, 234 g (3.6 mol) and CH2Cl2 (dichloromethane) 2376 g (28.05 mol) and the suspension was stirred and cooled to 5 0C. Acetic acid, 1701 g (28.3 mol) was added dropwise over a period of about 3.5 hours keeping the internal temp at 5- 8 0C. After the addition of acetic acid was complete, the reaction mixture was gradually warmed to 50 0C over a 1 hour period and then stirred at that temperature for 17 hours. The resulting suspension was then cooled to 20 0C. Crushed ice (5000 g) was then added into the reaction mixture and stirred. Thereafter, a ION NaOH solution (1080 g) was slowly added to the reaction mixture over a period of 1.0 hour keeping the internal temperature below 20 0C. More dichloromethane (2000 mL) and distilled water (3000 mL) were added into to the reaction mixture. The organic phase was separated from the aqueous phase. The aqueous phase was extracted with additional dichlorometrhane (I x 1000 mL) and the organic phases were combined. Solvent was removed from the combined organic phases using a Rotovap under reduced pressure. A light brown slurry was obtained at the end and was suspended in isopropanol (650 mL). The isopropanol was cooled in ice for 0.5 hour and the solids filtered. The solids were washed with more ice-cold IPA (200 mL) and then suctioned to dryness. The resulting white crystalline solid was air dried overnight to get 225 g of the target compound (86percent yield based on piperidone).
73.1% With acetic acid In water at 25℃; for 24 h; Step 1; Preparation of benzyI-4-phenylamino-piperidine-4-carbonitrile[00205] To a solution of 1 -benzyl -4-oxo-piperidine (226.8 g, 1.2 mol) and phenylamine(111.6 g, 1.2 mol) in acetic acid (1000 mL) was added dropwise the solution of potassium cyanide (117 g, 1.8 mol) in water (200 mL). The reaction mixture was stirred at 250C for 24 EPO <DP n="58"/>h anffthenllpi'uiE'M"lifo1ce-waef""" 'Hie" mixture was basified with ammonium hydroxide and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude benzyl-4-phenylamino- piperidine-4-carbonitrile (255.36 g, 73.1 percent), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.22-7.36 (m, 7 H)5 6.90-6.94 (m, 3 H), 3.65 (br s, IH)5 3.58 (s, 2 H)5 2.74-2.86 (m, 2 H)3 2.44-2.52 (m, 2 H)5 2.32-2.37 (m, 2 H)5 1.92-2.00 (m, 2 H).
Reference: [1] Bulletin des Societes Chimiques Belges, 1981, vol. 90, # 7, p. 749 - 756
[2] Journal of Organic Chemistry, 1992, vol. 57, # 14, p. 4037 - 4038
[3] Patent: WO2008/5423, 2008, A1, . Location in patent: Page/Page column 2; 5
[4] Synthetic Communications, 1997, vol. 27, # 5, p. 923 - 937
[5] Patent: WO2006/105035, 2006, A2, . Location in patent: Page/Page column 56-57
[6] Journal of Organic Chemistry, 1990, vol. 55, # 13, p. 4207 - 4209
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7720 - 7732
[8] Journal of Medicinal Chemistry, 1989, vol. 32, # 5, p. 968 - 974
[9] Journal of Medicinal Chemistry, 1996, vol. 39, # 16, p. 3169 - 3173
  • 25
  • [ 3612-20-2 ]
  • [ 62-53-3 ]
  • [ 968-86-5 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With acetic acid In dichloromethane at 5 - 50℃; for 20 h;
Stage #2: With sodium hydroxide In dichloromethane; water at 20℃; for 1 h;
Step 1
1-Benzyl-4-(phenylamino)piperidine-4-carbonitrile:
While maintaining the internal temperature of the mixture at 5-8° C., glacial acetic acid (250 g; 238 mL, 5.0 mol) was added dropwise to a stirred mixture of 1-benzyl-4-piperidone (30.0 g; 0.159 mol), aniline (59.0 g; 0.635 mol), potassium cyanide (41.3 g; 0.635 mol) and dichloromethane (316 mL) over a period of two hours.
After the addition was complete, the reaction mixture was gradually warmed to about 50° C. over a period of about 1 hour.
The mixture was stirred at this temperature for about 17 hours.
It was then cooled, and crushed ice (2 kg) was added.
While maintaining the internal temperature of the mixture below 20° C., a 10percent aqueous sodium hydroxide solution (180 g) was added dropwise over a period of 1 hour.
The mixture was then extracted with dichloromethane.
The aqueous layer was treated with an aqueous permanganate solution to destroy excess potassium cyanide, before discarding.
The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to obtain a brown colour residue, which was triturated with 2-propanol to obtain a solid.
This was solid was collected by filtration, washed with cold 2-propanol and dried to give the title compound as an off-white solid (37.0 g; 80percent).
m.p.142-146° C.; 1H NMR (400 MHz, CDCl3) δ 1.98-2.01 (m, 1H), 2.35 (d, J=13.2 Hz, 2H), 2.53 (t, J=11.0 Hz, 2H), 2.86-2.88 (m, 2H), 3.62 (s, 2H), 3.67 (br, exchangeable with D2O, 1H), 6.90-6.93 (m, 3H), 7.22-7.29 (m, 7H), IR (KBr) υ 3404, 3316, 3254, 3102, 3030, 2947, 2808, 2757, 2663, 2497, 2442, 2227, 1920, 1599, 1498, 1448, 1312, 1259, 1166, 1100, 749, 696 cm-1; MS 292 (M+1).
78% With acetic acid In isopropyl alcohol for 4 h; Cooling with ice; Reflux 1-Phenylmethyl-4-piperidinone (20.00 g, 0.106 mol), KCN (9.60 g, 0.147 mol), and aniline (13.60 g, 0.146 mol) in 180 mL isopropanol were cooled in an ice bath. Acetic acid (20 mL) was added dropwise and the addition funnel was rinsed with 20 mL isopropanol. The solution was heated at reflux for 4 h. The mixture was allowed to cool to room temperature and poured over an ice (120 g)/concentrated ammonium hydroxide (80 mL) mixture. The aqueous solution was extracted three times with chloroform. The organic layer was washed with brine. The organic solution was dried with MgSO4, filtered, and the volatiles were evaporated. The residue was recrystallized from isopropanol to provide 24.04 g of a white solid in a 78percent yield. mp 145-147° C.; 1H NMR (CDCl3) δ 7.35-7.23 (m, 6H), 6.93-6.90 (m, 4H), 3.65, (br s, 1H), 3.56 (br s, 2H), 2.81 (br d, 2H, J=11.91 Hz), 2.46 (t, 2H, J=10.30 Hz), 2.33 (d, 2H, J=13.28 Hz), 1.93 (t, 2H, J=10.30 Hz); 13C NMR (CDCl3) δ 143.4, 138.1, 129.4, 129.1, 128.5, 127.4, 62.7, 53.2, 49.4, 36.2
Reference: [1] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 12, p. 1421 - 1424
[2] Patent: US2010/16365, 2010, A1, . Location in patent: Page/Page column 23-24
[3] Patent: US8742111, 2014, B1, . Location in patent: Page/Page column 3
[4] Tetrahedron Letters, 2009, vol. 50, # 21, p. 2497 - 2500
[5] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6677 - 6678
  • 26
  • [ 3612-20-2 ]
  • [ 7677-24-9 ]
  • [ 62-53-3 ]
  • [ 968-86-5 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: at 0 - 40℃; for 1.16667 h;
Stage #2: With ammonia In water at 0℃;
Step 1
Trimethylsilylnitrile (7.1 ml, 53.0 mmol) was added dropwise to an acetic acid solution (50 mL) of 1-benzyl-4-piperidone (10.0 g, 53.0 mmol) and aniline (5.4 g, 58.0 mmol) over 10 minutes under ice-cooling with attention so that the reaction temperature did not exceed 40°C, and the mixture was stirred for 1 hour.
The reaction mixture was poured into a cold aqueous ammonia solution (mixture of 50 ml of aqueous concentrated ammonium hydroxide solution and 50 g of crushed ice), and an aqueous concentrated ammonium hydroxide solution was slowly added until pH of the mixture became 10.
The mixture was extracted with chloroform (3*100 ml), the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off.
To the resulting oily substance was added diethyl ether (20 ml), and precipitated white crystals were washed with diethyl ether, and dried to obtain 1-benzyl-4-(phenylamino)piperidine-4-carbonitril (13.6 g, 89percent).
1H-NMR(CDCl3) δ: 1.93 (2H, dt, J = 3.0Hz, 10.0Hz), 2.34 (2H, dt, J = 2.2Hz, 12.0Hz), 2.47 (2H, dt, J = 2.2Hz, 10.0Hz), 2.82 (2H, br d, J = 11.0Hz), 3.56 (2H, s), 6.90-7.35 (10H, m).
Reference: [1] Patent: EP1559428, 2005, A1, . Location in patent: Page/Page column 33
[2] Journal of Organic Chemistry, 1990, vol. 55, # 13, p. 4207 - 4209
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7131 - 7143
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 2, p. 238 - 250
  • 27
  • [ 3612-20-2 ]
  • [ 143-33-9 ]
  • [ 62-53-3 ]
  • [ 968-86-5 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 24, p. 7625 - 7644
  • 28
  • [ 3612-20-2 ]
  • [ 968-86-5 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 15, p. 5504 - 5510
[2] Journal of Organic Chemistry, 1999, vol. 64, # 15, p. 5504 - 5510
  • 29
  • [ 127354-23-8 ]
  • [ 3612-20-2 ]
  • [ 127354-24-9 ]
  • [ 968-86-5 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 13, p. 4207 - 4209
  • 30
  • [ 3612-20-2 ]
  • [ 67-66-3 ]
  • [ 62-53-3 ]
  • [ 85098-64-2 ]
YieldReaction ConditionsOperation in experiment
8%
Stage #1: With sodium hydroxide In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: at 0℃; for 0.333333 h;
1-Benzyl-4-(phenylamino)piperidine-4-carboxylic acid To a solution of aniline (2 g, 21 mmol) in tetrahydrofuran was added sodium hydroxide (4.3 g, 107 mmol) at 0°C. After stirring for 10 minutes at 0°C, to the resulting solution was added ferf-butyl 4-oxopiperidine-1 - carboxylate (43 g, 21 .6 mmol). The resulting suspension was stirred for 20 minutes at 0°C. To the suspension was added chloroform (12.7 g, 107 mmol). The reaction was stirred overnight before quenching with water (10 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The pH of aqueous layer was adjusted to pH 3 by addition of 5percent aqueous hydrochloride solution and extracted with ethyl acetate (3 χ 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 1 -benzyl-4-(phenylamino)piperidine-4- carboxylic acid as a brown solid (0.38 g, 8percent). LCMS (ESI): m/z = 311 .2 [M+H]+. 1 H-NMR (300 MHz, DMSO-d6): δ = 2.18-2.28 (m, 4H), 2.96-3.25 (m, 4H), 4.25-4.35 (m, 2H), 6.48-6.68 (m, 3H), 7.04-7.18 (m, 2H), 7.40-7.50 (m, 3H), 7.56-773 (m, 2H).
Reference: [1] Patent: WO2015/175171, 2015, A1, . Location in patent: Page/Page column 35
  • 31
  • [ 3612-20-2 ]
  • [ 85098-64-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7720 - 7732
  • 32
  • [ 3612-20-2 ]
  • [ 5052-95-9 ]
Reference: [1] Patent: WO2016/42452, 2016, A1,
  • 33
  • [ 3612-20-2 ]
  • [ 1021-25-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7131 - 7143
  • 34
  • [ 3612-20-2 ]
  • [ 541-41-3 ]
  • [ 29976-53-2 ]
YieldReaction ConditionsOperation in experiment
76% for 5 h; Heating Necked reaction flask equipped with a mechanical stirrer, a condenser and a thermometer was charged with 23.9 g (0.22 mol) of ethyl chloroformate and 100 ml of benzene, and 37.8 g (0.2 mol) of crude hydrolyzate (E) Mol) + 20ml benzene] solution, drop complete, stirring heating reaction for 5 hours.Water pump vacuum distillation ethyl chloroform and benzene, to mechanical pump vacuum distillation, steam distillation of low boiling material collection products were 26g, yield 76percent
Reference: [1] Patent: CN106187863, 2016, A, . Location in patent: Paragraph 0141; 0142; 0143
[2] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 59
  • 35
  • [ 3612-20-2 ]
  • [ 37663-46-0 ]
Reference: [1] Journal of Organic Chemistry, 1975, vol. 40, # 10, p. 1427 - 1433
[2] Journal of Organic Chemistry, 1975, vol. 40, # 10, p. 1427 - 1433
  • 36
  • [ 3612-20-2 ]
  • [ 52157-82-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 484 - 500
  • 37
  • [ 3612-20-2 ]
  • [ 53617-35-9 ]
Reference: [1] Patent: US2011/87021, 2011, A1,
  • 38
  • [ 3612-20-2 ]
  • [ 21987-29-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 4, p. 989 - 994
  • 39
  • [ 3612-20-2 ]
  • [ 26905-02-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
  • 40
  • [ 3612-20-2 ]
  • [ 3970-68-1 ]
Reference: [1] Patent: WO2013/96744, 2013, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 695 - 700
  • 41
  • [ 3612-20-2 ]
  • [ 74-88-4 ]
  • [ 34737-89-8 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 60℃;
To a solution of NaH (15 g, 0.38 mol, 60percent dispersion) in THF (600 niL) was added l-benzylpiperidin-4-one (60 g, 0.3 mol) in THF (100 niL) at 00C. The mixture was stirred for 30 min. Methyl iodide (67 g, 0.47 mol) was added and the reaction was stirred overnight at 600C. The reaction was cooled to room temperature, filtered, and the filtrate washed with water and extracted with EtOAc (3 x 300 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column on silica gel (PE : EtOAc = 5:1) to afford l-benzyl-3-methylpiperidin-4-one (30 g, 47percent) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): S 7.20-7.35 (m, 5H), 3.58 (s, 2H), 2.95-3.02 (m, 2H), 2.48-2.62 (m, 2H), 2.26-2.32 (m, IH), 2.10-2.18 (m, IH), 2.00 (q, IH), 0.81 (d, 3H).
25% With sodium chloride In tetrahydrofuran; water (8-1)
To a suspension (160 ml) of 3.2 g of sodium hydride in tetrahydrofuran (THF) was added a solution (15 ml) of 15.0 g of 1-benzyl-4-piperidone in THF in an ice bath, and the solution was stirred at room temperature for 30 minutes. 5.92 ml of methyl iodide was added to this solution, and the solution was stirred at 60° C. for 4 hours.
The salt precipitated was separated by filtration, and after concentrating the filtrate under reduced pressure, water was added to the concentrate.
The solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography, and from the fractions eluted with ethyl acetate-hexane (1:1 v/v) was obtained 3.98 g of 1-benzyl-3-methyl-4-piperidone (yield: 25percent).
2.50 g
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 0 - 60℃;
To a solution of 1-benzylpiperidin-4-one (5.50 g, 29.1 mmol) in THF (100 mL) was added NaH (1700 mg, 60percent in mineral oil, 43.7 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. To the resulting mixture was added Mel (6200 mg, 43.7 mmol) at 0 °C. After being heated with stirring at 60 °C overnight, the resulting reaction mixture was cooled to rt,diluted with sat. aqueous solution of NH4C1 (50 mL) and extracted with EA (50 mL) for three times. The combined organic layer was dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by flash column (eluting with 1percent MeOH in DCM) to give 1-benzyl-3- methyl-piperidin-4-one (2.50 g).
Reference: [1] Patent: WO2010/114971, 2010, A1, . Location in patent: Page/Page column 138
[2] Patent: US5789595, 1998, A,
[3] Patent: US4639522, 1987, A,
[4] Patent: WO2016/107832, 2016, A1, . Location in patent: Page/Page column 90
  • 42
  • [ 3612-20-2 ]
  • [ 74-88-4 ]
  • [ 34737-89-8 ]
  • [ 173186-91-9 ]
YieldReaction ConditionsOperation in experiment
29% With sodium hydride In tetrahydrofuran at 20 - 60℃; for 5.08333 h; Sodium hydride (4.20 g, 175.0 mmol) was suspended in THF (200 mL), and a solution of the piperidone (18.9 g, 99.9 mmol) and methyl iodide (17.9 g, 126.1 mmol) in THF (20 mL) was added dropwise at room temperature over 5 minutes. The mixture was then heated to 60 °C and stirred for 5 hours. The reaction was then filtered and the filtrate concentrated. The concentrate was poured into 150 mL of water and extracted with 120 mL portions of EtOAc three times. The extract was washed with brine, dried, and concentrated. The crude product was purified by column chromatography (gradient: 12percent EtOAc in hexanes to 50percent EtOAc in hexanes over 1200 mL). Both mono and di methylation occurred. Separation of both isomers by chromatography was quite facile. 3.53 g of the dimethylated product (16percent) was obtained. MS (EI) : m/z 218.1 (M + 1). 5.91 g (29percent) of the monomethylated product was obtained. MS (EI) : m/z 204.0 (M + 1).
Reference: [1] Patent: WO2005/26145, 2005, A2, . Location in patent: Page/Page column 102; 103
[2] Patent: US9409884, 2016, B2,
  • 43
  • [ 3612-20-2 ]
  • [ 37656-48-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 12, p. 1197 - 1205
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
  • 44
  • [ 3612-20-2 ]
  • [ 41979-39-9 ]
Reference: [1] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 208 - 215
  • 45
  • [ 3612-20-2 ]
  • [ 1205-72-7 ]
Reference: [1] Farmaco, Edizione Scientifica, 1980, vol. 35, # 11, p. 951 - 964
  • 46
  • [ 3612-20-2 ]
  • [ 616-38-6 ]
  • [ 3939-01-3 ]
YieldReaction ConditionsOperation in experiment
97.8% With hydrogenchloride; potassium <i>tert</i>-butylate In toluene Step A:
4-Oxo-1-(phenylmethyl)-3-piperidinecarboxylic acid methyl ester, hydrochloride .
A solution of 1-benzyl-4-piperidone (56.5 kg, 1.0 eq.) in toluene (189 L) was prepared at 15°C to 25°C.
A second reactor was charged with toluene (659 L), potassium tert-butoxide (71.9 kg, 2.25 eq.) and dimethyl carbonate (51.5 kg, 2.0 eq.) at 15°C to 25°C.
The resulting slurry was warmed to a temperature of 80°C to 90°C.
The solution of 1-benzyl-4-piperidone in toluene was added slowly to the slurry over 60 to 90 minutes.
After an additional 90 minutes, the reaction mixture was cooled to below 15°C.
The completed reaction was quenched with acetic acid (38.5 kg, 2.25 eq.) and water (367 L).
The two phase mixture was separated.
The organic layer was filtered to remove solids.
The organic filtrate was concentrated by distillation under reduced pressure to a volume of approximately 150 L. Toluene (799 L) was added to the concentrated mixture.
Addition of hydrogen chloride (gas, 11.0 kg, 1.05 eq.) afforded the hydrochloride salt as a precipitate.
The slurry was stirred at 10°C to 15°C for 30 minutes.
The solids were isolated by filtration, washed with approximately hexanes (130 L), and dried using vacuum to give 79.4 kg of 4-oxo-1-(phenylmethyl)-3-piperidinecarboxylic acid methyl ester, hydrochloride (97.8percent yield).
Analysis calculated for C14H17NO3*HCl: C 59.3; H 6.39; N 4.94; found: C 59.7 H, 6.65 N, 4.85.
97.8% With hydrogenchloride; potassium <i>tert</i>-butylate In toluene Step A:
4-Oxo-1-(phenylmethyl)-3-piperidinecarboxylic acid methyl ester, hydrochloride.
A solution of 1-benzyl-4-piperidone (56.5 kg, 1.0 eq.) in toluene (189 L) was prepared at 15° C. to 25° C.
A second reactor was charged with toluene (659 L), potassium tert-butoxide (71.9 kg, 2.25 eq.) and dimethyl carbonate (51.5 kg, 2.0 eq.) at 15° C. to 25° C.
The resulting slurry was warmed to a temperature of 80° C. to 90° C.
The solution of 1-benzyl-4-piperidone in toluene was added slowly to the slurry over 60 to 90 minutes.
After an additional 90 minutes, the reaction mixture was cooled to below 15° C.
The completed reaction was quenched with acetic acid (38.5 kg, 2.25 eq.) and water (367 L).
The two phase mixture was separated.
The organic layer was filtered to remove solids.
The organic filtrate was concentrated by distillation under reduced pressure to a volume of approximately 150 L. Toluene (799 L) was added to the concentrated mixture.
Addition of hydrogen chloride (gas, 11.0 kg, 1.05 eq.) afforded the hydrochloride salt as a precipitate.
The slurry was stirred at 10° C. to 15° C. for 30 minutes.
The solids were isolated by filtration, washed with approximately hexanes (130 L), and dried using vacuum to give 79.4 kg of 4-oxo-1-(phenylmethyl)-3-piperidinecarboxylic acid methyl ester, hydrochloride (97.8percent yield).
Analysis calculated for C14H17NO3.HCl: C 59.3; H 6.39; N 4.94; found: C 59.7 H, 6.65 N, 4.85.
Reference: [1] Patent: EP1031575, 2000, A1,
[2] Patent: US2002/2283, 2002, A1,
  • 47
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  • [ 113411-62-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1317 - 1319
  • 48
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  • [ 10272-49-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2560 - 2564
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  • [ 79098-85-4 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 9, p. 3186 - 3197
  • 50
  • [ 3612-20-2 ]
  • [ 85732-37-2 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 3, p. 1129 - 1139
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 3, p. 1129 - 1139
  • 51
  • [ 3612-20-2 ]
  • [ 80957-68-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5167 - 5182
[2] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 7, p. 2522 - 2529
[3] Patent: CN108250128, 2018, A,
  • 52
  • [ 3612-20-2 ]
  • [ 78056-60-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
  • 53
  • [ 3612-20-2 ]
  • [ 92197-36-9 ]
Reference: [1] Patent: WO2013/96744, 2013, A1,
  • 54
  • [ 3612-20-2 ]
  • [ 162045-53-6 ]
Reference: [1] ChemMedChem, 2017, vol. 12, # 15, p. 1183 - 1190
  • 55
  • [ 773837-37-9 ]
  • [ 3612-20-2 ]
  • [ 136624-42-5 ]
YieldReaction ConditionsOperation in experiment
47%
Stage #1: With ammonia; ammonium chloride In water at 20℃; for 0.333333 h;
Stage #2: for 24 h;
STEP A: 4-Amino-1 -benzylpiperidine-4-carbonitrile To a solution of ammonium chloride (17.3 g, 323 mmol) in water (200 mL) was added successively aqueous 25percent ammonia (25 mL, 332 mmol) and 1 -benzylpiperidin-4-one (1 1 .43 g, 60 mmol). The resulting mixture was stirred at room temperature for 20 min and sodium cyanide (14.7 g, 300 mmol) was added in portions over 15 min. After stirring for 1 day, the reaction mixture was partitioned between water (200 mL) and DCM (2 x 200 mL). The organic phase was dried over MgS04, filtered and concentrated in vacuo to yield a residue. The residue was purified by flash chromatography (silica gel, 50percent EtOAc/heptanes to 100percent EtOAc) to yield 4-amino-1 -benzylpiperidine-4- carbonitrile (6.15 g, 47percent). 1 H NMR (300 MHz, CDCI3) δ ppm 1 .69 - 1 .86 (m, 4 H), 2.00 (dt, J=13.1 , 2.1 Hz, 2 H), 2.27 - 2.45 (m, 2 H), 2.83 (dt, J=12.4, 3.6 Hz, 2 H), 3.55 (s, 2 H), 7.21 - 7.39 (m, 5 H); MS m/z 216 (M+H)+.
47%
Stage #1: With ammonia; ammonium chloride In water at 20℃; for 0.333333 h;
Stage #2: for 24.25 h;
STEP A:
4-Amino-1-benzylpiperidine-4-carbonitrile
To a solution of ammonium chloride (17.3 g, 323 mmol) in water (200 mL) was added successively aqueous 25percent ammonia (25 mL, 332 mmol) and 1-benzylpiperidin-4-one (11.43 g, 60 mmol).
The resulting mixture was stirred at room temperature for 20 min and sodium cyanide (14.7 g, 300 mmol) was added in portions over 15 min.
After stirring for 1 day, the reaction mixture was partitioned between water (200 mL) and DCM (2*200 mL).
The organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield a residue.
The residue was purified by flash chromatography (silica gel, 50percent EtOAc/heptanes to 100percent EtOAc) to yield 4-amino-1-benzylpiperidine-4-carbonitrile (6.15 g, 47percent).
1H NMR (300 MHz, CDCl3) δ ppm 1.69-1.86 (m, 4H), 2.00 (dt, J=13.1, 2.1 Hz, 2H), 2.27-2.45 (m, 2H), 2.83 (dt, J=12.4, 3.6 Hz, 2H), 3.55 (s, 2H), 7.21-7.39 (m, 5H); MS m/z 216 (M+H)+.
Reference: [1] ACS Combinatorial Science, 2016, vol. 18, # 6, p. 330 - 336
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4719 - 4722
[3] Patent: WO2014/39769, 2014, A1, . Location in patent: Page/Page column 286-287
[4] Patent: US2015/99730, 2015, A1, . Location in patent: Paragraph 0723; 0724
[5] Patent: US2010/130506, 2010, A1, . Location in patent: Page/Page column 108
[6] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 2475
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  • [ 136624-42-5 ]
Reference: [1] Patent: EP1032561, 2004, B1, . Location in patent: Page 17
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Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 5084 - 5093
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 2037 - 2061
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2465 - 2469
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  • [ 136624-42-5 ]
Reference: [1] Patent: US2005/277633, 2005, A1, . Location in patent: Page/Page column 17
  • 59
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  • [ 136624-42-5 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 24, p. 7625 - 7644
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  • [ 136624-42-5 ]
Reference: [1] Patent: US2011/98311, 2011, A1,
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Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 21 - 32
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  • [ 108612-54-0 ]
Reference: [1] Patent: US2012/71461, 2012, A1,
[2] Tetrahedron Letters, 2017, vol. 58, # 20, p. 1976 - 1979
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Reference: [1] Synthetic Communications, 2001, vol. 31, # 5, p. 787 - 797
  • 64
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  • [ 336191-17-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 7, p. 1103 - 1107
  • 65
  • [ 3612-20-2 ]
  • [ 74-88-4 ]
  • [ 34737-89-8 ]
  • [ 173186-91-9 ]
YieldReaction ConditionsOperation in experiment
29% With sodium hydride In tetrahydrofuran at 20 - 60℃; for 5.08333 h; Sodium hydride (4.20 g, 175.0 mmol) was suspended in THF (200 mL), and a solution of the piperidone (18.9 g, 99.9 mmol) and methyl iodide (17.9 g, 126.1 mmol) in THF (20 mL) was added dropwise at room temperature over 5 minutes. The mixture was then heated to 60 °C and stirred for 5 hours. The reaction was then filtered and the filtrate concentrated. The concentrate was poured into 150 mL of water and extracted with 120 mL portions of EtOAc three times. The extract was washed with brine, dried, and concentrated. The crude product was purified by column chromatography (gradient: 12percent EtOAc in hexanes to 50percent EtOAc in hexanes over 1200 mL). Both mono and di methylation occurred. Separation of both isomers by chromatography was quite facile. 3.53 g of the dimethylated product (16percent) was obtained. MS (EI) : m/z 218.1 (M + 1). 5.91 g (29percent) of the monomethylated product was obtained. MS (EI) : m/z 204.0 (M + 1).
Reference: [1] Patent: WO2005/26145, 2005, A2, . Location in patent: Page/Page column 102; 103
[2] Patent: US9409884, 2016, B2,
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  • [ 74-88-4 ]
  • [ 173186-91-9 ]
Reference: [1] Patent: WO2008/130584, 2008, A1, . Location in patent: Page/Page column 161
  • 67
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  • [ 343788-69-2 ]
Reference: [1] Patent: WO2008/119718, 2008, A1,
  • 68
  • [ 3612-20-2 ]
  • [ 80980-89-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 12, p. 1197 - 1205
  • 69
  • [ 3612-20-2 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: EP1403255, 2004, A1,
[2] Patent: EP1500643, 2005, A1,
  • 70
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  • [ 188975-88-4 ]
Reference: [1] Patent: EP1500643, 2005, A1,
  • 71
  • [ 3612-20-2 ]
  • [ 255051-14-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2560 - 2564
[2] Patent: WO2014/152013, 2014, A1,
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7731 - 7757
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888
  • 72
  • [ 3612-20-2 ]
  • [ 635713-68-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4719 - 4722
  • 73
  • [ 5326-23-8 ]
  • [ 3612-20-2 ]
  • [ 1017598-71-8 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3 h;
Stage #2: at -78℃; for 2 h;
The synthesis of the intermediate I-11.1 is described in EP2072519 A1, p. 36. At −78° C., a hexane solution (94 mL, 150.81 mmol) of 1.6 M n-butyllithium is added dropwise to a THF solution (110 mL) of 2,2,6,6-tetramethylpiperidine (16.14 g, 113.10 mmol) and obtained solution is stirred for 1 hour. Afterwards a THF solution (50 mL) of 6-chloronicotinic acid (6.0 g, 37.70 mmol) is added dropwise over 1 hour and the reaction mixture is stirred for 2 hours. A THF solution (50 mL) of 1-benzyl-4-piperidone (21.6 g, 113.10 mmol) is added dropwise at −78° C. After stirred for 2 hours, water (70 mL) is added, and the reaction mixture is warmed to room temperature. The aqueous layer is separated, and the organic layer is extracted with aqueous 1 N sodium hydroxide solution (2×75 mL). The obtained aqueous layer is extracted with diethyl ether (100 mL), and the aqueous layer is acidified (pH-1) by adding concentrated hydrochloric acid. After stirring for 1 hour, the precipitate is filtered off, washed with water, and dissolved in ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The residue is washed with diethyl ether. Yield 66percent, m/z 329 [M+H]+, rt 0.72 min, LC-MS Method Z012_S04.
Reference: [1] Patent: US2016/75704, 2016, A1, . Location in patent: Paragraph 0267-0271
[2] Patent: EP2072519, 2009, A1, . Location in patent: Page/Page column 36
  • 74
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  • [ 1258861-20-9 ]
Reference: [1] Journal of Chemical Research, 2017, vol. 41, # 2, p. 112 - 115
[2] Patent: CN106279114, 2017, A,
  • 75
  • [ 3612-20-2 ]
  • [ 83949-37-5 ]
Reference: [1] Patent: WO2011/33255, 2011, A1,
[2] Patent: WO2011/33255, 2011, A1,
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