* 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.
ISONIPECOTAMIDE (10G, 78. Ommoles) was dissolved in distilled water (100ML) and 37percent aqueous formaldehyde (7.6mL, equivalent to 2. 81g HCHO, 93. 6MMOLES) was added. Wet 10percent Pd-C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25 C and 50psi FOR 43H. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60x5cm) using 8percent-10percent-20percent (10percent CONC. ammonium hydroxide in METHANOL)-DICHLOROMETHANE as the eluant to give 1-methylisonipecotamide (7.15g, 64percent): FABMS: m/z 143.1 (MH+) ; HRFABMS: m/z 143.1184 (MH+). CALCD. FORC7H15N2O : m/z 143.1184 ; No.H (d6- DMSO) 1.50/1. 57 (4H, m, CH2), 1.76/1. 94 (4H, m, CH2), 2.10 (3H, s,-NCH3), 2.72 (1H, m, CH) and 6.68/7. 18 ppm (2H, M, CONH2); 8c (D6-DMSO) CH3 : 41.2 ; CH2: 28.5, 28.5, 54.9, 54.9 ; CH: 46.2 ; C: 176.7.
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 7, p. 1116 - 1119
[2] Patent: WO2004/22561, 2004, A1, . Location in patent: Page 110
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7520 - 7534
[4] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
2
[ 39546-32-2 ]
[ 4395-98-6 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: for 4 h; Inert atmosphere; Reflux Stage #2: With potassium hydroxide In waterCooling with ice
4-Pιperιdιnecarboxamιde (10 g, 78 mmol) was refluxed in thionyl chloride (35 mL) for 4 h until the suspension became homogeneous The reaction was cooled to rt and poured onto 300 g of crushed ice The ice slurry melted and the solution was treated with potassium hydroxide pellets until pH = 9 The reaction was concentrated to a residue which was partitioned between water and chloroform The aqueous layer was extracted with four portions of chloroform and the organic fractions were combined and concentrated The reaction yielded 3 1 g (36percent) of the 4- piperidmecarbonitrile as a brown oil 1H-NMR (400 MHz, DMSO-d6) δ ppm 2 84 - 2 98 (m, 1 H), 2 79 (ddd, J = 12 3, 6 0, and 3 7 Hz, 2 H), 2 44 - 2 66 (m, 2 H), 2 24 (brs, 1 H), 1 66 - 1 84 (m, 2 H), and 1 44 - 1 64 (m, 2 H)
32.7%
at 65 - 70℃; for 3 - 4 h;
Example 1; Thionyl chloride 232 gm (molar ratio thionyl chloride:piperidine-4-carboxamide is 2.53:1) is taken in a 500 ml four-necked reaction flask, fitted with glass agitator and a condenser. A vent is provided at the condenser top passing through a 10percent diluted solution of caustic lye to neutralize the vent gases. Piperidine-4-carboxamide 100 gm is added lot wise with continuous stirring over a period of 30 minutes, temperature increased from 32° to 65° C. due to the exothermicity of the reaction. The reaction mixture is maintained at 65°-70° C. for 3-4 hours and a sample is drawn and analyzed, 4-cyanopiperidine 94.78percent Area, Piperidine-4-carboxamide=Nil is obtained. The reaction mass is cooled to room temperature and poured over 400 gm crushed ice by maintaining the temperature at 0°-10° C. Then, 160 gm (46percent solution) caustic lye is added to the above mass while maintaining the temperature between 15°-20° C. and the pH is adjusted between 12 and 13. The alkaline reaction mass is extracted with (400 ml.x.4) toluene. The organic layer is separated and the solvent is recovered by atmospheric distillation. The concentrated mass is distilled under high vacuum (4-6 mm Hg) to obtain 52.5 gm (molar yield=61percent) 4-cyanopipeiridne with purity 99.75percent. Example 2; Thionyl chloride 70 gm (molar ratio, thionyl chloride:piperidine-4-carboxamide (1.50:1) is taken in a 250 ml 4-necked glass reactor fitted with an agitator and a condenser. A vent is provided at the condenser top passing through a 10percent diluted solution of caustic lye to neutralize the vent gases. Piperidine-4-carboxamide 50 gm is added lot wise and the same procedure as in Example 1 is followed. 27 gm (molar yield 62.8percent) 4-cyanopiperidine is obtained after final distillation with purity 99.0percent. Example 3; Thionyl chloride 465 gm (molar ratio, thionyl chloride:piperidine-4-carboxamide 10:1) is taken in a 500 ml, 4-necked glass reactor fitted with an agitator and a condenser. A vent is provided at the condenser top passing through a 10percent diluted solution of caustic lye to neutralize the vent gases. Piperidine-4-carboxamide 48 gm is added lot-wise and after following the same procedure as in Example 1, 13.5 gm (molar yield 32.7percent) of 4-cyanopiperidine is obtained with 98.75percent purity.
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
[2] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 155
[3] Patent: US2006/84808, 2006, A1, . Location in patent: Page/Page column 2
[4] Journal of Organic Chemistry, 1957, vol. 22, p. 984
[5] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 7, p. 822 - 829
[6] Patent: WO2004/99178, 2004, A1, . Location in patent: Page 37-38
[7] Patent: US2007/238723, 2007, A1, . Location in patent: Page/Page column 44-45
[8] Patent: EP1714961, 2006, A1, . Location in patent: Page/Page column 19
[9] Patent: CN104557356, 2017, B, . Location in patent: Paragraph 0143-0145; 0153; 0164; 0186; 0219; 0230
3
[ 39546-32-2 ]
[ 4395-98-6 ]
Reference：
[1] Patent: US4284636, 1981, A,
4
[ 39546-32-2 ]
[ 498-94-2 ]
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 136 - 142
5
[ 1453-82-3 ]
[ 39546-32-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 44, p. 14488 - 14492[2] Angew. Chem., 2018, vol. 130, # 44, p. 14696 - 14700,5
[3] Helvetica Chimica Acta, 1954, vol. 37, p. 1672,1676
[4] New Journal of Chemistry, 2008, vol. 32, # 6, p. 1027 - 1037
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
[2] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 7, p. 822 - 829
[3] Patent: US2011/136823, 2011, A1,
[4] Patent: EP1714961, 2006, A1,
19
[ 39546-32-2 ]
[ 24424-99-5 ]
[ 91419-48-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 4-methylmorpholine N-oxide In 1,4-dioxane
The ring nitrogen atom of isonipecotamide 1 (commercially available from Aldrich) was Boc-protected in 95percent isolated yield by using Boc20 in dioxane and NMO as the base.
95%
at 20℃; for 2 h;
Example 1: 4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester[0029] To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino- pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) drop wise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5v/vpercent, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10percent of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95percent) of product. TLC: dichloromethane-methanol 90: 10, Rf (product) = 0.28; Rf (starting material) = base line, iodine positive.
95%
With dmap In dichloromethane at 20℃; for 2 h;
To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino-pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) dropwise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5 v/v percent, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10percent of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95percent) of product.TLC: dichloromethane-methanol 90:10, Rf (product)=0.28; Rf (starting material)=base line, iodine positive.
89%
at 20℃; for 1 h;
ISONIPECOTAMIDE (1) (28.8 g, 0.22 mol) was suspended in chloroform (288 mL). To this was added 4- (dimethylamino) pyridine (DMAP) (23 mg, catalytic) followed by dropwise addition of a solution of BOC-anhydride (56 g, 0.26 mol, 1.14 equiv. ) in chloroform (57 mL). The solution was stirred at room temperature for 1 h and then partitioned between chloroform and 10percent citric acid solution. The organic phase was washed with citric acid solution and back extracted with chloroform. The combined organic extracts were washed with water, 10percent brine and dried (MgSO4). Filtration followed by evaporation of the filtrate gave the crude product as a pink solid. Crystallisation from ethyl acetate/hexane gave the title compound (2) as a colourless solid in 4 crops (45.5 g, 0.20 mol, 89percent)
82.4%
With sodium carbonate In 1,4-dioxane; water at 20℃; for 5 h;
Example 3N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)piperidine-4-carboxamideStep A: Preparation of tert-butyl 4-Carbamoylpiperidine-1-carboxylate. To a solution of isonipecotamide (500 mg, 3.90 mmol) in a mixture of 5percent aqueous sodium carbonate (7 ml) and 1,4-dioxane (3 ml) was added Boc-anhydride (1.30 ml, 5.85 mmol) and stirred for 5 h at room temperature. The pH was adjusted to 5-6 with acetic acid and volatiles were evaporated under vacuo. The residue was triturated with n-pentane and diethyl ether to yield 740 mg (82.4percent) of tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid.
80%
With dmap In dichloromethane at 20℃; Inert atmosphere
To a suspension of isonipecotamide (3.0 g, 23.4 mmol) and 4-dimethylaminopyridine (2.87 g, 23.4 mmol) in CH2Cl2in a reaction flask was added a solution of di-tert-butyl dicarbonate (6.1 g, 28.1 mmol) in CH2Cl2dropwise at room temperature with stirring. After stirring the reaction mixture at room temperature for 6 h, the solution was washed with phosphoric acid water solution (2.5 v/v percent), water, saturated NaHCO3(aq) and brine, respectively. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The white solid formed was obtained by filtration and washed with hexanes and dried to afford compound8(4.3 g, 80percent).1H-NMR (DMSO-d6,500 MHz) δ 7.26 (1H, s, NH2), 6.77 (1H, s, NH2), 3.94 (2H, d,J= 14.7 Hz, CH2), 2.72 (2H, bs, CH2), 2.24 (1H, t,J= 15.0 Hz, CH), 1.68 (2H, d,J= 15.0 Hz, CH2), 1.44–1.33 (11H, m, C(CH3)3+ CH2).
74%
With dmap In acetonitrile at 20℃;
To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 ml_), ferf-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCC , saturated aqueous NH4CI, brine and water. The organic phase was dried over Na2S04 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74percent) of the title product.HPLC: Rt: 4.23 min1H NMR (401 MHz, DMSO-d6) δ ppm 7.24 (br. s., 1 H), 6.75 (br. s., 1 H), 4.06 - 3.73 (m, 2 H), 2.71 (br. s., 2 H), 2.23 (tt, J = 3.8, 11.5 Hz, 1 H), 1.66 (dd, J = 2.7, 13.2 Hz, 2 H), 1.44 - 1.26 (m, 2 H), 1.36 (s, 9 H).
74%
With dmap In acetonitrile at 20℃;
tert-Butyl 4-carbamoylpiperidine-1-carboxylate To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 mL), tert-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, brine and water. The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74percent) of the title product. HPLC: Rt: 4.23 min 1H NMR (401 MHz, DMSO-d6) δ ppm 7.24 (br. s., 1H), 6.75 (br. s., 1H), 4.06-3.73 (m, 2H), 2.71 (br. s., 2H), 2.23 (tt, J=3.8, 11.5 Hz, 1H), 1.66 (dd, J=2.7, 13.2 Hz, 2H), 1.44-1.26 (m, 2H), 1.36 (s, 9H).
Reference：
[1] Patent: WO2004/2483, 2004, A1, . Location in patent: Page/Page column 21-22
[2] Patent: WO2011/153435, 2011, A1, . Location in patent: Page/Page column 12-13
[3] Patent: US2011/318418, 2011, A1, . Location in patent: Page/Page column 11
[4] Chemistry of Heterocyclic Compounds, 2009, vol. 45, # 12, p. 1503 - 1507
[5] Patent: EP1215208, 2002, A2, . Location in patent: Example J(4)
[6] Tetrahedron, 2004, vol. 60, # 18, p. 3967 - 3977
[7] Patent: WO2004/58750, 2004, A1, . Location in patent: Page 31; 30
[8] Patent: US2011/224225, 2011, A1, . Location in patent: Page/Page column 20
[9] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5213 - 5220
[10] Patent: EP1402900, 2004, A1,
[11] Patent: US2004/53973, 2004, A1,
[12] Patent: WO2012/113774, 2012, A1, . Location in patent: Page/Page column 40
[13] Patent: US2013/324551, 2013, A1, . Location in patent: Paragraph 0308; 0309; 0310
[14] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
[15] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 7, p. 822 - 829
[16] Patent: WO2004/2483, 2004, A1, . Location in patent: Page/Page column 39
[17] Patent: EP1221441, 2002, A2, . Location in patent: Page 185
[18] Patent: US2011/136823, 2011, A1, . Location in patent: Page/Page column 35
[19] Patent: CN105541830, 2016, A, . Location in patent: Paragraph 0022; 0056; 0057; 0058
20
[ 39546-32-2 ]
[ 206989-61-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 7, p. 822 - 829
21
[ 39546-32-2 ]
[ 135632-53-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139
22
[ 39546-32-2 ]
[ 214834-18-1 ]
Reference：
[1] Patent: WO2011/153435, 2011, A1,
[2] Patent: US2011/318418, 2011, A1,
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
[4] Patent: CN105541830, 2016, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5213 - 5220
With sodium hydroxide In water; acetone at 20℃; for 3 h;
Benzyl-4-carbamoylpiperidine-1-carboxylate To a solution of piperidine-4-carboxamide (5 g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol) in a mixture of water (30 mL) and acetone (40 mL), NaOH 1N (39 mL, 39 mmol) was added dropwise, while maintaining the pH between 6 and 8. The mixture was stirred at r.t. for 3 h; then acetone was evaporated and the resulting precipitate filtered and dried at 70° C. under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76percent). HPLC: Rt: 4.54 min 1H NMR (600 MHz, DMSO-d6) δ ppm 7.41-7.29 (m, 5H), 7.25 (br. s., 1H), 6.76 (br. s., 1H), 5.07 (s, 2H), 4.06-3.81 (m, J=13.2 Hz, 2H), 2.92-2.72 (m, 2H), 2.27 (tt, J=3.7, 11.5 Hz, 1H), 1.75-1.64 (m, 2H), 1.40 (dq, J=4.3, 12.4 Hz, 2H) HRMS (ESI) [M+H]+ calcd for C14H18O3N2 263.1390. found 263.1390.
Reference：
[1] Patent: US2013/324551, 2013, A1, . Location in patent: Paragraph 0314; 0315; 0316; 0317
[2] Patent: US5607944, 1997, A,
25
[ 39546-32-2 ]
[ 501-53-1 ]
[ 167757-45-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydroxide In water; acetone at 20℃;
To a solution of piperidine-4-carboxamide (5 g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol ) in a mixture of water (30 mL) and acetone (40 mL), NaOH 1 N (39 mL, 39 mmol) was added dropwise, while maintaining the pH between 6 and 8. The mixture was stirred at r.t. for 3 h; then acetone was evaporated and the resulting precipitate filtered and dried at 70°C under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76percent).HPLC: Rt: 4.54 min1H NMR (600 MHz, DMSO-d6) δ ppm 7.41 - 7.29 (m, 5 H), 7.25 (br. s., 1 H), 6.76 (br. s., 1 H), 5.07 (s, 2 H), 4.06 - 3.81 (m, J = 13.2 Hz, 2 H), 2.92 - 2.72 (m, 2 H), 2.27 (tt, J = 3.7, 11.5 Hz, 1 H), 1.75 - 1.64 (m, 2 H), 1.40 (dq, J = 4.3, 12.4 Hz, 2 H)HRMS (ESI) [M+H]+ calcd for Ci4Hi803N2 263.1390, found 263.1390.
With thionyl chloride; N,N-dibutylformamide In toluene at 20℃; for 18 h;
11.9 g [75.7 mmol] of dibutylformamide (99percent) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97percent) in 50 ml of toluene at 20°C over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20°C was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20°C. After the end of the addition, the mixture was stirred at 20°C for a further 18 hours. The suspension was filtered and the filter residue was washed with toluene. After drying there remained 9.63 g of a colourless solid. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 99.7percent (w/w). A yield of 86.5percent) of theory is calculated therefrom.
With hydrogen;palladium; In water; at 25℃; under 2585.81 Torr; for 43h;
ISONIPECOTAMIDE (10G, 78. Ommoles) was dissolved in distilled water (100ML) and 37% aqueous formaldehyde (7.6mL, equivalent to 2. 81g HCHO, 93. 6MMOLES) was added. Wet 10% Pd-C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25 C and 50psi FOR 43H. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60x5cm) using 8%-10%-20% (10% CONC. ammonium hydroxide in METHANOL)-DICHLOROMETHANE as the eluant to give 1-methylisonipecotamide (7.15g, 64%): FABMS: m/z 143.1 (MH+) ; HRFABMS: m/z 143.1184 (MH+). CALCD. FORC7H15N2O : m/z 143.1184 ; No.H (d6- DMSO) 1.50/1. 57 (4H, m, CH2), 1.76/1. 94 (4H, m, CH2), 2.10 (3H, s,-NCH3), 2.72 (1H, m, CH) and 6.68/7. 18 ppm (2H, M, CONH2); 8c (D6-DMSO) CH3 : 41.2 ; CH2: 28.5, 28.5, 54.9, 54.9 ; CH: 46.2 ; C: 176.7.
With 4-methylmorpholine N-oxide; In 1,4-dioxane;Product distribution / selectivity;
The ring nitrogen atom of isonipecotamide 1 (commercially available from Aldrich) was Boc-protected in 95% isolated yield by using Boc20 in dioxane and NMO as the base.
95%
dmap; In dichloromethane; at 20℃; for 2h;
Example 1: 4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester[0029] To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino- pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) drop wise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5v/v%, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10% of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95%) of product. TLC: dichloromethane-methanol 90: 10, Rf (product) = 0.28; Rf (starting material) = base line, iodine positive.
95%
With dmap; In dichloromethane; at 20℃; for 2h;
To a suspension of iosnipecotamide (255 g, 1.99 mol) and 4-dimethylamino-pyridine (204 mg, 1.82 mol) in methylene chloride (1500 mL) in a 5-lite of three-neck flask was added a solution of di-tert-butyl dicarbonate (502 g, 2.30 mol, 1.15 eq.) in methylene chloride (500 mL) dropwise at room temperature with mechanic stirring. A clear solution was reached at the end of the adding. After stirring at room temperature for two more hours, the solution was washed with phosphoric acid water solution (2.5 v/v %, 500 mL), water (500 mL), half saturated sodium bicarbonate water solution (500 mL), and 10% of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate. During the course of removing of the methylene chloride, ethyl acetate (100 ml) and heptane (200 mL) was added. After removing the methylene chloride, the white solid formed was filtrated, washed with hexane, and dried to give 414 g (95%) of product.TLC: dichloromethane-methanol 90:10, Rf (product)=0.28; Rf (starting material)=base line, iodine positive.
89%
dmap; In chloroform; at 20℃; for 1h;
ISONIPECOTAMIDE (1) (28.8 g, 0.22 mol) was suspended in chloroform (288 mL). To this was added 4- (dimethylamino) pyridine (DMAP) (23 mg, catalytic) followed by dropwise addition of a solution of BOC-anhydride (56 g, 0.26 mol, 1.14 equiv. ) in chloroform (57 mL). The solution was stirred at room temperature for 1 h and then partitioned between chloroform and 10% citric acid solution. The organic phase was washed with citric acid solution and back extracted with chloroform. The combined organic extracts were washed with water, 10% brine and dried (MgSO4). Filtration followed by evaporation of the filtrate gave the crude product as a pink solid. Crystallisation from ethyl acetate/hexane gave the title compound (2) as a colourless solid in 4 crops (45.5 g, 0.20 mol, 89%)
82.4%
With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 5h;
Example 3N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)piperidine-4-carboxamideStep A: Preparation of tert-butyl 4-Carbamoylpiperidine-1-carboxylate. To a solution of isonipecotamide (500 mg, 3.90 mmol) in a mixture of 5% aqueous sodium carbonate (7 ml) and 1,4-dioxane (3 ml) was added Boc-anhydride (1.30 ml, 5.85 mmol) and stirred for 5 h at room temperature. The pH was adjusted to 5-6 with acetic acid and volatiles were evaporated under vacuo. The residue was triturated with n-pentane and diethyl ether to yield 740 mg (82.4%) of tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid.
80%
With dmap; In dichloromethane; at 20℃;Inert atmosphere;
To a suspension of isonipecotamide (3.0 g, 23.4 mmol) and 4-dimethylaminopyridine (2.87 g, 23.4 mmol) in CH2Cl2in a reaction flask was added a solution of di-tert-butyl dicarbonate (6.1 g, 28.1 mmol) in CH2Cl2dropwise at room temperature with stirring. After stirring the reaction mixture at room temperature for 6 h, the solution was washed with phosphoric acid water solution (2.5 v/v %), water, saturated NaHCO3(aq) and brine, respectively. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and concentrated by evaporation. The white solid formed was obtained by filtration and washed with hexanes and dried to afford compound8(4.3 g, 80%).1H-NMR (DMSO-d6,500 MHz) delta 7.26 (1H, s, NH2), 6.77 (1H, s, NH2), 3.94 (2H, d,J= 14.7 Hz, CH2), 2.72 (2H, bs, CH2), 2.24 (1H, t,J= 15.0 Hz, CH), 1.68 (2H, d,J= 15.0 Hz, CH2), 1.44-1.33 (11H, m, C(CH3)3+ CH2).
78%
In water;
Reference Example G 33 1-tert-butoxycarbonylpiperidine-4-carboxamide To a solution of piperidine-4-carboxamide (5.0 g, 39 mmol) in water (30 mL) was added di-tert-butyl dicarbonate (9.2 mL, 40 mmol) slowly, and then the reaction mixture was stirred at room temperature for 24 hours. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give the title compound (6.9 g, yield 78%). m.p.: 163-165C
78%
In water;
Reference Example 33 1-tert-butoxycarbonylpiperidine-4-carboxamide To a solution of piperidine-4-carboxamide (5.0 g, 39 mmol) in water (30 mL) was added di-tert-butyl dicarbonate (9.2 mL, 40 mmol) slowly, and then the reaction mixture was stirred at room temperature for 24 hours. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give a title compound (6.9 g, yield 78%). m.p. 163-165 C.
74%
With dmap; In acetonitrile; at 20℃;
To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 ml_), ferf-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCC , saturated aqueous NH4CI, brine and water. The organic phase was dried over Na2S04 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74%) of the title product.HPLC: Rt: 4.23 min1H NMR (401 MHz, DMSO-d6) delta ppm 7.24 (br. s., 1 H), 6.75 (br. s., 1 H), 4.06 - 3.73 (m, 2 H), 2.71 (br. s., 2 H), 2.23 (tt, J = 3.8, 11.5 Hz, 1 H), 1.66 (dd, J = 2.7, 13.2 Hz, 2 H), 1.44 - 1.26 (m, 2 H), 1.36 (s, 9 H).
74%
With dmap; In acetonitrile; at 20℃;
tert-Butyl 4-carbamoylpiperidine-1-carboxylate To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 mL), tert-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, brine and water. The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74%) of the title product. HPLC: Rt: 4.23 min 1H NMR (401 MHz, DMSO-d6) delta ppm 7.24 (br. s., 1H), 6.75 (br. s., 1H), 4.06-3.73 (m, 2H), 2.71 (br. s., 2H), 2.23 (tt, J=3.8, 11.5 Hz, 1H), 1.66 (dd, J=2.7, 13.2 Hz, 2H), 1.44-1.26 (m, 2H), 1.36 (s, 9H).
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 12.25h;Product distribution / selectivity;
a) Isonipecotamide (28 g) was dissolved in water (100 ml) and cooled to 0C. A 1 M solution of NaOH (318 ml) was added, followed by the addition of Boc20 (47.2 g) in dioxane (100 ml) within 15 min. Stirring was continued for 12 h by slowly warming the reaction mixture to rt. The mixture was extracted with EtOAc (2x). The combined organic layers were subsequently washed with 1 M NaOH and water, dried with magnesium sulfate, filtered and evaporated to give 4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (39.77 g) which was used without further purification.
With diethylamine; In dichloromethane; at 20℃;
1) First Step : Synthesis of the t-butyl ester of 4-carbamoylpiperidine-1-carboxylic acid 2.56 g (20 mmol) of isonipecotamide were placed in a 50 ml round-bottomed flask and 10 ml of DCM, dried beforehand over magnesium sulfate, were then added. The isonipecotamide, which was partially soluble, remained in suspension. 5.62 ml (40 mmol ; 2 eq.) of diethylamine (DIEA) were then added to the medium, along with 4.8 g (1.1 eq.) of di-tert-butyl dicarbonate dissolved beforehand in a further 10 ml of DCM. The medium was stirred at room temperature until the isonipecotamide was fully dissolved. The reaction was monitored by TLC to ensure, by staining with ninhydrin, the disappearance of the isonipecotamide from the medium.At the end of the reaction, the organic phase was washed with basic aqueous 1M NaOH solution and then dried over magnesium sulfate and evaporated. 4.31 g of a white solid were obtained.1H NMR (CDCl3): delta=6.01 (s, 2H), 4.12 (m, 2H), 2.74 (m, 2H), 2.32 (m, 1H), 1.82 (m, 2H), 1.62 (m, 2H), 1.51 (s, 9H).MS m/z: 229 (M++1)
With triethylamine; In dichloromethane; at 20℃;
under the room temperature, the (12.8g, 0 . 01mol, 1eq), 200mlDCM, triethylamine (12.1g, 0 . 012mol, 1 . 2eq) adding the three-hole bottle. Boc2O is added to the reaction system (24g, 0.0105mol, 1.05eq). After the reaction is complete, the white solid obtained after turns on lathe does24g, crude yield is 105%, directly used for the next step.
41.4 g
Isopiperidinamide (25.5 g, 0.199 mol) was added dropwise to a solution of 4-dimethylaminopyridine (20.4 mg, 182 mol) in dichloromethane (140 mL), The resulting solution was stirred at room temperature. A dichloromethane (50 mL) of di-tert-butyl dicarbonate (50.2 g, 0.230 mol) was slowly added dropwise, and the reaction was stirred at room temperature for 2 h, and monitored by TLC. the reaction mixture was washed with 50 ml of phosphoric acid (2.5 v/v%), 50 ml of water, a half-saturated aqueous sodium hydrogen carbonate solution and 50 ml of 10% brine, and the organic phase was collected, dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, 10 ml of ethyl acetate and 20 ml of heptane were added, and filtered to compound 1 (41.4 g, 92.7% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) delta 7.28(s, 1H), 6.82(s, 1H), 3.92(d, J = 12.4 Hz, 2H), 2.71(s, 2H), 2.49-5.51(m, 2H), 2.23(ddd, J1 = 11.6 Hz, 7.8 Hz, 3.81Hz, 1H), 1.65(dd, J1=13.6 Hz, 3.4 Hz, 2H), 1.39(s, 9H).
With caesium carbonate; potassium iodide In various solvent(s) at 100℃; for 5h;
With potassium carbonate; potassium iodide In acetone for 4h; Reflux;
3.2. General Procedure for the Synthesis of Compounds 3a-d
General procedure: 4-Piperidinecarboxamide (1) (3.00 g, 23.4 mmol) and substituted Benzylchloride derivatives (2a-d) (28.1 mmol) were dissolved in 20 mL acetone. Then, anhydrous K2CO3 (6.47 g, 46.8 mmol) andcatalytic amount KI were added. The reaction mixture was refluxed for 4 h. After completion of thereaction, acetone was concentrated, and the residue was dissolved in water (60 mL) and extractedwith ethyl acetate (60 × 3 mL). The combined organic layers were dried over Na2SO4, filtered, and thesolvent was removed under reduced pressure. After concentration, the crude product was purifiedby silica gel column chromatograph (DCM: methanol = 60:1-5:1) to give target compounds 3a-d.
1-[(5-Methyl-3-phenylisoxazol-4-yl)carbonyl]piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), isonipecotamide (27.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H19N3O3: 313.1426, found 313.1431.
With tetraphosphorus decasulfide In toluene; butan-1-ol at 45 - 80℃;
3 Example 3: Reaction of Piperidine-4-Carboxamide 1 with In Situ Generated O,O’-Dibutyl Dithiophosphate
To a one-liter flask was charged P4S,0 (0.24 mole) and toluene (500 mL). While stirring the resulting slurry, ethanol (1.96 mole) was slowly added to the flask. During the ethanol addition, the flask temperature rose to 45 °C. After completion of the ethanol addition, the reaction mixture was slowly heated to reflux during which time the solids dissolved to give a clear solution. The solution was cooled to 70-80 °C and piperidine-4-carboxamide 1 (0.39 mole) was added to the flask in portions while maintaining the temperature at 70-80 °C. Once all of the piperidine-4-carboxamide 1 had been added, the reaction mixture was heated to reflux and held for 5- 7 hours then cooled to ambient temperature. ‘H and ‘3C analysis showed the conversion of the piperidine-4-carboxamide 1 to piperidine-4-carbothioamide 2 was approximately 85-90%. Water (100 mL) was then added to the flask and the flask was warmed to 50 °C, to dissolve the bottom phase into the water. The layers were separated and the bottom, aqueous layer containing the product was adjust to pH 13 using 50% NaOH. The slurry that formed was stirred for about 30 minutes and then filtered to recover the solids. The solids were washed with water (50 mL) and dried. The recovered solids represented a 67% recovered yield of piperidine-4-carbothioamide 2.The procedure of Example 2 was repeated using 1-butanol in place of the ethanol. Conversion of the piperidine-4-carboxamide 1 to piperidine-4-carbothioamide 2 by 1H NMR was 88%. After pH treatment, filtration, and drying, piperidine-4-carbothioamide 2 was obtained in 94% yield.
To a stirred mixture [OF PIPERIDINE-4-CARBOXAMIDE (1. 28] g, 10 mmol), tetrahydro-2H- pyran-4-carboxylic acid (1.43 g, 11 mmol) and diisopropylethylamine (2.09 mL, 11 mmol) in [N, N-DIMETHYLFORMAMIDE] was added HBTU (N-[(1H-1, 2, 3-benzotriazol-1- yloxy) (dimethylamino) methylene]-N-methylmethanaminium hexafluorophosphate, 4. [14 G, 11 MMOL) AT 0C.] After being stirred for [0.] 5h at [0C,] the mixture was stirred for 3h at ambient temperature. Then, the mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic extract was washed with brine, dried over magnesium sulfate and concentrated. This crude material was dissolved in tetrahydrofuran (50 mL) and added to the mixture of lithium aluminum hydride (1.90 g, 50 mmol) in tetrahydrofuran (50 mL) at [0C.] Then, the mixture was heated at [40C] and stirred for 5h. The mixture was cooled to [0 C] and quenched with sodium sulfate decahydrate (3.8 g) and potassium fluoride (9.0 g). After vigorous stirring for [0.] [5H,] the insoluble materials were filtered off. The filtrate was concentrated to give 2.19g (99%) of the title compound as a colorless viscous oil. MS [(ESI)] m/z: 213 (M+H) +. [H-NMR] [(CDC13)] [8] : 1.20-1. 28 (2 H, [M),] 1.50-1. 78 (8 H, [M),] 2.35 (2 H, s), 2.55-2. 58 (2 H, [M),] 2.82-2. 90 (2 H, [M),] 3.30-3. 42 (2 H, [M),] 3.49 (2 H, s), 3.92-4. 00 (2 H, [M).] Signal due to NH2 was not observed
biphenyl-2-yl-carbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester[ No CAS ]
[ 864750-70-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Example 1 Biphenyl-2-ylcarbamic Acid 1-(2-[4-(4-Carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl Ester To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and IPA (400 mL). The reaction mixture was cooled to 0-10 C. with an ice bath and a solution of the product of Preparation 5 (11 g, 22.7 mmol) in IPA (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10 C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3*250 mL). The aqueous phase was then cooled to 0-5 C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3*300 mL) and the combined organic layers were washed with water (100 mL), brine (2*50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M+H+] calcd for C35H43N5O4, 598.3; found, 598.6. Rf=2.32 min (10-70 ACN: H2O, reverse phase HPLC).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 95℃; for 3h;
Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the reaction mixture is heated at 95 0C for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45 0C to yield the title compound as a white solid. MS (ES+) mle 278 (MH+)
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 2h;
A stirred suspension comprising 6-chloro-nicotinic acid ethyl ester (1.86 g, 10.0 mmol), piperidine-4-carboxamide (1.54 g, 12.0 mmol) and DIPEA (2.1 mL, 12 mmol) in DMSO (7 mL) is heated to 90C for 2 hours. MeOH (8 mL) is then added as the reaction mixture cools and the resulting precipitate is filtered, washed with water followed by ether and dried in vacuo (45C) to yield the titled compound as a white powder.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 95℃; for 3h;
Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the <n="89"/>reaction mixture is heated at 95 0C for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45 0C to yield the title compound as a white solid. MS (ES+) m/e 278 (MH*)
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 2h;
Step BC1: 4-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2I]bipyridinyl-5I-carboxylic acid ethyl esterA stirred suspension comprising 6-chloro-nicotinic acid ethyl ester (1.86 g, 10.0 mmol), piperidine-4-carboxamide (1.54 g, 12.0 mmol) and DIPEA (2.1 mL, 12 mmol) in DMSO (7 mL) is heated to 900C for 2 hours. MeOH (8 mL) is then added as the reaction mixture cools and the resulting precipitate is filtered, washed with water followed by ether and dried in vacuo (45C) to yield the titled compound as a white powder.
5-[2-Ethoxy-5-(4-carbamoylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
In methanol; ethanol; dichloromethane;
EXAMPLE 9 5-[2-Ethoxy-5-(4-carbamoylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-Carbamoylpiperidine (703 mg, 5.50 mmol) was added to a stirred suspension of 5-(5-chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (750 mg, 1.80 mmol) in ethanol (50 ml) at room temperature. The resulting mixture was stirred for 4 days before removing the solvent by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of dichloromethane and methanol (100 ml) and the solution washed with saturated aqueous sodium carbonate solution (100 ml). The aqueous phase was further extracted with dichloromethane-methanol mixtures (3*100 ml) and all the organic fractions were combined, dried (MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a mixture of methanoldimethylformamide gave the title sulphonamide as an off-white solid (446 mg, 49%), m.p. 274-276 C. Found: C,55.36; H,6.01; N,16.65. C23 H29 N6 O5 S requires C,55.08; H,5.83; N,16.75%.
With sodium hydroxide; In water; acetone; at 20.0℃; for 3.0h;pH 6- 8;
Benzyl-4-carbamoylpiperidine-1-carboxylate To a solution of piperidine-4-carboxamide (5 g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol) in a mixture of water (30 mL) and acetone (40 mL), NaOH 1N (39 mL, 39 mmol) was added dropwise, while maintaining the pH between 6 and 8. The mixture was stirred at r.t. for 3 h; then acetone was evaporated and the resulting precipitate filtered and dried at 70 C. under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76%). HPLC: Rt: 4.54 min 1H NMR (600 MHz, DMSO-d6) delta ppm 7.41-7.29 (m, 5H), 7.25 (br. s., 1H), 6.76 (br. s., 1H), 5.07 (s, 2H), 4.06-3.81 (m, J=13.2 Hz, 2H), 2.92-2.72 (m, 2H), 2.27 (tt, J=3.7, 11.5 Hz, 1H), 1.75-1.64 (m, 2H), 1.40 (dq, J=4.3, 12.4 Hz, 2H) HRMS (ESI) [M+H]+ calcd for C14H18O3N2 263.1390. found 263.1390.
With sodium hydroxide; In water; acetone;
EXAMPLE V 1-Benzyloxycarbonyl-piperid-4-yl-carboxylic acid amide 39 ml of 1N sodium hydroxide solution are slowly added dropwise to a solution of 5.0 g of piperid-4-yl-carboxylic acid amide and 5.54 ml of benzylchloroformate in 30 ml of water and 40 ml of acetone so as to keep the pH constant at between 6 and 8. The mixture is stirred for one hour at ambient temperature. Then the acetone is evaporated off under reduced pressure and the precipitate is suction filtered and dried. Yield: 8.8 g (86% of theory), Rf value: 0.55 (silica gel; methylene chloride/methanol/conc. ammonia=9:1:0.1)
EXAMPLE 1Biphenyl-2-ylcarbamic Acid 1 -(2- { |"4-(4-Carbamoylpiperidin- 1 -ylmethvD benzoylimethylamino) ethyl')piperidin-4-vl EsterTo a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10 0C with an ice bath and a solution of biphenyl-2-ylcarbamic acid l-{2- [(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10 0C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with IN HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3 x 250 mL). The aqueous phase was then cooled to 0-5 C with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3 x 300 mL) and the combined organic layers were washed with water (100 mL), brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M + H+] calc'd for C35H43N5O4 598.3; found 598.6. Rj=232 min (10-70 ACNiH2O, reverse phase HPLC).
Step B: Biphenyl-2-yl-carbamic acid 1-{2-[(4-carbamoylbenzoyl)methylamino ethyl}piperidin-4-yl ester (non-isolated form) Isonipecotamide (15.4, 120 mmol, 2.0 eq.) and IPA (200 mL) were added to the solution of biphenyl-2-yl-carbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester from the previous step. Liquid (200 mL) was distilled off and additional IPA (400 mL) was added under reduced pressure at 60 C. Liquid (400 mL) was distilled off over a period of 1.5 hours and additional IPA (600 mL) was added. Liquid (100 mL) was distilled off and the remaining solution was cooled to 30 C. to yield a hazy white mixture, which was then added to Na2SO4 (18 g). The flask was rinsed with IPA (100 mL) and added to the solution. The resulting mixture was cooled to room temperature and AcOH (20 mL, 360 mmol, 6.0 eq.) was added. The mixture was cooled to 18 C. with an ice bath and NaHB(OAc)3 (38.2 g, 180 mmol, 3.0 eq.) was added over 5 minutes. The mixture was allowed to warm up to 25 C. and was maintained at that temperature for 2 hours. Solvent was removed under reduced pressure, and the remaining material was used directly in the next step.; Step C: Biphenyl-2-yl-carbamic acid 1-{2-[(4-carbamoylbenzoyl)methylamino ethyl}piperidin-4-yl ester (isolated solid)iPrOAc (300 mL) was added to the material, followed by the addition of water (200 mL). The pH of the solution was adjusted to pH 1 with 3N HCl (150 mL). The layers were separated and the organic layer was discarded. The aqueous layer was collected, and iPrOAc (300 mL) was added. The pH of the solution was adjusted to basic pH with 50 wt % NaOH (100 mL). The resulting mixture was stirred for 15 minutes and the layers were separated. The organic layer was filtered and seeded with micronized crystalline freebase of biphenyl-2-yl-carbamic acid 1-{2-[(4-carbamoylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (Form III; prepared as described in U.S. Patent Application Publication No. 2011/0015163 to Woollham) and stirred overnight at room temperature to yield a white slurry. Stirring was continued for 8 hours at room temperature and for 16 hours at 5 C. (cold room). The mixture was slowly filtered under pressure. The cake was washed with cold iPrOAc (2×20 mL) and dried under nitrogen to yield a white solid (27.5 g). The material was further dried in a vacuum oven at 30 C. for 24 hours to yield 25.9 g.
With potassium carbonate In water; acetonitrile at 15 - 25℃; for 0.25h;
1
With reference to Scheme HB, above, wherein Path B is followed in Step 2, compound 2Ba (isonipectoamide, article of commerce, used as received) (36.5 g, 285 mmol), acetonitrile (150 ml_), and saturated aqueous potassium carbonate solution (150 ml_) were added to a 1 liter jacketed vessel. To this mixture was charged 3-chloropropane sulfonyl chloride (40.0 g, 285 mmol), keeping the temperature between 15 0C and 25 0C. The reaction was then stirred for about 15 minutes. MTBE (500 ml_) was then charged, and the resulting precipitated product A1a was filtered, and washed with MTBE (3 x 100 ml_). The solids were dried under vacuum oven at 20 to 30 0C to yield 51.2 g (77.3%) of product A1 a as a white solid .1H NMR (DMSO, 400 MHz): 57.31 (1 H, s), 6.86 (1H, s), 3.58 (2H, ddd, J = 12.0, 3.2, 3.2 Hz), 2.81 (2H, ddd, J = 12.0, 12.0, 2.4 Hz), 2.57 (1 H, m), 2.21 (1 H, dddd, J = 10.8, 10.8, 3.2, 3.2 Hz), 1.79 (2H, dddd, J = 13.2, 2.8, 2.8, 2.8 Hz)1 1.53 (2H, dddd, J = 13.6, 13.6, 13.6, 4.0 Hz), 0.99 - 0.88 (4H, m). MP: 151 0C
Stage #1: 4-carboxamidopiperidine; 3-chloro-n-propanesulfonyl chloride With triethylamine In acetonitrile at 20℃; for 6h;
Stage #2: With citric acid In water; ethyl acetate; acetonitrile
3
With reference to Scheme MB (primary Scheme), Step 1, compound 2Ba (isonipectoamide) (54.7 g, 424 mmol) acetonitrile (750 ml_), and triethylamine (47.2 g, 466 mmol) were charged to a 2 liter jacketed flask and agitated at about 20 0C. The flask was charged 3-chloropropanesulfonyl chloride (75.0 g, 424 mmol) dissolved in acetonitrile (120 ml_) through an addition funnel over one hour, keeping the temperature of the reaction mixture at about 20 0C, and stirred for four to five hours after addition. To the agitating reaction mixture were added 10% aqueous citric acid (500 ml_) and ethyl acetate (500 mL). The layers were allowed to split, and the bottom, aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined and washed with 10% aqueous citric acid (400 mL) and brine (200 mL). The batch was concentrated under reduced pressure, and the resulting solids were washed with MTBE to yield 53.0 g (46.5 %)compound 2Bb as an off-white solid.1H NMR (DMSO, 400 MHz): δ 7.32 (1 H, s), 6.86 (1H, s), 3.74 (2H1 dd, J = 6.4, 6.4 Hz), 3.58 (2H, m), 3.14 (2H, m), 2.80 (2H, ddd, J = 12.0, 12.0, 2.4 Hz), 2.20 (1 H, dddd, J = 11.4, 11.4, 3.8, 3.8 Hz), 2.09 (2H, m), 1.78 (2H, m), 1.51 (2H1 m). MP: 171 0C
With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS);
All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis.
Stage #1: 5-bromo-4-chloropyrimidine hydrochloride With triethylamine In N,N-dimethyl-formamide for 0.5h;
Stage #2: 4-carboxamidopiperidine In N,N-dimethyl-formamide at 20℃; for 16h;
29
To a solution of 5-bromo-4-chloropyrimidine hydrochloride 21 (0.10 g, 0.36 mmol) in DMF (2 ml.) was added triethylamine (0.51 ml_, 3.6 mmol). After stirring for 30 min, a solution of isonipecotamide (0.14 g, 1.1 mmol) in DMF (2 ml.) was added and the mixture was stirred at r.t. for a further 16 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 ml.) and extracted with EtOAc (2 x 25 ml_). The combined organic extracts were washed with water (25 ml_), brine (25 ml_), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2CI2, MeOH, 98:2) to furnish the title compound as a white solid (60 mg, 58%), m.p. 188-190 0C; umax (CHCI3)/ cm"1 3012,2853, 1682, 1566, 1447, 1359, 1 144, 1017, 950; mlz (ESI) Ci0H14BrN4O requires285.0346, found [M+H]+ 285.0344.
With triethylamine; In ethanol; at 120℃; for 2h;Microwave irradiation;
EXAMPLE 2. 1- 5-BROMOTHIAZOL-2-YL)PIPERIDINE-4-CARBOXAMIDE (XJB02-010)[0109] A mixture of <strong>[4175-78-4]2,5-dibromothiazole</strong> (1.42 g, 5.85 mmol), piperidine-4- carboxamide (1.50 g, 11.7 mmol) in EtOH (5.00 mL) and TEA (2.50 mL) was heated in mu¥ at 120 C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc and dichloromethane. The organic layer was separated, dried Na2S04, and concentrated as light yellow solid. The crude mixture was purified with Biotage with 0-25% MeOH in CH2C12 to give 1.35 g (80%) product as a white solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 7.30 (br. s., 1 H), 7.18 (s, 1 H), 6.81 (br. s., 1 H), 3.80 (dt, 7=12.7, 3.3 Hz, 2 H), 3.02 (td, 7=12.6, 3.0 Hz, 2 H), 2.34 (tt, 7=11.5, 3.8 Hz, 1 H), 1.77 (dd, 7=14.0, 3.6 Hz, 2 H), 1.49 - 1.63 (m, 2 H); LCMS RT = 3.746 min, m/z 290.01 [M+H+] .
With triethylamine; In ethanol; at 120℃; for 2h;Microwave irradiation;
EXAMPLE 3. 1-(5-BROMO-1,3,4-THIADIAZOL-2-YL)PIPERIDINE-4-CARBOXAMIDE (XJB03- 058)[0110] A mixture of 2,5-dibromo-l,3,4-thiadiazole (500 mg, 2.05 mmol), piperidine- 4-carboxamide (263 mg, 2.05 mmol) in EtOH (2.00 mL) and TEA (1.00 mL) was heated mu¥ at 120 C for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with methanol and dichloromethane. The organic layer was separated, dried Na2S04, and concentrated as light brown solid. The crude mixture was purified with Biotage using 0-20% MeOH in CH2C12 followed by cartridge filtration to give 525 mg (88%) product as a yellow solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 7.31 (br. s., 1 H), 6.84 (br. s., 1 H), 3.79 (dt, 7=12.9, 3.3 Hz, 2 H), 3.16 (td, 7=12.6, 2.9 Hz, 2 H), 2.36 (tt, 7=11.4, 3.8 Hz, 1 H), 1.79 (dd, 7=13.7, 3.5 Hz, 2 H), 1.42 - 1.68 (m, 2 H); LCMS RT = 3.483 min, m/z 290.9[M+H+] ; HRMS (ESI) m/z calcd for C8Hi279BrN4OS [M+H+] 290.9915.
With triethylamine; In ethanol; at 100℃; for 1h;Microwave irradiation;
EXAMPLE 1 1-(4-BROMOTHIAZOL-2-YL)PIPERIDINE-4-CARBOXAMIDE (XJBOl-018) [0108] A mixture of <strong>[4175-77-3]<strong>[4175-77-3]2,4-dibromothiazol</strong>e</strong> (2.06 g, 8.48 mmol), piperidine-4- carboxamide (1.30 g, 10.1 mmol) and TEA (2.50 mL) in ethanol (5.00 mL) was heated in mu\\.yen. at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with methanol and dichloromethane. The organic layer was separated, dried with Na2S04, and concentrated as light brown solid. The crude mixture was purified by Biotage with 0-10percent MeOH in CH2C12 with 1percent TEA to give 2.08 g (85percent) product as a white solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 7.31 (br. s., 1 H), 6.85 (s, 1 H), 6.82 (br. s., 1 H), 3.77 - 3.90 (m, 2 H), 3.03 (td, 7=12.5, 2.8 Hz, 2 H), 2.29 - 2.39 (m, 1 H), 1.78 (dd, 7=13.5, 3.1 Hz, 2 H), 1.50 - 1.63 (m, 2 H); LCMS RT = 4.134 min, m/z 289.9 [M+H+] .
With triethylamine In methanol at 50 - 60℃; for 24h;
3.3-10-1
3-10-1: Preparation of [3-fluoro-4(4-carbamoylpiperidino)]nitrobenzene To 50 ml of methanol were sequentially added 5 g (31.4 mmol) of 3,4-difluoronitrobenzene, 5.26 ml (37.7 mmol) of triethylamine and 4.4 g (34.6 mmol) of isonipecotamide, followed by reaction at a temperature of 50 to 60° for 24 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 6.7 g (yield: 80%) of the desired compound which was subjected to the subsequent reaction without further purification. Mass (M+): 268.1 1H-NMR (DMSO-d6): 1.66(m, 2H), 1.81(m, 2H), 2.33(m, 1H), 2.94(t, 2H), 3.69(d, 2H), 6.85(s, 1H), 7.16(t, 1H), 7.33(s, 1H), 7.98(d, 2H).
80%
With triethylamine In methanol at 50 - 60℃; for 24h;
3.3-10-1
Example 3-10-1 Preparation of [3-fluoro-4-(4-carbamoylpiperidino)]nitrobenzene To 50ml of methanol were sequentially added 5g (31.4mmol) of 3,4-difluoronitrobenzene, 5.26ml (37.7mmol) of triethylamine and 4.4g (34.6mmol) of isonipecotamide, followed by reaction at a temperature of 50 to 60°C for 24 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 6.7g (yield: 80%) of the desired compound which was subjected to the subsequent reaction without further purification. Mass (M+): 268.1 1H-NMR (DMSO-d6): 1.66(m, 2H), 1.81(m, 2H), 2.33(m, 1H), 2.94(t, 2H), 3.69(d, 2H), 6.85(s, 1H), 7.16(t, 1H), 7.33(s, 1H), 7.98(d, 2H).
1-(5-chloro-2-formylphenyl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 20h;Sealed tube;
[00170] A sealed tube was charged with <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (1 g, 6.30 mmol), piperidine-4-carboxamide (0.970 g, 7.57 mmol), and K2CO3 (2.78 g, 20.2 mmol). DMA (8 mL) was added and the mixture was stirred at 140 C for 20 h. The reaction was cooled to rt, then diluted with EtOAc (200 mL). The organic layer was washed with brine (3x) and with sat. NH4Cl (1x). The organic layers were dried over Na2SO4, filtered and concentrated to yield a solid. The solid was purified on silica gel by flash column chromatography to afford 1-(5-chloro-2- formylphenyl)piperidine-4-carboxamide as a yellow solid (703 mg, 41 % yield). 1H NMR (400 MHz, DMSO-d67.19- 7.10 (m, 1H), 6.85 (s, 1H), 3.33- 3.21 (m, 2H), 2.96- 2.81 (m, 2H), 2.31- 2.20 (m, 1H), 1.89- 1.71 (m, 4H).
With thionyl chloride; N,N-dibutylformamide; In toluene; at 20℃; for 18h;
11.9 g [75.7 mmol] of dibutylformamide (99%) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97%) in 50 ml of toluene at 20C over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20C was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20C. After the end of the addition, the mixture was stirred at 20C for a further 18 hours. The suspension was filtered and the filter residue was washed with toluene. After drying there remained 9.63 g of a colourless solid. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 99.7% (w/w). A yield of 86.5%) of theory is calculated therefrom.
1-(6-nitropyridin-2-yl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 180℃; for 2.5h;Microwave irradiation; Inert atmosphere;
In a 20 ml microwave vial, <strong>[94166-64-0]2-chloro-6-nitropyridine</strong> (1.0 g, 6.3 mmol) was dissolved in dioxane (10 ml) and piperidine-4-carboxamide (1.05 g, 1.3 eq) was added followed by Hunig's base (3.3 ml, 3 eq). The reaction was subjected to in the microwave for 2.5 h at 180 C. The reaction mixture was diluted with water, the mixture was extracted twice with hot ethyl acetate, treated with brine, dried with MgS04, filtered and the solvent was removed in vacuo to give the crude product. The crude product was refluxed with DCM (10 ml), the solution was allowed to cool and washed with DCM to give the purified crude product as a solid. The solid was recrystallized from 2% hexane/ ethyl acetate to give [l-(6-nitropyridin-2-yl)piperidine-4-carboxamide (0.53 g solid, 33% yield, HPLC Rf 2.18 min, MS m/z (M+l) 251.3, (M-l) 249.2). TLC ethyl acetate Rf 0.26.
1-[2-[4-(bromomethyl)-N-methylbenzoylamino]ethyl]piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate[ No CAS ]
[ 864750-70-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydroxide; In dimethyl sulfoxide; at 80℃; for 2h;
1- [2- [4- (bromomethyl) -N-methylbenzoylamino] ethyl] piperidin-4-yl [1,1'-biphenyl] -2-ylcarbamic acid Esters (8.0 g, 14.5 mmol), compounds of formula (III) (3.7 g, 29.0 mmol), sodium hydroxide (1.74 g, 43.5 mmol) were added to 80 ml of DMSO, and the temperature was raised to 80 C for 2 h. TLC detection (dichloro Methane: methanol = 10: 1 + 1d ammonia water), the raw material reaction is complete. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was adjusted to pH 2-3 with 1N hydrochloric acid, and the phases were separated. The aqueous phase was adjusted to pH 9-10 with saturated sodium carbonate, extracted with ethyl acetate, dried over magnesium sulfate, and spin-dried. An oily substance was added to toluene, the temperature was raised to full dissolution, the temperature was reduced to crystallize, and suction filtration was performed to obtain 6.6 g of ribavirin, yield: 76%.
1-[2-[4-(chloromethyl)-N-methylbenzoylamino]ethyl]piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate[ No CAS ]
[ 864750-70-9 ]
Yield
Reaction Conditions
Operation in experiment
83.3%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 10h;
1- [2- [4- (chloromethyl) -N-methylbenzoylamino] ethyl] piperidin-4-yl [1,1'-biphenyl] -2-ylcarbamic acid Ester (8.0g, 15.8mmol),A compound of formula (III) (2.4 g, 19.0 mmol),Potassium carbonate (3.3g, 23.7mmol) was added to 80ml of DMF, and the reaction was stirred at room temperature for 10h.TLC detection (dichloromethane: methanol = 10: 1 + 1d aqueous ammonia) The reaction of the raw materials was complete.The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was adjusted to pH 2-3 with 1N hydrochloric acid.Phase separation, the aqueous phase was adjusted to pH 9-10 with saturated sodium carbonate, extracted with ethyl acetate, dried over magnesium sulfate,Spin-dry to obtain an oil. Add this oil to toluene, warm to full solution, and crystallize by cooling.Suction filtration, 7.9 g of rivinasine, yield: 83.3%.
1-(6-methyl-2-phenylpyrimidin-4-yl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With triethylamine; In N,N-dimethyl-formamide; for 4.0h;Reflux;
A mixture of <strong>[29509-92-0]4-chloro-6-methyl-2-phenylpyrimidine</strong> (1 g, 4.89 mmol) and piperidine-4-carboxamide (0.627 g, 4.89 mmol) and trimethylamine (1.02 mL, 7.34 mmol) in anhydrous DMF (25 mL) was heated to reflux for 4 hours, upon completion, the reaction mixture was cooled to room temperature, and then was concentrated to dry, the residue was stirred in a mixed solution of EtOAc (10 mL) and water (20 mL) for about 30 min. and then the solid product was collected by filtration to obtain 1.4 g compound, then it was re-crystallized from EtOH/H20, after dry obtained 900 mg of the title compound as a white solid in 62% yield. MS (MH+) 297.
Multi-step reaction with 5 steps
1.1: sodium sulfate / isopropyl alcohol / 2 h / 60 °C
1.2: 0.17 h / 25 °C
1.3: 2.25 h / 0 - 25 °C
2.1: sodium hydroxide; water / 8 h / 25 °C
3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1 h / 25 °C
3.2: 1 h / 25 °C
4.1: hydrogenchloride / tetrahydrofuran; water / 6 h / 25 °C
5.1: acetic acid; sodium sulfate / tetrahydrofuran / 2 h / 25 °C
5.2: 2 h / 0 - 25 °C
Multi-step reaction with 2 steps
1.1: sodium tris(acetoxy)borohydride / N,N-dimethyl-formamide / 1 h / 20 - 25 °C
2.1: sodium carbonate / dichloromethane / 0.5 h / 20 - 25 °C
2.2: 3.5 h / 20 - 25 °C
Multi-step reaction with 3 steps
1: sodium tris(acetoxy)borohydride / dichloromethane / 12 h
2: potassium hydroxide / methanol / 8 h / 65 °C
3: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride / ethanol / 20 °C
Stage #1: C29H31N3O4*C2H2O4 With anhydrous sodium carbonate In dichloromethane at 20 - 25℃; for 0.5h;
Stage #2: 4-carboxamidopiperidine With sodium tris(acetoxy)borohydride In N,N-dimethyl-formamide at 20 - 25℃; for 1h;
4; 5; 13 Example 4: Preparation of Revefenacin (1)
Oxalate salt (6b) (100g, 0.174 moles, 1.0 eq) and 5% sodium bicarbonate solution (1000 ml) were stirred in MDC (500 ml) at 20-25°C for 30 mins. The organic layer was separated, washed with water (500 ml) and concentrated under reduced pressure to yield free base of compound (6).Compound (6) (100g, 0.205 moles, 1.0 eq) and Compound (7) (66g, 0.514 moles, 2.5 eq) were stirred in DMF (500 ml) at room temperature. To the reaction mass was added sodium triacetoxyborohydride (153 g, 0.72 moles, 3.5 eq). The reaction mass was stirred for 1 hour at 20-25°C and quenched in a mixture of 5% sodium bicarbonate solution ( 1000 ml ) and MDC ( 500 ml). Stirred for 15 mins, organic layer was separated and washed with water. The solvent was removed under reduced pressure and the residue was stirred in acetonitrile (600 ml). The solution was heated to 50-55°C for 15-20 mins and then cooled to 20-25°C. The reaction mass was further stirred for 4 hours at 20-25°C. The solids were isolated byfiltration, washed with acetonitrile (200 ml) and dried under vacuum at 40-45°C to yield Revefenacin (100g, 80%). HPLC purity > 99.0%
1‐(azulene‐1‐carbonyl)piperidine‐4‐carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
Stage #1: phosgene; azulene In toluene at 20℃; for 4h;
Stage #2: piperidine-4-carboxamide With triethylamine In tetrahydrofuran for 2h; Inert atmosphere;
N,N-Dimethylazulene-1-carboxamide (13).
General procedure: A 20 % solution of phosgene in toluene; (382 mg, 3.9 mmol) was added to a stirred solution of azulene (500 mg; 3.9 mmol) in toluene (8.0 ml) at room temperature. After 4 h volatiles were evaporated under reduced pressure. This crude intermediate was added under nitrogen atmosphere to a stirred solution of dimethylamine hydrochloride (215 mg; 3.2 mmol) and triethylamine (795 mg; 7.9 mmol) in THF (10 ml). After 2 hours stirring, the mixture was evaporated under reduced pressure, taken up in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was separated, evaporated, and the crude product was purified by preparative HPLC to yield 13 as a purple solid (35 mg; 7%).
5%
Stage #1: phosgene; azulene In toluene at 20℃; for 4h;
Stage #2: piperidine-4-carboxamide With triethylamine In tetrahydrofuran for 2h; Inert atmosphere;
N,N-Dimethylazulene-1-carboxamide (13).
General procedure: A 20 % solution of phosgene in toluene; (382 mg, 3.9 mmol) was added to a stirred solution of azulene (500 mg; 3.9 mmol) in toluene (8.0 ml) at room temperature. After 4 h volatiles were evaporated under reduced pressure. This crude intermediate was added under nitrogen atmosphere to a stirred solution of dimethylamine hydrochloride (215 mg; 3.2 mmol) and triethylamine (795 mg; 7.9 mmol) in THF (10 ml). After 2 hours stirring, the mixture was evaporated under reduced pressure, taken up in ethyl acetate (25 ml) and washed with brine (10 ml). The organic layer was separated, evaporated, and the crude product was purified by preparative HPLC to yield 13 as a purple solid (35 mg; 7%).
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