* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With ammonium cerium (IV) nitrate; water; acetic acid In dichloromethane at 20℃; for 1 h; Inert atmosphere
The substrate (1 equiv) was added to a solution of CAN (20 mol percent) in minimum amount of water (roughly 15 equiv). The reaction mixture was dissolved in dichloromethane and stirred magnetically. Acetic acid (10 equiv) was added to the solution and left to stir at rt for the required time mentioned in Table 2. Upon completion of the reaction, the solvent was evaporated under reduced pressure and worked up in the following methods. Method A: The solid residue was washed twice with petroleum ether to remove the by product trityl alcohol. The residue was then dissolved in methanol and filtered through a short pad of celite. Removal of the solvent under reduced pressure yielded the free amine. Method B: Water and acetic acid were removed from the reaction mixture in vacuo. The residue was dissolved in dry dichloromethane, followed by the addition of triethylamine (2.5 equiv) and acetic anhydride or benzoyl chloride (1.5 equiv). After the completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate twice. The combined organic layer was washed with water and brine and finally dried (Na2SO4). Solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to afford the acylated amine.
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
10
[ 128094-80-4 ]
[ 2971-79-1 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1932, vol. 4, p. 259,263
11
[ 857778-39-3 ]
[ 2971-79-1 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1932, vol. 4, p. 259,263
12
[ 67-56-1 ]
[ 2971-79-1 ]
[ 1690-75-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
With formaldehyd; formic acid In water for 3 h; Heating / reflux
To a stirred solution of methyl isonipecotate (L. OOG, 7.00 mmol) in methanol (25 ml) was added formic acid (5.52g, 12.00 mmol) and a solution of formaldehyde (2.67g, 35.00 mmol, 40percent aqueous) and the reaction heated at reflux. After 3 hours the reaction was cooled and concentrated under reduced pressure. The aqueous solution was basified with NAHC03 and extracted with DCM (3 x 30 ml), dried (MGSO4) and concentrated under reduced pressure to give a brown liquid (L. OOG, 910-.) ; b (270 MHz; CDC13 ; Me4Si), 1.69-2. 03 (6 H, m), 2.23-2. 32 (4H, m), 2.78- 2.83 (2H, m), 3.68 (3 H, s); M/Z (APCI) 158 (100percent [M+H] +), 126 (33, C7H120N).
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 1761,1765
[2] Archiwum Chemji i Farmacji, 1936, vol. 3, p. 109,113[3] Chem. Zentralbl., 1937, vol. 108, # II, p. 74
15
[ 2971-79-1 ]
[ 100-39-0 ]
[ 10315-06-7 ]
Yield
Reaction Conditions
Operation in experiment
88%
With triethylamine In chloroform at 20℃;
To A solution of METHYL PIPERIDINE-4-CARBOXYLATE (10. 00 G, 6. 4 MMOL) AND triethylamine (10. 32 G, 10. 2 MMOL) IN CHC13 (100 ML), BENZYL BROMIDE (14. 69 G, 8. 6 mmol) was added under argon atmosphere while cooling with a water and ice bath. The mixture was stirred at room temperature overnight. CHCI3 and water were added and the two phases were separated. The aqueous phase was extracted with CHCI3. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 13. 80 G OF THE DESIRED COMPOUND AS AN ORANGE solid (YIELD : 88percent)
78%
With potassium carbonate In acetonitrile at 85℃; Inert atmosphere
General procedure: A mix of methyl piperidine-4-carboxylate or ethyl 2-(piperidin-4-yl)acetate (10 mmol) in acetonitrile (20 ml), 1a–j (11 mmol),anhydrous K2CO3 (12 mmol) was refluxed under nitrogen for 8 hat 85 C. The mixture was then cooled and filtered and the solvent removed in vacuum. The residue was dissolved in ethyl acetate(50 ml) and washed with water (15 ml). Drying and removal of the solvent followed by chromatography (ethyl acetate/petroleumether = 1:4) afforded desired product 2a–j.
Reference：
[1] Arkivoc, 2010, vol. 2010, # 10, p. 132 - 148
[2] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 43-44
[3] Synthesis, 2002, # 7, p. 911 - 915
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4324 - 4338
16
[ 2971-79-1 ]
[ 100-44-7 ]
[ 10315-06-7 ]
Yield
Reaction Conditions
Operation in experiment
98.6%
With triethylamine In 1,2-dichloro-ethane at 10 - 20℃; for 1.5 h; Reflux; Large scale
In the 1000L reactor, 360 kg of 1,2-dichloroethane was recovered in Example 2, and 69.54 kg of new 1,2-dichloroethane was added.Under stirring, 143.18 kg of methyl piperidinecarboxylate and 121.43 kg of triethylamine were added, and benzyl chloride 139.24 kg was added dropwise at a temperature of 10 to 20°C.After the dripping is completed, the temperature is gradually raised to reflux for 1.5 hours. The reaction of the raw material is completely cooled to 20 to 30° C., and 150 kg of water is added for 30 minutes to separate the liquid.The organic layer was dried, filtered, and the filtrate was concentrated to obtain 230.04 kg of methyl N-benzyl-4-piperidinecarboxylate;The molar yield was 98.6percent and the purity was 99.61percent.The 1,2-dichloroethane was recovered for the next reaction.
Reference：
[1] Patent: CN107903206, 2018, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025
[2] Patent: WO2008/31227, 2008, A1, . Location in patent: Page/Page column 37
[3] ChemSusChem, 2016, vol. 9, # 1, p. 67 - 74
17
[ 2971-79-1 ]
[ 10315-07-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4324 - 4338
18
[ 2971-79-1 ]
[ 24424-99-5 ]
[ 124443-68-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine In dichloromethane at 25℃; for 12 h;
Synthesis of 9-(Azetidin-1-yl)-9-phenyl-3-azaspiro[5.5]undecane Trifluoroacetate (A4); Step-1: 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate; To a stirred solution of methyl isonipecotate (127.2 mmol, 1 eq) in dichloromethane (200 ml) were added di-tert-butyldicarbonate (190.8 mmol, 1.5 eq) and triethylamine (254.4 mmol, 2.0 eq). The reaction mixture was stirred for 12 h at 25° C. It was then diluted with dichloromethane (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was separated, dried over Na2SO4, concentrated and employed in the next step without further purification. Yield: 98percent
95.5%
With triethylamine In dichloromethane at 20℃; for 8 h;
The 1L round-bottom flask is added in piperidine-4-carboxylic acid methyl ester (30g, 0.21mol), dissolved in 500 ml of in DCM, constant voltage dropping funnel for dropping (Boc)2O (45.72g, 0 . 21mol), triethylamine (42.3g, 0 . 42mol), stirring the mixture at room temperature for, 8 hours after the completion of the reaction, the volume of water to wash DCM layer 3 times, and evaporation drying of colorless oily organic 97.5g, yield 95.5percent.
86%
With triethylamine In dichloromethane at 20℃; for 1 h;
A. Synthesis of l-fert-butyl-4-methyl piperidine-l,4-dicarboxylate; [0065] Methyl isonipecotate (5 mL, 33 mmol), di-tert-butyl-dicarbonate (7 g, 33 mmol) and TEA (6.3 mL, 49.5 mmol) were stirred in DCM (100 mL) under N2 at rt for 1 h. The reaction was diluted to twice its volume with DCM, washed twice with saturated sodium bicarbonate solution followed by one wash with H2O. The organic layer was separated, dried over MgSO4 and concentrated to yield crude product (6.9 g, 86percent) as a clear colorless oil that was sufficiently pure to use in subsequent reactions.
75%
With triethylamine In dichloromethane at 20℃; for 16 h;
To a solution of methyl piperidine-4-carboxylate (3.0 g, 21.0 mmol, 1.0 eq) in CH2C12 (70 mL) were added Et3N (3.18 g, 31.5 mmol, 1.5 eq) and (Boc)20 (5.04 g, 23.1 mmol, 1.1 eq). Then the reaction mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel column (PE: EA = 3:1) to give 1-tert- butyl 4-methyl piperidine-l,4-dicarboxylate as colorless gum (3.8 g, Y: 75percent). ESTMS (M+H) +: 244.1. 1H NMR (400 MHz, CDC13) δ: 4.03-4.00 (m, 2H), 3.67 (s, 3H), 2.86- 2.79 (m, 2H), 2.48-2.42 (m, 1H), 1.89-1.85 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 18, p. 5036 - 5040
[2] Patent: US2010/113417, 2010, A1, . Location in patent: Page/Page column 36
[3] Patent: CN105541798, 2016, A, . Location in patent: Paragraph 0120; 0121
[4] Patent: WO2008/31227, 2008, A1, . Location in patent: Page/Page column 21
[5] Patent: WO2012/109108, 2012, A1, . Location in patent: Page/Page column 121
[6] Patent: WO2007/71035, 2007, A1, . Location in patent: Page/Page column 36-37
[7] Patent: WO2009/61676, 2009, A2, . Location in patent: Page/Page column 70-71
[8] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2827 - 2840
[9] Patent: US2006/63775, 2006, A1, . Location in patent: Page/Page column 18
[10] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3085 - 3092
[11] Patent: WO2014/150132, 2014, A1, . Location in patent: Page/Page column 44
[12] Patent: WO2016/8064, 2016, A1, . Location in patent: Page/Page column 39
[13] Patent: WO2016/10801, 2016, A1, . Location in patent: Page/Page column 33
[14] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 42
19
[ 2971-79-1 ]
[ 91419-52-2 ]
Reference：
[1] Patent: WO2016/65582, 2016, A1,
20
[ 2971-79-1 ]
[ 501-53-1 ]
[ 138163-07-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2354 - 2359
[2] Patent: US2007/129345, 2007, A1, . Location in patent: Page/Page column 18
[3] Patent: US2016/52883, 2016, A1, . Location in patent: Paragraph 0085; 0123
21
[ 2971-79-1 ]
[ 187834-88-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3085 - 3092
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16 h;
Step 1 : DIPEA (4 mL, 23.20 mmol) was added to 5-bromo-2-chloropyrimidine (3.0 g, 15.50 mmol) in acetonitrile (80 mL). Then, methyl isonipecotate (3.321 g, 23.20 mmol) was added to the solution. The reaction mixture was stirred at rt for Ex.9a 16h. The solvent was concentrated to dryness. Water and EtOAc were added to quench the reaction. The organic layer was separated and concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [0:100]. The product fractions were combined and concentrated to dryness to afford methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate Ex.9a (1 .84 mg, 41 percent) as white solid.
To A solution of METHYL PIPERIDINE-4-CARBOXYLATE (10. 00 G, 6. 4 MMOL) AND triethylamine (10. 32 G, 10. 2 MMOL) IN CHC13 (100 ML), BENZYL BROMIDE (14. 69 G, 8. 6 mmol) was added under argon atmosphere while cooling with a water and ice bath. The mixture was stirred at room temperature overnight. CHCI3 and water were added and the two phases were separated. The aqueous phase was extracted with CHCI3. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 13. 80 G OF THE DESIRED COMPOUND AS AN ORANGE solid (YIELD : 88%)
78%
With potassium carbonate; In acetonitrile; at 85℃;Inert atmosphere;
General procedure: A mix of methyl piperidine-4-carboxylate or ethyl 2-(piperidin-4-yl)acetate (10 mmol) in acetonitrile (20 ml), 1a-j (11 mmol),anhydrous K2CO3 (12 mmol) was refluxed under nitrogen for 8 hat 85 C. The mixture was then cooled and filtered and the solvent removed in vacuum. The residue was dissolved in ethyl acetate(50 ml) and washed with water (15 ml). Drying and removal of the solvent followed by chromatography (ethyl acetate/petroleumether = 1:4) afforded desired product 2a-j.
With 4-methyl-morpholine; In acetonitrile; for 0.5h;
Benzyl chloroformate (11.0 mL, 0.0768 mol) was added into a solution of methyl piperidine-4-carboxylate (10.0 g, 0.0698 mol) and 4-methylmorpholine (15.4 mL, 0.140 mol) in acetonitrile (20.0 mL). After 30 min, the mixture was diluted with NaHCO3 (7.5%), extracted with ethyl acetate (AcOEt) (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to afford 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (12 gram) which was directly used in next step without further purification. 2) 1-Benzyl 4-methyl 4-(2-chloroethyl)piperidine-1, 4-dicarboxylate
With triethylamine In dichloromethane at 20℃; for 16h;
9.A
A solution of 2.86 g (20 mmol) of methyl isonipecotate and 2.53 g (2.5 mmol) of triethylamine in 10 mL of dry dichloromethane was cooled to 0 °C, and a solution of 4.02 g (22 mmol) of 2,5-dimethylphenylacetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into 20 mL of water. The organic layer was washed with water and brine, dried (MgSC^) and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and hexanes to give 4.95 g (87.5 % yield) of the title compound as white crystals. 1H NMR (CDCl3) 5 1.5-1.7 (m, 2H), 1.78-1.98 (m, 2H), 2.22 (s, 3H), 2.28 (s, 3H), 2.50-2.58 (m, IH), 2.85-3.10 (m, 2H), 3.65 (s, 2H), 3.70 (s, 3H), 3.71-3.98 (m, IH), 4.45-4.52 (m, IH), 6.90-7.08 (m, 3H)
87.5%
With triethylamine In dichloromethane at 20℃; for 16h;
9.A
EXAMPLE 9 Preparation of 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-oxazolecarboxamide (Compound 153) Step A: Preparation of methyl 1-[(2,5-dimethylphenyl)acetyl]-4-piperidine-carboxylate. A solution of 2.86 g (20 mmol) of methyl isonipecotate and 2.53 g (2.5 mmol) of triethylamine in 10 mL of dry dichloromethane was cooled to 0 0C, and a solution of 4.02 g (22 mmol) of 2,5-dimethylphenylacetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into 20 mL of water. The organic layer was washed with water and brine, dried (MgSO^ and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and hexanes to give 4.95 g (87.5 % yield) of the title compound as white crystals. EPO 1H NMR (CDCl3) δ 1.5-1.7 (m, 2H), 1.78-1.98 (m, 2H), 2.22 (s, 3H), 2.28 (s, 3H), 2.50-2.58 (m, IH), 2.85-3.10 (m, 2H), 3.65 (s, 2H), 3.70 (s, 3H), 3.71-3.98 (m, IH), 4.45-4.52 (m, IH), 6.90-7.08 (m, 3H).
With triethylamine; In 1,2-dichloro-ethane; at 10 - 20℃; for 1.5h;Reflux; Large scale;
In the 1000L reactor, 360 kg of 1,2-dichloroethane was recovered in Example 2, and 69.54 kg of new 1,2-dichloroethane was added.Under stirring, 143.18 kg of methyl piperidinecarboxylate and 121.43 kg of triethylamine were added, and benzyl chloride 139.24 kg was added dropwise at a temperature of 10 to 20C.After the dripping is completed, the temperature is gradually raised to reflux for 1.5 hours. The reaction of the raw material is completely cooled to 20 to 30 C., and 150 kg of water is added for 30 minutes to separate the liquid.The organic layer was dried, filtered, and the filtrate was concentrated to obtain 230.04 kg of methyl N-benzyl-4-piperidinecarboxylate;The molar yield was 98.6% and the purity was 99.61%.The 1,2-dichloroethane was recovered for the next reaction.
With potassium carbonate; In acetonitrile; for 3h;Heating / reflux;
A. Synthesis of methyl l-benzylpiperidin-4-carboxylate; [0095] A mixture of methyl isonipecotate (14.3 g, 100 mmol) in acetonitrile (120 ml), benzyl chloride (13.9 g, 110 mmol), anhydrous K2CO3 (16.6 g, 120 mmol) was refluxed under nitrogen for 3 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (150 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (ethyl acetate: petroleum ether= 1: 3) afforded desired product (21.2 g).
Stage #1: hexylbenzene; acryloyl chloride With aluminium trichloride In dichloromethane at 20℃; for 2h;
Stage #2: isonipecotic acid methyl ester In tetrahydrofuran at 20℃; Further stages.;
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 16h;
To a stirring solution of 4-(2-bromo-ethyl)-phenol (EXAMPLE 5; 5.05 g, 25 mmol) in CH3CN (100 mL) was added piperidine-4-carboxylic acid methyl ester (5.07 mL, 37.5 mmol), followed by N,N-diisopropylethylamine (8.7 mL, 50 mmol). The reaction mixture was stirred at 60 C. for 16 h, and then allowed to cool to room temperature. CH2Cl2 (250 mL) was added, and the resulting solution was washed with H2O (2×30 mL), dried, filtered, and then concentrated under reduced pressure to afford 5.2 g (79%) of a tan solid. MS (ESI): mass calculated for C15H21NO3, 263.15; m/z found, 264.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.97 (d, J=8.2, 2H), 6.70 (d, J=8.6, 2H), 3.67 (s, 3H), 2.99 (d, J=11.5, 2H), 2.76-2.68 (m, 2H), 2.60-2.54 (m, 2H), 2.40-2.30 (m, 1H), 2.18 (t, J=10.8, 2H), 1.99-1.90 (m, 2H), 1.90-1.78 (m, 2H).
79%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 16h;
EXAMPLE 33; 1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}-PIPERIDINE-4-CARBOXYLIC acid methyl ester; P ; A. 1-R2- (4-HYDROXY-PHENYL)-ETHVLL-PIPERIDINE-4-CARBOXVLIC ACID METH RL ESTER; TO a stirring solution OF 4- (2-BROMO-ETHYL)-PHENOL (EXAMPLE 5; 5.05 g, 25 MMOL) in CH3CN (100 mL) was added piperidine-4-carboxylic acid methyl ester (5. 07 mL, 37.5 MMOL), followed BY N, N-DIISOPROPYLETHYLAMINE (8. 7 mL, 50 MMOL). The reaction mixture was stirred at 60 C for 16 h, and then allowed to cool to room temperature. CH2CI2 (250 mL) was added, and the resulting solution was washed with H20 (2 x 30 mL), dried, filtered, and then concentrated under reduced pressure to afford 5.2 g (79%) of a tan solid. MS (ESI) : mass calculated for C15H21NO3, 263.15 ; m/z found, 264.3 [M+H] +. 1H NMR (400 MHz, CDC13) : 6.97 (d, J = 8.2, 2H), 6.70 (d, J = 8.6, 2H), 3. 67 (s, 3H), 2.99 (d, J = 11.5, 2H), 2.76-2. 68 (m, 2H), 2.60-2. 54 (m, 2H), 2.40-2. 30 (m, 1H), 2.18 (T, J = 10.8, 2H), 1.99-1. 90 (m, 2H), 1.90-1. 78 (m, 2H)
With hydrogenchloride; sodium hydroxide; In 1,4-dioxane; water;
Example 10A Methyl N-(4-fluoro-3-methylphenyl)piperidine-4-carboxylate starting with 10.6 g (74.0 mmol) of methyl piperidine-4-carboxylate and 4.67 g (24.7 mmol) of <strong>[51437-00-4]5-bromo-2-fluorotoluene</strong>, the general procedure [E] gives 2.74 g (40% of theory) of product. HPLC (method 1): Rt=3.48 min Examples 11A to 17A from the table below can be prepared in accordance with the general procedure [E]. General Procedure [F]: Hydrolysis of the N-arylpiperidine-4-carboxylic Esters 1.0 equivalent of the N-arylpiperidine-4-carboxylic ester is dissolved in dioxane, and 2.0 equivalents of 1N aqueous sodium hydroxide solution are added. The mixture is stirred at 80 C. for 16 hours, and after the reaction has ended (the reaction is monitored by analytical HPLC) the mixture is concentrated. The residue is then taken up in water and adjusted to pH=5 using 1N hydrochloric acid. The resulting precipitate is filtered off, washed with a little water and cyclohexane and dried at room temperature under high vacuum. If the purity of the product is not high enough, the product is purified by preparative HPLC on an RP phase.
Stage #1: isonipecotic acid methyl ester; 1,1'-Thiocarbonyldiimidazole In tetrahydrofuran at 20℃; for 1.5h;
Stage #2: With hydrazine In tetrahydrofuran for 4h;
2
REFERENCE SYNTHETIC EXAMPLE 2; Synthesis of methyl l-hydrazinothiocarbonylpiperidine-4- carboxylate; To a solution of methyl isonipecotate (1.0 g, 7.0 mmol) in tetrahydrofuran was added thiocarbonyl diimidazole (1.24 g, 6.98 mmol) at room temperature, and the reaction solution was stirred at room temperature for1.5 hours and then stirred with hydrazine monohydrate(700 mg, 14.0 mmol) for 4 hours. After addition of saturated aqueous sodium chloride, the reaction solution was extracted with ethyl acetate and chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 114%) .Morphology: pale yellow solid LC/MS: condition 5, retention time 0.52 (min)LC/MS (ESI+)m/z; 218, [M+l] +
100%
Stage #1: isonipecotic acid methyl ester; 1,1'-Thiocarbonyldiimidazole With hydrazine In tetrahydrofuran at 20℃; for 1.5h;
Stage #2: With hydrazine In tetrahydrofuran for 4h;
6 Methyl 1-hydrazinothiocarbonylpiperidine-4-carboxylate
REFERENCE SYNTHETIC EXAMPLE 6 Methyl 1-hydrazinothiocarbonylpiperidine-4-carboxylate Methyl isonipecotinate (1.0 g, 6.98 mmol) in tetrahydrofuran was mixed with thiocarbonyldiimidazole (1.24 g, 6.98 mmol) at room temperature and then stirred at room temperature for 1.5 hours and stirred with hydrazine monohydrate (700 mg, 14.0 mmol) for another 4 hours. The reaction solution was mixed with saturated aqueous sodium chloride and extreacted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the crude preparation of the desired product (114% yield). Morphology: pale yellow solid LC/MS: Condition 3, retention time 0.52 (min) LC/MS (ESI+) m/z; 218 [M+1]
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; for 36h;Heating / reflux;
(a) Methyl 1-(5-bromo-3 -methylpyridin-2-yl)piperidine -4-carboxylate; EPO <DP n="213"/>5-Bromo-2-chloro-3-methylpyridine (1.23 g, 5.96 mmol), methyl piperidine-4-carboxylate (1.7 g, 12 mmol) and DIPEA (1.6 ml, 9.0 mmol) where combined in DMA (2 ml) and heated for 36 h. The reaction was cooled and diluted with EtOAc (75 ml) and washed with 0.5 N HCl (30 ml), water (2 x 40 ml), brine (30 ml) and dried (Mg5O4). The crude reaction mixture was concentrated in vacuo and purified by column chromatography (15% EtOAc/hexanes) to provide methyl 1-(5-bromo-3-methylpyridin-2-yl)piperidine-4-carboxylate. Yield: 0.49 g (26%).1HNMR (400 MHz, CDCi): 6 1.82-1.92 (2H, m), 2.00-2.05 (2H3 m), 2.25 (3H, s), 2.45-2.52 (1H, m), 2.77-2.83 (2H, m), 3.39-3.42 (2H, m), 3.71 (3H, s), 7.51 (1H, d, J= 2.2 Hz), 8.16 (1H, d, J= 2.2 Hz).M5 m/z: 313/315 (M+l, Br pattern).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 110℃; for 14h;
(b) Ethyl 6-(4-(methxycarbonyl)piperidin-1-yl)-2,4-dimethylnicotinate; Ethyl 6-chloro-2,4-dimethyhiicotinate (1.04 g. 4.9 mmol), methyl piperidine-4-carboxylate (1.4 g, 9.7 mmol) and DIPEA (2.3 ml, 15 mmol) were combined in DMA (8 ml) and heated at 110 C for 14 hours: The reaction was cooled and partitioned between saturated aqueous NH4Cl (100 ml) and EtOAc (200 ml). The organic phase was washed with additional NH4Cl (2 x 75 ml), water (3 x 75 ml) and brine (50 ml). The organic phase was then dried (Mg5O4), concentrated in vacuo and purified by column chromatography (15% to 20% EtOAc in hexanes) to provide ethyl 6-(4-(methoxycarbonyl)piperidin-1-yl)-2,4-dimethyhiicotinate. Yield: 1.15 g (74%).1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.68-1.78 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.46 (3H, s), 2.52-2.58 (1H, m), 2.93-2.99 (2H, m), 3.70 (3H, s), 4.28-4.36 (4H, m), 6.28 (1H, s). M5 "V2: 321 (M+l).
74%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 110℃; for 14h;
(b) Ethyl 6-(4-(methxycarbonyl)piperidin-1-yl)-2,4-dimethylnicotinate; Ethyl 6-chloro-2,4-dimethyhiicotinate (1.04 g. 4.9 mmol), methyl piperidine-4-carboxylate (1.4 g, 9.7 mmol) and DIPEA (2.3 ml, 15 mmol) were combined in DMA (8 ml) and heated at 110 C for 14 hours: The reaction was cooled and partitioned between saturated aqueous NH4Cl (100 ml) and EtOAc (200 ml). The organic phase was washed with additional NH4Cl (2 x 75 ml), water (3 x 75 ml) and brine (50 ml). The organic phase was then dried (Mg5O4), concentrated in vacuo and purified by column chromatography (15% to 20% EtOAc in hexanes) to provide ethyl 6-(4-(methoxycarbonyl)piperidin-1-yl)-2,4-dimethyhiicotinate. Yield: 1.15 g (74%).1H NMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.68-1.78 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.46 (3H, s), 2.52-2.58 (1H, m), 2.93-2.99 (2H, m), 3.70 (3H, s), 4.28-4.36 (4H, m), 6.28 (1H, s). M5 "V2: 321 (M+l).
(a) 5-Chloro-6-(4-(methoxycarbonyl)piperidin-1-yl)nicotinic acid; A suspension of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> (50.0 g, 260 mmol) and methyl piperidine-4- carboxylate (46.6 g, 325 mmol) in DMA (350 mL) was heated to 12OC until complete consumption of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> was observed by HPLC analysis. The reaction mixture was concentrated under reduced pressure, diluted with DCM (100 mL), washed with IN HCl (400 mL), brine (400 mL), dried (Mg5O4) and concentrated under reduced pressure to afford 5-chloro-6-(4-(methoxycarbonyl)piperidin-1-yl)nicotinic acid, which was used without further purification. Yield: 75.1 g (96 %).; (a) 5-Chloro-6-(4-(methoxycarbonyl)piperidin-1-yl)nicotinic acid; EPO <DP n="216"/>A suspension of 5, 6-dichloronicotinic acid (25.0 g, 130 mmol), methyl piperidine-4- . carboxylate (23.3 g, 163 mmol) and DIPEA (45.4 mL, 260 mmol) in DMA (200 mL) was heated to 120C until complete consumption of starting material was observed by HPLC analysis. The reaction mixture was concentrated under reduced pressure and partitioned between DCM (500 mL) and IM HCl (250 mL). The organic layer was washed with brine (250 mL), dried (Mg5O4) and concentrated under reduced pressure to afford 5-chloro-6-(4- (methoxycarbonyl)piperidin- 1-yl)nicotinic acid.1HNMR (400 MHz, CDCl5): 6 1.86-1.95 (2H, m), 2.03-2.07 (2H, m), 2.55-2.62 (1H, m), 3.03-3.09 (2H, m), 3.72 (3H, s), 4.12-4.15 (2H, m), 8.15 (1H, s), 8.79 (1H, s). M5 m/z: 299 (M+l).
methyl 1-(2-phenoxyethyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydrogencarbonate; In acetonitrile; at 100℃; for 16h;
To a stirred solution of (2-bromoethoxy)benzene (1 g, 5 mmol) in CH3CN (50 mL) wereadded methyl piperidine-4-carboxylate (0.715g, 5 mmol, 1 equiv) and sodium bicarbonate (1.26 g, 15 mmol, 3 equiv) at room temperature. The reaction mixture was heated atlOOand stirred for 16 h. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extract was washed with brine, filtered and dried over sodium sulphate. The solvent was removed under reduced pressure. Purificationusing silica gel column chromatography (20% EtOAc Hexanes as eluent) afforded 1 gmethyl 1-(2-phenoxyethyl) piperidine-4-carboxylate (Yield = 76%). ESI+ MS: m/z: 264.1 ([M+Hj).
65%
With sodium hydrogencarbonate; In acetonitrile; at 80℃; for 20h;
To a stirred solution of methyl isonipecotate (4. 00G, 28.00 mmol) and <strong>[589-10-6]phenoxyethyl bromide</strong> (4. 00g, 20.00 mmol) in acetonitrile (30 ml) was added sodium hydrogen carbonate (7. 00G, 84.00 mmol) and the reaction stirred at 80C for 20 hours. The reaction was cooled, filtered and concentrated under reduced pressure to give a crude brown oil. Purification by column chromatography (7% methanol: dichloromethane) gave the required compound as a light brown oil (4.8g, 65%). oH (270 MHz; CDCL3 ; ME4SI), 1.71-2. 37 (7H, m), 2.79 (2H, t, J 6. 0), 2.93-3. 0 (2H, m) 3.68 (3H, s), 4.10 (2H, t, J 6.0), 6.89-6. 97 (3H, m), 7.24-7. 32 (2H, m). HPLC 99%, m/z (APCI), 264.20 (100% [M+H] +), 232 (40, C14HL802N), 170 (47, C9H1602N).
With caesium carbonate; In dimethyl sulfoxide; at 20 - 70℃; for 2.5h;
Step 1. To a solution of <strong>[160538-51-2]3-fluoro-4-nitrobenzaldehyde</strong> 63 (0.793 g, 5 mmol) in DMSO (5 mL) was added methyl piperidine-4-carboxylate (0.7 mL, 5 mmol) and cesium carbonate (1.76 g, 5 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 70 C. for 2 h, and diluted with EtOAc. The organic phase was washed with water (1*), brine (1*), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 60% EtOAc in hexanes) gave methyl 1-(5-formyl-2-nitrophenyl)piperidine-4-carboxylate 64 (0.931 g, 68% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1; found 293.1 (M++1).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;
1
To a stirred solution of 4-fluoro nitrobenzene (la, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80 °C for 10h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxylate (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24h. After completion of the reaction ethanol is evaporated under vaccum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4- nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27 °C) and fallowed by reflux at temperature 85 °C for 2.5h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1 -(4-nitrophenyl)-4-piperidyl]-2,3-dihydro- 1,3,4- oxadiazol-2-one (Sa, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65 °C for 4h, after completion of reaction methanol is evaporated under vaccum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4- aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2h at room temperature (27 °C), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to affordpure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2- furamide (8a, 323 mg, 81%). 1H NMR (CDCl3, 300 MHz): δ 1.84-1.97 (m, 2H), 2.05-2.13 (m, 2H), 2.67-2.75 (m, 1H), 2.82-2.91 (m, 2H), 3.64-3.69 (m, 2H), 6.92 (d, 2H, J= 9.06 Hz), 7.34 (d, 1H, J=3.77 Hz), 7.38 (d, 1H, J= 3.77 Hz), 7.53 (d, 1H, J=9.06 Hz), 8.23 (bs, 1H); MS (ESI): m/z (400) (M+1)+.
85%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;
1
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy- late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vaccum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and fallowed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vaccum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro -1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
52%
With potassium carbonate In acetonitrile for 18h; Reflux; Inert atmosphere;
With potassium carbonate In acetonitrile Reflux;
70.A methyl 1-(4-nitrophenyl)piperidine-4-carboxylate
A solution of 1-fluoro-4-nitrobenzene (3.5 g, 24.81 mmol), methyl piperidine-4-carboxylate (4.26 g, 29.77 mmol) and K2CO3 in 40 mL of ACN, was stirred at reflux overnight. The mixture was added to 150 mL of water, extracted with EA, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (10:1˜2:1) to give 3.84 g of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate.
308 g
With triethylamine In acetonitrile Reflux;
310.A A) methyl 1-(4-nitrophenyl)piperidine-4-carboxylate
A) methyl 1-(4-nitrophenyl)piperidine-4-carboxylate [1044] A mixture of methyl piperidine-4-carboxylate (2.70 g), 1-fluoro-4-nitrobenzene (6.00 g) and triethylamine (6.80 g) in acetonitrile (60 mL) was refluxed overnight, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.80 g). MS(ESI+): [M+H]+ 265.1. MS (ESI+), found: 265.2.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 150℃; for 1.5h;
285
The resulting mixture was extracted with ethyl acetate and hydrochloric acid (0.2 N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a Biotage flash column chromatography using ethyl acetate and hexanes (1 : 1 ratio) to give a yellow solid as l-(4- nitrophenyl)-piperidine-4-carboxylic acid methyl ester (490 mg). 1H-NMR is consistent with the structure.
G.a
Piperidine-4-carboxylic acid methyl ester (1.5 eq.) is added to a solution of cyclopropanecarboxylic acid (5-brorno-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (leq) in tert-butanol. The reaction is heated at 1200C for 16hr. The excess of solvent is evaporated. The crude is purified by flash chromatography 1:2 petrol/EtOAc.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;
EXAMPLE 6; 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amineStep 1. Methyl l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylate[0321] To a solution of methyl piperidine-4-carboxylate (7.1 g, 50 mmol) in DMF (50 mL), was added <strong>[111196-81-7]2-chloro-5-ethylpyrimidine</strong> (14 g, 100 mmol) and diisopropylethylamine (10 mL). The reaction mixture was heated to 1000C for 2 h. The solution is then poured into ice water (500 mL), and extracted with ethyl acetate (2 x 200 mL). Purification by silica gel chromatography (gradient 10% to 50% ethyl acetate/hexanes) afforded methyl l-(5-ethylpyrimidin-2-yl)piperidine-4- carboxylate as a light yellow oil (8.6 g, 69%). LCMS: 250.2 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 1.0 g (5.2 mmol) of 3-nitro-2,5-dichloropyridine inN,N- dimethylformamide (20 mL) is added 0.75 g (5.8 mmol) of methyl isonipocoate followed by 7 g (50 mmol) of potassium carbonate. The mixture is stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 1.1 g (71%) of 5'-chloro-3'-nitro-3,4,5,6-tetrahydro-2H- [l,2']bipyridinyl-4-carboxylic acid methyl ester as a red oil.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃;
Synthesis of Methyl 1-(2-fluoro-6-nitrophenyl)piperidine-4-carboxylate (lnt-20A mixture of <strong>[6921-22-8]difluoronitrobenzene</strong> (0.34 mL, 3.10 mmol), methyl isonipecotate (0.51 mL, 3.78 mmol), and diisopropyiethylamine (1 .08 mL, 6.20 mmol) in acetonitrile (15 mL) was heated at 80C overnight. The solvents were removed in vacuo. Chromatographic purification (20% ethyl acetate :hexane) of the residue gave lnt-20a (0.85 g, 97%) as a yellow oil.
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 1.0h;Inert atmosphere; Microwave irradiation;
General procedure: A solution of 56 (1.50 g, 7.16 mmol), the appropriate secondary amine (8.59 mmol, 1.20 equiv) and diisopropylethylamine (1.50 mL, 8.59 mmol) in n-butanol (15 mL)was heated in a microwave reactor using variable wattage to 140 C for 1 h. The mixture was concentrated and purified by flash column chromatography on silica, eluting with 9:1 dichloromethane/methanol, to give gave 58-63.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;
5
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80 °C for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12h. After completion of the reaction ethanol is evaporated under vaccum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,Ndimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27 °C) and fallowed by reflux at temperature 85 °C for 2.5h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65 °C for 4h, after completion of reaction methanol is evaporated under vaccum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, I mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2h at room temperature (27 °C), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%). 1H NMR (CDCl3, 300 MHz): δ 1.85-1.99 (m, 2H), 2.06-2.11 (m, 2H), 2.67-2.77 (m, 1H), 2.82-2.91 (m, 2H), 3.64-3.69(m, 2H), 6.95 (t, 1H, J= 9.06 Hz), 7.27 (dd, 1H, J=1.55, 7.55 Hz), 7.38 (d, 1H, J= 3.77 Hz), 7.41 (d, 1H, J= 3.77 Hz), 7.56 (dd, 1H, J=2.26, 11.25 Hz), 8.30 (bs, 1H); MS (ESI): m/z (418) (M+1)+.
86%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;
5
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vaccum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and fallowed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vaccum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3 ,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
(E)-ethyl α-cyano-2-(methyl isonipecotat-1-yl)-5-cyanocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol; at 78℃; for 1h;
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield.
methyl 1-[(4-tert-butoxycarbonylphenyl)methyl]piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
The mixture of methyl piperidine-4-carboxylate (690 mg,4.82 mmol, 1.0 eq), <strong>[121579-86-0]tert-butyl 4-(chloromethyl)benzoate</strong> (1.09 g,4.82 mmol, 1.0 eq) and KzCOs (1.33 g, 9.64 mmol, 2.0 eq) in DMF (10 mL) was stirred at 80oC for 16 h. To the mixture was added ethyl acetate (20 mL). The mixture was washed with water (15 mL *3). The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate:3O:1 to 10:1) to afford methyl l-f(4+ert-butoxycarbonylphenyl)methyl]piperidine-4-carboxylate (1.50 g, 4.50 mmol, 93percentyield) as a yellow oil. LCMS m/2334 [M+H]+.
methyl 1-(5-fluoropyridin-2-yl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.8 g
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 120℃; for 2h;
To a solution of methyl piperidine-4-carboxylate (4.6 ml, 34.22 mmol) and <strong>[31301-51-6]2-chloro-5-fluoropyridine</strong> (1.5 g, 11.4 mmol) in dry toluene (25 ml) sodium tert-butoxide (1.37 g,14.25 mmol), BINAP (212 mg, 0.34 mmol), and tris(dibenzylideneacetone)dipalladium(0)(104 mg, 0.114 mmol) were added. The mixture was heated to 120C and stirred at thistemperature for 2 hr then cooled to rt Water (30m1) and EtOAc (20 ml) were added. Phases were separated, and the aqueous layer was extracted (2x) with EtOAc. The combined organic phases were dried over Na2504 and evaporated. Crude product was purified by flash chromatography (Silica, Cy/EtOAc from 1/0 to 8/2) to give the title compound (1.8 g, 7.6 mmol, purity: 97 % by UV a/a, recovery: 66 %). MS (m/z) 239 (M+H).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 15h;
(1) A suspension of Compound 1 (30.5 g), Compound 2 (25 g), and potassium carbonate (33 g) in N-methylpyrrolidone (150 mL) was stirred at 130C for 15 hours. The reaction mixture was cooled to room temperature, then water and ethyl acetate were added thereto, stirred, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline, dried, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=98:2-85:15) to give Compound 3 (48.28 g) as a yellow viscous material. MS (ESI): m/z 316 [M+H]+
methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;
9.1 Step 1: Preparation of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate.
To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) in N,N-dimethylformamide (30 mL) were added methyl piperidine-4-carboxylate (2.88 g, 20.09 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 3,3-tetramethyluronium hexafluorophosphate) (6.35 g, 16.7 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (6.49 g, 50.2 mmol, 8.77 mL). The mixture was stirred at 20 °C for 3 h and then quenched by addition of water (40 mL). The mixture was extracted with ethyl acetate (80 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate 5:1 to 1:1) to give methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol, quantitative), as a yellow oil. LCMS (ESI) m/z 305.1 [M÷H]÷.
methyl 1-(2-cyanophenyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.39%
With potassium carbonate In dimethyl sulfoxide at 120℃; for 2h;
344.1 Step 1: Methyl 1-(2-cyanophenyl)piperidine-4-carboxylate
A mixture of methyl piperidine-4-carboxylate (1.50 g, 10.48 mmol), 2- fluorobenzonitrile (1.27 g, 10.48 mmol) and K2C03 (3.62 g, 26.20 mmol) in DMSO (15.00 mL) was kept stirring at 120 °C for 2 h. The mixture was diluted with EtOAc (200 mL), washed with water (50 mL x 3) and brine (40 mL). The organic layer was dried over Na2SO4 for 20 mins, filtered and concentrated under vacuum. The residue was purified by CombiFlash (UV 254, silica gel, 40 g, EAPE from 2O%7O%) to give the product methyl 1-(2-cyanophenyl)piperidine-4- carboxylate (1.98 g, 8.11 mmol, 77.39% yield) as yellow solid. ESI-MS (EI, m/z): 245.2 [M+H]+
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;
Step 1 : DIPEA (4 mL, 23.20 mmol) was added to 5-bromo-2-chloropyrimidine (3.0 g, 15.50 mmol) in acetonitrile (80 mL). Then, methyl isonipecotate (3.321 g, 23.20 mmol) was added to the solution. The reaction mixture was stirred at rt for Ex.9a 16h. The solvent was concentrated to dryness. Water and EtOAc were added to quench the reaction. The organic layer was separated and concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [0:100]. The product fractions were combined and concentrated to dryness to afford methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate Ex.9a (1 .84 mg, 41 %) as white solid.
To a solution of methyl 4-piperidinecarboxylate (1.0 g, 6.98 mmol, 1 eq) in ethanol (10 mL) was added DIPEA (4.5 g, 34.92 mmol, 5 eq) the mixture was stirred at room temperature for 15 min, then 5-bromo-2-chloropyrimidine (1.35 g, 6.98 mmol, 1 eq) was added and the mixture was stirred at 70 C for 1 hour. The mixture was concentrated to get methyl l-(5-bromopyrimidin-2- yl)piperidine-4-carboxylate (2 g, 6.66 mmol, 95.41% yield) as a yellow solid used directly in the next step. MS m/e: 302 ([M+H+]+).
methyl 1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
490 mg
With potassium carbonate; at 90℃;Microwave irradiation;
A solution of methyl piperidine-4-carboxylate (LXXXII) (254 mg, 1.77 mmol), <strong>[78385-26-9]3-(bromomethyl)-3-methyloxetane</strong> (LXXXIII) (439 mg, 2.66 mmol), and potassium carbonate (736 mg, 5.32 mmol) in MeOH (5 mL) was heated by microwave irradiation at 90 C. overnight. The solvent was removed under vacuum and the residue taken up in DCM and filtered. The organic layer was evaporated to give methyl 1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxylate (LXXXIV) as a brown oil (490 mg) which was used without further purification. ESIMS found for C12H21NO3 m/z 228.2 (M+H).
<strong>[16499-61-9]4-chloro-6-fluoroquinazoline</strong> 2 [1] (2.00 g, 10.95 mmol) and 1,4-dioxane (20 mL) were added into a round bottom flask and stirred for 5 min, followed by addition of methyl 4-piperidinecarboxylate (1.63 mL, 12.05 mmol) to the above mixture. The resulting mixture was heated to reflux for 7 h and then cooled to room temperature. The formed precipitate was filtered off, washed with 1,4-dioxane and dried to give 3 as a white solid. Yield: 77.3%;
methyl 1-(3-amino-6-chloropyridazin-4-yl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.2%
In acetonitrile; at 90℃; for 16h;Inert atmosphere;
To a stirred solution of <strong>[446273-59-2]4-bromo-6-chloropyridazin-3-amine</strong> (0.38 g, 1.84 mmol) in acetonitrile (7 mL) was added methyl piperidine-4-carboxylate (1.31 g, 9.22 mmol ) at RT and stirred for 16 h at 90 C under nitrogen atmosphere. Then the reaction mixture was quenched with cold water (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash using 60 % ethyl acetate in hexane as eluent to afford title compound (0.36 g, 72.2 %) 1H NMR (400 MHz, DMSO-d6): d 6.86 (s, 1H), 6.09 (s, 2H), 3.63 (s, 3H), 3.68-3.51 (m, 3H), 2,68-2,61 (m, 2H), 1.93-1.81 (m, 4H); LC-MS: m/z 271.0 (M+l)+.
methyl 1-(6-nitropyridin-2-yl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation; Inert atmosphere;
In a 20 ml microwave vial, <strong>[94166-64-0]2-chloro-6-nitropyridine</strong> (0.79 g, 5 mmol) was dissolved in dioxane (10 ml) and methyl piperidine-4-carboxylate (0.72 g, 1 eq) was added followed by Hunig's base (0.96 ml, 1.1 eq). The reaction was subjected to in the microwave for 1 h at 150 C. (0773) The reaction mixture was diluted with water, the mixture was extracted ethyl acetate, treated with brine, dried with MgS04, filtered and the solvent was removed in vacuo to give the crude product. (0774) The crude product was purified by flash chromatography eluting with 15% ethyl acetate/ hexane to give methyl l-(6-nitropyridin-2-yl)piperidine-4-carboxylate (554 mg solid, 42% yield, MS m/z (M+l) 266). TLC 40% ethyl acetate/ hexane Rf 0.35.
methyl 1-(4-phenylpyridin-3-yl)piperidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium tertiary butoxide In toluene at 110℃; for 6h; Inert atmosphere;
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