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Chemical Structure| 135716-08-4
Chemical Structure| 135716-08-4
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Product Details of [ 135716-08-4 ]

CAS No. :135716-08-4 MDL No. :MFCD12912655
Formula : C14H23NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :NJORMFNJZLXLCN-UHFFFAOYSA-N
M.W : 269.34 Pubchem ID :10333298
Synonyms :

Calculated chemistry of [ 135716-08-4 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.71
Num. rotatable bonds : 6
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 76.63
TPSA : 55.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.44
Log Po/w (XLOGP3) : 1.74
Log Po/w (WLOGP) : 2.13
Log Po/w (MLOGP) : 1.75
Log Po/w (SILICOS-IT) : 1.92
Consensus Log Po/w : 2.2

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.21
Solubility : 1.66 mg/ml ; 0.00616 mol/l
Class : Soluble
Log S (Ali) : -2.53
Solubility : 0.796 mg/ml ; 0.00296 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.02
Solubility : 2.6 mg/ml ; 0.00964 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.1

Safety of [ 135716-08-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 135716-08-4 ]

* 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 [ 135716-08-4 ]
  • Downstream synthetic route of [ 135716-08-4 ]

[ 135716-08-4 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 135716-08-4 ]
  • [ 59184-90-6 ]
Reference: [1] Patent: US2014/187581, 2014, A1,
[2] Patent: WO2013/42135, 2013, A1,
  • 2
  • [ 135716-08-4 ]
  • [ 89151-44-0 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With palladium 10% on activated carbon; hydrogen In methanolInert atmosphere
Stage #2: With diisobutylaluminium hydride In diethyl ether at -20℃; for 0.166667 h;
The above resulting product (639mg,2.4mmol) dissolved in 6ml of methanol, Underargon added the argon was replaced with hydrogen three times and reaction was carried out overnightin a hydrogenation apparatus (4 atm H2). The reaction solution was filteredthrough celite and washed with ethyl acetate. The filtrate was concentrated andseparated by column chromatography to give a white solid, 722 mg, 100percent yield. theabove resulting product(506mg,1.9mmol) dissolved in 10ml of ether, reaction was colled down to -20 ° C, added diisobutylaluminum hydride(1.0M,5mL,5mmol), reaction was carried out for 10 minutes until the starting material disappeared. Then Poured into saturated sodium potassium tartrate solution, stirred at room temperature for 3 hours to clarify the reaction mixture,the aqueous phase was extracted three times with ether and the organic phases were combined and washed with saturated NaClsolution and dried over Na2SO4, After Concentration, carriedout column chromatography separation to obtain a White solid, 368mg, yield 86percent.
Reference: [1] Patent: CN102952072, 2016, B, . Location in patent: Paragraph 0110-0111
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[3] Patent: US2012/71461, 2012, A1,
[4] Patent: CN107793408, 2018, A,
[5] Patent: WO2018/68297, 2018, A1,
[6] Patent: US6140333, 2000, A,
  • 3
  • [ 135716-08-4 ]
  • [ 157688-46-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1880 - 1886
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
  • 4
  • [ 867-13-0 ]
  • [ 79099-07-3 ]
  • [ 135716-08-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 20℃; for 22 h;
Reference Example 1-1
t-Butyl 4-(2-ethoxy-2-oxoethylidene)-1-piperidine carboxylate
To a solution of ethyl diethylphosphoryl acetate (28.3g) in tetrahydrofuran (200 ml) was added 60percent sodium hydride (4.82g) under ice cooling and the mixture was stirred for 30 minutes, and then a solution of N-butoyxcarbonyl-4-piperidone (20g) in tetrahydrofuran (200 ml) was added dropwise thereto.
The mixture was stirred for 22 hours at room temperature.
After the completion of the reaction, water (200 ml) was added and extraction was carried out with ethyl acetate.
After the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, the concentrated residue obtained was then purified using silica gel column chromatography and eluted with hexane/ethyl acetate (6/1) to obtain the title compound (27.3 g, 100percent) as a colorless powder.
1H NMR (CDCl3) δ 1.28 (3H, t, J=7.4Hz), 1.47 (9H, s), 2.24-2.33 (2H, m), 2.90-2.98 (2H, m), 3.43-3.55 (4H, m), 4.16 (2H, q, J=7.4Hz), 5.70-5.73 (1H, m).
97%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 18 h;
the NaH(60percentin οil, 500mg, 12.5mml) added to 10 mL of tetrahydrofuran, under argon protection the reaction was cool inan ice bath then added Triethylphosphonoacetate(2.2ml,12.5mmol), ice bath was removed and the reaction was carriedout at room temperature for 1 hour. The reaction mixture was cooled again to 0° C in an ice bath and N-Boc-piperidone (997 mg, 5 mmol) was dissolved in 1 mLof tetrahydrofuran and then slowly added dropwise into the reaction system, Theice bath was removed and the reaction was carried out at room temperature for18 hours until the reaction was complete. addition of saturated NH4Clsolution to quench the reaction and extracted three times with ethyl acetate.combined organic phases then it was washed sequentially with saturated NaHCO3solution, saturated NaCl solution and dried over anhydrous Na2SO4.After concentration, carried out columnchromatography separation to obtain 1.3g of a white solid,yield 97percent.
89%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 5 - 10℃; for 2 h;
Stage #2: at 5 - 20℃; for 2 h;
Potassium tert-butoxide (720 mmol) was added to THF (600 mL), A solution of triethyl phosphonoacetate (600 mmol) in THF (120 mL) was added dropwise at 5 to 10°C. After stirring, add 2h A solution of starting material 1 (540 mmol) in THF (100 mL) was added dropwise at 5 to 10°C. After the addition, Room temperature reaction 2h, Stop the reaction, The reaction was quenched by the dropwise addition of water (100 mL). The reaction solution was extracted with ethyl acetate (200 mL×3). Combine the ethyl acetate layers, Followed by water (100mL×2), Saturated brine (100mL × 2) wash, Drying with anhydrous sodium sulfate, filter, Concentrated 130 g of white solid (Intermediate 2), Yield 89percent
81%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1 h;
Stage #2: at 20℃;
To a solution of t-BuOK (11.52 g, 120 mmol) in dry THF (200 mL) was added ethyl 2- (diethoxyphosphoryl) acetate (23.6 g, 105 mmol) at 0. After stirring for 1h at 0, tert-butyl 4-oxopiperidine-1-carboxylate (20 g, 100 mmol) in 50 mL of dry THF was added dropwise to the mixture, and the resulting solution was stirred at rt for 2h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) , extracted with EtOAc (200 mL × 3) . The organic layer was collected, washed with saturated aqueous solution of Na2CO3 (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (silica gel: 300-400 mesh, PE/EtOAc 20/1) to afford tert-butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate (22 g, 81) . LRMS m/z (M-100) 170.1 found, 170.1 required.
78%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 2 h;
Stage #3: With water In tetrahydrofuran; mineral oil
Stage (i):
tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1 eq) in THF (50 ml) was slowly added dropwise to an ice-cold (0° C.) suspension of NaH (1.56 g, 65.32 mmol, 1.3 eq) in THF (50 ml), and stirring was carried out for 30 min.
Triethyl phosphonoacetate (12.96 ml, 65.32 mmol, 1.3 eq), dissolved in THF (50 ml), was added and stirring was carried out for 2 h at RT.
The reaction mixture was hydrolyzed with water (5 ml) and concentrated.
The residue was taken up in water (150 ml) and extracted with ethyl acetate (2*300 ml).
The combined organic phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure.
After purification by column chromatography (silica gel, 3percent ethyl acetate in hexane), the desired product was obtained in the form of a white solid. Yield: 78percent (10.5 g, 39.03 mmol).
73%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1 h;
Stage #2: at 0℃; for 12 h;
At 0 deg. C, ethyl 2- (diethoxyphosphoryl)acetate (6.18 g, 27.6 mmol) in anhydrous THF (100mL) solution was added slowly portionwise NaH (1.2 g, 30.1 mmol, 60percent), and the mixture was stirred at 0 deg.C for 1 hour. And then tert-butyl-4-oxo-piperidine-1-carboxylate (5 g, 25.1 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at 0 deg.C for 12 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was complete. To the reaction mixture was added water (50mL) to quench the reaction, and extracted with EtOAc (100mL), the organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound (4.95 g, yield 73percent) as a white solid.
62% With potassium carbonate In N,N-dimethyl-formamide at 80℃; Step 1 . tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine- l -carboxylate. A mixture of tert-buty I 4-oxopiperidine- l -carboxylate (300 g, 1 .51 mol, 1 .00 equiv), ethyl 2-(diethoxyphosphoryl)acetate (405 g, 1 .8 1 mol, 1 .20 equiv) and potassium carbonate (31 4 g, 2.26 mol, 1 .50 equiv) in DMF (4.5 L) was stirred overnight at 80°C. The reaction was cooled to rt and then quenched by the addition of 5 L of water/ice. The precipitate was col lected by fi ltration and air-dried to give 252 g (62percent) of tert- butyl 4-(2-ethoxy-2-oxoethylidene)piperidine- l -carboxylate as a wh ite solid. TLC: ethyl acetate/petroleum ether = 1 2. t- = 0.6

Reference: [1] Heterocycles, 2001, vol. 54, # 2, p. 747 - 755
[2] Patent: EP1498125, 2005, A1, . Location in patent: Page/Page column 84-85
[3] Patent: WO2018/152329, 2018, A1, . Location in patent: Page/Page column 48
[4] Patent: CN102952072, 2016, B, . Location in patent: Paragraph 0109
[5] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[6] Patent: CN107793408, 2018, A, . Location in patent: Paragraph 0168; 0171
[7] Patent: WO2018/68297, 2018, A1, . Location in patent: Page/Page column 135
[8] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074
[9] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 123; 131
[10] Russian Journal of Organic Chemistry, 2014, vol. 50, # 7, p. 953 - 959[11] Zh. Org. Khim., 2014, vol. 50, # 7, p. 973 - 978,6
[12] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0220; 0221; 0222; 0223
[13] Patent: WO2013/127269, 2013, A1, . Location in patent: Page/Page column 189
[14] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[15] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 167 - 170
[16] Patent: WO2005/33108, 2005, A1, . Location in patent: Page/Page column 48
[17] Patent: US2003/191316, 2003, A1, . Location in patent: Page/Page column 32
[18] Organic Letters, 2011, vol. 13, # 7, p. 1698 - 1701
[19] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1880 - 1886
[20] Patent: EP2444402, 2012, A1, . Location in patent: Page/Page column 47
[21] Chemistry Letters, 2012, vol. 41, # 12, p. 1703 - 1705
[22] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8597 - 8601[23] Angew. Chem., 2013, vol. 125, # 33, p. 8759 - 8763,5
[24] Patent: WO2014/15495, 2014, A1, . Location in patent: Page/Page column 37; 38
[25] Patent: WO2014/18764, 2014, A1, . Location in patent: Page/Page column 40
[26] Russian Journal of Organic Chemistry, 2014, vol. 50, # 1, p. 54 - 58[27] Zh. Org. Khim., 2014, vol. 50, # 1, p. 61 - 65,5
[28] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5502 - 5506
[29] Patent: WO2015/17305, 2015, A1, . Location in patent: Page/Page column 61; 62
[30] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 44-45
[31] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 43
[32] Patent: WO2016/60941, 2016, A1, . Location in patent: Page/Page column 51
[33] Angewandte Chemie - International Edition, 2017, vol. 56, # 33, p. 9868 - 9871[34] Angew. Chem., 2017, vol. 129, p. 10000 - 10003,4
[35] Patent: CN107540659, 2018, A, . Location in patent: Paragraph 0190
  • 5
  • [ 79099-07-3 ]
  • [ 1099-45-2 ]
  • [ 135716-08-4 ]
YieldReaction ConditionsOperation in experiment
93% at 100℃; for 1 h; Step 1 : A mixture of ieri-butyl 4-oxopiperidine-l-carboxylate 165a (10.0 g, 50.2 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (26.2 g, 75.3 mmol) in toluene (200 mL) was stirred at 100°C for lh. See Figure 6. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to afford ieri-butyl 4-(2- ethoxy-2-oxoethylidene)piperidine-l-carboxylate 165b (12.6 g, 93percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 5.72 (s, 1H), 4.16 (q, / = 7.2 Hz, 2H), 3.52 - 3.45 (m, 4H), 2.94 (t, / = 5.6 Hz, 2H), 2.28 (t, J = 5.6 Hz, 2H), 1.48 (s, 9H), 1.29 (t, J = 7.6 Hz, 3H).
76% for 10 h; Reflux To a stirred solution of 1-Boc-4-piperidone (2.0 grams, 10.03 mmol) in benzene (40 mL) at room temperature was added Wittig reagent (5.23 grams, 15 mmol).
The reaction mixture was refluxed for 10 hours and the volatiles were removed under reduced pressure to obtain a crude mass which was purified by silica gel column chromatography to obtain t-butyl 4-ethoxycarbonylmethylene piperidine-1-carboxylate (2.05 grams).
Yield: 76percent.
1H-NMR (CDCl3): δ 5.71 (s, 1H), 4.16 (q, 2H), 3.55-3.45 (m, 4H), 2.94 (t, J=5.7 Hz, 2H), 2.28 (t, J=5.6 Hz, 2H), 1.47 (s, 9H), 1.28 (t, J=7.1 Hz, 3H); Mass (m/z): 270 (M+H)+.
Reference: [1] Patent: WO2015/949, 2015, A1, . Location in patent: Page/Page column 117
[2] Patent: US2014/187581, 2014, A1, . Location in patent: Paragraph 0155-0157
[3] European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 363 - 380
  • 6
  • [ 79099-07-3 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: EP1489078, 2004, A1, . Location in patent: Page 189
[2] Patent: EP1386920, 2004, A1, . Location in patent: Page 45
  • 7
  • [ 311-46-6 ]
  • [ 79099-07-3 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: US2003/229074, 2003, A1, . Location in patent: Page 20
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5652 - 5656
  • 8
  • [ 10419-80-4 ]
  • [ 79099-07-3 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 61; 62
  • 9
  • [ 867-13-0 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: US5073557, 1991, A,
[2] Patent: EP470668, 1992, A1,
  • 10
  • [ 867-13-0 ]
  • [ 79099-07-3 ]
  • [ 84839-56-5 ]
  • [ 135716-08-4 ]
Reference: [1] Russian Journal of Organic Chemistry, 2014, vol. 50, # 1, p. 54 - 58[2] Zh. Org. Khim., 2014, vol. 50, # 1, p. 61 - 65,5
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 6, p. 641 - 644
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 33, p. 7413 - 7425
  • 11
  • [ 79099-07-3 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: US6140333, 2000, A,
  • 12
  • [ 50893-53-3 ]
  • [ 24424-99-5 ]
  • [ 40110-55-2 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: US6518423, 2003, B1,
  • 13
  • [ 24424-99-5 ]
  • [ 135716-08-4 ]
Reference: [1] European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 363 - 380
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[3] Patent: WO2016/65582, 2016, A1,
[4] Patent: WO2016/122994, 2016, A1,
[5] Patent: US6140333, 2000, A,
  • 14
  • [ 41979-39-9 ]
  • [ 135716-08-4 ]
Reference: [1] European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 363 - 380
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
  • 15
  • [ 41661-47-6 ]
  • [ 135716-08-4 ]
Reference: [1] Patent: WO2016/65582, 2016, A1,
[2] Patent: WO2016/122994, 2016, A1,
  • 16
  • [ 135716-08-4 ]
  • [ 135716-09-5 ]
YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 2 h; A mixture of tert-butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate (22 g, 81.8 mmol) and wet 10Pd/C (2.2 g) in ethanol (160 mL) was degassed and backfilled with H2 (three times) . The mixture was stirred under H2 balloon at rt for 2h. The catalyst was filtered off and the filtrate was concentrated to afford tert-butyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylate (22.5 g, 100) . LRMS m/z (M-100) 172.1 found, 172.1 required.
95.8% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 5 h; To a stirred solution of t-butyl 4-ethoxycarbonylmethylene piperidine-l- carboxylate (2.05 grams, 7.62 mmol, obtained in above step) in ethanol (30 mL) at room temperature was added Pd/C (10 wt percent, 600 mg). Hydrogen balloon pressure was applied on the reaction for 5 hours. The reaction mixture was filtered through a pad of celite and the volatiles were removed under reduced pressure to obtain t-butyl-4- ethoxycarbonylmethyl piperidine-l-carboxylate (1.98 grams). Yield: 95.8 percent.Ή - NMR (CDC13): δ 4.20-4.0 (m, 4H), 2.83 - 2.65 (m, 2H), 2.23 (d, J = 6.8 Hz, 2H), 2.0 - 1.88 (m, 1H), 1.75 - 1.68 (m, 2H), 1.45 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H), 1.25 - 1.05 (m, 2H);Mass (m/z): 272 (M+H)+.
95.8% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 5 h; To a stirred solution of t-butyl 4-ethoxycarbonylmethylene piperidine-1-carboxylate (2.05 grams, 7.62 mmol, obtained in above step) in ethanol (30 mL) at room temperature was added Pd/C (10 wt percent, 600 mg).
Hydrogen balloon pressure was applied on the reaction for 5 hours.
The reaction mixture was filtered through a pad of celite and the volatiles were removed under reduced pressure to obtain t-butyl-4-ethoxycarbonylmethyl piperidine-1-carboxylate (1.98 grams).
Yield: 95.8percent.
1H-NMR (CDCl3): δ 4.20-4.0 (m, 4H), 2.83-2.65 (m, 2H), 2.23 (d, J=6.8 Hz, 2H), 2.0-1.88 (m, 1H), 1.75-1.68 (m, 2H), 1.45 (s, 9H), 1.26 (t, J=7.0 Hz, 3H), 1.25-1.05 (m, 2H);
Mass (m/z): 272 (M+H)+.
89% With hydrogen In ethanol at 20℃; for 12 h; Inert atmosphere Stage (ii):
tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate
tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (5.0 g, 18.58 mmol, 1 eq) was dissolved in ethanol (20 ml) and degassed for 30 min with argon. Pd-C (500 mg, 10percent) was added and hydrogenation was carried out for 12 h at RT under balloon pressure (H2).
After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and washed with ethanol (200 ml), and the filtrate was concentrated under reduced pressure. Yield: 89percent (4.5 g, 16.6 mmol).

Reference: [1] Heterocycles, 2001, vol. 54, # 2, p. 747 - 755
[2] Patent: WO2018/68297, 2018, A1, . Location in patent: Page/Page column 135; 136
[3] Patent: WO2018/152329, 2018, A1, . Location in patent: Page/Page column 48
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 6, p. 641 - 644
[5] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[6] Patent: WO2013/42135, 2013, A1, . Location in patent: Page/Page column 18; 19
[7] Patent: US2014/187581, 2014, A1, . Location in patent: Paragraph 0158-0161
[8] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 123-124; 131-132
[9] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
[10] Patent: US5753664, 1998, A,
[11] Patent: US5073557, 1991, A,
[12] Patent: US2003/191316, 2003, A1, . Location in patent: Page/Page column 32
[13] Patent: US2003/229074, 2003, A1, . Location in patent: Page 20
[14] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1880 - 1886
[15] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8597 - 8601[16] Angew. Chem., 2013, vol. 125, # 33, p. 8759 - 8763,5
[17] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 62
[18] Patent: US2016/333021, 2016, A1, . Location in patent: Paragraph 0370
[19] Patent: CN107793408, 2018, A, . Location in patent: Paragraph 0168; 0172
[20] Patent: US6140333, 2000, A,
  • 17
  • [ 135716-08-4 ]
  • [ 135716-12-0 ]
  • [ 135716-09-5 ]
Reference: [1] Patent: EP470668, 1992, A1,
  • 18
  • [ 135716-08-4 ]
  • [ 169206-67-1 ]
Reference: [1] Patent: WO2014/15495, 2014, A1,
[2] Patent: WO2014/18764, 2014, A1,
[3] Patent: WO2016/65582, 2016, A1,
[4] Patent: WO2015/17305, 2015, A1,
[5] Patent: CN105330698, 2016, A,
[6] Patent: WO2016/122994, 2016, A1,
[7] Patent: WO2016/60941, 2016, A1,
  • 19
  • [ 135716-08-4 ]
  • [ 146093-46-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 13, p. 2167 - 2172
  • 20
  • [ 135716-08-4 ]
  • [ 561314-57-6 ]
Reference: [1] Patent: CN105330698, 2016, A,
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N-Boc-3-Methylenepiperidine

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Chemical Structure| 149709-59-1

[ 149709-59-1 ]

(R)-Ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate

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Chemical Structure| 159635-22-0

[ 159635-22-0 ]

tert-Butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate

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Amides

Chemical Structure| 912444-89-4

[ 912444-89-4 ]

1-tert-Butyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

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Chemical Structure| 828243-30-7

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3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 184368-74-9

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1-tert-Butyl 4-methyl 5,6-dihydropyridine-1,4(2H)-dicarboxylate

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Chemical Structure| 149353-75-3

[ 149353-75-3 ]

4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 170838-26-3

[ 170838-26-3 ]

2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Esters

Chemical Structure| 912444-89-4

[ 912444-89-4 ]

1-tert-Butyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

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Chemical Structure| 184368-74-9

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Chemical Structure| 210962-44-0

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Chemical Structure| 80221-26-7

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Chemical Structure| 135716-09-5

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tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

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Related Parent Nucleus of
[ 135716-08-4 ]

Aliphatic Heterocycles

Chemical Structure| 912444-89-4

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1-tert-Butyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

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Chemical Structure| 828243-30-7

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3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 149353-75-3

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4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 170838-26-3

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2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 159635-49-1

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tert-Butyl 4-methylenepiperidine-1-carboxylate

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3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 149353-75-3

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4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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Chemical Structure| 170838-26-3

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2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)benzoic acid

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tert-Butyl 4-methylenepiperidine-1-carboxylate

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