* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 27, p. 6496 - 6502
[2] Journal of the American Chemical Society, 2000, vol. 122, # 45, p. 11270 - 11271
[3] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2693 - 2698
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3674 - 3680
[5] Tetrahedron, 2008, vol. 64, # 28, p. 6635 - 6644
[6] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2827 - 2840
[7] Patent: WO2014/150132, 2014, A1, . Location in patent: Page/Page column 44
[8] Patent: WO2016/8064, 2016, A1, . Location in patent: Page/Page column 39
[9] Patent: WO2016/10801, 2016, A1, . Location in patent: Page/Page column 33
[10] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 49
[11] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 42
18
[ 498-94-2 ]
[ 2971-79-1 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1932, vol. 4, p. 259,263
[2] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
[3] Tetrahedron, 1995, vol. 51, # 30, p. 8355 - 8362
[4] Patent: WO2004/104001, 2004, A2, . Location in patent: Page 59
19
[ 498-94-2 ]
[ 50-00-0 ]
[ 68947-43-3 ]
Yield
Reaction Conditions
Operation in experiment
98.1%
With hydrogen In water at 16 - 25℃;
Load isonipicotic acid (1 kg, 7.74 mol), water (10 L), formaldehyde (37percent solution in water, 720 g, 8.87 mol, 1.15 eq. ) and wet Pd/C catalyst (10percent; 55percent paste, 100 g) into a stainless steel hydrogenation reactor. Pressurize the reactor with H2 (3 bar) and stir the reaction mixture overnight at 200-300 rpm at 16-25°C. Stop the reaction and filter off the catalyst. Wash the filtrate with water (500 ml) and concentrate under vacuum. Distill off the remaining water from the residue using ethanol (2x 1 L). Dry the solid overnight under vacuum at 50°C to obtain the title product as an off-white solid (1087 g, 98. 1percent yield).
76%
With hydrogen In water at 20℃; for 18 h;
Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37percent formaldehyde (125 ml). 10percent Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours. [00375] The catalyst was filtered, washed with water, and the filtrate was concentrated under reduced pressure. The residue was slurried in water and concentrated in vacuo. The residue was slurried in ethanol and concentrated in vacuo to give a white solid. Drying under vacuum at ambient temperature for 18 h gave 42.2 g (76percent) of a white solid, [00376] mp 173-5° C. MS(m/e): 143 (M+). [00377] Analysis for C7H13NO2: [00378] Calcd: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.24; H, 9.59; N. 9.71.
18%
for 20 h; Heating / reflux
Reference Example 249: l-MethvI-piperidine-4-carboxylic acid . A solution of 4-piperidine carboxylic acid (1.0 g, 7.75 mmol) in a mixture of90percent formic acid (3 mL) and 37percent formaldehyde solution (2 mL) was heated at reflux for 20 h. The volatiles were removed in vacuo and cone. HCl added to the residue. The reaction mixture was extracted with dichloromethane and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and dried to afford 1-methyl- piperidine-4-carboxylic acid (0.20 g, 18 percent).
Reference：
[1] Patent: WO2003/84949, 2003, A1, . Location in patent: Page/Page column 45; 46
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10118 - 10129
[3] Patent: US6777428, 2004, B1, . Location in patent: Page column 24
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 4, p. 449 - 459
[5] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 161-162
[6] Journal of the American Chemical Society, 1949, vol. 71, p. 2825
[7] Patent: US2833775, 1955, ,
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 1995, vol. 36, # 2, p. 193 - 204
[9] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 21
20
[ 498-94-2 ]
[ 64-17-5 ]
[ 1126-09-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 0℃; for 48 h; Reflux
Isonipecotic acid (1.29g, 10.0 mmol) was dissolved in absolute ethanol (50 ml). The solution was cooled to 0οC and thionyl chloride (2.91 ml, 40.0 mmol) added dropwise. The solution was then stirred and refluxed for 48 h. The solvent was removed in vacuo yielding yellow oil, which was dissolved in EtOAc and washed with 10percent NaOH. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to afford a clear oil (1.48 g, 94percent). 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.07 (dt, J = 12.6, 3.6 Hz, 2H, 2 × CHpip), 2.61 (td, J = 12.3, 2.7 Hz, 2H, 2 × CHpip), 2.38 (tt, J = 11.3, 3.9 Hz, 1H, CH), 1.94 - 1.78 (m, 2H, 2 × CHpip), 1.59 (adtd, J = 13.4, 11.4, 4.0 Hz, 2H, 2 × CHpip), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3).Mass Spectrum (ESI): m/z 158.2 [M+H]+.
92%
With sulfuryl dichloride In N,N-dimethyl-formamide at 80℃; for 6 h; Inert atmosphere
To a solution of isonipecotic acid 1 (500 g, 3.87 mol) inmethanol (1.5 L), thionyl chloride (371 g, 5.03 mol) wasadded dropwise in nitrogen atmosphere at 0 °C. After addition,reaction was heated to reflux temperature under nitrogenatmosphere for 6 h. Excess methanol was distilled out to give yellow paste which was dissolved in ethyl acetate (1 L)and neutralized with saturated sodium bicarbonate solution.Organic layer was dried by using sodium sulphate and concentratedto afford 2 (560 g, 92percent) as colorless liquid. IR(neat) cm-1: 3296, 2949, 2856, 2812, 2739, 1734; 1H NMR(CDCl3, 400 MHz) : 1.02-1.05 (3H, t, J=7.2 Hz, CH3),1.33-1.43 (2H, m, CH2), 1.63-1.67 (2H, dd, CH2), 2.14-2.21(1H, m, CH), 2.37-2.44 (2H, m, CH2), 2.83-2.87 (2H, m,CH2), 3.88-3.93 (2H, q, J=7 Hz, CH2). 13C NMR (CDCl3,100 MHz) : 14.1, 29.0, 41.4, 45.6, 60.2, 175.0.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7106 - 7109
[2] Letters in Organic Chemistry, 2015, vol. 12, # 4, p. 277 - 279
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 5, p. 505
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2693 - 2698
[5] European Journal of Medicinal Chemistry, 2000, vol. 35, # 7-8, p. 699 - 706
[6] RSC Advances, 2016, vol. 6, # 26, p. 21577 - 21589
21
[ 498-94-2 ]
[ 1126-09-6 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1938, vol. 10, p. 380,381
[2] Journal of the Chemical Society, 1937, p. 1523,1525
22
[ 498-94-2 ]
[ 1690-75-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 807 - 814
23
[ 498-94-2 ]
[ 108-86-1 ]
[ 115-46-8 ]
Yield
Reaction Conditions
Operation in experiment
415 g
Stage #1: With magnesium In tetrahydrofuranReflux Stage #2: at 50 - 120℃; for 11 h; Inert atmosphere
Ina 3 L round bottom flask equipped with mechanical stirrer and a water bath the following materials are poured: magnesium turnings (100 g, 4.16 mmol), tetrahydrofuran (650 mL), bromobenzene (43.6 g, 0.277 mmol). The mixture is heated to reflux while stirring and as soon as the reaction is started a solution of brombenzene (608.4 g, 3.87 mmol) is slowly added at such a rate so as to maintain reflux. When the addition is complete,the mixture is refluxed until magnesium is almost completely dissolved. Then isonipecotic acid (4a) (200 g) and toluene(300 mL) are added to phenyl magnesium bromide (4b) (Grignardre agent) kept at 50 °C. The mixture is refluxed at atmospheric pressure for about 1 h. Then, the reaction is kept under pressure with nitrogen (0.4 to 1.5 atm) and the mixture is heated again between 105 and 120 °C. for 10 h. After this, the reaction mixtureis allowed to cool, the pressure of the reaction is slowly decreased and the mixture is slowly poured into 4 L of cold water. Yield 415 g of the azacyclonol [16] compound 4c of the title (Scheme-I).
Reference：
[1] Asian Journal of Chemistry, 2017, vol. 29, # 10, p. 2113 - 2115
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h;
Step 1: Synthesis of 1-benzylpiperidine-4-carboxylic acid To a stirred solution of piperidine-4-carboxylic acid (5.0 g, 38.7 mmol) in DMF (20 mL) was added K2CO3 (13.3 g, 96.8 mmol) followed by drop wise addition of benzyl bromide (9.2 mL, 77.5 mmol). Reaction was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion, reaction mass was diluted with cold water (100 mL) and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, evaporated under reduced pressure to give crude product. Purification of the compound was done by silica gel (100-200 Mesh) column chromatography eluent 20percent EtOAc: hexane to obtain 1-benzylpiperidine-4-carboxylic acid (5.0 g, 59percent) as light yellow oil. MS: 220.14 [M++1]
With triethylamine In 1,2-dichloro-ethane at 20 - 83.5℃; for 10 h;
775 g of 1,2-dichloroethane was added to a 2000 ml reaction flask.129.16 g of 4-piperidinecarboxylic acid and 131.55 g of triethylamine are added with stirring.Controlled temperature below 20 °C added benzyl chloride 189.87g.After the dripping is slowly heated up to 83.5°C, the reaction is refluxed for 10h.The reaction solution was dropped to room temperature and stirred with 300 g of water.The liquid was separated; the organic layer was washed with 150 g of saturated saline, and the organic layer was collected and dried;The filtrate was filtered and concentrated to give an oil of N-benzyl-4-piperidinecarboxylic acid 201.96 g;Molar yield 92.1percent,The liquid purity is 97.21percent.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 350 - 364
[2] Patent: CN107879969, 2018, A, . Location in patent: Paragraph 0024-0027
28
[ 498-94-2 ]
[ 501-53-1 ]
[ 10314-98-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydrogencarbonate; sodium carbonate In water; acetonitrile at 0 - 20℃; for 2 h;
To a solution of isonipecotic acid (1.29g, 10 mmol) in a mixture of CH3CN/H2O (2:3, 0.1M), NaHCO3 (1.5eq) and Na2CO3 (1.5 eq) were added (pH~ 10-11). Once the mixture was cooled to 0 °C, Cbz-Cl (1.42 mL,1.7 g, 10 mmol). was slowly added The resulting solution was stirred for 2 h at rt. After completion ofthe reaction, the mixture was acidified by dropwise addition of a 1 N HCl aqueous solution. Then, CH3CNwas removed by evaporation, followed by the extraction with EtOAc (3x). Finally the combined organicphase was washed with brine, dried over Na2SO4, and concentrated to afford the desired product inquantitative yield, which was used in the next reaction without further purification.
96%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃;
Stage (i): 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid Water (75 ml) was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C. and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was subsequently stirred at room temperature for 5 h (TLC control). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml), and the mixture was washed with ethyl acetate (2*150 ml). The aqueous phase was rendered acidic with dilute aqueous HCl and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96percent)
96%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃;
Stage (i): 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid To piperidine-4-carboxylic acid (25 g) in THF (75 ml) there was added water (75 ml) followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 hours at room temperature (TLC monitoring). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2*150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96percent)
96%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; Stage #2: With hydrogenchloride In water
To piperidine-4-carboxylic acid (25 g) in THF (75 ml) there was added water (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2.x.150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated under vacuum. Yield: 48.5 g (96percent)
96%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 25℃;
Water (75 ml), followed by sodium bicarbonate (30.8 g), was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the conversion was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2.x.150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96percent)
96%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃;
Step (i): 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid Water (75 ml) was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C. and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 5 h (TLC control) When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml), and the mixture was washed with ethyl acetate (2*150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96percent)
96%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water Stage #2: at 0 - 20℃; for 5 h;
Synthesis of the amine unit AMN-08: 9-Pyridin-4-yloxy)-3- azaspiro[5.5]undecane dihydrochloride (AMN-08); Stage (i): 1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid; Water (75 ml) was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0 0C and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 5 h (TLC control).. When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml), and the mixture was washed with ethyl acetate (2 x 150 ml). The aqueous phase was acidified with dilute aqueous HCI solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96 percent)
91%
With potassium carbonate In 1,4-dioxane; water at 0 - 20℃;
To a solution of piperidine-4-carboxylic acid in a 1:1 mixture Of H2O/ dioxane (0.4 M), 5 eq OfK2CO3 were added before dropwise introduction at 0 °C of 1.1 eq of benzyl chloroformate. The reaction was stirred at RT overnight. The reaction was first washed with Et2O. The aqueous phase was acidified to pH 2 with aqueous HCl (6N) before being extracted with EtOAc (3x). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the product (91 percent); MS (ES+) m/z 264 (M+H)+
72%
With sodium hydrogencarbonate In water at 20℃; for 20 h;
To an aqueous solution (i.e., 300 ml of distilled water) of isonipecotic acid (10.0 g, 77.4 mmol) and sodium bicarbonate (19.5 g, 232 mmol) was added benzyl chloroformate (11.5 ml, 80.9 mmol). The reaction solution was stirred at room temperature for 20 hours, and ethyl acetate was added thereto then the solution was separated. Concentrated hydrochloric acid was added to the aqueous layer to bring a pH level to 1, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure to give a title compound (14.7 g, 55.8 mmol, 72percent) as a colorless oil product. 1H-NMR (400 MHz, CDCl3) δ: 1.69 (2H, m), 1.93 (2H, m), 2.51 (1H, m), 2.96 (2H, m), 4.11 (2H, m), 5.13 (2H, s), 7.29-7.39 (5H, m).
71%
With sodium hydrogencarbonate In diethyl ether
(1) A diethyl ether (50 ml) solution of benzyl chloroformate (36 g, 0.21 mols) was dropwise added to an aqueous solution (200 ml) of isonipecotic acid (25 g, 0.19 mols) and sodium hydrogencarbonate (49 g, 0.58 mols) with stirring at room temperature. After the addition, this was further stirred at room temperature for 15 hours. The reaction mixture was acidified with concentrated hydrochloric acid added thereto, and then extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether/hexane, and taken out through filtration. A colorless crystal of N-benzyloxycarbonylisonipecotic acid (36 g, 71 percent) was obtained. m.p. 79-80°C 1H-NMR (CDCl3) δ: 1.57-1.77(2H,m), 1.90-1.96(2H,m), 2.45-2.59(1H,m), 3.89-3.03(2H,m), 4.06-4.13(2H,m), 5.13(2H,s),
64%
With sodium hydroxide In water; toluene at 0 - 20℃; for 6.5 h; Alkaline aqueous solution
To a stirred solution of pipehdine-4-carboxylic acid (5.0 g, 38.7 mmol) and NaOH (1.86 g, 46.5 mmol) in H2O (15 ml) was added dropwise a 50percent solution of benzyl chloroformate in toluene (13.6 ml_, 40.6 mmol) over a period of half an hour at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was acidified with dil. HCI (pH 3) and extracted with ethyl acetate (3x100 ml). The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (silica gel, elution with 30percent ethyl acetate/n- hexanes) to afford piperidine-1 ,4-dicarboxylic acid monobenzyl ester (Vl) (6.5 g, 64percent) as a pale yellow oil.HPLC purity λ = 220 nm: 95percent. ESMS: m/z = 264 (M+1 ).
86%
With sodium hydrogencarbonate In water; ethyl acetate; toluene
STR76 Step A: N-CBZ-isonipecotic acid Benzyl chloroformate (16.4 mL, 115 mmol) in toluene (50 mL) was added dropwise to a stirred solution of 12.9 g (100 mmol) of isonipecotic acid (Aldrich) and 21.0 g (250 mmol) of sodium bicarbonate in 200 mL of water. After 14 h, the mixture was extracted with ether (3*50 ml) and the ether layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2, causing the product to precipitate. The product was partitioned into ethyl acetate (3*50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 22.6 g (86percent) of N-CBZ-isonipecotic acid as a viscous oil.
Reference：
[1] Synlett, 2017, vol. 28, # 3, p. 376 - 380
[2] Tetrahedron, 1997, vol. 53, # 32, p. 10983 - 10992
[3] Patent: US2010/152158, 2010, A1, . Location in patent: Page/Page column 31
[4] Patent: US2010/173889, 2010, A1, . Location in patent: Page/Page column 60
[5] Patent: US2010/222324, 2010, A1, . Location in patent: Page/Page column 57
[6] Patent: US2010/234340, 2010, A1, . Location in patent: Page/Page column 41
[7] Patent: US2010/249095, 2010, A1, . Location in patent: Page/Page column 120
[8] Patent: WO2010/142402, 2010, A1, . Location in patent: Page/Page column 142-143
[9] Patent: US5583146, 1996, A,
[10] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692
[11] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 6, p. 967 - 970
[12] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 397 - 416
[13] Patent: WO2006/38039, 2006, A1, . Location in patent: Page/Page column 17; 29
[14] Journal of Medicinal Chemistry, 1988, vol. 31, # 3, p. 613 - 617
[15] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 807 - 809
[16] Patent: EP2009006, 2008, A1, . Location in patent: Page/Page column 47
[17] Patent: EP1123918, 2001, A1,
[18] Organic Letters, 2018,
[19] Journal of Medicinal Chemistry, 1980, vol. 23, # 12, p. 1306 - 1310
[20] Patent: WO2009/47359, 2009, A1, . Location in patent: Page/Page column 137
[21] Journal of Medicinal Chemistry, 2000, vol. 43, # 26, p. 4964 - 4972
[22] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479
[23] Patent: US2005/192302, 2005, A1, . Location in patent: Page/Page column 50
[24] Patent: US5399568, 1995, A,
[25] Patent: US5798337, 1998, A,
[26] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 7
[27] Patent: US4977159, 1990, A,
[28] Patent: WO2003/99808, 2003, A1, . Location in patent: Page 46-47
[29] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 70
[30] Patent: WO2004/94379, 2004, A2, . Location in patent: Page 22
[31] Patent: EP1553074, 2005, A1, . Location in patent: Page/Page column 47
[32] Patent: WO2012/158810, 2012, A1, . Location in patent: Page/Page column 112
[33] Patent: WO2010/132601, 2010, A1, . Location in patent: Page/Page column 541
29
[ 498-94-2 ]
[ 1885-14-9 ]
[ 10314-98-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In water at 0 - 25℃; for 18 h;
Example SA 2-[(PIPERIDINE-4-CARBONYL)-AMINO]-PROPIONIC acid tert-butyl ester A solution of isonipecotic acid (25 g, 194 mmol) in 3 N NaOH (130 mL) at 0°C was treated with CbzCl over 15 min with vigorous stirring. Then the reaction mixture was stirred at ambient temperature for 18 h and partitioned with diisopropyl ether (2x250 mL). The aqueous layer was separated, made acidic with 4 N HC1, and extracted with EtOAc (2x250 mL). The combined organic layers were dried (MGS04), filtered and concentrated under reduced pressure to provide piperidine-1, 4-dicarboxylic acid monobenzyl ester (40.2 g) as a clear colorless viscous oil. A portion of this material (26.5 g, 100 mmol) in THF (100 mL) was treated with DMF (5 drops) followed by dropwise addition of oxalyl chloride (8.67 mL, 100 mmol). When the evolution of gas had ceased the mixture was stirred for an additional 30 min and concentrated under reduced pressure. The residue obtained was evaporated from toluene (1X75 mL). The resulting acid chloride was dissolved in THF (220 mL) and treated with (L)-ALANINE-TERT-BUTYL ester HC1 salt (18.2 g, 100 mmol) and N, N-diisopropyl- ethylamine (52 mL, 300 mmol) at 0°C. The mixture was warmed to ambient temperature and stirred for two hours. To this DMAP (240 mg, 1.90 mmol) was added in one portion and the resulting white sus- pension was stirred for 65 h. The reaction mixture was quenched with 4 M HC1 and partitioned with EtOAc. The organic phase was separated, washed with a solution of aqueous NAHC03 followed by brine, dried (MGS04), filtered and concentrated under reduced pressure to provide 4- (L-TERT-BUTOXYCARBONYLETHYL- CARBAMOYL)-PIPERIDINE-L-CARBOXYLIC acid benzyl ester. This was subjected to hydrogenolysis next.;Example 11F PIPERIDINE-1, 4-DICARBOXYLIC acid monobenzyl ester A 2000 mL flask was charged with isonipecotic acid (100 g, 776 mmol) and 3 N NaOH (550 mL), and was cooled with an ice bath to 14°C (internal temperature). CbzCl (145 mL) was added dropwise and the temperature gradually rose to 25°C during the addition over 20 min. The mixture was vigorously stirred and the cooling bath removed. The mixture was stirred overnight and the next morning poured directly into a 2 L sep. funnel and extracted with diisopropyl ether (2XLOOOML). The aqueous layer was acidified with 4 N HC1, extracted with EtOAc (2X1000 mL), dried over MGSO4, filtered and concentrated affording 210 g of acid, as a clear colorless viscous oil which was crystallized upon cooling. This was dried to provide the title compound (208 g, 100percent). LH NMR (400 MHz, DMSO-d6) 10.67 (s, 1H), 7.42-7. 30 (m, 5H), 5.13 (s, 2H), 4.08-4. 02 (m, 2H), 3.10-2. 89 (m, 2H), 2.5 (m, 1H), 1.94-1. 89 (m, 2H), 1.621. 52 (m, 2H).
With sodium carbonate In water; acetonitrile at 20℃; for 16 h;
To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na2CO3 (8.21 g, 77.4 mmol) in water (100 mL) was added a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN (100 mL). The reaction was stirred at ambient temperature for about 16 h and then concentrated under reduced pressure. The resulting aqueous solution was quenched with NH4Cl and was then extracted with EtOAc (2.x.100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56 g, 22percent): LC/MS (Table 2, Method a) Rt=1.93 min; MS m/z: 262 (M-H)-.
With hydrogenchloride; triethylamine In tetrahydrofuran at 70℃; for 0.25 h; Microwave irradiation
A mixture of isonipecotic acid 1 (129 mg, 1.0 mmol), benzoyl chloride 2 (140 mg, 1.0 mmol) and Et3N (0.32 mL, 2.5 mmol) in THF (5 mL) was stirred under microwave irradiation (120 W) at 70 °C for 15 min. The reaction mixture was acidified using 1 M HCl (10 mL) and extracted with dichloromethane (3 * 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 5percent ethyl acetate in hexane, followed by 80percent ethyl acetate in hexane as eluent to yield 3 (94percent) as white solid. Mp 136-138 °C. 1H NMR (400 MHz, CDCl3) δ 1.71-1.85 (m, 3H), 2.03-2.06 (m, 1H), 2.59 (tt, 1H, J = 10.4, 4.1 Hz), 3.04-3.12 (m, 2H), 3.72-3.76 (m, 1H), 4.48-4.52 (m, 1H), 7.36-7.44 (m, 5H), 11.16 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ 40.4, 41.4, 46.8, 126.7, 128.3, 129.6, 135.3, 170.7, 178.3. HRMS (ESI): calcd for C13H14NO3 [M-H]-, 232.0973; found, 232.0979.
85%
Stage #1: With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22 h; Stage #2: With hydrogenchloride In water at 0℃;
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol,1.0 equiv) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol, 5.0 equiv) were added, and the mixture was cooled to 0°C. A solution of benzoyl chloride (8.980 mL, 77.425 mmol, 1.0 equiv) in THF (35mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mLseparating funnel and washed with EtOAc (3 × 150 mL). The aqueous phase was cooled to 0 °C and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Büchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 12 as a white solid (85percentyield). This product was used in the next step without further purification. Rf = 0.55 (MeCN-H2O-MeOH= 3:1:1); mp 118–122 °C. IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1169,1014, 791, 731, 707, 628, 577. cm-1. 1H NMR (400 MHz,DMSO-d6): δ = 1.49 (2 H, bs), 1.83 (2 H, bd, J = 45.68 Hz), 2.52–2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1H, bs), 7.34–7.46 (5 H, m), 12.32 (1 H, bs). 13C NMR (100 MHz,DMSO-d6): δ = 27.62, 28.24, 40.06, 40.74, 46.38, 126.61, 128.38, 129.31,136.23, 168.96, 175.481. HRMS (ESI+): m/z calcd for C13H16NO3: 234.1130; found 231.1125. Anal. Calcd for C13H15NO3: C,66.94; H, 6.48; N, 6.00. Found C, 67.22; H, 6.78; 6.22.
85%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22 h;
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol) were added, and the mixture was cooled to 0 °C. A solution of benzoyl chloride (8.980 imL, 77.425 mmol) in THF (35 imL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3 χ 150 ml_). The aqueous phase was cooled to 0 °C and adjusted to pH 1 -2 with 6 M aq HCI. The white precipitate was collected in a Buchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 1 -benzoylpiperidine-4-carboxylic acid. This product was used in the next step without further purification.Product appearance: white solid.Yield: 85percent.Melting point: 1 18-122 °C . TLC: Rf = 0.55 (MeCN-H2O-MeOH = 3:1 :1 ) .IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1 169, 1014, 791 , 731 , 707, 628, 577. cm"1 (0361) [0333] 1H NMR (400 MHz, DMSO-d6): δ = 1 .49 (2 H, bs), 1 .83 (2 H, bd, J = 45.68 Hz), 2.52-2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1 H, bs), 7.34-7.46 (5 H, m), 12.32 (1 H, bs).13C NMR (100 MHz, DMSO-d6): δ = 27.62, 28.24, 40.06, 40.74, 46.38, (0363) 126.61 , 128.38, 129.31 , 136.23, 168.96, 175.48.HRMS (ESI+): m/z calculated for C13H16NO3: 234.1 130; found 231 .1 125. CHN analysis: Calculated for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: (0366) C, 67.22; H, 6.78; N, 6.22.
Reference：
[1] Bioorganic Chemistry, 2018, vol. 80, p. 245 - 252
[2] Tetrahedron Letters, 2014, vol. 55, # 12, p. 2037 - 2039
[3] Patent: WO2016/151484, 2016, A1, . Location in patent: Paragraph 0327
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139
[5] Patent: US5948786, 1999, A,
[6] Patent: US6248755, 2001, B1,
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2305 - 2308
[8] Journal of the American Chemical Society, 2015, vol. 137, # 17, p. 5654 - 5657
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
34
[ 498-94-2 ]
[ 95-54-5 ]
[ 38385-95-4 ]
Yield
Reaction Conditions
Operation in experiment
38%
Stage #1: With hydrogenchloride In water for 48 h; Reflux Stage #2: With sodium hydroxide In water
This compound is synthesized as described by adaptation of the following reference: J. Heterocyclic Chem., 1989, 26, 54. A mixture of benzene- 1 ,2-diamine (12.6 g, 116 mmol), piperidine-4-carboxylic acid (15 g, 116 mmol) and 4M aqueous HCl (250 mL) is stirred and heated under reflux for 48 h. The reaction mixture is cooled to room temperature and is made basic by addition of 5M aqueous NaOH. The precipitate formed is collected by suction filtration, washed with water and dried in the vacuum oven to afford 8.8 g (38percent) of 2-(piperidin-4-yl)-lH-benzimidazole. m/z =202 [M++H].
36 g
at 115 - 120℃; for 20 h;
Orthophenylenediamine (20 g), polyphosphoric acid (120 g) and isonipecotic acid (26.5 g) were taken into a reaction flask and the resulting mixture was heated to 115-120°C, followed by stirring for 20 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to 90°C, quenched with distilled water (260 ml) and then cooled to room temperature (25-30°C). The resulting mass was further cooled to 10-15°C,followed by adjusting the pH of the reaction mass to 9-10 with dilute sodium hydroxide solution, and then stirring for 30 minutes at 10-15°C. The separated solid was filtered and washed with distilled water. The wet material was dried at 40-45°C. Methanol (720 ml) was added to the resulting material and stirred for 1 hour at room temperature. The resulting mass was filtered and washed with methanol (250 ml). The resulting filtrate was concentrated under reduced pressure to give 36 g of 2-(4-Piperidinyl)- 1H-benzimidazole.
Reference：
[1] Patent: US6660751, 2003, B1, . Location in patent: Page column 7,8
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 695 - 699
[3] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 707 - 718
[4] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 541 - 543
[5] Patent: WO2010/80357, 2010, A1, . Location in patent: Page/Page column 41-42
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5435 - 5448
[7] Patent: WO2011/143444, 2011, A2, . Location in patent: Page/Page column 7; 87-90
[8] Medicinal Chemistry Research, 2011, vol. 20, # 5, p. 558 - 565
[9] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 509 - 516
[10] Patent: WO2018/42305, 2018, A1, . Location in patent: Page/Page column 15; 16
35
[ 498-94-2 ]
[ 95-55-6 ]
[ 51784-03-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 707 - 718
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1974, vol. 10, p. 92 - 95[4] Khimiya Geterotsiklicheskikh Soedinenii, 1974, vol. 10, p. 104 - 107
[5] Patent: US5968923, 1999, A,
[6] Patent: US6037342, 2000, A,
[7] Patent: US6660751, 2003, B1, . Location in patent: Page column 8
[8] Patent: CN103965186, 2016, B, . Location in patent: Paragraph 0086
36
[ 67-56-1 ]
[ 498-94-2 ]
[ 24424-99-5 ]
[ 124443-68-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: at 20℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 0 - 20℃;
b. Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester; To a mixture of isonipecotic acid (39.0 g, 302 mmol) in MeOH (300 mL) was bubbled HCl gas. The flask was tightly capped and stirred at rt for 1.5 h, at which point the homogeneous solution was concentrated, taken up in DCM (2.x.125 mL), and repeatedly concentrated under reduced pressure to give a white solid largely free of MeOH. To this was added TEA (43.6 mL, 313 mmol) and DCM (80 mL), and this slurry was stirred on an ice bath while a solution of (Boc)2O (60.9 g, 279 mmol) in DCM (100 mL) was added dropwise with stirring over 10 min at 0° C. After 1 h stirring at 0° C., the ice bath was removed and the slurry was stirred at rt overnight. The slurry was then diluted with ether (700 mL), washed with 0.5M NaH2PO4 (1.x.400 mL), 4 M NaCl (1.x.450 mL), dried (Na2SO4), and concentrated under reduced pressure to provide the title compound as a clear light amber oil that crystallized upon standing (65.3 g, 96percent). 1H-NMR (300 MHz, CDCl3) δ 4.10-3.95 (br m, 2H), 3.69 (s, 3H), 2.92-2.75 (br m, 2H), 2.45 (m, 1H), 1.93-1.82 (m, 2H), 1.70-1.55 (m, 2H), 1.46 (s, 9H).
Reference：
[1] Patent: US2006/281772, 2006, A1, . Location in patent: Page/Page column 51
[2] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
A solution of 4-piperidinecarboxylic acid (500 g, 3.87 mol) and methanol (2.5 L) was added to the reaction flask, and thionyl chloride (460.4 g, 3.87 mol) was added dropwise, and the temperature was gradually increased during the dropwise addition Temperature rise to 80 reflux reaction 3h. The reaction solution was concentrated under reduced pressure at 50 ° C to give 687 g of a white solid, the yield was 98.8percent
Reference：
[1] Patent: CN106146386, 2016, A, . Location in patent: Paragraph 0040; 0041; 0042; 0043
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5359 - 5368
[3] Patent: US2009/124624, 2009, A1, . Location in patent: Page/Page column 16
[4] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2009, vol. 64, # 11-12, p. 1617 - 1624
39
[ 498-94-2 ]
[ 7462-86-4 ]
Reference：
[1] Patent: US6069143, 2000, A,
40
[ 498-94-2 ]
[ 358-23-6 ]
[ 126501-70-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 0℃;
Example 17A1 1 -(2,2,2-trifluoroacetyl)piperidine-4-carboxylic acid To a solution of piperidine-4-carboxylic acid (4 g , 30.97mmol) in dichloromethane (20 mL) was added dropwise triflate anhydride(7.8g). The resulting mixture was stirred at 0 °C overnight. Upon dilution with water, the combined organic layers were concentrated. The residue was purified by column chromatography on silica gel to give Example 17A1 in 70percent yield as a white solid.
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1594 - 1600
[2] Analytical Chemistry, 2002, vol. 74, # 24, p. 6397 - 6401
[3] Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2519 - 2525
[4] Journal of Medicinal Chemistry, 2001, vol. 44, # 21, p. 3339 - 3342
[5] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3143 - 3160
[6] Patent: EP1175402, 2005, B1, . Location in patent: Page/Page column 30
42
[ 498-94-2 ]
[ 50-00-0 ]
[ 71985-80-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With formic acid In water at 90 - 100℃; Stage #2: With hydrogenchloride In water at 65 - 75℃;
Charge isonipecotic acid (1.00 wt, l .Oeq, 600 g) to a reaction vessel. Charge palladium on charcoal (10percentwt, 50percent wet paste, 0.05wt, 30 g) to the reaction vessel. Charge purified water (4.0 vol, 2.4 L) to the reaction vessel. Heat the resulting mixture to 90 to 95°C. Charge formic acid (1.2 vol, 1.4wt, 4.0eq, 720 mL) to the vessel at 90 to 95°C(expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5vol, 300 mL) to the vessel at 90 to 95°C. Charge formaldehyde (37percent w/w aqueous solution, 0.74vol, 0.8 lwt, 1.3eq, 444 mL) to the vessel at 90 to 95°C (expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95°C. Stir the resulting mixture at 90 to 100°C until complete by HPLC analysis (pass criterion <0.1percent area isonipecotic acid, expected 3 hours). Cool the resulting mixture to 20 to 30°C. Filter the reaction mixture through GF/F. Wash the filter cake with purified water (2 x l.Ovol) at 20 to 30°C. Concentrate the combined filtrates to ca 2 vol at atmospheric pressure. As necessary adjust the temperature to 65 to 75°C. Charge cone. Hydrochloric acid (0.95 vol, 1.14wt, 1.5eq, 570 mL) to the vessel at 65 to 75°C. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at >70°C and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at >70°C and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8wt, 6.0 L) to the vessel at >70oC and concentrate the solution to ca 3 vol at atmospheric pressure. Check the water content by KF analysis of the supernatant liquors using AX reagent (pass criterion<0.1percentw/w). Cool the reaction mixture to 20 to 25°C. Stir the reaction mixture for 1 to 2 hours at 20 to 25°C. Filter the reaction mixture at 20 to 25°C. Wash the filter cake with acetonitrile (2 x 1.0 vol, 0.8 wt, 2 x 600 mL). Dry the product at up to 50°C until <0.5percent w/w by LOD and <0.2percentw/w water (KF, AX reagent). Expected yield: 80 to 90percentth, 111 to 125percentw/w; Isolated yield: 755 g (91percentth, 125w/w). Figure 5 shows a typical NMR spectrum of l-Methylpiperidine-4-carboxylic acid (D20)
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 807 - 814
[2] Patent: WO2011/123654, 2011, A1, . Location in patent: Page/Page column 29-30
[3] Patent: WO2010/83384, 2010, A2, . Location in patent: Page/Page column 61
43
[ 498-94-2 ]
[ 71985-80-3 ]
[ 50675-21-3 ]
Reference：
[1] Patent: US4757079, 1988, A,
44
[ 498-94-2 ]
[ 1193-65-3 ]
Reference：
[1] Letters in Organic Chemistry, 2015, vol. 12, # 4, p. 277 - 279
45
[ 498-94-2 ]
[ 55695-51-7 ]
Reference：
[1] Farmaco, Edizione Scientifica, 1957, vol. 12, p. 853,862
Reference：
[1] Tetrahedron, 1997, vol. 53, # 32, p. 10983 - 10992
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 661 - 664
[3] Synlett, 2017, vol. 28, # 3, p. 376 - 380
49
[ 498-94-2 ]
[ 138163-07-2 ]
Reference：
[1] Patent: EP2009006, 2008, A1,
50
[ 498-94-2 ]
[ 24424-99-5 ]
[ 84358-13-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In tetrahydrofuran at 20℃; for 1 h; Cooling with ice
According to the above synthetic line of PT106,Compound 9 (1 g, 7.74 mmol) was dissolved in NaOH solution (2 M, 10 mL)A solution of BOC anhydride (2.53 g, 11.61 mmol) in THF (10 mL) was slowly added under ice-cooling,The reaction was stirred at room temperature for 1 hour,The THF was removed on a rotary evaporator and the aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid,Then extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and filtered,The filtrate was concentrated on a rotary evaporator and dried in vacuoWhite solid compound 10 (1.78 g, 7.76 mmol, yield 100percent).
99%
With hydrogenchloride; sodium hydroxide In <i>tert</i>-butyl alcohol
EXAMPLE 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0° C. 4-Piperidinecarboxylic acid (13) (108 g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0° C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5° C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40° C. The resulting solution was cooled to 5° C. in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3*500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40° C.) to give the title compound (14) as a white solid (189.5 g, 99percent yield).
99%
With hydrogenchloride In sodium hydroxide; <i>tert</i>-butyl alcohol
EXAMPLE 57 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (IM, 150 mL), and t-butanol (100 mL) at 0° C. was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0° C. and extracted with ether (3*200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuum to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150° C.
99%
With hydrogenchloride; sodium hydroxide In <i>tert</i>-butyl alcohol
EXAMPLE 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0° C. 4-Piperidinecarboxylic acid (13) (108 g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0° C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5° C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40° C. The resulting solution was cooled to 5° C. in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3*500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40° C.) to give the title compound (14) as a white solid (189.5 g, 99percent yield).
99%
With hydrogenchloride In sodium hydroxide; <i>tert</i>-butyl alcohol
EXAMPLE 57 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (1M, 150 mL), and t-butanol (100 mL) at 0° C. was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0° C. and extracted with ether (3*200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150° C.
97%
Stage #1: for 0.25 h; Stage #2: With sodium hydroxide; water In 1,4-dioxane at 20℃; Stage #3: With hydrogenchloride In water
Example 11 : (2RS)-I- [2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -piperidine- 4-carboxylic acid (2,3-dihydro-benzo[l,4]dioxin-6-yl)-amide:11 i. Piperidine-1 ,4-dicarboxylic acid mono-tert-butyl ester.To a solution of isonipecotic acid (12.9 g, lOO mmol) in dioxane (10O mL) and water (100 mL) was slowly added a solution Of BoC2O (24 g, 1.1 eq.) in dioxane (100 mL). After15 min, \\M NaOH (10O mL) was added and the mixture stirred at rt overnight. The mixture was concentrated in vacuo and the residue partitioned between ether and \\M HCl(120 mL). The aq. phase was extracted with ether (2 x 200 mL) and the combined org. extracts were washed with brine, dried over MgSO4 and concentrated. The expected compound was isolated as a colourless solid (22.4 g, 97percent yield) and used as such in the next step.1H NMR (DMSO d6) δ: 12.5 (s, IH); 3.83 (m, 2H); 2.82 (m, 2H); 2.40 (m, IH); 1.78 (m,2H); 1.39 (s, 9H); 1.34 (m, 2H).
97%
Stage #1: for 0.25 h; Stage #2: With sodium hydroxide In 1,4-dioxane; water at 20℃;
To a solution of isonipecotic acid (12.9 g, 100 mmol) in dioxane (100 mL) and water (100 mL) was slowly added a solution of Boc2O (24 g, 1.1 eq.) in dioxane (100 mL). After 15 min, 1M NaOH (100 mL) was added and the mixture stirred at rt overnight. The mixture was concentrated in vacuo and the residue partitioned between ether and 1M HCl (120 mL). The aq. phase was extracted with ether (2*200 mL) and the combined org. extracts were washed with brine, dried over MgSO4 and concentrated. The expected compound was isolated as a colourless solid (22.4 g, 97percent yield) and used as such in the next step. 1H NMR (DMSO d6) δ: 12.5 (s, 1H); 3.83 (m, 2H); 2.82 (m, 2H); 2.40 (m, 1H); 1.78 (m, 2H); 1.39 (s, 9H); 1.34 (m, 2H).
97%
Stage #1: With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 0 - 20℃; for 22.75 h; Stage #2: With hydrogenchloride In water; <i>tert</i>-butyl alcohol at 0 - 5℃; for 0.5 h;
To a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (1M, 150 mL), and t-butanol (100 mL) at 0°C was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0°C and extracted with ether (3 x 200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuum to afford the title compound (14) as a fluffy white solid (28.4 g, 99percent); mp 149-150°C.; Example 58 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) A 3-L three-neck flask containing 1.0 L (1 mol) of 1N NaOH was cooled to 0°C. 4-Piperidinecarboxylic acid (13) (108g, 0.84 mol) and 500 mL of t-butanol were then added to the aqueous solution which was maintained at 0°C. A solution of 200 g (0.92 mol) of di-t-butyldicarbonate in 500 mL of t-butanol was placed in a pressure equalizing addition funnel and added to the reaction mixture over a 45 minute period while maintaining the temperature below 5°C. After completion of the addition, the reaction was allowed to warm to room temperature and then stirred an additional 22 hours. The cloudy reaction mixture was reduced to one half of its original volume using a rotary evaporator at 40°C. The resulting solution was cooled to 5°C in a 3 L flask, then 500 mL (1.5 mol) of 3N HCl was added to the cooled solution over a 30 minute period. The resulting thick slurry was extracted with tetrahydrofuran (3 x 500 mL) and the combined extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvent was then evaporated (20 mm Hg, 40°C) to give the title compound (14) as a white solid (189.5 g, 99percent yield).; Example 59 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Solid di-t-butyldicarbonate (300 g, 1.37 mol) was added to a solution of 4-piperidinecarboxylic acid (13) (162 g, 1.25 mol) in aqueous NaOH (1N, 1.5 L) and t-BuOH (1.5 L) at 4°C over 30 minutes. The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated (40°C/20 torr) to half of its volume. Aqueous HCl (3N, 750 mL) was added to the concentrated solution at 4°C over 30 minutes. The resulting slurry was extracted with ethyl ether (3 x 2 L). The combined ethereal solutions were dried (MgSO4). The mixture was filtered and the filtrate was concentrated (30°C/20 torr) to give the title compound (14) after air drying (277 g, 97percent); m.p. 145-147°C. 1H NMR (CDCl3) δ 4.01 (d, 2H, J = 12.0 Hz, CHN's), 2.83 (dd, 2H, J = 12.0 Hz, CHN's), 2.5 (m, 1H, CH), 1.9 (m, 2H), 1.6 (m, 2H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 180.2, 154.7, 79.8, 43.0, 40.8, 28.4, 27.7; MS (CI,CH4)m/z (rel. Intensity) 230 (MH+, 32percent), 174 (100), 156 (71), 130 (25); IR (KBr) 3451, 3208, 3002, 2974, 2932, 1734, 1661, 1452, 1431, 1393, 1369, 1283, 1170, 1159, 1035, 924, 862 cm-1; Anal. Calc'd for C11H19NO4 (229.3): C, 57.62; H, 8.35; N, 6.11. Found: C, 57.68; H, 8.62; N, 6.00.; Example 60 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) To a solution of 4-piperidinecarboxylic acid (13) (700 g, 5.42 mol) in aqueous NaOH (1N, 6.5 L) and t-butanol (6.5 L) at 0°C was added di-t-butyldicarbonate (1295.8 g, 5.94 mol) slowly over 30 minutes. The reaction mixture was stirred overnight at ambient temperature. The resulting solution was concentrated (48°C/20 torr) to half of its volume and quenched by the addition of HCl (10percent, 2.6 L). The white solid which precipitated was filtered off, washed with water (1L) and air-dried to give the title compound (14) (1178 g, 100percent yield); m.p. 144-146°C. 1H NMR (CDCl3) δ 4.1 (d, 2H, J=12.0 Hz), 2.91 (t, 2H, J=12.0 Hz), 2.5 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H), 1.52 (s, 9H).
96%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 19 h;
(c) l-(toer/-Butoxycarbonyl)piperidine-4-carboxylic acidDi-tert-butyl dicarbonate (7.2 g, 33 mmol) was added in portions to a solution of isonipecotic acid (3.9 g, 30 mmol) in THF/water/NaOH (60/30/30 1 M) at rt, the mixture was stirred for 19 h. The organic solvent was concentrated in vacuo and the alkaline water phase was washed with dimethylether (2 x 15 mL). The solution was then acidified with 1 M KHSO4 (70 mL) and the water phase was extracted with dimethylether (1 xlOO + 1 x 50 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid as a white powder. Yield: 6.60 g (96percent).1H-NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.60-1.71 (2H, m), 1.87-1.96 (2H, m), 2.44- 2.54 (IH, m), 2.81-2.92 (2H, m), 3.95-4.09 (2H, m).
95%
With potassium carbonate In dichloromethane at 20℃; for 18 h;
[0210] Isonipecotic acid (5.51 g, 0.022 mol) was dissolved in dichloromethane (110 ml). Di-t-butyl dicarbonate ((Boc)2O) (7.31 g, 0.033 mol) and potassium carbonate (K2CO3) (9.62 g, 0.67 mol) were added to the resulting solution and the solution was stirred at room temperature for 18 hrs. After completion of the reaction by addition of water, the solution was extracted with ethylacetate, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol, 10/1) to give the white title compound (7.36 g, 95.0 percent). 1H NMR (400 MHz, CD3OD) δ 3.97 (m, 2H), 2.88 (br, 2H), 2.48 (m, 1H), 1.88 (m, 2H), 1.54 (m, 2H), 1.44 (s, 9H)
94%
Stage #1: With sodium hydroxide In tetrahydrofuran at 20℃; for 2.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)-=228.0.
94%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 2.5 h;
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid; Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)-=228.0.
94%
With sodium hydroxide In 1,4-dioxane; water at 20℃;
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25percent). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
94%
With triethylamine In 1,4-dioxane at 4 - 20℃; for 21 h;
A solution of 24 (50 g, 387 mmol) and triethylamine (110 mL) in dioxane (400 mL) at 4°C was treated with BoC2O (93 g, 426 mmol). The cooling bath was removed and the solution allowed to warm to room temperature. After 2 Ih, the volume was reduced by two-thirds under vacuum. The residue was poured into ethyl acetate (250 mL) and water (250 mL). Saturated aqueous NaHCO3 (250 mL) was added and the organic phase was separated and discarded. <n="40"/>The aqueous phase was acidified with 10percent HCl and extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried (Na2SO4), and concentrated to provide 25 as a white powder (82 g, 94percent).
93%
With sodium carbonate In 1,4-dioxane; water at 20℃;
Piperidine-4-carboxylic acid (5G, 38.7 mmol, leq. ) was dissolved in SODIUM CARBONATE SOLUTION (4. 5G, 42.61MMOL, 2.2 EQ. ), 70ML, AND 1,4-DIOXANE (30ML). A solution of di-tert-butyldicarbonate (9. 3G, 42. 61mmol, L. LEQ.) in 1,4-dioxane (40ml) was added dropwise and the resulting mixture was stirred overnight at room temperature. The organic solvent was removed under reduced pressure and the resulting solution was acidified with HCI 37percent till pH 2. The obtained suspension was filtered, the white solid washed with diethyl ether (5ml). The mother liquor has been extracted with ethyl acetate (120ML) and the previous solid was added. The organic solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give a white solid that was dried at 80°C under vacuum to give the title compound. Yield 93percent, 8.2g. Analytical data: m. p. 133°-135°C. H NMR (DMSO-D6) 12.3 (1H br s); 3.85 (2H, d); 2.8 (2H, br); 2.35 (1H, t); 1.8 (2H, d) ; 1.4 (1 1H, M).
91%
With hydrogenchloride; sodium hydroxide; nitrogen In ethanol; water
EXAMPLE 56 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50° C. and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6° C. exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5° C. and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58° C.) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151° C. 1H-NMR (CDCl3) 64.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.
91%
With sodium hydrogencarbonate; citric acid In 1,4-dioxane; water
a N-tert-butoxycarbonylisonipecotic acid Di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added to the mixture of isonipecotic acid (3.90 g, 30 mmol) and NaHCO3 (5.05 g, 60 mmol) in 1:1 1,4-dioxane/water (100 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, acidified to pH 6 using 10percent citric acid and extracted with ethyl acetate (3*100 mL). The organic phase was washed with brine (2*50 mL) and dried over Na2 SO4. The solvent was evaporated to give the title compound as a white solid (6.25 g, 91percent). 1 H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.63 (m, 2H), 1.88 (dd, 2H, J=1.5, 6.6 Hz), 2.45 (m, 1H), 2.83 (t, 2H, J=11.4 Hz), and 4.00 (d, 2H, J=6.7 Hz).
91%
With sodium hydrogencarbonate; citric acid In 1,4-dioxane; water
e N-(tert-butoxycarbonyl)isonipecotic acid Isonipecotic acid (3.90 g, 30 mmol), NaHCO3 (5.05 g, 60 mmol) were dissolved in 1:1 1,4-dioxane:water (100 mL). Di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was acidified to pH=6 using 10percent citric acid and extracted into ethyl acetate (3*100 mL). The organic phase was then washed with brine (2*50 mL), dried over Na2 SO4, and concentrated in vacuo to give the title compound as a white solid (6.25 g, 91percent). 1 H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.63 (m, 2H), 1.88 (dd, 2H), 2.45 (m, 1H), 2.83 (t, 2H), 4.00 (d, 2H).
91%
With hydrogenchloride; sodium hydroxide; nitrogen In ethanol; water
EXAMPLE 56 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50° C. and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6° C. exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5° C. and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58° C.) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151° C. 1H NMR (CDCl3) δ 4.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.
91%
Stage #1: With sodium hydroxide In ethanol; water at 5 - 56℃; for 1.25 - 22.25 h; Stage #2: With hydrogenchloride In ethanol; water at 5℃; for 2 h;
Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50°C and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6 °C exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5°C and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58°C) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151°C. 1H NMR (CDCl3) δ 4.10 (m, 2H), 2.84 (t, 2H, J=11.7 Hz), 2.47 (m, 1H), 1.90 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H, (CH3)Si)); 13C NMR (CDCl3) δ 180.0, 154.8, 79.8, 43.1; 40.9; 28.5; 27.5.; Example 61 Scheme G, step a: 1,4-Piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) 4-Piperidinecarboxylic acid (10 kg, 77.4 mol) and 50 L of water were charged to a suitable vessel maintained under nitrogen. The stirred mixture was cooled to 5°C. 20percent Sodium hydroxide (17 kg, 85 mol) and 70 L of ethanol were charged while maintaining a reaction temperature of 5°C. A solution of di-t-butyl dicarbonate (17.8 kg, 81.6 mol) in 65 L of ethanol was charged to the stirred reaction mixture over a period of 15 minutes. Cooling was discontinued and the reaction mixture was stirred for a total of 22 hours. A total of 150 L of solvent was distilled from the reaction mixture below 50°C at 150 torr. The residue was diluted with 110 L of water and the stirred mixture was cooled to 5°C. The stirred mixture was diluted with 22 L of water and 33percent hydrochloric acid (10 kg). After stirring at 5°C for 2 hours, product was filtered off, washed with 2 x 5 L, then dried below 40°C at 150 torr to give 16.5 kg, 93percent yield.
91%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 3 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water
A solution of isonipecotic acid (18) (2.6 g, 20 mmol) in 1,4-dioxane/H2O (3:2, 100 mL) was treated with NaHCO3 (8.4 g, 100 mmol, 20 mL H2O), followed by t-Boc2O (4.8 g, 22 mmol) at room temperature. After stirring for 3 h, the solution was acidified with 1 N HCl (50 mL), extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with saturated solution of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give a white solid (19) (4.16 g, 91percent). 1H NMR (500 MHz, CDCl3) δ4.02 (br s, 2H), 2.86 (t, J=12.0 Hz, 2H), 2.50 (tt, J=11.0, 4.0 Hz, 1H), 1.91 (dd, J=13.0, 2.5 Hz, 2H), 1.65 (m, 2H), 1.46 (s, 9H), MS (ESI-) m/z 228.65 (M-H-).
90%
With sodium carbonate In 1,4-dioxane; water
Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After 4 hr, the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90percent).
90%
With sodium carbonate In 1,4-dioxane; water
Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After four hours the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90percent).
90%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
Isonipecotic acid (5.00 g, 38.7 mmol) and K2CO3 (10.7 g, 77.4 mmol) were dissolved in 75 mL of H2O. At 0 °C, a solution of di-tert-butyl dicarbonate (8.89 mL, 38.7 mmol) in 10 mL of THF was added and the mixture was stirred at room temperature overnight. Then, THF was removed and the aqueous layer was washed with Et2O, brought to pH = 2 with HCl 1 M (80 mL) and extracted with EtOAc. The solvent was removed under vacuum to afford 24 as a white solid (8.00 g, 90percent). Spectral data were in accordance with the literature [37].
89%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1 h; Stage #2: With potassium hydrogensulfate In water; ethyl acetate
Isonipecotic acid (3 g, 23.2 mmol) was dissolved in dioxane/NaOH (1M) (1/1) (70 mL). Boc-anhydride (5.57 g, 25.5 mmol) was added to the solution at 0°C, which was then allowed to warm up to room temperature and stirred for lh. The solution was concentrated in vacuo and ethyl acetate (10 mL) was added. The mixture was acidified to pH 2 using saturated aqueous KHS04. The organic layer was dried over Na2S04 and evaporated to give 4.7 g (89percent) of N-Boc isonipecotic acid G as a colorless solid. G was used in the coupling step with the amine E (100mg, 0.22 mmol) following the general method. The intermediate H was purified by column chromatography eluting with ethyl acetate/cyclohexane (1/1). H was treated with dichloromethane/trifluoroacetic acid (8/2) (2 mL) for 2h at room temperature. Saturated aqueous NaHCO3 was then added carefully until pH 9 was reached and the dichloromethane layer was separated, dried over Na2S04, filtered and the solvent removed in vacuo to give the free amine 99mg (81 percent over two steps).
86%
With potassium carbonate In tetrahydrofuran; water at 20℃; for 12 h;
Compound 10 (10 g, 77.5 mmol) and potassium carbonate (21.4 g, 155 mmol) were dissolved in water (150 mL) and asolution of Boc anhydride (16.9 g, 77.5 mmol) in THF (50 mL)wasslowly added dropwiseunder ice-cooling.After the reaction was added dropwise at room temperature 12h, the reaction afterrotary evaporation to remove THF, 1N hydrochloric acid to adjust pH to 1, large amount of solid precipitated was filtered, the resulting solid was washed with water again, washed and driedto give compound. 11 (30.4 g of, 86percent).
85%
With sodium hydroxide In 1,4-dioxane
1.2 Synthesis of N-Boc-isonipecotic acid (1) To a solution of isonipecotic acid (15 g, 117.2 mmol) in 40 mL dioxane and 40 mL 1M NaOH was added di-tert-butyl dicarbonate (28.14 g, 129 mmol). The mixture was allowed to stir at room temperature. After 12 hours the mixture was then partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3.0 with 1N HCl and extracted with ethyl acetate (4*100 mL). The organic phases were washed with brine, dried (MgSO4) and concentrated to give a white solid (22.96 g, 85percent); m/z (M+H)+ 230.2 (C11 H19 NO4).
85%
Stage #1: With sodium hydroxide In 1,4-dioxane; water for 18 h; Stage #2: With hydrogenchloride In water
Piperidine-4-carboxylic acid (12.9 g, 100 mmol) was dissolved in a rapidly stirred mixture of dioxane (100 mL) and IM sodium hydroxide (300 mmol). Di-t-butyldicarbonate (22 g, 100 mmol) was added. After 18 hours the volatiles were evaporated. The aqueous residue was acidified with IM hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to give the intermediate piperidine-l,4-dicarboxylic acid mono-tert- butyl ester as a white solid (19.6 g, 85percent). 1HNMR (300MHz, DMSO-d6): D (ppm) 12.20 (s, IH), 3.85-3.80 (m, 2H), 2.85-2.77 (m, 2H), 2.44-2.35 (m, 2H), 1.80-1.75 (m, 2H), 1.44-1.31 (m, 1 IH). A portion of this intermediate (2.29 g, 10 mmol) was mixed with potasium carbonate (1.7 g, 12 mmol) and benzyl bromide (1.2 mL, 10 mmol) in acetonitrile (20 mL). Heated the reaction to 60 0C for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, then dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with 0-25percent ethyl acetate in methylene chloride. Obtained the title compound (2.3 g, 72percent) as a colorless oil. 1H NMR (300MHz, DMSO-d6): D (ppm): 7.41-7.30 (m, 5H), 5.10 (s, 2H), 3.86-3.81 (m, 2H), 2.87-2.78 (m, 2H), 2.64-2.55 (m, IH), 1.85-1.80 (m, 2H), 1.49-1.38 (m, HH).
75%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1) - To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0°C, was added dropwise a solution of di-tbutyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). The reaction mixture wasgradually warmed to r.t. and stirred overnight. The solvents were evaporated and theresidue was dissolved in DCM. DCM layer was washed with iN HC1 (3 x 100 mL),water, dried over sodium sulfate, and concentrated in vacuo to give pure 1 (13.03 g,75percent) as a white powder. ‘H NMR (500 MHz, CDC13) ö 4.02 (br s, 2H), 2.85 (t, J =11.5 Hz, 2H), 2.49 (m, 1H), 1.90 (d, J= 11.5 Hz, 2 H), 1.65 (m, 2H), 1.45 (s, 9H); ‘3CNMR (125 MHz, CDC13) ö 180.1, 154.7, 79.7, 40.7, 28.3, 27.6. MS calc’d for C,,H,8N04 (M-H) 228.1241, found 228.1240.
75%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃;
To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0° C., was added dropwise a solution of di-t-butyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). The reaction mixture was gradually warmed to r.t. and stirred overnight. The solvents were evaporated and the residue was dissolved in DCM. DCM layer was washed with 1N HCl (3*100 mL), water, dried over sodium sulfate, and concentrated in vacuo to give pure 1 (13.03 g, 75percent) as a white powder. 1H NMR (500 MHz, CDCl3) δ 4.02 (br s, 2H), 2.85 (t, J=11.5 Hz, 2H), 2.49 (m, 1H), 1.90 (d, J=11.5 Hz, 2H), 1.65 (m, 2H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 180.1, 154.7, 79.7, 40.7, 28.3, 27.6. MS calculated for C11H18NO4 (M-H)- 228.1241, found 228.1240.
73%
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 10 - 20℃; for 3 h;
To a stirred solution of isonipecotic acid (6.0 g, 46.6 mmol) in tert-BuOH (18 mL), NaOH solution (12 mL, 3.71 g, 92.8 mmol in 12 mL water) was added at 10-15 °C, followed by di-tert-butyl dicarbonate (10.1 g, 46.6 mmol) and the mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and washed with petroleum ether (3 x 25 mL). The pH of the aqueous layer was adjusted to 6-6.5 using citric acid and was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound. Yield: 73percent (10.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 3.83-3.80 (m, 2H), 2.80-2.49 (m, 2H), 2.39-2.36 (m, 1 H), 1.79-1.75 (m, 2H), 1.41-1 .34 (m, 11 H).
61%
Stage #1: With sodium hydroxide In 1,4-dioxane at 20℃; for 21 h; Stage #2: With hydrogenchloride; water In 1,4-dioxane; ethyl acetate
Piperidine-l,4-dicarboxylic acid mono-tert-butyl ester HVB01031 C11H19NO4 MW 229.28Di-t-butyl dicarbonate (3.4 g, 15.6 mmol) and sodium hydroxide (6.2 g, 154.5 mmol) were added to a solution of isonipecotic acid (2 g, 15.5 mmol) in 1,4-dioxane (50 ml) and water (50 ml). Stirred at room temperature for 21 h. Concentrated in-vaco to approximately 15 ml, diluted with ethyl acetate and acidified to pH 3-4 using hydrochloric acid (IM). Extracted with ethyl acetate and washed with water. Organic layers dried over anhydrous magnesium sulphate and evaporated to dryness, to afford a white solid, 2.16 g, 61 percent. m.p. 151-153 0C, Rf: 0.72 (10percent MeOH in DCM)51H NMR (270 MHz5 CDCl3)δ 1.4 (9H5 s, CH3), 1.64 (2H5 m, CH2), 1.89 (2H5 dd, J=3.0, 13.4 Hz, CH2), 2.5 (IH, m, CH), 2.83 (2H5 1, J=I 1.1 Hz5 N-CH2), 4.03 (2H5 d5 J=12.0 Hz, N-CH2).; Piperidine-l,4-dicarboxylic acid mono-tert-butyl ester HVB01031 C11H19NO4 MW229.28Di-/-butyl dicarbonate (3.4 g, 15.6 mmol) and sodium hydroxide (6.2 g, 154.5 mmol) were added to a solution of isonipecotic acid (2 g, 15.5 mmol) in 1,4-dioxane (50 ml) and water (50 ml). Stirred at room temperature for 21 h. Concentrated in-vaco to approximately 15 ml, diluted with ethyl acetate and acidified to pH 3-4 using hydrochloric acid (IM). Extracted with ethyl acetate and washed with water. Organic layers dried over anhydrous magnesium sulphate and evaporated to dryness, to afford a white solid, 2.16 g, 61 percent. m.p. 151-153 0C, Rf: 0.72 (10percent MeOH in CHCl3), 1H NMR (270 MHz, CDCl3)B 1.4 (9H, s, CH3), 1.64 (2H, m, CH2), 1.89 (2H, dd, J=3.0, 13.4 Hz, CH2), 2.5 (IH, m, CH), 2.83 (2H, t, J=ILl Hz, N-CH2), 4.03 (2H, d, J=12.0 Hz, N-CH2).
49%
at 80℃; for 2 h;
Step A 1-N-(tert-Butoxycarbonyl-4-piperidine carboxylic acid or 1-N-(tert -butoxycarbonyl)isonipecotic acid Isonipecotic acid (5g; 1 equivalent) is dissolved in water (50 ml) and a solution of di-tert -butyldicarbonate (8.62g; 1.02 equivalents) in THF (70 ml) is added with stirring. The mixture is stirred at 80°C for 2 h and then evaporated to dryness. The residue is partitioned between dichloromethane and brine and the dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a silica gel column (30 X 5cm) using 15percent (10percent concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (4.3109g; 49percent yield), CIMS: m/z 230 (MH+).
7.63 mmol, 98%
With triethylamine In dichloromethane; ethyl acetate
Step A: N-(t-Butoxycarbonyl)piperidine-4-carboxylic acid To a suspension of 1.0 g (7.74 mmol) of piperidine-4-carboxylic acid in 20 mL of methylene chloride at room temperature was added 1.13 mL of triethylamine (0.82 g, 8.1 mmol, 1.05 eq) followed by 1.87 mL of di-t-butyl-dicarbonate (1.77 g, 8.1 mmol, 1.05 eq). The mixture was stirred at room temperature for 48 hours then concentrated under vacuum. The residue was redissolved in ethyl acetate and the solution washed with 5percent citric acid and brine, then dried over magnesium sulfate, filtered and evaporated under vacuum to afford 1.75 g (7.63 mmol, 98percent) of the product. 1 H NMR (200 MHz, CD3 OD): 1.42 (s,9H), 1.50 (m,2H), 1.84 (m,2H), 2.46 (m,1H), 2.86 (t,9 Hz,2H), 3.91 (t,3 Hz,1H), 3.98 (t,3 Hz,1H). FAB-MS: calculated for C11 H19 NO 4 229; found 230 (M+H,17percent).
90%
With sodium hydroxide In 1,4-dioxane; water
Step E N-BOC-Isonipecotic acid To a cold solution of 12.4 g (0.31 mmol, 1.0 eq) of sodium hydroxide in 300 ml of water and 600 ml of dioxane was added 40.0 g (0.31 mmol, 1.0 eq) of isonipecotic acid, followed by 84.0 g (38 mmol, 1.2 eq) of di-t-butyl dicarbonate. The mixture was stirred at ambient temperature for 5 h then partitioned between ethyl acetate and 0.5N citric acid. The organic phase was washed with water, brine, dried over sodium sulfate, and concentrated. The crystalline product was collected by filtration, washed with hexane, and dried under vacuum. Yield: 64.0 g (90percent), 1H NMR (300 MHz, CDCl3) δ10.78 (1H, exc), 4.0 (2H, d), 2.85 (2H, t), 2.48 (1H, m), 1.9 (2H, m), 1.65 (2H, m), 1.42 (9H, s). MS (FAB, M+H) 230.1.
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Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide In water
a) Piperidine-1,4-dicarboxylic acid, 1-tert-butyl ester Di-tert-butyl dicarbonate (101.1 g, 464 mM) was added dropwise to a solution of isonipecotic acid (60 g, 464 mM) and sodium hydroxide (37.6 g, 940 mM) in water (86 ml) and tert-butyl alcohol (176 ml) with stirring. After the end of the addition, the above mixture was added with tert-butyl alcohol (100 ml), and stirred at room temperature for three hours. The resulting solution was diluted with water (200 ml), and extracted twice with 150 ml of pentane. The aqueous layer was acidified with 70 g of potassium bisulfate with cooling, and extracted with ethyl acetate. Standard workup gave the title compound as a white powder (102.3 g. yield 96percent). Melting point: 144-146°C.
1-(1,1-Dimethylethoxycarbonyl)Piperidine-4-Carboxylic Acid Di-t-butyldicarbonate (23.42 g, 107.3 mmol) in dichloromethane (100 mL) was added slowly to a mixture of 4-piperidinecarboxylic acid (12.60 g, 97.6 mmol) and triethylamine (13.60 mL, 9.87 g, 97.6 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 18 h. N,N-Dimethylethylenediamine (3.46 mL, 2.87 g, 32.5 mmol) was added and the mixture was stirred at room temperature for 30 min. Dichloromethane (100 mL) was added and the mixture was washed with aqueous citric acid (10percent, 2*200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (21.05 g, 94percent). 1H NMR (250MHz, CDCl3) δ4.02 (2H, m), 2.86 (2H, m), 2.49 (1H, m), 1.91 (2H, m), 1.64 (2H, m), and 1.46 (9H, s).
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Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydroxide In water at 0 - 30℃; for 3 h;
Example 1 — Preparation of 1-(Ethoxycarbonyl) piperidine-4-Carboxylic AcidTo a solution of (154.8 gm) Sodium hydroxide in (750 ml) purified water, Isonipecotic acid(250gm) was added at 0-10°C, followed by the slow addition of ethyl chloroformate (231 ml) at 5-20°C. The reaction mixture was heated to 20-30°C and maintained for 3 hrs at the sametemperature. After completion of the reaction, the reaction mass was acidified to a pH 1-2 byaddition of hydrochloric acid. Then toluene (750 ml) was added to the reaction mass and stirred for15 minutes at 25-30 °C. The organic layer was separated and concentrated under vacuum at below70°C to obtain a residue. The resi4ue_was_mixed. with cyclohexane (1250 ml) at 60-70°C, thencooled to 25-30°C and maintain for I hour at the same temperature. The resulted contents werefiltered, and washed with cyclohexane (1250 ml) and dried at 50-55°C. Percentage Yield: 92percent
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With nickel; potassium carbonate at 180 - 185℃; Hydrogenation;
With sodium hydroxide In water at 25 - 30℃; Electrochemical reaction;
With hydrogenchloride; platinum Hydrogenation;
With hydrogen In water at 80 - 95℃; for 1.5h;
3.3; 3.4
(4) 4-picolinic acid was used as a raw material, water was used as a reaction solvent, and added to the reaction vessel, and then the catalyst prepared above was added, and after uniformly mixing, nitrogen gas was introduced for 5 minutes in advance, and then hydrogen gas was introduced thereto, and the temperature was raised to 80-95 ° C, the reaction is 1.5h, after the reaction is completed, it is cooled to room temperature, the catalyst and water are removed, methanol is added to the liquid for crystallization, and centrifuged to obtain 4-piperidinecarboxylic acid; wherein, the mass ratio of 4-picolinic acid and catalyst 1:0.005;
With ruthenium-carbon composite; hydrogen at 120℃; for 2h; Autoclave; High pressure;
2 Example 2
After removing the immobilized enzyme from the liquid obtained by enzyme catalysis in Example 1,Add the ruthenium carbon catalyst into the autoclave and stir,Warm up to 120°C to react until no hydrogen is absorbed,Continue to react for at least 2 hours,Cooling and discharging,The dot plate has no fluorescence; it is evaporated to dryness, then washed with ethanol, filtered, the filter cake is dried, and the filtrates are combined. The addition amount of pyridine-4-carboxylic acid is 150 g (calculated according to the liquid concentration obtained by enzyme catalysis in Example 1), and the addition amount of the ruthenium carbon catalyst is 10 g.Carry out 4 batches according to the above steps, and the results are as follows:The sum of the dry product of each batch and the combined filtrate is 399.3g, and the theoretical receivable is 419.5g, so the yield is 95.18%.
With hydrogen;palladium 10% on activated carbon; In water; at 16 - 25℃;
Load isonipicotic acid (1 kg, 7.74 mol), water (10 L), formaldehyde (37percent solution in water, 720 g, 8.87 mol, 1.15 eq. ) and wet Pd/C catalyst (10percent; 55percent paste, 100 g) into a stainless steel hydrogenation reactor. Pressurize the reactor with H2 (3 bar) and stir the reaction mixture overnight at 200-300 rpm at 16-25°C. Stop the reaction and filter off the catalyst. Wash the filtrate with water (500 ml) and concentrate under vacuum. Distill off the remaining water from the residue using ethanol (2x 1 L). Dry the solid overnight under vacuum at 50°C to obtain the title product as an off-white solid (1087 g, 98. 1percent yield).
76%
With hydrogen;palladium 10% on activated carbon; In water; at 20℃; under 3102.97 Torr; for 18h;
Isonipecotic acid (50 g, 0.387 mole) was dissolved in water (500 ml) and 37percent formaldehyde (125 ml). 10percent Palladium on carbon (50 g) was added and the mixture was shaken under a hydrogen atmosphere at 60 psi at room temperature for 18 hours. [00375] The catalyst was filtered, washed with water, and the filtrate was concentrated under reduced pressure. The residue was slurried in water and concentrated in vacuo. The residue was slurried in ethanol and concentrated in vacuo to give a white solid. Drying under vacuum at ambient temperature for 18 h gave 42.2 g (76percent) of a white solid, [00376] mp 173-5° C. MS(m/e): 143 (M+). [00377] Analysis for C7H13NO2: [00378] Calcd: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.24; H, 9.59; N. 9.71.
18%
In formic acid; water; for 20h;Heating / reflux;
Reference Example 249: l-MethvI-piperidine-4-carboxylic acid . A solution of 4-piperidine carboxylic acid (1.0 g, 7.75 mmol) in a mixture of90percent formic acid (3 mL) and 37percent formaldehyde solution (2 mL) was heated at reflux for 20 h. The volatiles were removed in vacuo and cone. HCl added to the residue. The reaction mixture was extracted with dichloromethane and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and dried to afford 1-methyl- piperidine-4-carboxylic acid (0.20 g, 18 percent).
With hydrogen;10% palladium on activated charcoal; In water; at 20℃; under 2250.23 Torr;
Compounds 108, 109, 143, 144 and 145 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme.
With sodium hydroxide; PPA; In dichloromethane; water;
Preparation 163 4-(2-Benzoxazolyl)piperidine A mixture of 2-aminophenol (20 g, 183 mmol), isonipecotic acid (23.7 g, 1 mol. equiv.) and polyphosphoric acid (50 ml) was heated together for 2 hours with stirring. The reaction mixture was cooled, poured onto ice (400 g) and solid sodium hydroxide (85 g) added until the solution achieved pH8. The solid was filtered off, slurried in water (500 ml) and filtered to give the title compound (4.5 g). A second crop of the title compound was obtained by extracting the above filtrate with dichloromethane (4*200 ml). The combined organic extracts were dried using anhydrous magnesium sulphate, filtered and the solvent removed from the filtrate under reduced pressure to give the title compound (9 g). 1 H-NMR (CDCl3):delta=1.9-2.1 (m,3H), 2.15-2.3(m,2H), 2.8-2.9(m,2H), 3.1-3.3(m,3H), 7.3-7.35(m,2H), 7.5-7.55(m, 1H), 7.7-7.75(m,1H) ppm.
With PPA; In water;
INVENTIVE EXAMPLE 15 2-(4-Piperidyl)benzoxazole 2-Aminophenol (200 mg) and 4-piperidinecarboxylic acid (236 mg) were mixed with polyphosphoric acid (1 g) and stirred with heating at 180 C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 2-(4-piperidyl)benzoxazole (311.5 mg).
With phosphoric acid; at 180℃; for 2h;
0.45mol O-amino phenol and 0.45mol4-piperidine carboxylic acid is added to 25g in poly-phosphoric acid, the temperature is increased to 180 C, stirring reaction 2h, after the reaction liquid-cooled but, in reverse into the water, filtering, the filtrate concentrated potassium hydroxide to adjust the pH value is 12, dichloromethane is used for extraction, the organic layer with anhydrous magnesium sulfate drying, to remove the solvent, get strawcoloured solid 2 - (piperidin-4-yl) benzo [d] oxazole, melting point: 110-112C.
Charge isonipecotic acid (1.00 wt, l .Oeq, 600 g) to a reaction vessel. Charge palladium on charcoal (10%wt, 50% wet paste, 0.05wt, 30 g) to the reaction vessel. Charge purified water (4.0 vol, 2.4 L) to the reaction vessel. Heat the resulting mixture to 90 to 95C. Charge formic acid (1.2 vol, 1.4wt, 4.0eq, 720 mL) to the vessel at 90 to 95C(expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5vol, 300 mL) to the vessel at 90 to 95C. Charge formaldehyde (37% w/w aqueous solution, 0.74vol, 0.8 lwt, 1.3eq, 444 mL) to the vessel at 90 to 95C (expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95C. Stir the resulting mixture at 90 to 100C until complete by HPLC analysis (pass criterion <0.1% area isonipecotic acid, expected 3 hours). Cool the resulting mixture to 20 to 30C. Filter the reaction mixture through GF/F. Wash the filter cake with purified water (2 x l.Ovol) at 20 to 30C. Concentrate the combined filtrates to ca 2 vol at atmospheric pressure. As necessary adjust the temperature to 65 to 75C. Charge cone. Hydrochloric acid (0.95 vol, 1.14wt, 1.5eq, 570 mL) to the vessel at 65 to 75C. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at >70C and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at >70C and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8wt, 6.0 L) to the vessel at >70oC and concentrate the solution to ca 3 vol at atmospheric pressure. Check the water content by KF analysis of the supernatant liquors using AX reagent (pass criterion<0.1%w/w). Cool the reaction mixture to 20 to 25C. Stir the reaction mixture for 1 to 2 hours at 20 to 25C. Filter the reaction mixture at 20 to 25C. Wash the filter cake with acetonitrile (2 x 1.0 vol, 0.8 wt, 2 x 600 mL). Dry the product at up to 50C until <0.5% w/w by LOD and <0.2%w/w water (KF, AX reagent). Expected yield: 80 to 90%th, 111 to 125%w/w; Isolated yield: 755 g (91%th, 125w/w). Figure 5 shows a typical NMR spectrum of l-Methylpiperidine-4-carboxylic acid (D20)
This compound is synthesized as described by adaptation of the following reference: J. Heterocyclic Chem., 1989, 26, 54. A mixture of benzene- 1 ,2-diamine (12.6 g, 116 mmol), piperidine-4-carboxylic acid (15 g, 116 mmol) and 4M aqueous HCl (250 mL) is stirred and heated under reflux for 48 h. The reaction mixture is cooled to room temperature and is made basic by addition of 5M aqueous NaOH. The precipitate formed is collected by suction filtration, washed with water and dried in the vacuum oven to afford 8.8 g (38%) of 2-(piperidin-4-yl)-lH-benzimidazole. m/z =202 [M++H].
With PPA; at 180℃;
Example 2 ~ Synthesis and SAR of Diphenylbutylpiperidines Autophagy Inducers Based on Pimozide (2)Diphenylbutylpiperidines compounds, such as those described herein, can be prepared by SN2 substitution of halodiphenylbutyl compounds with piperidines (as described in Janneke, W.; Hulshof, H. F.; Vischer, H.P.; Verheij, S. A.; Fratantoni, Martine, J. S.; Iwan, J. P. Bioorg. Med. Chem. Lett. 2006, 14, 7213).As part of structure-activity relationship studies, modification of left-hand side of compound 2 were explored (Figures 13 and 14). Interestingly, compound 109 showed 2- fold increase in the activity of inducing autophagyModifications of the right-hand side of compound 2 were also explored. For example, synthetic variations on the P-1-56 fused ring scaffold are described in Figures 15 and 16. Reductive amination of N-Bocpiperidone with o-aminophenol was followed by cyclization with triphosgene and removal the Boc group. Substitution of the MsO group of piperidine 114 with compounds 113, 116 or 118 (6,5-fused heterocycles) followed by deprotection of Boc group by TFA afforded the desired compound 115, 117 or 119 (He, Y.; Yang, J., et al. Bioorg. Med. Chem. Lett. 2004, 14, 695). Reductive amination of N- Bocpiperidone 121 with o-aminophenol 120 followed by cyclization of 122 withtriphosgene and deprotection the Boc group yielded compound 123 (Flyren, K.; Bergquist, L. O.; et al. Bioorg. Med. Chem. Lett. 2007, 17, 3421). Treatment of piperidone 125 with indole gave compound 126, which was converted to compound 127 by hydrogenation. Reductive amination of 121 with indoline, prepared by reduction of indole, anddeprotection gave compound 130.Cyclization of compounds 120, 131 or 132 with 4-piperidinecarboxylic acid 133 give the desired compounds 134, 135 or 136 (He, Y.; Yang, J., etal. Bioorg. Med. Chem. Lett. 2004, 14, 695). Reductive amination of N-Boc piperidone with isoindoline prepared by reduction of phthalimide 137 and deprotection of the Boc group gave compound 138. Substitution of MsO group of piperidine 141 with phthalimide potassium salt followed by deprotection of Boc group afforded the desired compound 142. Treatment of 4-hydroxy piperidine 144 with 1,2,3-benzotriazole by Mitsunobu reaction followed by deprotection afforded two compounds 145 and 146 (Ruckle, T.; Biamonte, M., et al. J. Med. Chem. 2004, 47, 6921). Cyclization of compounds 121, 131 or 132 wuth 4-piperidine carboxylic acid gave compounds 134, 135 or 136 (respectively).Figures 18 and 19 showed the biological activity of selected P-l-56 compounds. As mentioned above, compound 109 showed 2-fold increased potent activity comparable to compound 2. A series of compounds with CN group have also been prepared; interestingly, some showed good results (147 vs 155, 151 vs 159, 153 vs 161) while some did not (149 vs 157, 150 vs 158, 152 vs 160). In the left series, compounds 149, 150, 152 and 153 showed 3 to 5-fold increased activity comparable to compound 2, while compounds 148, 151 and 154 showed no activity. In the right series, compounds 157, 158 and 160 showed 3 to 7-fold increased activity comparable to compound 2, while compounds 156 and 162 showed no activity. All of the above results indicate that the 4-position of piperidine ring can tolerate 6,5-fused heterocycle groups.The biological activity results of P-2-56 compounds is shown in Figure 20. These results suggested that compounds 163 and 166 are comparable to compound 2, while compounds 169 and 178 showed about a 4-fold increase in activity. However, compounds 164, 165, 170 and 177 showed no activity. Comparing the three isoelectronic compounds at the bottom of Figure 20, compound 166 showed the best result, while compounds 167 and 168 showed the same results. In contrast, compound 178 also showed the best result, while compounds 179 and 180 showed no activity.Encouraged by the biological activity results of DPBPs with 6,5-fused ring linked to the piperidine ring, compounds with 6,6-fused ring shown in Figures 21-24 were also prepared. Reductive amination of N-Boc piperidone with compound 182, prepared by reduction of isoquinoline 137, and deprotection of the Boc group gave compound 183. Cyclization of anthranilamide 184 with N-benzylpiperidone 185 followed by reduction of compound 186 afforded intermediate compound 187 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull. 1985, 33, 1116). Cyclization 187 with CDI and deprotection of the Boc group gave compound 189. Cyclization 187 with different regents gave compounds 191, 193, 195 and 197 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull. 1985, 33, 1116; and Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104).The biological activity results of P-2-66 compounds is shown in Figures...
36 g
at 115 - 120℃; for 20h;
Orthophenylenediamine (20 g), polyphosphoric acid (120 g) and isonipecotic acid (26.5 g) were taken into a reaction flask and the resulting mixture was heated to 115-120C, followed by stirring for 20 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to 90C, quenched with distilled water (260 ml) and then cooled to room temperature (25-30C). The resulting mass was further cooled to 10-15C,followed by adjusting the pH of the reaction mass to 9-10 with dilute sodium hydroxide solution, and then stirring for 30 minutes at 10-15C. The separated solid was filtered and washed with distilled water. The wet material was dried at 40-45C. Methanol (720 ml) was added to the resulting material and stirred for 1 hour at room temperature. The resulting mass was filtered and washed with methanol (250 ml). The resulting filtrate was concentrated under reduced pressure to give 36 g of 2-(4-Piperidinyl)- 1H-benzimidazole.
With hydrogenchloride; In water; for 36h;Reflux;
Step A: 1,2-diaminobenzene (1.0 g, 9.25 mmol, 1 eq) was added to a 100 mL round bottom flask equipped with a stir bar. Piperdine-4-carboxylic acid (3.5 g, 27.8 mmol, 3 eq) was added to the flask, followed by aqueous 4 M HCl (30 mL). The reaction was heated for 36 hours under reflux and monitored by LCMS. Upon conversion of the starting material, the reaction was cooled to 0 C. and basified with sodium hydroxide pellets. The resulting sodium salt crashed out of solution, which was collected by filtration to afford a crude yellow solid. The solid, 2-(piperidin-4-yl)-1H-benzo[d]imidazole, was used without any further purification.
Trifluroacetic anhydride (TFAA) (300 ml) is added to isonipecotic acid (96 g) at 0C and the reaction mixture is heated at reflux for 4h. Excess TFAA is removed under vacuo, the reaction mixture is taken up in EtOAc, washed with water and concentrated to give 160 g of the amide. 50 g of this amide is treated with SOCl2 (300 ml) and the reaction mixture heated at reflux overnight. Excess thionyl chloride is then removed under vacuo to give 54 g of the acid chloride.
(5S,8R,13R,15aS)-5-Hydroxymethyl-4,7,15-trioxo-8-[(piperidine-4-carbonyl)-amino]-tetradecahydro-10,11-dithia-3a,6,14-triaza-cyclopentacyclotetradecene-13-carboxylic acid[ No CAS ]
A solution of 4-piperidinecarboxylic acid (500 g, 3.87 mol) and methanol (2.5 L) was added to the reaction flask, and thionyl chloride (460.4 g, 3.87 mol) was added dropwise, and the temperature was gradually increased during the dropwise addition Temperature rise to 80 reflux reaction 3h. The reaction solution was concentrated under reduced pressure at 50 C to give 687 g of a white solid, the yield was 98.8%
With thionyl chloride; at -10 - 20℃; for 22h;
1.3. Methyl(piperidin-4-yl)carboxylate Hydrochloride 5.0 g (38.7 mmol) of isonipocotic acid are added slowly to a solution of 9.3 mL of thionyl chloride (129 mmol) in 50 mL of methanol, while keeping the temperature below -10 C. The mixture is stirred at room temperature for 22 hours. The reaction medium is evaporated under reduced pressure. 6.8 g of the expected derivative are obtained in the form of the hydrochloride.1H NMR (DMSO-d6, 250 MHz) delta ppm: 1.7-1.85 (m, 2H); 1.9-2.05 (m, 2H); 2.6-2.75 (m, 1H); 2.8-3.0 (m, 2H); 3.15-3.3 (m, 2H); 3.64 (s, 3H); 8.9-9.3 (m, 2H, NH2+).
With thionyl chloride; at 0 - 20℃; for 16h;Inert atmosphere;
To a stirring solution of piperidine-4-carboxylic acid (SM) (50 g, 0.387 mol) in methanol (500 mL) was added thionyl chloride (50.6 mL, 0.696 mol) drop wise at 0 C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), volatiles were concentrated under reduced pressure to afford crude compound 1 (71.5 g) as an off-white solid. NMR (500 MHz, DMSO-d6) d 9.14 (br s, 1H), 8.96 (br s, 1H), 3.62 (s, 3H), 3.19 (br d, J = 12.8 Hz, 2H), 2.98 - 2.82 (m, 2H), 2.71 - 2.65 (m, 1H), 1.99 - 1.94 (m, 2H), 1.84 - 1.69 (m, 2H). LCMS (ESI): m/z 287.3 [2M+H]+.
he piperidine-4-carboxylic acid (6.78g, 52.5mmol) was added to acetic anhydride (50mL), theThe temperature was raised to 50 C for 16 hours.The reaction solution was concentrated,Water (300 mL) and ethyl acetate (400 mL) were added,Dispensing,The organic phase was washed with saturated brine (200 mL)Dried over anhydrous sodium sulfate,concentrate,The resulting solid was added to ethanol (50 mL)The product was removed by filtration (8.51 g, yield: 94.8%).
92%
at 130℃; for 5h;
Intermediate 10: (4-fluoro-phenyl) -piperidin-4-yl-methanone (10)6.4g (49.5mmol) of isonipecotic acid are placed in the presence of 40ml of acetic anhydride. The reaction medium is heated to 1300C for 5h and then dry concentrated. After triturating with petroleum ether, the formed crystals are filtered. 7.79g of solid are obtained (92%) . 0.5g (2.92mmol) of the obtained solid are placed in ImL of 1,2- dichloroethane in the presence of 0.92mL (12.56mmol) of thionyl chloride, and this solution is then stirred for Ih at room temperature. The medium is dry concentrated and then the residue is taken up with 2mL of 1,2- dichloroethane . This solution is added to a mixture of 0.9Og (6.72 mmol) of AlCl3 and 1.29mL (13.73 mmol) of fluorobenzene in ImL of 1, 2-dichloroethane . The reaction medium is heated to 800C for 3h. After the solution has returned to room temperature, it is poured on ice water, then the medium is extracted with dichloromethane . After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH: 95-5) . 0.44 g of an oil are isolated(60%) . TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 95-5,Rf=O .38. The obtained oil is placed in 6mL of 6N hydrochloric acid and the mixture is heated to 1000C for18h. The medium is neutralized by adding a concentrated soda solution and extracted with ethyl acetate. After drying on MgSO4, the organic phases are dry concentrated. 0.23 g of intermediate 10 are obtained as an oil (62%) . TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 95-5, Rf=O.13.
92.9%
Add 4-piperidinecarboxylic acid (1.03g, 8mmo1) and 10mL acetic acid to a 50mL eggplant-shaped bottle, Heat to reflux and react for about 10 hours. Add 10mL of acetic anhydride,After refluxing for 1 hour, the solvent was distilled off. The product cooled to a lumpy solid.Wash thoroughly with petroleum ether and dry to obtain 1.3 g of beige solid with a yield of 92.9%. TLC shows pure points.
90%
for 6h;Reflux;
To a 250 mL four-necked flask equipped with a condenser tube with a drying tube was added 4-piperidinecarboxylic acid (38.8 g, 0.30 mol), 58mL acetic anhydride was slowly warmed to the reflux continued 6h, the reaction is complete by TLC, the reaction solution was cooled to room temperature, a large number of light brown solid precipitated solid was filtered off with suction, the solid washed with an appropriate amount of methyl t-butyl ether extraction filter. A light brown solid was obtained which was recrystallized from methanol to give 46.3 g of a white solid in 90% yield.
89.8%
In ethyl acetate; at 20 - 60℃; for 2.16667h;Product distribution / selectivity;
Isonipecotic acid (10.0 g, 0.078 mol) and ethyl acetate (30.0 ml) were charged at room temperature. Acetic anhydride (11.9 g, 1.50 eq) was dropwise added over about 10 min. while retaining not more than 20C. After stirring at 55+-5C for 2 hrs., the mixture was allowed to cool to room temperature over 1 hr., ice-cooled and stirred at not higher than 10C for 1 hr. The precipitated crystals were collected by filtration and washed with diisopropyl ether (10 ml*2) and dried in vacuo at 50C to give the title compound (11.9 g, yield 89.8%) as white crystals. 1H-NMR (300MHz, DMSO) delta: 1.32-1.51(2H,m), 1.76-1.84(2H,m), 1.98(3H,s), 2.43-2.50(1H,m), 2.65-2.68(1H,m), 3.04-3.12(1H,m), 3.71-3.75(1H,m), 4.16-4.20(1H,m).
86.2%
In chloroform; at 20℃;
Isonipectoic acid (6.46 g, 50.0 iranol) suspended in CH2Cl2 (100 ml) was dropwise added a solution of acetic anhydride (5.61 g, 55.0 iranol) in CH2Cl2 (10 ml). The reaction mixture was strirred at room temperature night over and evaporated in vacuo. The residue was recrystallized from EtOH to leave the product as a white solid (7.38 g, 86.2 %) .1H-NMR (300 MHz, DMSO-d(?):delta 12.24 (s, 1 H), 4.20-4.16 (m, 1 H), 3.75-3.71 (m, 1 H), 3.12-3.03 (m. 2 H), 2.72-2.64 (m, 1 H), 2.50-2.43 (m, 1 H), 1.98 (s, 3 H), 1.85-1.75 (m, 2 H), 1.50-1.45 (m, 1 H), 1.45-1.30 (m, 1 H)
79%
With pyridine; at 140℃; for 2h;
Isonipecotic acid 8 (20.0 g, 155 mmol) and pyridine (12.5 mL, 155.3 mmol) were added to 30 mL of AC2O at room temperature. The reaction mixture was stirred at 140 C for 2 h and then cooled down to room temperature. The excess AC2O was evaporated under vacuum and then 40 mL EtOAc/Ether (1/1, V/V) was added to the residue. The mixture was stirred to afford precipitate solid. The solid was separated by filtration and washed with EtOAc/Ether (1/1, V/V) to give 9 (20.9 g, 79% yield) as a white solid. Mp 178 - 180 C 1H NMR (400 MHz, CD3OD): delta 4.293 (m, 1H), 3.805 (m, 1H), 3.145 (m, 1H), 2.789 (m, 1H), 2.525 (m, 1H), 2.036 (s, 3H), 1.855 (m, 2H), 1.516 (m, 2H). MS (ESI) m/z: [M+H]+ 172.14.
79%
With hydrazine hydrate; at 130℃; for 3h;Reflux;
A suspension of piperidine-4-carboxylic acid (5 g, 38.7 mmol) in acetic anhydride (36.5 ml, 387 mmol) was heated at 130C for 3h (the reaction mixture became homogeneous). After 3h, the reaction mixture was evaporated in vacuo to give a brown oilwhich crystallized during the night. The solid was triturated in iPr2O and filtered to efford 1- acetylpiperidine-4-carboxylic acid (6.42 g, 30.8 mmol, 79 % yield) as a cream solid. MS (m/z) 172 (M+H).
78.9%
With pyridine; at 140℃; for 2h;
20.0 g (154.8 mmol) of piperidinecarboxylic acid, 30 ml (317.4 mmol) of acetic anhydride, 12.5 ml of pyridine(155.3 mmol) in a 100 ml round bottom flask and refluxed at 140 C for 2 hours to give a brown solution. Most of the solution is evaporated under reduced pressureTo obtain an emulsion and cooling. To the above emulsion was added 40 ml of a solution of ethyl acetate-diethyl ether (v / v = 1: 1), and the mixture was stirred and stirredThe residue was filtered and washed with ethyl acetate-diethyl ether (v / v = 1: 1) to give a white solid, 20.9 g 78.9 %
78.43%
at 130℃; for 6h;
Step-1: Synthesis of 1-acetylpiperidine-4-carboxylic acid To a solution of piperidine-4-carboxylic acid (5.0 g) in acetic anhydride (50 mL) was heated at 130 C. for 6 h, Completion of reaction was monitored by TLC. On completion all volatiles were evaporated under reduced pressure obtained crude which was triturated with petroleum ethers solid precipitated out which was filtered off, solid was dried under vacuum obtained 1-acetylpiperidine-4-carboxylic acid (5.20 g, 78.43%) as off white solid.
75.4%
In water; at 0 - 60℃; for 3.33333h;Product distribution / selectivity;
Isonipecotic acid (129.2 g, 1.00 mol) was dissolved in water (390 mL), and acetic anhydride (153.1 g, 1.50 mol) was added dropwise under ice-cooling for about 10 min. (dropwise addition at 15-18C for about 10 min.). After stirring at 55+-5C for 2 hrs., the mixture was allowed to cool to room temperature and stirred under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with cold diisopropyl ether (125 mL *2) and dried under reduced pressure at 40C for 8 hrs. to give the title compound (129.1 g, yield 75.4%). 1H-NMR (300MHz, CDCl3) delta: 4.40 (1H, dt, J=13.4Hz), 3.79 (1H, dt, J =13.6Hz), 3.17 (1H, dt, J =13.9Hz), 2.87 (1H, dt, J =Hz), 2.62-2.55 (3H, s), 2.01-1.94 (2H, m), 1.75-1.65 (2H, m)
A. A solution of 51.6 g of isonipecotic acid in 200 ml of acetic anhydride is refluxed for 2 hours and allowed to stir at ambient temperature for 16 hours. The solution is concentrated and the resulting residue is triturated in ether. The solid is collected by filtration and recrystallized from an isopropyl alcohol-diisopropyl ether mixture giving 1-acetylisonipecotic acid as a white solid.
With triethylamine; In 1,2-dichloro-ethane; at 20 - 83.5℃; for 10h;
775 g of 1,2-dichloroethane was added to a 2000 ml reaction flask.129.16 g of 4-piperidinecarboxylic acid and 131.55 g of triethylamine are added with stirring.Controlled temperature below 20 C added benzyl chloride 189.87g.After the dripping is slowly heated up to 83.5C, the reaction is refluxed for 10h.The reaction solution was dropped to room temperature and stirred with 300 g of water.The liquid was separated; the organic layer was washed with 150 g of saturated saline, and the organic layer was collected and dried;The filtrate was filtered and concentrated to give an oil of N-benzyl-4-piperidinecarboxylic acid 201.96 g;Molar yield 92.1%,The liquid purity is 97.21%.
EXAMPLE 73 Preparation of N-acetylisonipecotic acid Isonipecotic acid (25.0 g, 0.19 mol) was dissolved in acetic anhydride (100 mL) and the solution stirred at reflux for 8 h, then the solvent was removed under reduced pressure and the crude compound crystallized from MeOH/ether to afford the title compound as a white solid (24.4 g, 74%). m.p. 171 C. 1H NMR (DMSO): 1.2-1.5 (m, 2H), 1.65-1.85 (m, 2H), 1.942 (s, 3H), 2.35-2.5 (m, 1H), 2.641 (t, J=11.7 Hz, 1H), 3.038 (t, J=11.7 Hz, 1H), 3.69 (d, J=13.5 Hz, 1H), 4.15 (d, J=13.2 Hz, 1H), 12.22 (bs, 1H). IR (KBr): 1721, 1613, 1316, 1202 (cm-1). MS (m/z): 171, 128, 82.
74%
In acetic anhydride;
A) N-Acetylisonipecotic acid. Isonipecotic acid (25.0 g, 0.190 mol) was dissolved in acetic anhydride (100 mL) and the solution stirred at reflux for 8 h, then the solvent was removed under reduced pressure and the crude compound crystallized from MeOH/ether to afford the title compound as a colorless solid (24.4 g, 74%): mp 171 C.; 1 H NMR (DMSO-d6) 1.20-1.50 (m, 2H), 1.65-1.85 (m, 2H), 1.94 (s, 3H), 2.35-2.50 (m, 1H), 2.64 (t, J=11.7 Hz, 1H), 3.04 (t, J=11.7 Hz, 1H), 3.69 (d, J=13.5 Hz, 1H), 4.15 (d, J=13.2 Hz, 1H), 12.2 (bs, 1H).
With acetic anhydride; In methanol;
A. N-ACETYLISONIPECOTIC ACID STR42 Isonipecotic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7 grams) (232.5 mmoles) were dissolved in MeOH (100 ml.) and the mixture was stirred at 25 C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the product compound (Yield: 12.8 grams, 97%, MH+
With acetic anhydride;
A. 1-Acetyl-piperidine-4-carboxylic acid A mixture of 129.2 g (1.00 mmol) of isonipecotic acid and 400 mL of acetic anhydride was refluxed for 2.5 h. The mixture was allowed to cool to room temperature and stirred for 17 h. The precipitated solids were filtered, washed with diethyl ether and dried under vacuum to give 150.1 g of 51A as a white solid.
In acetic anhydride;
PREPARATION 1 1-Acetylpiperidine-4-carboxylic acid STR9 Piperidine-4-carboxylic acid (208 g, 1.63 moles) was dissolved in acetic anhydride and the resulting solution heated at reflux under a nitrogen atmosphere for 48 hours. The flask contents were allowed to cool then concentrated under reduced pressure to give a pale yellow oil which solidified on standing. Recrystallisation from propan-2-ol then afforded the title compound as an off white solid (160 g, 0.94 moles, 58%), mp 164-166 C. (IPA-ethylacetate), deltaH (300 MHz;CDCl3) 1.7 (2H, m), 2.0 (2H, m), 2.2 (3H, s), 2.6 (1H, m), 2.85 (1H, m), 3.2 (1H, m), 3.8 (1H, m), and 4.4 (1H, m).
In dichloromethane; di-isopropyl ether; acetic anhydride;
A) 100 g of piperidine-4-carboxylic acid were heated under reflux and with stirring at a temperature of 135 C. for 4 hours in 400 ml of acetic anhydride. The mixture was then allowed to cool to room temperature. To work up the reaction mixture it was evaporated to remove acetic anhydride, toluene being added several times towards the end of the evaporation. After the evaporation a beige-colored solid crude product remained as a residue. This was suspended in 300 ml of a mixture of diisopropyl ether and dichloromethane, cooled to a temperature of 0 C. and filtered. 65 g of crude acetylpiperidine-4-carboxylic acid having a melting point of 180 to 182 C. were obtained. The filtrate was diluted while hot with 200 ml of water, and further 1-acetylpiperidine-4-carboxylic acid deposited as a precipitate and was filtered out. 42.91 g of the acid were obtained, so that the total yield of 1-acetylpiperidine-4-carboxylic acid was 107.9 g.
In acetic anhydride;
1-acetylpiperidine-4-carboxylic acid 1-Acetylpiperidine-4-carboxylic acid is prepared by bringing a solution of piperidine-4-carboxylic acid in acetic anhydride to reflux for 2 hours and then stirring for 16 hours at room temperature. The solution is then concentrated and the residue is triturated in ether. The solid compound is recovered by filtration. Recrystallization solvent: isopropanol/isopropyl ether Melting point: 180-182 C.
With acetic anhydride; In methanol;
A. N-Acetylisonipecotic Acid STR121 Isonipecotic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7 grams) (232.5 mmoles) were dissolved in MeOH (100 ml.) and the mixture was stirred at 25 C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the title compound (Yield: 12.8 grams, 97%, MH+ 172).
With acetic anhydride; In methanol;
A. N-ACETYLISONIPECOTIC ACID STR138 Isonipecotic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7 grams) (232.5 mmoles) were dissolved in MeOH (100 ml.) and the mixture was stirred at 25 C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the title compound (Yield: 12.8 grams, 97%, MH+ 172).
With acetic anhydride; In diethyl ether; di-isopropyl ether;
EXAMPLE 25 4-(4-Fluorobenzyl)-piperidine A mixture of 300 g (2.32 mol) of isonipecotic acid and 1,200 ml of acetic anhydride is heated under reflux for 2 hours in a 4 liter reactor equipped with a mechanical stirrer, a condenser and a thermometer, and the mixture is left to stand overnight. 1 liter of diethyl ether is added to the mixture, which is starting to crystallise, the solid is filtered off and the cake is washed with diethyl ether (4*500 ml), drained and recrystallized from a 40/60 mixture of diisopropyl ether/isopropyl alcohol. 153 g are isolated in a first crop and 141 g in a second crop. The N-acetylisonipecotic acid obtained melts at 148 C.
In acetic anhydride;
Step A N-acetyl isonipecotic acid chloride 1000 g isonipecotic acid are suspended in 4000 g acetic anhydride and heated to reflux for 2 hours. The mixture is thereafter evaporated to dryness under reduced pressure. The crystalline residue is taken up in 6000 ml ether. The residue is separated by succion-filtration, washed with ether and dried. 965 g N-acetyl isonipecotic acid are recovered, melting at 180-182.
The mixture of 100 g of isonipecotic acid and 40 ml of acetic anyhydride is refluxed for 2 hours and then allowed to stir at room temperature overnight. The reaction mixture is then evaporated under reduced pressure and the residue triturated with diethyl ether. The resulting solids are recrystallized from a mixture of isopropanol and diethyl ether to afford the N-acetyl isonipecotic acid, melting at 175.
With hydrogenchloride; triethylamine; In tetrahydrofuran; at 70℃; for 0.25h;Microwave irradiation;
A mixture of isonipecotic acid 1 (129?mg, 1.0?mmol), benzoyl chloride 2 (140?mg, 1.0?mmol) and Et3N (0.32?mL, 2.5?mmol) in THF (5 mL) was stirred under microwave irradiation (120?W) at 70?C for 15?min. The reaction mixture was acidified using 1?M HCl (10?mL) and extracted with dichloromethane (3?*?25?mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 5% ethyl acetate in hexane, followed by 80% ethyl acetate in hexane as eluent to yield 3 (94%) as white solid. Mp 136-138?C. 1H NMR (400?MHz, CDCl3) delta 1.71-1.85 (m, 3H), 2.03-2.06 (m, 1H), 2.59 (tt, 1H, J?=?10.4, 4.1?Hz), 3.04-3.12 (m, 2H), 3.72-3.76 (m, 1H), 4.48-4.52 (m, 1H), 7.36-7.44 (m, 5H), 11.16 (br s, 1H). 13C NMR (100?MHz, CDCl3) delta 40.4, 41.4, 46.8, 126.7, 128.3, 129.6, 135.3, 170.7, 178.3. HRMS (ESI): calcd for C13H14NO3 [M-H]-, 232.0973; found, 232.0979.
85%
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol,1.0 equiv) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol, 5.0 equiv) were added, and the mixture was cooled to 0C. A solution of benzoyl chloride (8.980 mL, 77.425 mmol, 1.0 equiv) in THF (35mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mLseparating funnel and washed with EtOAc (3 × 150 mL). The aqueous phase was cooled to 0 C and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Buechner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 12 as a white solid (85%yield). This product was used in the next step without further purification. Rf = 0.55 (MeCN-H2O-MeOH= 3:1:1); mp 118-122 C. IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1169,1014, 791, 731, 707, 628, 577. cm-1. 1H NMR (400 MHz,DMSO-d6): delta = 1.49 (2 H, bs), 1.83 (2 H, bd, J = 45.68 Hz), 2.52-2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1H, bs), 7.34-7.46 (5 H, m), 12.32 (1 H, bs). 13C NMR (100 MHz,DMSO-d6): delta = 27.62, 28.24, 40.06, 40.74, 46.38, 126.61, 128.38, 129.31,136.23, 168.96, 175.481. HRMS (ESI+): m/z calcd for C13H16NO3: 234.1130; found 231.1125. Anal. Calcd for C13H15NO3: C,66.94; H, 6.48; N, 6.00. Found C, 67.22; H, 6.78; 6.22.
85%
With potassium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 22h;
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol) were added, and the mixture was cooled to 0 C. A solution of benzoyl chloride (8.980 imL, 77.425 mmol) in THF (35 imL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3 chi 150 ml_). The aqueous phase was cooled to 0 C and adjusted to pH 1 -2 with 6 M aq HCI. The white precipitate was collected in a Buchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 1 -benzoylpiperidine-4-carboxylic acid. This product was used in the next step without further purification.Product appearance: white solid.Yield: 85%.Melting point: 1 18-122 C . TLC: Rf = 0.55 (MeCN-H2O-MeOH = 3:1 :1 ) .IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1 169, 1014, 791 , 731 , 707, 628, 577. cm"1 (0361) [0333] 1H NMR (400 MHz, DMSO-d6): delta = 1 .49 (2 H, bs), 1 .83 (2 H, bd, J = 45.68 Hz), 2.52-2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1 H, bs), 7.34-7.46 (5 H, m), 12.32 (1 H, bs).13C NMR (100 MHz, DMSO-d6): delta = 27.62, 28.24, 40.06, 40.74, 46.38, (0363) 126.61 , 128.38, 129.31 , 136.23, 168.96, 175.48.HRMS (ESI+): m/z calculated for C13H16NO3: 234.1 130; found 231 .1 125. CHN analysis: Calculated for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: (0366) C, 67.22; H, 6.78; N, 6.22.
With potassium carbonate; In water;
Reference Example 2 Synthesis of 1-benzoylisonipecotic acid STR100 To an ice cold solution of isonipecotic acid (90 g, 0.697 mol) and potassium carbonate (81 g, 1.31 mol) in water (1.3 liter) was added dropwise benzoyl chloride (81 ml, 0.697 mol) over a period of about an hour at about 5 C. The mixture was stirred at room temperature overnight. The reaction mixture was acidified with 6N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water and then dried over magnesium sulfate and the solvent was evaporated in vacuo. Crystallization from isopropyl alcohol-diethyl ether to give the titled compound (154.4 g). Melting point: 143-144 C.
With hydrogenchloride; sodium hydroxide; In dichloromethane; water;
Step A 1-Benzoyl-isonipecotic Acid To a solution of 10 g of isonipecotic acid in 100 mL of H2O was added 31 mL of 5 N NaOH at 0 C. The reaction was warmed to room temperature and stirred for 0.5 hr. The reaction was again cooled to 0 C. and 11.97 g of benzoyl chloride was added. The reaction was then warmed to room temperature and stirred for 1.5 hr. Concentrated HCl was then added until a precipitate formed. The mixture was extracted with 3*150 mL of EtOAc and the combined organic layers were dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. Ether was then slowly added to precipitate the product which was filtered to give 8 g of the title compound. 1H NMR (500 MHz) 1.83 (m, 3H), 2.10 (m, 1H), 2.65 (m, 1H), 3.12 (m, 2H), 3.79 (m, 1H), 4.53 (m, 1H), 7.38 (m, 5H).
General procedure: 4-Piperidine carboxylic acid was dissolved in 5 volumes of anhydrous dichlorometane and 2 equivalents of BSA were added and stirred for 2 hours at rt; at this solution was added 1.1 eq of desired acyl or sulfonyl chloride and the mixture was stirred overnight. The solution was concentrated under reduced vacuum, NaHCO3 10% was added and the resulting solution was stirred for 30 min at rt; this aqueous solution was transferred in a separatory funnel and washed with dichlorometane, then 6N HCl was added until pH 2, dichlorometane was added for diluting the solution and the desired acid compound was extracted in the organic phase; the organic layer was washed with water until neutrality and brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the acid derivative 12.The 4 piperidine carboxylic acid derivative 12 was converted in the corresponding acyl chloride 13 by treatment with 1.2 eq of oxalyl chloride in dichloromethane and a catalytic amount of DMF. After 2 hours the solvent was removed in vacuum and the residue redissolved and concentrated twice with dichloromethane; the crude was dissolved with 5volumes of dichloromethane and to this solution was added an aqueous solution ( 5 volumes) of NH2OH*HCl (1 eq) and NaHCO3 (2 eq). The mixture was stirred overnight. Then 1N HCl was added till pH =5 and the solution was transferred into a separatory funnel. Dichloromethane was added and the organic layer was washed with H2O till neutrality and brine, then dried over Na2SO4 and concentrated under reduced pressure to obtain the crude hydroxamic acid that was purified by flash chromatography (silica, MeOH/dichloromethane) if necessary.
In tetrahydrofuran; hydrogenchloride; methanol; water;
a methyl 4-piperidinecarboxylate hydrochloride Isonipecotic acid (40 g, 310 mmol) was suspended, with stirring, in 250 mL of dry methanol and treated with HCl gas (lecture bottle) until solution was obtained. The solution was then cooled in an ice bath and treatment with HCl gas continued for an additional 20 min. After 2.5 h, the reacion mixture was stripped of solvent using a water aspirator (30 C.) and the resulting heavy, white cake suspended in 150 mL dry THF and filtered. The filter cake was washed with two portions of 50 mL THF, followed by washing with 3*50 ml Et2 O, dried briefly in air (suction). The pale-yellow filtrate was discarded. Drying the slightly off-white solid was completed over-night in a desiccator (CaSO4) under high vacuum. The title compound (43.25 g) was obtaind analytically pure. Anal. (C7 H14 ClNO2) calcd: C, 46.80; H, 7.86; N, 7.80; Cl, 19.73. found C, 46.66; H, 7.78; N, 19.82. TLC Rf=0.63 (silica gel, 3:1 ethanol/conc. aq. ammonium hydroxide).
With sodium hydroxide; In water; at 0 - 30℃; for 3h;
Example 1 - Preparation of 1-(Ethoxycarbonyl) piperidine-4-Carboxylic AcidTo a solution of (154.8 gm) Sodium hydroxide in (750 ml) purified water, Isonipecotic acid(250gm) was added at 0-10C, followed by the slow addition of ethyl chloroformate (231 ml) at 5-20C. The reaction mixture was heated to 20-30C and maintained for 3 hrs at the sametemperature. After completion of the reaction, the reaction mass was acidified to a pH 1-2 byaddition of hydrochloric acid. Then toluene (750 ml) was added to the reaction mass and stirred for15 minutes at 25-30 C. The organic layer was separated and concentrated under vacuum at below70C to obtain a residue. The resi4ue_was_mixed. with cyclohexane (1250 ml) at 60-70C, thencooled to 25-30C and maintain for I hour at the same temperature. The resulted contents werefiltered, and washed with cyclohexane (1250 ml) and dried at 50-55C. Percentage Yield: 92%
91.9%
With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 2h;
5.16 g (40 mmol) of the starting material 4-piperidinecarboxylic acid was added to a 100 ml round bottom flask, Na2CO3 5.04 g (48 mmol) and 40 mL of water was added. 5.13 g (48 mmol) was dissolved in 40 mL of tetrahydrofuran, added dropwise to a round bottom flask and stirred at room temperature for 2 h. The reaction was evaporated to remove tetrahydrofuran rotary end, was added 60mL of water, adjusted to pH 2 with 2MHCl, extracted with EA (30mL × 3), combined EA phases were dried over anhydrous MgSO4, filtered and rotary-dry products acquired Intermediate 1 as a white solid. Yield 91.9%.
In sodium hydroxide;
13c 4-Carboxy-1-ethoxycarbonylpiperidine 4-Carboxy-1-ethoxycarbonylpiperidine is prepared from piperidine-4-carboxylic acid (Aldrich, Steinheim, FRG), for example by reacting piperidine-4-carboxylic acid with ethyl chloroformate in aqueous sodium hydroxide solution for 2 h at from 0 to 5 C. The title compound is extracted from the aqueous phase by shaking with toluene. The toluene phase containing the dissolved title compound is dried over Na2 SO4 and directly subjected to further use.
With thionyl chloride; hydroxylamine hydrochloride; acetic anhydride;aluminium trichloride; In hydrogenchloride; ethanol;
EXAMPLE 1 (RS)-3-[1-(benzocyclobuten-1-ylmethyl)-4-piperidyl]-6-fluoro-1,2-benzisoxazole hydriodide PROCESS No. 1 STAGE A: 1-Acetyl-4-piperidinecarboxylic acid 100 g of 4-piperidinecarboxylic acid and 400 ml of acetic anhydride are mixed. The mixture is brought to reflux for 2 hours and then left overnight at room temperature. The reaction medium is concentrated and the residue is ground with ethyl ether, filtered off and then washed with ethyl ether to obtain the expected compound. Yield: 79%. Melting point: 175 C. STAGE B: 1-Acetyl-4-piperidinecarbonyl chloride 52 g of the acid obtained in the preceding stage are added portionwise to 320 ml of thionyl chloride. After stirring overnight, the precipitate formed is filtered off and washed several times with isopropyl ether to isolate the expected product, which is used immediately without further purification. Yield: 80%. STAGE C: 1-Acetyl-4-(2,4-difluorobenzoyl)piperidine 54.3 g of aluminum chloride and 130 ml of dichloroethane are mixed. 24 g of 1,3-difluorobenzene are added and the acid chloride obtained in the preceding stage is then added portionwise. The reaction medium is brought to reflux for 6 hours and then left overnight at room temperature. It is hydrolyzed with ice and 190 ml of concentrated hydrochloric acid. The mixture is extracted 5 times with 100 ml of dichloromethane and the organic phase is dried over anhydrous magnesium sulfate to obtain the expected compound. Yield: 53%. Melting point: 97 C. STAGE D: 4-(2,4-Difluorobenzoyl)piperidine 30 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine are brought to reflux in 113 ml of 6N hydrochloric acid for 6 hours. The reaction medium is then concentrated and the residue obtained is crystallized in isopropanol. The expected compound is isolated after filtration. Yield: 83%. Melting point: 230 C. STAGE E: 4-(2,4-Difluorobenzoyl)piperidine oxime hydrochloride 3 g of the compound obtained in the preceding stage, 3 g of hydroxylamine hydrochloride and 2.7 g of N,N-diethylethylenediamine are added to 30 ml of ethanol, and the mixture is brought to reflux for 8 hours. It is left overnight at room temperature and filtered and the residue isolated is rinsed with ethanol to obtain 4-(2,4-difluorobenzoyl)piperidine oxime hydrochloride. Yield: 54%. Melting point: >260 C. Proton nuclear magnetic resonance spectrum (solvent DMSO-d6): 1.7 ppm, m, 2H; 1.9 ppm, m, 2H; 2.70 ppm, m, 1H; 2.9 ppm, m, 2H; 3.25 ppm, m, 2H; 7.15 ppm, td, 1H; 7.3 ppm, m, 2H; 9.0 ppm, 1H exchangeable; 11.1 ppm, 1H exchangeable.
D. To a solution of 1 g of isonipecotic acid in 10 ml of water was added 1.07 g potassium carbonate and this was stirred for 15 minutes at room temperature. 0.961 g <strong>[1184-90-3]aminoiminomethanesulfonic acid</strong> was then added portionwise over 20 minutes. The solution was stirred for 2 hours at room temperature, concentrated in vacuo to one-half of the original volume and the resulting precipitate collected by filtration. The resulting solid wasrecrystallized from water to give N-amidino-4-piperidine carboxylic acid.
With potassium carbonate; In water;
A. N-amidino-4-piperidine carboxylic acid was prepared essentially by the method of Miller, et al, Synthesis, 777 (1986), which is incorporated herein by reference. To a solution of 1 g of isonipecotic acid in 10 ml of water was added 1.07 g potassium carbonate and this was stirred for 15 minutes at room temperature. 0.961 g <strong>[1184-90-3]aminoiminomethanesulfonic acid</strong> was then added portionwise over 20 minutes. The solution was stirred for 2 hours at room temperature, concentrated in vacuo to one-half of the original volume and the resulting precipitate collected by filtration. The resulting solid was recrystallized from water to give N-amidino-4-piperidine carboxylic acid. This was dissolved in an aqueous solution of tetrahydrofuran.
With hydrogenchloride; formaldehyd; In formic acid;
EXAMPLE 1 Preparation of 1-Methylpiperidine-4-carboxaldehyde 4.5 mL(0.06 mole) of formaldehyde solution (37%) was slowly added to a stirred solution of isonipecotic acid (3.88 g, 0.03 mole) in 97% formic acid (6.9 g, 0.15 mole). The mixture was heated to 90-100 C. A vigorous evolution of carbon dioxide began after 2-3 min. Heat was removed until gas evolution subsided and then the mixture was heated at 95-100 C. for 8 hours. Aqueous 4N hydrochloric acid (15 mL) was added and the solution was evaporated to dryness. The white syrupy residue was crystallized from isopropyl alcohol to give 1-methylisonipecotic acid hydrochloride as white crystals: mp220-240; IR (KBr) 3460, 2960, 2600, 1720, 1465, 1400, 1365, 1300, 1270, 1250, 1205, 1180, 1160, 1040, 980, 955, 920, 875, 830, 720 and 630 cm-1; NMR spectrum showed N-CH3 group at delta2.87.
With triethylamine; for 0.166667h;Heating / reflux;
Ethyl 6-chloro-5-cyano-2-methylnicotinate (3.00g, 13.35 mmol), Piperidine-4-carboxylic acid (1.897g, 14.69 mmol), and TEA (2.703 g, 26.71 mmol) were mixed and the mixture was refluxed for 10 minutes. LC/MS showed full conversion. The reaction mixture was evaporated, water/EtOAc 1:1 (100 mL) was added and the water phase was acidified to pH3. The EtOAc phase was separated and the water phase was extracted with an additional EtOAc (40 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 3.8 g of a crude material. Purification with preperative BPLC at pH=7 (0.1 M NH4OAC/CH3CN) with subsequent switch to pH=3 gave the pure product. Yield: 1.9 g (45 %). EPO <DP n="128"/>1H NMR ^OO MHZ, CDCi): 5 1.38 (t,J= 7.1 Hz, 3H), 1.94-1.82 (m, 2H), 2.13-2.05 (m, 2H)3 2.75-2.66 (m, 5H), 3.37-3.27 (m, 2H), 4.33 (q, J= 7.1 Hz, 2H), 4.63-4.55 (m, 2H), 8.36 (s, IH)MS m/z: 318 (M+l).
With triethylamine; for 0.166667h;Heating / reflux;
Ethyl 6-chloro-5-cyano-2-methylnicotinate (3.00 g, 13.35 mmol), piperidine-4-carboxylic acid (1.897 g, 14.69 mmol), and TEA (2.703 g, 26.71 mmol) were mixed and the mixture was refluxed for 10 minutes. LC/MS showed full conversion. The reaction mixture was evaporated, water/EtOAc 1:1 (100 mL) was added and the water phase was acidified to pH3. The EtOAc phase was separated and the water phase was extracted with an additional EtOAc (40 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 3.8 g of a crude material.Purification with preparative HPLC (Kromasil C8, 10 mum at pH=7 (0.1 M NH4OAc/CH3CN) with subsequent switch to pH=3) gave the pure product. Yield: 1.9 g (451H NMR (400 MHz, CDCl3): delta 1.38 (t, J=7.1 Hz, 3H), 1.94-1.82 (m, 2H), 2.13-2.05 (m, 2H), 2.75-2.66 (m, 5H), 3.37-3.27 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.63-4.55 (m, 2H), 8.36 (s, 1H)MS m/Z: 318 (M+1).
A) l-(l-Methyl-6-oxo-l ,6-dihvdro-pyridazin-3-yl)-piperidine-4-carboxylic acid. Triethylamine (2.S mL, 20 mmol) was added to a mixture of 6-chloro-2-methyl-2H- pyridazm-3-one (578 mg, 4.00 mmol) and piperidine-4-carboxylic acid (775 mg, 6.00 mmol) in 6.5 mL ethanol / water 3 : 1 in a microwave vial and heated at ISO 0C for 15 hours. After cooling to room temperature 2 M sodium hydroxide (4 mL) was added to the reaction mixture, Ethanol and triethylamine were removed in vacuo and the basic aqueous solution was heated at 70 C for 1.5 hours, diluted to 50 mL and washed twice with 20 mL ethyl acetate. The pH was adjusted to 5 using aqueous hydrochloric acid (a precipitate formed) and the volume of the mixture was reduced to 20 mL. The mixture was placed in the refrigerator over night and the solids were collected by filtration, washed with a small amount of water and dried under vacuum to give 497 mg of the sub-title compound (52 %).1H NMR (400 Hz, dimethyl sulphoxide-d6 as solvent and internal reference) delta(ppm) 1.54 (m, 2H), 1.84 (m, 2H), 2.40 (m, IH), 2.76 (m, 2H), 3.47 (s, 3H), 3.74 (m, 2H), 6.78 (d, IH7 J= 9.6 Hz), 7.47 (d, IH, J= 9.6 Hz).
52%
A) l-(l-Methyl-6-oxo-l,6-dihvdro-pyridazin-3-yl)-piperidine-4-carboxylic acid. Triethylamine (2.8 mL, 20 mmol) was added to a mixture of 6-chloro-2-m.eth.yl- 2H- pyridazin-3-one (578 mg, 4.00 mmol) and piperidine-4-carboxylic acid (775 mg, 6.00 mmol) in 6.5 mL ethanol / water 3 : 1 in a microwave vial and heated at 180 0C for 15 hours. After cooling to room temperature 2 M sodium hydroxide (4 mL) was added to the reaction mixture. Ethanol and triethylamine were removed in vacuo and the basic aqueous solution was heated at 70 0C for 1.5 hours, diluted to 50 mL and washed twice with 20 mL ethyl acetate. The pH was adjusted to 5 using aqueous hydrochloric acid (a precipitate formed) and the volume of the mixture was reduced to 20 mL. The mixture was placed in the refrigerator over night and the solids were collected by filtration, washed with a small amount of water and dried under vacuum to give 497 mg of the sub-title compound (52 %).1H NMR (400 Hz5 dimethyl sulphoxide-d6 as solvent and internal reference) delta(ppm) 1.54 (m, 2H), 1.84 (m, 2H), 2.40 (m, IH), 2.76 (m, 2H), 3.47 (s, 3H), 3.74 (m, 2H), 6.78 (d, IH, J= 9.6 Hz), 7.47 (d, IH, J= 9.6 Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 95℃;
A solution of isonipectoamide (10.9 g, 85.0 mmol), 2-(4-fluorophenyl)ethyl bromide (15.7 g, 77.3 mmol), and K2CO3 (2.3 g, 167 mmol) was prepared in DMF (280 mL) and stirred under argon at 90-95 C. overnight. The cooled solution was concentrated to a white oily solid. The solid was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed 2× with water, dried (MgSO4), filtered, and evaporated to an oily solid. The solid was recrystallized from EtOAc to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide as a white powder, m.p. 177-178 C. (decomp.). Anal. Calcd. for C14H19FN2O: C, 67.18; H, 7.65: N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.
To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (272 mg, 1.71 mmol) in DMSO (2 mL) was added methyl-3-amino-3-phenylpropanoate (553 mg, 2.57 mmol) and potassium carbonate (709 mg, 5.13 mmol), and the suspension stirred at room temperature for 24 hours. 4-Piperidinecarboxylic acid (335 mg, 2.59 mmol) was added, and the resulting suspension stirred at room temperature for 24 hours, and then heated at 100 C. for 3 hours. The suspension was cooled to room temperature, and diluted with water. The aqueous solution was extracted with ethyl acetate, and the separated aqueous layer acidified with dilute hydrochloric acid (pH<4), and re-extracted with ethyl acetate. The second organic extracts were evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluding with a mixture of dichloromethane and methanol (96:4) to afford the title compound, 1H NMR: (CDCl3) 7.36-7.22 (m, 5H), 7.02 (t, J=8.06, 1H), 6.34 (dd, J=8.06, 1.10, 1H), 6.19 (d, J=8.06, 1H), 4.89-4.85 (m, 1H), 3.66 (s, 3H), 3.25-3.21 (m, 2H), 2.87-2.77 (m, 4H), 2.48-2.41 (m, 1H), 2.02-1.82 (m, 4H).
To isonipecotic acid (41.5 g; 320 mmol) was added 1,4-dioxane (200 mL). Thus, an inhomogeneous solution was obtained. Thereto was added 41.5 mL of concentrated sulfuric acid over 30 minutes. Into this inhomogeneous solution was bubbled 100 g of isobutene over 5 hours. After completion of the bubbling, the mixture was cooled to 0° C. and 750 mL of 2-N aqueous NaOH solution was added thereto. The resultant mixture was ascertained to be basic. Thereafter, a reaction product was extracted with 500 mL of diethyl ether, and the extract was dried with sodium sulfate and then concentrated to obtain 5.98 g of t-butyl isonipecotate as the target compound.
Stage #1: isonipecotic acid With N,O-bis-(trimethylsilyl)-acetamide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;
Stage #2: benzenesulfonyl chloride In dichloromethane
General procedure for the synthesis of 4 piperidine hydroxamic acids 1a-4a (Scheme 1)
General procedure: 4-Piperidine carboxylic acid was dissolved in 5 volumes of anhydrous dichlorometane and 2 equivalents of BSA were added and stirred for 2 hours at rt; at this solution was added 1.1 eq of desired acyl or sulfonyl chloride and the mixture was stirred overnight. The solution was concentrated under reduced vacuum, NaHCO3 10% was added and the resulting solution was stirred for 30 min at rt; this aqueous solution was transferred in a separatory funnel and washed with dichlorometane, then 6N HCl was added until pH 2, dichlorometane was added for diluting the solution and the desired acid compound was extracted in the organic phase; the organic layer was washed with water until neutrality and brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the acid derivative 12.The 4 piperidine carboxylic acid derivative 12 was converted in the corresponding acyl chloride 13 by treatment with 1.2 eq of oxalyl chloride in dichloromethane and a catalytic amount of DMF. After 2 hours the solvent was removed in vacuum and the residue redissolved and concentrated twice with dichloromethane; the crude was dissolved with 5volumes of dichloromethane and to this solution was added an aqueous solution ( 5 volumes) of NH2OH*HCl (1 eq) and NaHCO3 (2 eq). The mixture was stirred overnight. Then 1N HCl was added till pH =5 and the solution was transferred into a separatory funnel. Dichloromethane was added and the organic layer was washed with H2O till neutrality and brine, then dried over Na2SO4 and concentrated under reduced pressure to obtain the crude hydroxamic acid that was purified by flash chromatography (silica, MeOH/dichloromethane) if necessary.
Stage #1: N′-hydroxybenzo[d][1,3]dioxole-5-carboximidamide With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 1h;
Stage #2: isonipecotic acid In acetonitrile at 20℃; for 12h;
With triethylamine In methanol at 50 - 60℃; for 5h;
3.3-12-1
3-12-1: Preparation of [3-fluoro-4-(4-carboxylicpiperidino)]nitrobenzene To 100 ml of methanol were sequentially added 5 g (31.4 mmol) of 3,4-difluoronitrobenzene, 5.26 ml (37.7 mmol) of triethylamine and 4.5 g (34.6 mmol) of isonipecotic acid, followed by reaction at a temperature of 50 to 60° for 5 hours. After the reaction was complete, the reaction liquid was cooled to room temperature. The resulting solid was filtered, washed with about 50 ml of methanol and then dried under vacuum at about 40° to afford 8.09 g (yield: 96%) of the desired compound. Mass (M+): 269.1 1H-NMR (DMSO-d6): 1.67(m, 2H), 1.91(m, 2H), 2.50(m, 1H), 3.00(m, 2H), 3.67(m, 2H), 7.15(m, 1H), 7.96(m, 2H).
96%
With triethylamine In methanol at 50 - 60℃; for 5h;
3.3-12-1
Example 3-12-1 Preparation of [3-fluoro-4-(4-carboxypiperidino)]nitrobenzene To 100ml of methanol were sequentially added 5g (31.4mmol) of 3,4-difluoronitrobenzene, 5.26ml (37.7mmol) of triethylamine and 4.5g (34.6mmol) of isonipecotic acid, followed by reaction at a temperature of 50 to 60°C for 5 hours. After the reaction was complete, the reaction liquid was cooled to room temperature. The resulting solid was filtered, washed with about 50ml of methanol and then dried under vacuum at about 40°C to afford 8.09g (yield: 96%) of the desired compound. Mass (M+): 269.1 1H-NMR (DMSO-d6):1.67(m, 2H), 1.91(m, 2H), 2.50(m, 1H), 3.00(m, 2H), 3.67(m, 2H), 7.15(m, 1H), 7.96(m, 2H).
5-bromo-2-(piperidin-4-yl)-1,3-benzoxazole
Polyphosphoric acid (7.1 ml; CAS 8017-16-1) was heated up to 1800, followed by the addition of piperidine-4-carboxylic acid (1.06 g, 8.21 mmol) and 2-amino-4-bromophenol (1.54 g, 8.21 mmol), and the mixture was stirred for 30 min at 1800. The hot mixture was poured onto ice and basified with solid potassium hydroxide. The mixture was extracted with ethyl acetate three times, the combined organic layers were washed with saturated NaCI-solution, filtered over a hydrophobic filter and the solvent was evaporated under reduced pressure, yielding the title compound as a brown solid (2.08 g, 95 % purity, 86 % yield).1H NMR (400 MHz, DMSO-d6) d ppm 1.60 - 1 .71 (m, 2 H) 1 .94 - 2.01 (m, 3 H) 2.59 (td, 2 H) 2.95 - 3.02 (m, 2 H) 3.08 (s, 1 H) 7.52 (dd, 1 H) 7.67 (d, 1 H) 7.94 (d, 1 H)LC-MS (Method 2): Rt = 1 .02 min; MS (ESIpos): m/z = 281 .1 [M+H]+
Stage #1: isonipecotic acid; 2-amino-4-bromo-phenol at 190℃; for 3.5h;
Stage #2: With sodium hydroxide In water at 25 - 28℃;
Intermediate 5: 5-Bromo-2-(piperidin-4-yl)benzo[rf]oxazole: 2-amino-4- bromophenol (1.2 g, 5.8 mmol) and piperidine-4-carboxylic acid (0.74 g, 5.8 mmol) were dissolved in polyphosphoric acid (30 g). This mixture was heated at 190 °C for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (AcOEt/H20) followed removal of AcOEt afforded the titled compound (0.8 g) as a pale-yellow gummy solid.
Intermediate 9: 6-bromo-2-(piperidin-4-yl)benzo[d]oxazole: 2-amino-5- bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190 C for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H20) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification.
Example 17A1 1 -(2,2,2-trifluoroacetyl)piperidine-4-carboxylic acid To a solution of piperidine-4-carboxylic acid (4 g , 30.97mmol) in dichloromethane (20 mL) was added dropwise triflate anhydride(7.8g). The resulting mixture was stirred at 0 C overnight. Upon dilution with water, the combined organic layers were concentrated. The residue was purified by column chromatography on silica gel to give Example 17A1 in 70% yield as a white solid.
1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)piperidine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In methanol at 0 - 20℃; for 2.25h;
92%
With potassium carbonate In methanol at 0℃; for 2h;
A 1-(7-Nitrobenzo[c][1,2,5]oxadiazol-4-yl)piperidine-4-carboxylic acid
4-Chloro-7-nitrobenzofurazan (NBD) (500 mg, 2.51 mmol) in MeOH (20 ml) was added dropwise to a suspension of piperidine-4-carboxylic acid (971 mg, 7.52 mmol) and potassium carbonate (1.04 g, 7.52 mmol) in MeOH (15 ml) at 0°C. Once the addition was complete the ice-bath was removed and the reaction was stirred for 2 h at which time all s.m. had been consumed according to TLC. The reaction mixture was concentrated to about 15 ml and cooled to 0°C. HC1 (1 M, 25 ml) was carefully added resulting in the formation of a red suspension. The mixture was stirred for 10 min, filtered and washed with ice cold water (10 ml). The solid was recrystallized from hot MeOH to give the product (672 mg, 92%) as red needles. - MR (400 MHz, DMSO- d6): δ 12.4 (br s, 1 H), 8.45 (d, J = 9.2 Hz, 1 H), 6.66 (d, J = 9.2 Hz, 1 H), 4.66 (d, J = 13.7 Hz, 2 H), 3.67 (ddd, J = 14.0, 11.2, 3.0 Hz, 2 H), 2.76 (tt, J = 10.3, 4.3 Hz, 1 H), 2.11-2.03 (m, 2 H) 1.76 (dtd, J = 14.4, 10.9, 3.9 Hz, 2 H).13C- MR (62.5 MHz, DMSO-de): δ 175.3, 145.2, 144.9, 144.7, 136.3, 120.6, 103.4, 49.2, 39.3, 27.9. HRMS (ESI+) Ci2Hi2N403Na [M+Na]+calc 315.0700, found 315.0687
27%
With sodium hydroxide In water; N,N-dimethyl-formamide at 0 - 20℃; for 4.58333h;
1 CO2H-NBD
NBD-C1 (500 mg, 2.51 mmol) was dissolved in dimethylformamide (DMF,5 ml) and dropwise added to a solution of piperidine-4-carboxylic acid (971 mg, 7.52 mmol) in aqueous NaOH (1 M, 7.5 ml) at 0 °C. After 5 min the dark red reaction mixture was allowed to warm to RT. Another portion of piperidine-4-carboxylic acid (647 mg, 5.01 mmol) in NaOH (1 M, 5.0 ml) was added after 2 h and stirring was continued for 2.5 h. The reaction was poured into aqueous HC1 (1 M, 100 ml) and the red precipitate was filtered off. The crude product was recrystalized from hot EtOH/MeOH to afford the product (199 mg, 27%) as red crystals. 1H-NMR (400 MHz DMSO-d6) d 12.41 (br s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 4.66 (d, J = 13.7 Hz, 2H), 3.67 (ddd, J= 14.0, 1 1.2, 3.0 Hz, 2H), 2.76 (tt, J = 10.3, 4.3 Hz, 1H), 2.1 1-2.03 (m, 2H) 1.76 (dtd, J= 14.4, 10.9, 3.9 Hz, 2H). HRMS (ESI+) C^H^OsNa [M+Na] calc 315.0700, found 315.0687
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in ethanol (25 mL). Triethylamine (1.78 mL, 12.6mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 7.6 mmol, 60%) as a white solid. OH (d6- DMSO) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%
With triethylamine; In ethanol; at 80℃; for 16h;
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture wascooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. H(400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m,2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%
With triethylamine; In ethanol; at 80℃; for 16h;
2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid(1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes,then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. 0H (DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%
With triethylamine; In ethanol; at 80℃; for 16h;
INTERMEDIATE 5 1 -(5 -Boronopyrimidin-2-yl)piperidine-4-carboxylic acid2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture wascooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. H(400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m,2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%
With triethylamine; In ethanol; at 80℃; for 16h;
INTERMEDIATE 6 l-(5-Boronopyrimidin-2-yl)piperidine-4-carboxylic acid 2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid, deltapi (DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
60%
With triethylamine; In ethanol; at 80℃; for 16h;
INTERMEDIATE 41 -(5 -Boronopyrimidin-2-yl)piperidine-4-carboxylic acid2-Chloropyrimidin-5 -ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. deltaEta (400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
With triethylamine; In ethanol; at 80℃; for 4h;
(2-Chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) was dissolved in EtOH (15 mL) and piperidine-4-carboxylic acid (816 mg, 6.32 mmol) was added, followed by triethylamine (881 mu, 6.32 mmol). The reaction mixture was heated at 80C for a total of 4 h. The reaction mixture was concentrated to dryness and 10 mL of water was added. The resulting suspension was cooled to 0C for 30 minutes, then filtered, and the solid was washed with minimal water. Only a trace amount of precipitate was isolated so this was recombined with the filtrate and concentrated to dryness to afford the title compound. The crude product was used without purification. Method C HPLC-MS: MH+ mlz 252, RT 0.70 minutes
With triethylamine; In ethanol; at 80℃; for 4h;
(2-Chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) was dissolved in EtOH (15 mL) and piperidine-4-carboxylic acid (816 mg, 6.32 mmol) was added, followed by triethylamine (881 muL, 6.32 mmol). The reaction mixture was heated at 80 C. for a total of 4 h. The reaction mixture was concentrated to dryness and 10 mL of water was added. The resulting suspension was cooled to 0 C. for 30 minutes, then filtered, and the solid was washed with minimal water. Only a trace amount of precipitate was isolated so this was recombined with the filtrate and concentrated to dryness to afford the title compound. The crude product was used without purification. Method C HPLC-MS: MH+ m/z 252, RT 0.70 minutes.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 190℃; for 4h;Inert atmosphere;
(1) A suspension of Compound 1 (20 g), piperidine-4-carboxylic acid (15.9 g), and potassium carbonate (34.12 g) in N-methylpyrrolidone (160 mL) was stirred under nitrogen atmosphere at 190C for 4 hours. The reaction mixture was poured into an ice-cooled aqueous solution of hydrochloric acid (1 mol/L, 480 mL), a saturated aqueous solution of sodium hydrogen carbonate was added thereto to neutralize it, then diluted with water, and extracted with ethyl acetate twice. The resultant organic layers were combined, washed with water and saturated saline, magnesium sulfate and active carbon were added thereto, the mixture was stirred, then filtrated, and the filtrate was concentrated under reduced pressure. The residue was powdered with isopropylether, collected by filtration, and then dried to give Compound 2 (14.1 g) as a colorless solid. MS (APCI): m/z 352/354 [M+H]+
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Step 1: Synthesis of 1-benzylpiperidine-4-carboxylic acid To a stirred solution of piperidine-4-carboxylic acid (5.0 g, 38.7 mmol) in DMF (20 mL) was added K2CO3 (13.3 g, 96.8 mmol) followed by drop wise addition of benzyl bromide (9.2 mL, 77.5 mmol). Reaction was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion, reaction mass was diluted with cold water (100 mL) and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, evaporated under reduced pressure to give crude product. Purification of the compound was done by silica gel (100-200 Mesh) column chromatography eluent 20% EtOAc: hexane to obtain 1-benzylpiperidine-4-carboxylic acid (5.0 g, 59%) as light yellow oil. MS: 220.14 [M++1]
(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol piperdine-4-carboxylic acid complex[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In water; acetone; at 40℃; for 6h;
Into a 250 mL RB flask, were added, (2S ,3R,4R,5S ,6R)-2- [3- [[5-(4-fluorophenyl)-2-thienylj methylj -4-methyl-phenylj -6-(hydroxymethyl) tetrahydropyran-3 ,4,5-triol of formula (1) (25g, 0.05 moles), acetone (125 ml), piperdine-4- carboxylic acid (7.2 g, 0.05), and DM water (12.5 ml). The reaction mixture was heated to 40 C and stirred for 6h and then cooled to ambient temperature. The resulting precipitated solid was cooled to 0-5 C, stirred for lh and filtered and dried at 50-55 C under reduced pressure to yield (26.1 g, 80% ) complex of formula (5)as an off white solid.Analytical data:JR (cm-i) KBr: 3477, 3355, 2970, 2915, 2524, 2489, 1699, 1644, 1576, 1509, 1369, 1225,1045, 1013.1HNMR (400 MHz; CD3OD+D20; ppm): 7.55 (dd, 2H); 7.31 (s, 1H), 7.25 (d, 1=8.0 Hz; 3H)),7.18 (d, 1=7.6 Hz, 1H), 7.11 (d, 1=3.6 Hz, 1H), 7.07 (t, 1=8.8 Hz, 2H), 6.71 (d, 1=3.6 Hz, 1H),4.12-4.15 (m, 1H), 3.88 (d, 1=12 Hz, 1H), 3.68-3.72 (m, 1H), 3.33-3.53 (m, 6H), 2.94-3.01 (m,2H), 2.34-2.42 (m, 1H),2.30 (s, 3H), 2.03-2.08 (m, 2H), 1.79-1.89 (m, 2H).13CNMR (400 MHz; CD3OD+D20; ppm): 181.60; 164.56; 144.98, 142.38, 139.33, 137.71;132.29, 131.35, 130.40, 128.i0(d, JC-F=8.OHz); 127.50, 127.18, 123.92, 116.75 (d, ICF=22.OHz), 83.30, 81.97, 79.57, 76.19, 71.77, 62.95, 44.76, 42.74, 34.87, 27.19, 19.35.Mass: 574.8 (M+i)PXRD (20 (±0.2): 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60,18.00,19.01,19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58,26.02, 26.23,26.71,28.34, 29.10, 31.33, 32.21, 33.61.
1-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 g
With potassium carbonate; In N,N-dimethyl-formamide; for 2.0h;Reflux;
10 g of <strong>[4887-94-9]2-chloro-5-methyl-1H-benzo[d]imidazole</strong> was added to 130 ml of N,N-dimethylformamide,Add 15g of anhydrous potassium carbonate and 9g of piperidine-4-carboxylic acid,Heated at reflux for 2 hours,cool down,Add water and ethyl acetate extractionLiquid separation,Collect the organic phase,concentrate,The residue was separated on a silica gel column to give 7 g of 1-(5-methyl-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Microwave irradiation; Inert atmosphere;
To a solution of piperidine-4-carboxylic acid (1.77 g, 13.7 mmol) in NMP (5 ml) was added <strong>[1480-64-4]3-chloro-2-fluoropyridine</strong> (1.50 g, 11.4 mmol), followed by diisopropyl ethylamine (6.00 ml, 34.3mmol). The mixture was heated in a microwave oven at 180C for 1 hour. The reaction mixturewas diluted with ethyl acetate and washed with water and brine. The organic phase was driedover sodium sulfate, filtered and concentrated to give 2.53 g (10.5 mmol, 92%) of 1-(3-chloropyridin-2-yl)piperidine-4-carboxylic acid, which was used for subsequent reactions withoutfurther purification.
1-pyrazin-2-ylmethyl-piperidine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[00226] To a suspension of isonipecotic acid (300 mg, 2.3mmol, 1 eq) in DMA (15mL) was added pyrazine 2-carboxaldehyde (377 mg, 3.5mmol, 1.5eq) and acetic acid (133uL, 2.3 mmol, 1 eq). After 5 min, sodium triacetoxyborohydride (738 mg, 3.5mmol, 1.5 eq) was added and the reaction mixture stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in MeOH (3ml_) and loaded onto SCX-2 cartridge. The cartridge was washed with MeOH, and the compound eluted using 1 M ammonia in methanol. The product-containing fractions were concentrated under reduced pressure to give the 1-pyrazin-2-ylmethyl-piperidine-4-carboxylic acid (435 mg) as a brown gum. AnalpH2_MeOH_4MIN Rt: 0.33 min, m/z 222.3 [M+H]+ The crude product was used directly in subsequent reactions without further purification.
With sodium hydroxide In water at 0 - 20℃; for 3h; Inert atmosphere;
16%
With sodium hydroxide In water at 0 - 20℃; for 3h;
94 Example 94: Synthesis of Intermediate 2.61
To a precooled (0 °C) solution of 4-piperidine carboxylic acid (1.0 g, 7.7 mmol) in 1M aq. NaOH (15 mL) was added methanesulfonyl chloride (0.72 mL, 9.3 mmol). The resulting mixture was stirred at 0 °C to room temperature for 3 h, then quenched slowly with 6 M aq. HCl and diluted with EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the product as a white solid (264 mg, 16% yield). 1H NMR (500 MHz, Chloroform-d) d 3.73- 3.62 (m, 2H), 2.94- 2.83 (m, 2H), 2.79 (s, 3H), 2.11- 2.01 (m, 2H), 1.94- 1.77 (m, 3H); 13C NMR (126 MHz, CDCl3) d 179.40, 45.14, 39.85, 35.23, 27.51; IR (ATR) vmax 2936, 1697, 1320, 1141, 920, 776, 518 cm-1; AMM (ESI) m/z 208.0641 [calc for C7H14NO4S (M+H)+ 208.0644].
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