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Structure of 73874-95-0 * Storage: {[proInfo.prStorage]}
* 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.
J-Butyl-l-benzylpiperidin-4-ylcarbamate (3.80 g, 13.1 mmol) obtained in Preparation Example 1-i was dissolved in 26 ml of methanol in a 100 ml vessel, and a catalytic quantity of 10percent active palladium/carbon was added thereto, and the resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon and the solvent was removed under reduced pressure therefrom. Then, the residue was subjected to a silica gel column chromatography to obtain 2.64 g of the title compound (yield 99percent).1H-NMR (200 MHz, CD3OD) δ 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m, 2H), 3.42 (m, 2H), 3.60 (br, IH). LC/MS (M+H): 201; r-Butyl-l-benzylpiperidin-4-ylcarbamate (3.80 g, 13.1 mmol) obtained in Preparation Example 2-i was dissolved in methanol (26 ml) in a 100 ml vessel, and a catalytic quantity of 10percent active palladium/carbon was added thereto. The resulting mixture was reacted under a hydrogen atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon and the solvent was removed under reduced pressure. Then, the mixture was subjected to a silica gel column chromatography to obtain 2.64 g of the title compound (yield 99percent).1H-NMR (200 MHz, CD3OD) δ 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m, 2H), 3.42 (m, 2H), 3.60 (br, IH). LC/MS (M+H): 201; /-Butyl- l-benzylpiperidin-4-ylcarbamate (3.801 g, 13.1 mmol) obtained in Preparation Example 4-i was dissolved in 26 ml of methanol in a100 ml vessel, and a catalytic quantity of 10percent active palladium/carbon was added thereto, and the resulting mixture was reacted under a hydrogen5 atmosphere for 12 hrs. After the completion of reaction, the reaction mixture was filtered through a cellite pad to remove the active palladium/carbon catalyst and the solvent was removed under reduced pressure therefrom. Then, the residue thus obtained was subjected to a silica gel column chromatography to obtain 2.64 g of the title compound (yieldLO 99percent).1H-NMR (200 MHz, CD3OD) δ 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m, 2H), 3.42 (m, 2H), 3.60 (br, IH).LC/MS (M+H): 201.
99%
With hydrogen In methanol for 12 h;
f-Butyl-l-benzylpiperidin-4-ylcarbamate (3.80 g, 13.1 mmol) obtained in Preparation Example I was dissolved in 26 ml of methanol in the 100 ml reaction vessel, catalytic quantities of 10percent active palladium/carbon was added thereto, and reacted under the hydrogen for 12 hrs. After the completion of the reaction, the reduction mixture was filtered through a cellite pad to remove palladium/carbon and the solvent was removed under a reduced pressure. Then, the mixture was subjected to silica gel column chromatography to obtain 2.64 g of the title compound (yield: 99percent).1H-NMR (200 MHz5 CD3OD) δ 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m,2H), 3.42 (m, 2H)5 3.60 (br, IH). LC/MS (M+H): 201
96%
With hydrogen In methanol at 20℃;
To a solution of the compound obtained in the above step (1) (72.6 g) in methanol (350 mL) was added 20 percent palladium-carbon (17.5 g) and the mixture was stirred at room temperature under hydrogen-gas atmosphere overnight. The reaction mixture was filtered by a membrane filter and the filtrate was concentrated in vacuo to obtain 4-(tert-butoxycarbonyl)aminopiperidine (48.3 g, yield: 96 percent) as a pale yellow solid. MS(APCI)m/z; 201 [M+H]+
94%
With hydrogenchloride; 10 wt% Pd(OH)2 on carbon; water; hydrogen In methanol
Tert-butyl 1-benzylpiperidin-4-ylcarbamate (500 mg, 1.72 mmol) was dissolved in methanol (10 ml) and stirred. 36percent aqueous HCl (169 µl, 1.72 mmol) was added followed by Pd(OH)2/C (525 mg, 689 µmol). Oxygen was then removed under reduced pressure and H2 added to the system (via a balloon) and stirred overnight. The reaction mixture was then filtered through celite and fitrate reduced in vacuo. DCM was then added and washed with 2M NaOH, H2O, saturated NaCl, dried with anhydrous Na2SO4, filtered and concentrated in vacuo to yield a yellow oil (321 mg, 94percent). 1H NMR (300 MHz, MeOH) δ 3.63 - 3.46 (m, 1H, CH), 3.34, (s, NH), 3.23 (ad, J = 12.9 Hz, 2H, 2 × CHpip), 2.97 - 2.71 (m, 2H, 2 × CHpip), 2.08 - 1.09 (m, 2H, 2 × CHpip), 1.61 - 1.40 (m, 11H, 2 × CHpip, 3 × Boc CH3). Mass Spectrum (ESI): m/z 201.2 [M+H]+.
76%
With hydrogen In ethanol at 20℃; for 16 h;
A solution of the ester 2 from above (66 g, 227.27 mmol) in 1 1 of ethanol is hydrogenated under normal pressure with 10 g of Pd/C (10percent) for 16 hours at room temperature. The mixture is filtered over celite and evaporated under reduced pressure. Recrystallisation from ether gave 34.5 g (76percent) of white crystals. MS (ESI) : 201 [M+H] +, 401 [2M+H] +, 1H-NMR (DMSO-d6) : b (ppm) 6.7 (br d, NH), 3.22 (br m, 1H), 2.88 (dt, 2H), 2.39 (dt, 2H), 1.8 (brs, NH), 1.6 (dt, 2H), 1.35 (s, 9H), 1.18 (dt, 2H).
Reference：
[1] Patent: WO2008/54154, 2008, A1, . Location in patent: Page/Page column 33; 34; 76; 77; 162-164
[2] Patent: WO2007/52938, 2007, A1, . Location in patent: Page/Page column 18
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2706 - 2715
[4] Patent: WO2007/46550, 2007, A1, . Location in patent: Page/Page column 117
[5] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5345 - 5352
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7106 - 7109
[7] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 6, p. 788 - 790
[8] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 3, p. 802 - 814
[9] Patent: WO2005/77932, 2005, A2, . Location in patent: Page/Page column 26; 30
[10] Patent: WO2004/78749, 2004, A1, . Location in patent: Page 14
[11] Patent: US6858629, 2005, B1, . Location in patent: Page/Page column 7; 9
[12] Patent: US6399616, 2002, B1,
[13] Patent: US6602872, 2003, B1,
[14] Patent: US5922717, 1999, A,
[15] Patent: US5700801, 1997, A,
[16] Patent: US6200989, 2001, B1,
[17] Patent: US6878712, 2005, B1, . Location in patent: Page/Page column 29
[18] Patent: JP2005/82508, 2005, A, . Location in patent: Page/Page column 23
[19] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3157 - 3162
[20] Medical Science Monitor, 2017, vol. 23, p. 3311 - 3317
[21] Patent: US6140333, 2000, A,
[22] Patent: WO2004/24710, 2004, A1, . Location in patent: Page 16
2
[ 50541-93-0 ]
[ 24424-99-5 ]
[ 73874-95-0 ]
Reference：
[1] Patent: US2003/162772, 2003, A1,
[2] Patent: WO2016/191412, 2016, A1, . Location in patent: Page/Page column 33
[3] Medical Science Monitor, 2017, vol. 23, p. 3311 - 3317
[4] Patent: US6140333, 2000, A,
3
[ 159874-20-1 ]
[ 73874-95-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479
[2] Patent: US5798337, 1998, A,
4
[ 50541-93-0 ]
[ 73874-95-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 6, p. 788 - 790
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2706 - 2715
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3157 - 3162
[4] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 3, p. 802 - 814
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 6, p. 788 - 790
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3157 - 3162
[3] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 3, p. 802 - 814
7
[ 50541-93-0 ]
[ 24424-99-5 ]
[ 73889-19-7 ]
[ 73874-95-0 ]
Reference：
[1] Patent: US2001/51727, 2001, A1,
8
[ 220394-91-2 ]
[ 73874-95-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2475 - 2479
9
[ 100-52-7 ]
[ 73874-95-0 ]
[ 73889-19-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2680 - 2693
[2] Patent: WO2017/49295, 2017, A1, . Location in patent: Paragraph 00399
10
[ 100-44-7 ]
[ 73874-95-0 ]
[ 73889-19-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 834 - 864
[2] Letters in Drug Design and Discovery, 2014, vol. 11, # 9, p. 1070 - 1078
11
[ 100-39-0 ]
[ 73874-95-0 ]
[ 73889-19-7 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 6, p. 1681 - 1686
[2] ACS Chemical Neuroscience, 2017, vol. 8, # 11, p. 2496 - 2511
12
[ 73874-95-0 ]
[ 160357-94-8 ]
Reference：
[1] Patent: WO2018/167276, 2018, A1,
13
[ 73874-95-0 ]
[ 127285-08-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 14, p. 4511 - 4525
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 16, p. 4191 - 4195
[3] Patent: EP1433788, 2004, A1, . Location in patent: Page 41
14
[ 73874-95-0 ]
[ 402927-97-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 22, p. 6549 - 6560
[2] Patent: WO2014/184327, 2014, A1,
[3] Bioorganic Chemistry, 2015, vol. 61, p. 21 - 27
15
[ 124-63-0 ]
[ 73874-95-0 ]
[ 287953-38-2 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 20℃; for 16 h; Cooling with ice
5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgS04 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1 -Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91 percent; ESI-MS: 279 [M+H]+
89%
With triethylamine In dichloromethane at 20℃; for 1 h;
EXAMPLE 4; Preparation of 4-(2-chloro-6-fluoro-benzoylamino)- 1 H-pyrazole-3 -carboxylic acid ( 1 -methanesulphonyl-piperidin-4-yl)-amide4A. 4-Amino-1H-pyrazole-3-carboxylic acid (l-methanesulphonyl-piperidin-4-yl) amideTo a stirred solution of 4-(N-BOC amino)piperidine (2.5 g, 12.5 mmoles) in dichloromethane (30 ml) was added triethylamine (2.1 ml, 15.0 mmoles), and then EPO <DP n="165"/>dropwise methanesulphonyl chloride (1.06 ml, 13.8 mmoles). The solution formed was stirred at room temperature for one hour. The reaction mixture was partitioned between EtOAc and water. The organic portion was washed with water, 2N HCl, brine, dried (MgSO4) filtered and evaporated in vacuo to give 4-(N-BOC-amino)-l- methanesulphonylpiperidine as a white solid (3.1g, 89percent).
55%
With triethylamine In dichloromethane at 20℃; for 4 h;
General procedure: To a stirred solution of 2 (0.20 g, 1.00 mmol) in anhydrous DCM(5 mL) was added Et3N (0.42 mL, 3.00 mmol) at room temperature.Then 3a–i (3.96 mmol) was added in small portions at room temperature.The reaction was stirred for 4 h at this temperature and then quenched the reaction with saturated aqueous solution ofNaHCO3. The aqueous layer was extracted with ethyl acetate(3 10 mL). The combined organic layers were dried over anhydrousNa2SO4, filtered, and concentrated. Silica gel flash columnchromatography (EtOAc/hexanes = 1:2) of the residue gave 4a–ias the product. Dissolved 4a–i (0.34 g, 0.97 mmol) in 25 mL TFAat room temperature, the reaction was stirred at room temperature for 10 h. Distilled the TFA under vacuum and then diluted with saturated aqueous solution of NaHCO3. The aqueous layer wasextracted with ethyl acetate (3 10 mL). The combined organiclayers were dried over anhydrous Na2SO4, filtered, and concentrated.Silica gel flash column chromatography (EtOAc/hexanes =1:1) of the residue gave 5a–i as the product.
A mixture of 2,6-dibromo-pyridine (3.5 g, 14.77 mmol) and piperidin-4-yl-carbamic acid te/f-butyl ester (1.478 g, 7.38 mmol) is heated to 130 0C in a sealed vessel for 6.5 h and 160 0C for 3 h. The residue is cooled and dissolved in CH2CI2 , washed with saturated NaHCO3 (X2), brine, dried (Na2SO4), filtered and concentrated. The residue is then separated via flash chromatography (SiO2, 10-30percent EtOAc/hexanes gradient) to give an intermediate, (6'-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-carbamic acid te/f-butyl ester (0.83 g, 32percent). MS (ESI) m/z 356.0, 358.0 (M+1 ), which is taken on to next step.
With triethylamine In dichloromethane at 0℃; for 2 h;
To a solution of ie -butyl piperidin-4-yl carbamate (5.0 g, 25 mmol) in DCM (80 mL) at 0 °C were added EtiN (3.8 g, 38 mmol) and AC2O (2.6 g, 25 mmol). The resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (30 mL), separated and the organic layer was washed with saturated NaHCC>3 (30 mL), dried over a2S04 and concentrated to give the desired compound (5.6 g, 93percent yield) as a pale yellow solid. LCMS- C: T 1 .88 min; m/z 265.1 [M+Na]+
89%
at 0℃; for 2 h;
Acetic anhydride (4.71 mL, 49.9 mmol) was added to a solution of terf-butyl piperidin-4- ylcarbamate (10.0 g, 49.9 mmol) and triethylamine (10.4 mL, 74.9 mmol) in anhydrous DCM (100 mL) at 0 °C. The reaction mixture was stirred at 0 C for 2 hours before water (-100 mL) and DCM (-50 mL) were added. The organic phase was separated, washed with a saturated aqueous NaHCC solution (-100 mL) and dried (MgS04). The solvent was removed in vacuo to give the title compound as a white solid (10.72 g, 89percent). 1H NM (400 MHz, CDCIa) δ 4.54 - 4.42 (m, 2H), 3.80 - 3.70 (m, 1 H), 3.70 - 3.58 (m, 1 H), 3.12 (ddd, J = 14.2, 1 1.8, 2.9 Hz, 1 H), 2.78 - 2.65 (m, 1 H), 2.07 (s, 3H), 2.05 - 1.97 (m, 1 H), 1.96 - 1 .87 (m, 1 H), 1.43 (s. 9H), 1.36 - 1.20 (m, 2H).
80%
With triethylamine In dichloromethane at 0℃; for 2 h;
To a solution of tert-butyl piperidin-4-ylcarbamate (5.0 g, 25.0 mmol) in DCM (80 mL) at 0 00 was added Et3N (3.8 g, 37.5 mmol) and Ac20 (2.6 g, 25.0 mmol). The mixture was stirred at 0 00 for 2 hours. The reaction was quenched by the addition of water (30 mL) and theorganic layer separated and washed with a saturated aqueous solution of NaHCO3 (30 mL),dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (4.8 g,80percent). LCMS: RT 1 .88 mm; m/z 265.1 [M+Na].
With triethylamine In dichloromethane at 0 - 20℃; for 1 h;
To a stirred suspension of 4-boc aminopiperidine (CAS Number 73874-95-0, available from Combi Blocks) (5.00 g, 24.960 mmol) in dichloromethane (30 ml) was added triethylamine (10.40 ml, 74.88 mmol) and acetyl chloride (2.1 1 ml, 29.950 mmol) at 0°C and the resulting reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was poured into water (100 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (30percent ethyl acetate in hexane) yielding ie f-butyl (1 -acetylpiperidin-4-yl) carbamate (6.61 g, 27.310 mmol). MS: ES+ 243.6 (M+1 ).
cis-1,1-dimethylethyl [1-(1-cyano-4-methoxycyclohexyl)-4-piperidinyl]carbamate[ No CAS ]
trans-1,1-dimethylethyl [1-(1-cyano-4-methoxycyclohexyl)-4-piperidinyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; at 20℃; for 2h;
Potassium cyanide (320mg; 5 mmol) was added to a mixture of 1 ,1-dimethylethyl 4- piperidinylcarbamate (1.Og), 4-(methyloxy)cyclohexanone (D3; 640mg; 5 mmol), and 2.5M hydrochloric acid (2.0ml; 5 mmol). After 2h at room temperature the mixture was partitioned between water and dichloromethane. Drying and evaporation gave the title compound as a mixture of cis and trans isomers, 1.1g.
With hydrogenchloride; In methanol; water; for 16h;
(ii) 1-Isopropyl-piperidin-4-ylamine To 4.8 g (1-Isopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester in 15 ml methanol, 20 ml methanolic hydrochloric acid (8M) were added and the mixture was stirred for 16 h. Removal of the solvent under reduced pressure yielded a white solid, which was coevaporated twice with 20 ml toluene. The product was obtained as its hydrochloride. Yield: 5.42 gMS (ES+): m/e= 143.
1-(6-chloro-5-trifluoromethylpyridin-2-yl)piperidin-4-yl-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With caesium carbonate; In 1,4-dioxane; for 64h;Heating / reflux;
A stirred mixture of D7 (5.0 g, 25 MMOL), 2, 6-dichloro-3-trifluoromethyl- pyridine (5.4 g, 25 MMOL) and cesium carbonate (12.22 g, 37.5 MMOL) in 1,4- dioxane (75 mL) was heated at reflux under argon for 64h. To the mixture, which was cooled to ambient temperature, was added water (250 mL) and DCM (250 mL) with shaking and the layers were separated. The aqueous phase was further extracted with DCM (250 mL) and the combined organic extracts were dried (MGS04) and evaporated in vacuo to an oil. This material was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compounds (5.0 g, 13.2 mmol, 53%). Mass Spectum: C16H2135CIF3N302 REQUIRES 379; Found 380 (MH+).
tert-butyl (1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 24.0h;
A stirred suspension of D7 (5.5 g, 27.5 MMOL), 3, 6-DICHLORO-5- TRIFLUOROMETHYLPYRIDINE (3.83 mL, 27.5 MMOL) (for synthesis see Tetrahedron, 1985,41, 4057) and potassium carbonate (11.4 g, 82.6 MMOL) in dry N, N-DMF (100 mL) was heated at 120C for 24h. After cooling to ambient temperature, the mixture was poured into water (1 L), stirred for 1 h and then filtered. The residue was washed with water (3 x 150 mL and dried (MGS04) to afford the title compound (9.8 g).
A mixture of 5- (Benzyloxy)-2-bromopyridine (2.1 g, 8.0 mmol) and tert-butyl piperidin-4-ylcarbamate (6.4 g, 32 mmol) in DMSO (120 ml) was stirred at 150 C for 24 hours and poured onto water (100 ml). The whole was extracted with ethyl acetate (75 ml x 2). The combined extracts were washed with brine, dried over MGS04, and evaporated in vacuum. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1 as eluent) to afford the titled compound. (1.0 g, 33%) LH NMR (CDC13) o : 7.97 (d, J = 3.1 Hz, 1H), 7.45-7. 28 (m, 5H), 6.62 (dd, J = 9.2 Hz, J = 3.1 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.01 (s, 2H), 4.53-4. 38 (m, 1H), 4.08-3. 97 (m, 2H), 3.75-3. 57 (m, 1H), 2.95-2. 84 (m, 2H), 2.09-1. 98 (m, 2H), 1.66-1. 40 (m, 11 H) ppm.
[1-(isoquinoline-5-sulfonyl)piperidin-4-yl]carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With triethylamine; In dichloromethane; at 0℃;
To a solution of 4-(N-BOC-AMINO)-PIPERIDINE (891 mg, 4.45 mmol) and triethylamine (0.61 ml, 4.4 mmol) in dichloromethane (30 ml) was added in small portions the isoquinolin-5-ylsulphonyl chloride hydrochloride (494 mg, 2.17 mmol) with stirring and cooling on ice. Water (50 ml) was added to the reaction mixture after stirring overnight. The organic layer was then separated and washed twice with water, dried (MGS04) and concentrated in vacuo. The obtained crude was recrystallised with DICHLOROMETHANE/HEXANE to afford the target compound as a white solid (398 mg, 1.02 mmol, 47%). Characterising Data: (C19H25N304S) : 1H NMR (CDCL3, 250 MHz) 8 1.40 (S, 9H), 1. 86-1. 98 (M, 4H), 2.67-2. 77 (M, 2H), 3.40-3. 49 (BS, 1H), 3.75-3. 80 (M, 2H), 4.37-4. 42 (BS, 1H), 7.72 (t, J= 8 Hz, 1H), 8.23 (d, J= 8 Hz, 1H), 8.38 (D, J= 8 Hz, 1H), 8.46 (d, J= 7 Hz, 1H), 8.68 (d, J= 6 Hz, 1H), 9. 36 (s, 1H).
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 72h;
Example 3: Synthesis OF 3-AMINO-6- (4-AMINO-PIPERIDIN-1-YL)-4-FLUORO- BENZOLB] THIOPHENE-2-CARBOXYLIC acid amide H N i N O F NHZ NN O N i HN 0- HS-NH, N F N O F F THF, 50 C, 3h DMF, 15h F 0A0 F NH2 HCI NH2 na ff) / MeOH, 3 days 0 H2N~ 3 '3 To a solution of 1.0 g (6.4 mmol) of 2, 4,6-trifluorobenzonitrile in MEOH (25 mL) was added 1.3 g (6.5 mmol) OF 4-N-BOC-AMINO-PIPERIDINE along with 1.2 mL (6.7 mmol) of N, N-diisopropylethylamine. The mixture was stirred at room temperature for 3 days then concentrated under reduced pressure to provide a white, solid. The solid was washed with large amounts OF H20 and dried under vacuum. The solid was RECRYSTALLIZED from hexane /EtOAc to provide 1.23 g (56%) of [1- (4-CYANO-3, 5-difluoro-phenyl) -piperidin-4-yl]- carbamic acid tert-butyl ester as a white solid.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 1.5h;Microwave;
TEA (0.243 ML, 1.74 mmol) and 6-CHLORO-2-(METHYLTHIO) pyrimidin-4-amine (0.309 g, 1.74 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.35 g, 1.74 mmol) in NMP (4 ML). Using a Smith Microwave Synthesizer, the mixture was subjected to single- mode microwave at 150 °C for 90 minutes. The mixture was partitioned between water and EtOAc and washed (x2) with water. The organic phase was dried over magnesium sulphate and concentrated to give the title compound (0.294 g). MS (ES) (MH+) : 340 for CL6H26N402S
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.166667h;Microwave;
tert-Butyl piperidin-4-ylcarbamate (972 mg, 4.85 mmol), was dissolved in anhydrous NMP (5 ml). Methyl 2, 6-DICHLOROISONICOTINATE (Intermediate 24, 1 g, 4.85 mmol) was added followed by TEA (675 mul, 4.85 MMOL). The mixture was heated under microwave conditions at 150 C for 10 minutes. Water (50 ML) and EtOAc (100 MI) were added, the aqueous phase was treated with solid NACI and extracted with EtOAc (4 x 100 ML). The EtOAc layer was dried, concentrated in vacuo and purified by flash chromatography eluting with hexane: EtOAc (4: 1) to give the title product as an off-white solid. (1.4 g). MS (ES, M+H) : 370 for C, 7H24CIN304 1H NMR No. : 1.38 (m, 2H); 1.49 (s, 9H); 1.93 (m, 2H); 2.29 (m, 1H) ; 3.17 (m, 2H); 3.48 (s, 1H) ; 3.94 (s, 3H); 4. 38 (m, 2H); 7.02 (s, 1H) ; 7.31 (s, 1H) ; 7.81 (s, 1H) ; 8.49 (s, 1H)
With triethylamine; In dimethyl sulfoxide; at 120℃; for 17h;
tert-Butyl {l-[4-(trifluoromethyl)pyridin-2-yl]piperidin"4-yl}carbamate; A solution of <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (1.0Og, 4.42mmol), tert-butyl piperidine-4- ylcarbamate (0.93g, 4.65mmol) and TEA (0.67mL, 4.86mmol) in DMSO (5mL) was heated at 1200C for 17h. The reaction mixture was evaporated to dryness, Et2O was added, and the organic phase was washed with water, brine and evaporated to dryness. The residue was purified using the Biotage Horizon HRFC system eluting with 22percent EtOAc in petroleum ether EPO <DP n="195"/>(40-60°C) to give the title compound (1.08g, 71percent) as a solid. 1H NMR(500MHz, CDCl3): 8.30 (d, IH), 6.82 (s, IH), 6.77 (d, IH), 4.49 (bs, IH), 4.36-4.22 (m, 2H), 3.74 (bs, IH), 3.06 (td, 2H), 2.10-2.04 (m, 2H), 1.56-1.38 (m, 11H); 13C NMR(CDCl3): 159.4, 155.4, 149.5, 140.1, 139.9, 124.5,122.4, 108.1, 102.7, 79.8, 48.3, 44.4, 32.3, 28.6; Mass Spectrum: M+H 5 346.
ethyl 2-[4-(N-tert-butoxycarbonyl-amino)piperidin-1-yl]pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With potassium carbonate; In acetonitrile; at 20℃;
A solution of 2-(methylsulfonyl)- 5-pyrimidinecarboxylic acid, ethyl ester (0.094 mol)in acetonitrile (240ml) was added at room temperature to a solution of 4-piperidinyl-carbamic acid, 1,1-dimethylethyl ester (0.078 mol) and potassium carbonate (0.156mol) in acetonitrile (120ml) under NI flow. The mixture was stirred at roomtemperature overnight, poured out into ice water and extracted with EtOAc. Theorganic layer was washed with water, dried (MgSC>4), filtered, and the solvent wasevaporated. The residue was crystallized from diethyl ether. The precipitate was filteredoff and dried, yielding 14.4g (53percent) of intermediate 66, melting point 160°C.
With potassium carbonate; In acetonitrile; at 20℃; for 15h;
A solution of <strong>[148550-51-0]2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester</strong> (0.0434 mol) in acetonitrile is added under nitrogen to a solution of 4-N-(tertbutoxycarbonyl) aminopiperidine (0.0362 mol) and potassium carbonate (0.0724 mol). The mixture was stirred at room temperature for 15 hours, poured out onto ice. The precipitate was filtered, washed with water and DIPE and dried yielding 7.9g of intermediate 4.
[1-(6-amino-5-formyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 1h;
To a mixture of <strong>[14160-93-1]4-amino-6-chloro-pyrimidine-5-carbaldehyde</strong> (226 mg, 1.44 mmol) and 4-(N-BOC amino)-piperidine (318 mg, 1.59 mmol) in CH3CN (2 mL) was added DIEA (372 mg, 2.88 mmol). The mixture was heated at 90 C. with stirring for 1 h, cooled to room temperature. The precipitate was filtered off, washed with CH3CN (3*5 mL) and dried in vacuo to afford a white solid (400 mg, 86%). 1H NMR (DMSO-d6) delta 9.66 (s, 1H), 8.22 (br, 1H), 8.03 (s, 1H), 7.77 (br, 1H), 6.91 (d, J=7.90 Hz, 1H), 3.99 (m, 2H), 3.54 (m, 1H), 3.18-3.29 (m, 2H), 1.79 (m, 2H), 1.40 (m, 2H), 1.38 (s, 9H); LC/MS (ESI) calcd for C15H24N5O3 (MH)+ 322.2, found 322.2.
86%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 1h;
a. [1-(6-Amino-5-formyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester To a mixture of <strong>[14160-93-1]4-amino-6-chloro-pyrimidine-5-carbaldehyde</strong> (226 mg, 1.44 mmol) and 4-(N-BOC amino)-piperidine (318 mg, 1.59 mmol) in CH3CN (2 mL) was added DIEA (372 mg, 2.88 mmol). The mixture was heated at 90 C. with stirring for 1 h, cooled to room temperature. The precipitate was filtered off, washed with CH3CN (3*5 mL) and dried in vacuo to afford a white solid (400 mg, 86%). 1H NMR (DMSO-d6) delta 9.66 (s, 1H), 8.22 (br, 1H), 8.03 (s, 1H), 7.77 (br, 1H), 6.91 (d, J=7.90 Hz, 1H), 3.99 (m, 2H), 3.54 (m, 1H), 3.18-3.29 (m, 2H), 1.79 (m, 2H), 1.40 (m, 2H), 1.38 (s, 9H); LC/MS (ESI) calcd for C15H24N5O3 (MH)- 322.2, found 322.2.
cis-1,1-dimethylethyl [1-(4-methoxycyclohexyl)-4-piperidinyl]carbamate[ No CAS ]
trans-1,1-dimethylethyl [1-(4-methoxycyclohexyl)-4-piperidinyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
A mixture of <strong>[13482-23-0]4-methoxycyclohexanone</strong> (D3, 4.5g, 40mmol), dichloromethane (200ml), 1 ,1-dimethylethyl 4-piperidinylcarbamate (9.Og; 45mmol) and sodium triacetoxyborohydride (16.Og, 80mmol) was stirred at room temperature for 18h, then partitioned between dichloromethane and water at pH9. Drying, evaporation, and chromatography (5Og silica, 0-10% methanol in dichloromethane + NH3) gave the title compound as a mixture of cis and trans isomers, 7.Og.
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
Description 6. 1 ,1 -Dimethylethyl [1-(4-methoxycyclohexyl)-4-piperidinyl]carbamate (D6); A solution of <strong>[13482-23-0]4-methoxycyclohexanone</strong> (D5, 4.5g) in dichloromethane (200ml) at room temperature under argon was treated with 1 ,1-dimethylethyl 4-piperidinylcarbamate (9.Og) and sodium triacetoxyborohydride (16.Og) then stirred at room temperature for 18h, then partitioned between dichloromethane and water at pH9. Drying, evaporation and chromatography (5Og silica, 0-10% methanol in dichloromethane) gave the title compound as a mixture of cis and trans isomers, 7.Og.
Description 7. cis/trans-lambda, 1 -Dimethylethyl [1 -(4-methoxycyclohexyl)-4- piperidinyljcarbamate (D7); A solution of <strong>[13482-23-0]4-methoxycyclohexanone</strong> (D6, 4.5g) in dichloromethane (200ml) at room temperature under argon was treated with 1 ,1-dimethylethyl 4-piperidinylcarbamate (9.Og) and sodium triacetoxyborohydride (16.Og) then stirred at room temperature for 18h, then partitioned between dichloromethane and water at pH9. Drying, evaporation, and chromatography (5Og silica, 0-10% methanol in dichloromethane) gave the title compound as a mixture of cis and trans isomers, 7.Og.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;
Description 8; l-(3,4,5-Trifluoro-benzyl)-piperidin-4-ylamine (D8); A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (2.5 g, 12.4 mmol), 3,4,5- trifluorobenzyl bromide (2.5 g, 11.3 mmol) and diisoproylethylamine (2.9 ml, 16.9 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (15.6 ml) was added and the reaction was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D8 (2.9 g, 96%) as a solid. Ci2Hi5F3N2 requires 244; Found 245 (MH+)
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h;
a) Synthesis of [1-(1-Methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (Compound 61) <strong>[78667-04-6]2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride</strong> (800 mg, 1 eq.) and 4-(N-Boc-amino)piperidine (959 mg, 1 eq.) were dissolved in CH2Cl2 (48 mL) and Diisopropyl Ethyl Amine (DIEA) (2.5 mL, 3 eq.) was added. The reaction mixture was stirred at room temperature for 48 h. Solvent was evaporated, the residue dissolved in CH2Cl2 and washed with saturated NaHCO3 aqueous solution and water, dried over MgSO4, and evaporated to dryness to give 1.25 g of a yellow powder (89 %) LC: tR=2.6 min; MS (ESI+): m/z = 295 (M+H)+; 1H NMR (DMSO-d6): delta 7.05 (s, 1H), 6.73 (m, 2H), 3.61 (s, 3H), 3.45 (s, 2H), 3.18 (m, 1H), 2.68 (d, J=11.8 Hz, 2H), 1.95 (t, J=11.6 Hz, 2H), 1.64 (d, J=10.7 Hz, 2H), 1.36 (s, 9H), 1.29 (m, 2H).
With triethylamine; In tetrahydrofuran; at 50℃; for 2h;
Reference Example 35 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-nitropyridine-4-carboxylic acid [Show Image] A solution of <strong>[907545-47-5]2-chloro-5-nitropyridine-4-carboxylic acid</strong> (1.50 g, 7.41 mmol), tert-butyl piperidin-4-ylcarbamate (1.48 g, 7.41 mmol) and triethylamine (3.1 mL, 22.2 mmol) in THF (19 mL) was stirred with heating at 50°C for 2 hr. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1 to 1:0) to give the title compound (1.57 g, yield 58percent) as a powder. EI(pos) 311.1 [M+H-tBu]+
3-Cyano-2,6-dichloro-4-trifluoromethylpyridine (482 mg, 2.00 mmol) was dissolved in 10 mL of absolute EtOH. To this solution at 0 C was added 4-N-boc-aminopiperidine (401 mg, 2.00 mmol) followed by triethylamine (0.30 mL, 2.2 mmol). This mixture was stirred at 0 C for 1 h. A stock solution of mercaptoacetonitrile (1.2 mL, 2.4 mmol) was added followed by triethylamine (0.30 mL, 2.2 mmol). This reaction mixture was heated at 80 C for 4 h. Water was added and the resulting solid was collected by filtration to give a yellow crystalline product (0.59 g, 67%).
4-Bromo-1 H-indole-2-carboxylic acid (3 g, 12.5 mmol) is dissolved in 30 ml of DMF and the solution is cooled to 0C. After addition of Huenigs base (6. 4 ml, 37.5 mmol), the mixture is stirred for 15 min. Then piperidin-4-yl-carbamic acid ter-butyl ester 3 (2.5 g, 12.5 mmol) is added, followed by PyBOP (7.2 g, 13.7 mmol). The reaction mixture is stirred for 18 h at room temperature. Then ethyl acetate is added and conc sodium hydroxide until a pH of 11 is reached. The organic layers are washed with brine, dried over sodium sulphate and evaporated. The crude product is further purified by flash-chromatography (silica gel, ethyl acetate/cyclohexane 1: 1) Yield : 5.13 g (97%). MS (ESI) : 420,422 [M-H]-, 1H-NMR (DMSO-d6) : 5 (ppm) 11.9 (m, 1H), 8.48 (d, 1H), 7.45 (d, 1H), 7.27 (d, 1H), 7.21 (s, 1H), 7.11 (dd, 1H), 2.86 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H), 1.42 (m, 2H).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 75℃; for 168h;
N,N-Diisopropylethylamine (0.64 mL, 3.7 mmol) was added to terf-butyl piperidin-4- ylcarbamate (368 mg, 1 .84 mmol) in 1 ,4-dioxane (3.0 mL) at room temperature, followed by <strong>[6226-25-1]2,2,2-trifluoroethyl trifluoromethanesulfonate</strong> (512 mg, 2.20 mmol), and the reaction was stirred at 75 C for 7 days. The mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with EtOAc:hexanes (1 :4) to give the title compound (501 g, 92% yield). 1H NMR (400 MHz, CD3SOCD3) delta 1 .36 (s, 9 H), 1 .37 (dq, J = 12, 4 Hz, 2 H), 1 .64 (br d, J = 1 1 Hz, 2 H), 2.30 (dt, J = 1 1 , 2 Hz, 2 H), 2.83 (br d, J = 12 Hz, 2 H), 3.09 (q, J = 10 Hz, 2 H), 3.12-3.26 (m, 1 H), 6.76 (d, J = 8 Hz, 1 H); LC-MS (LC-ES) M+H = 283.
With triethylamine; In tetrahydrofuran; at 75℃;
(I-77) To a suspension of 1.0 g (0.005 mole) of 4-Boc-aminopiperidine and 2.78 mL (0.020 mole) of triethyl amine in 14 mL of tetrahydrofuran was added 1.16 g (0.005 mole) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. After stirring at 75 degrees overnight, the mixture was cooled and saturated sodium carbonate was added. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with saturated sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluding with ethyl acetate-hexane (gradient, 100:0-20:80) gave 1.27 g of [1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid.
Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.00 equip), tetrahydrofuran (20 mL), To this was added sodium hydride (480 mg, 20.00 mmol, 2.00 equip) at 0 C. The resulting solution was stirred for 0.5 h at 0 C., and <strong>[6226-25-1]2,2,2-trifluoroethyl trifluoromethanesulfonate</strong> (2.784 g, 11.99 mmol, 1.20 equip) was added. The resulting solution was stirred for 2 h at 0 C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3*50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate as yellow oil. LCMS (ES, m/z) 283 [M+H]+
STEP 1: tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.00 equip), tetrahydrofuran (20 mL), To this was added sodium hydride (480 mg, 20.00 mmol, 2.00 equip) at 0 C. The resulting solution was stirred for 0.5 h at 0 C., and <strong>[6226-25-1]2,2,2-trifluoroethyl trifluoromethanesulfonate</strong> (2.784 g, 11.99 mmol, 1.20 equip) was added. The resulting solution was stirred for 2 h at 0 C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3*50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate as yellow oil. LCMS (ES, m/z) 283 [M+H]+
With triethylamine; In dichloromethane; at 0 - 20℃;
4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide To a cooled (0 degrees) mixture of 3.7 g (0.019 mole) of piperidin-4-yl-carbamic acid tert-butyl ester in 60 mL of dichloromethane, was added 2.1 g (0.020 mole) of triethylamine, followed by 4.2 g (0.017 mole) of <strong>[357913-53-2]3-(methylsulfonyl)-1-propanol-1-methanesulfonate</strong>. The mixture was stirred at room temperature for 18 hours, then diluted with water and the organic layer washed twice with 40 mL of water, once with 40 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluding with dichloromethane-methanol (gradient, 100:0-90:10) to give 3.6 g of [1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.
A mixture of 2,6-dibromo-pyridine (3.5 g, 14.77 mmol) and piperidin-4-yl-carbamic acid te/f-butyl ester (1.478 g, 7.38 mmol) is heated to 130 0C in a sealed vessel for 6.5 h and 160 0C for 3 h. The residue is cooled and dissolved in CH2CI2 , washed with saturated NaHCO3 (X2), brine, dried (Na2SO4), filtered and concentrated. The residue is then separated via flash chromatography (SiO2, 10-30percent EtOAc/hexanes gradient) to give an intermediate, (6'-bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-carbamic acid te/f-butyl ester (0.83 g, 32percent). MS (ESI) m/z 356.0, 358.0 (M+1 ), which is taken on to next step.
Preparation 19: r-Isobutyl-l,4'-bipiperidin-4-yl-4-amine hydrochloride; [0133] To a solution of l-(isobutyl)piperidin-4-one (3.10 g, 20 mmol) and 4-(BOC amino)piperidine (4.0 g, 20 mmol) in THF (80 mL) was added AcOH (60 drops) and sodium triacetoxyborohydride (12.72 g, 60 mmol). This solution was allowed to stir 4 hours. Water (75 mL) was then added to the reaction, the layers separated, and the organic discarded. The aqueous layer was basified with sodium carbonate (100 mL sat.) and the product extracted into EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to yield r-(cyclopropylmethyl)-l,4'-bipiperidin-4-amine hydrochloride (1.7 g, 25%). MS (ES) [M+H] found 340. tert-hutyX l'-isobutyl-l,4'-bipiperidin-4- ylcarbamate (1.7 g, 5 mmol) was dissolved in MeOH (30 mL), conc.HCl was added (3 niL) and the mixture was heated to 70 0C for 3 hours. The mixture was then cooled and the product was filtered off, washed with diethyl ether, and dried to yield l'-isobutyl-l,4'- bipiperidin-4-amine hydrochloride (1.71 g, quant, yield) as a white solid. MS (ES) [M+H] found 240.
tert-Butyl piperidin-4-ylcarbamate (1.98 g, 9.9 mmol) was dissolved in 40 ml acetonitrile. Potassium carbonate (11 g, 80 mmol) was added and the suspension stirred. <strong>[15848-22-3]5-Bromopentyl acetate</strong> (2.0 ml, 12 mmol) was added and the mixture stirred at reflux for 5 h. The mixture was removed from the oil bath, 20 ml water was added and the mixture was left to stir overnight, cooling to room temperature. The mixture was evaporated to near-dryness, and the residue was diluted with brine. The aqueous was extracted three times with ethyl acetate, the combined organics were dried over sodium sulfate and evaporated. The residue was purified by column chromatography (MeOH-DCM gradient, 5:95, increasing 10:90, 15:85 and finally 20:80) to give 0.90 g (3.0 mmol, 30%) of the title compound. 1H NMR (200 MHz, CHLOROFORM-d) ppm 4.47 (1 H, d, J=6.2 Hz), 3.64 (2 H, t, J=6.2 Hz), 3.49 (1 H, br. s.), 2.89 (2 H, br. d, J=11.7 Hz), 2.38 (2 H, t, J=7.4 Hz), 1.86 - 2.19 (4 H, m), 1.48 - 1.68 (8 H, m), 1.44 (9 H, s). LRMS: m/z 287 (M+1)
Diisopropylethylamine (10.9 ml, 62.4 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in THF (150 ml) at room temperature. To this mixture was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol) portion wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was concentrated and the resulting residue suspended in HCl (1M solution, 100 ml), the resulting solid precipitate was collected by filtration, washed with water and dried under vacuum give the title compound (9.2 g, 96% yield) as a white solid. Tr=1.28 min m/z (ES+) (M+Na+) 407.
52%
With triethylamine; In 1,4-dioxane; for 3h;Reflux;
A solution of 10 mmol of 1 in 10 ml of dioxane was treated with 4- carboxyphenyisulphonyl chloride (10 mmol) and triethy famine (22 mmoi). This reaction mixture was stirred at reflux for 3 hours, then cooled and concentrated. The residue was treated with water, and acidified with HCt. The formed precipitate was filtered off, carefully washed with water and dried, affording 2 as a white solid (2 g, 52 %).
Preparation of 4-Methyl-ri,4'1bipiperidinyl-4-olTo a suspension of piperidin-4-yl-carbamic acid iert-butyl ester (723 mg, 3.6 mmol) in DCE (20 mL) was added <strong>[3970-68-1]4-methylpiperidin-4-ol</strong> (500 mg, 4.4 mmol). After 30 minutes, sodium triacetoxyborohydride (1.54 g, 7.3 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 mL) and dichloromethane (75 mL). The organic phase was separated, dried (Na2S04), filtered and evaporated in-vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 100 g column, 0-10% methanol in dichloromethane) to afford crude 4-hydroxy-4-methyl-[l,4']bipiperidinyl-l'- carboxylic acid ie/t-butyl ester. This crude material was dissolved in dichloromethane (10 mL) and TFA (2 mL) added. After 30 minutes at ambient temperature, the reaction mixture was concentrated in-vacuo and the resultant residue loaded onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless oil (285 mg, 40% over two steps). NMR (300 MHz, CDC13): 3.15 (d, J = 12.3 Hz, 2H), 2.62-2.60 (m, 6H), 2.42-2.39 (m, 1H), 1.84 (d, J = 12.6 Hz, 2H), 1.67- 1.64 (m, 5H), 1.46-1.44 (m, 2H), 1.24 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 0.5h;
a) tert-Butyl 1-(6-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-ylcarbamate; To a mixture of <strong>[37552-81-1]4-chloro-6-(trifluoromethyl)pyrimidine</strong> (0.82 g, 4.49 mmol) and Boc-4-aminopiperidine (1.17 g, 5.84 mmol) in NMP (5.7 mL) was added DIPEA (1.10 mL, 6.29 mmol) and after 30 minutes the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.43 g, 92%) as a white solid. MS ISP (m/e): 347.2 [(M+H)+].
92%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 0.5h;
To a mixture of <strong>[37552-81-1]4-chloro-6-(trifluoromethyl)pyrimidine</strong> (0.82 g, 4.49 mmol) and Boc-4- aminopiperidine (1.17 g, 5.84 mmol) in NMP (5.7 mL) was added DIPEA (1.10 mL, 6.29 mmol) and after 30 minutes the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.43 g, 92%) as a white solid.MS ISP (m/e): 347.2 [(M+H)+].
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 3h;Inert atmosphere;
To a stirred solution of <strong>[4994-86-9]4-chloro-2-methylpyrimidine</strong> (1 g, 7.77 mmol) in 1, 4- dioxane (30 mL) under a argon atmosphere were added diisopropyl ethyl amine (1.35 g, 10.50 mmol) and tert-butyl piperidin-4-ylcarbamate (1.7 g, 8.55 mmol) at RT. The reaction mixture was stirred at 150 C for 3 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 5% MeOH: DCM to afford tert-butyl (1 -(2-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (1.5 g, 66%) as an off-white solid. ?H-NMR (DMSO-d6, 500 MHz): oe 8.04-8.02 (m, 1H), 6.83- 6.82 (m, 1H), 6.61-6.60 (m, 1H), 4.27-4.25 (m, 2H), 3.51 (s, 1H), 2.96-2.91 (m, 2H), 2.33 (s, 3H), 1.77-1.74 (m, 2H), 1.37 (s, 9H), 1.28-1.22 (m, 2H); LC-MS: 293.3 (M+1); (column; XBridge C-18 (50 x 3.0 mm, 3.5 jim); RT 2.90 mm. 5 mM NH4OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (R1: 0.2).
66%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 3h;
[0180] To a stirred solution of <strong>[4994-86-9]4-chloro-2-methylpyrimidine</strong> (1 g, 7.77 mmol) in 1, 4- dioxane (30 mL) was added diisopropylethylamine (1.35 g, 10.50 mmol) and tert-butyl piperidin-4-ylcarbamate (1.7 g, 8.55 mmol). The reaction mixture was heated to 150 C and stirred for 3 h. After consumption of the starting materials (monitored by TLC), the mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 5% (0390) MeOH:DCM to afford tert-butyl (l-(2-methylpyrimidin-4-yl) piperidin-4-yl) carbamate (1.5 g, 66%) as an off-white solid. 1H-NMR (DMSO-< 5, 500 MHz): delta 8.04-8.02 (m, 1H), 6.83- 6.82 (m, 1H), 6.61-6.60 (m, 1H), 4.27-4.25 (m, 2H), 3.51 (s, 1H), 2.96-2.91 (m, 2H), 2.33 (s, 3H), 1.77-1.74 (m, 2H), 1.37 (s, 9H), 1.28-1.22 (m, 2H); LC-MS: 293.3 (M+l); (column; X- Bridge C-18 (50 3.0 mm, 3.5 mupiiota); RT 2.90 min. 5 mM NH4OAc: ACN; 0.80 mL/min); TLC: 50% EtOAc:hexanes (Rf. 0.2).
64%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation;
a) [1-(2-Methyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester; A suspension of Boc-4-aminopiperidine (715.3 mg, 3.5 mmol), <strong>[4994-86-9]4-chloro-2-methylpyrimidine</strong> (521 mg, 3.85 mmol) and N,N-diisopropylethyl amine (899 L, 5.25 mmol) in dioxane (14 mL) was heated to 150 C. in the microwave for 30 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained after stirring of the crude product with diethyl ether and drying as white crystals (649.5 mg, 64%).MS ISP (m/e): 293.2 (100) [(M+H)+], 237.1 (37) [(M-isobutene+H)+].1H NMR (CDCl3, 300 MHz): (ppm)=8.11 (d, 1H), 6.33 (d, 1H), 4.46 (m, 1H), 4.32 (m, 2H), 3.72 (s, 1H), 3.00 (m, 2H), 2.50 (s, 3H), 2.03 (m, 2H), 1.46 (s, 9H), 1.38 (m, 2H).
64%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation;
A suspension of Boc-4-aminopiperidine (715.3 mg, 3.5 mmol), <strong>[4994-86-9]4-chloro-2-methylpyrimidine</strong> (521 mg, 3.85 mmol) and Nu,Nu-diisopropylethyl amine (899 L, 5.25 mmol) in dioxane (14 mL) was heated to 150 C in the microwave for 30 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained after stirring of the crude product with diethyl ether and drying as white crystals (649.5 mg, 64%).MS ISP (m/e): 293.2 (100) [(M+H)+], 237.1 (37) [(M -isobutene +H)+].1H NMR (CDCI3, 300 MHz): (ppm) = 8.11 (d, 1H), 6.33 (d, 1H), 4.46 (m, 1H), 4.32 (m, 2H), 3.72 (s, 1H), 3.00 (m, 2H), 2.50 (s, 3H), 2.03 (m, 2H), 1.46 (s, 9H), 1.38 (m, 2H).
With sodium t-butanolate;palladium diacetate; CyJohnPhos; In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;
a) [1-(3-Methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester; Palladium (II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17.4 mg, 0.048 mmol) were stirred under nitrogen at room temperature in dioxane (1.7 mL) for 10 minutes. Sodium tert-butylat (44 mg, 0.33 mmol), Boc-4-aminopiperidine (61.3 mg, 0.3 mmol), and 5-chloro-3-methyl-[1,2,4]-thiadiazole (44.4 mg; 0.33 mmol) were added and the reaction was heated to 150 C. for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from n-heptane/EtOAc 9:1 to 1:1 (v/v) as eluent. The title compound was obtained as a yellow solid (39 mg, 44%).MS ISP (m/e): 299.2 (43) [(M+H)+], 243.2 (100) [(M-isobutene+H)+].1H NMR (DMSO-D6, 300 MHz): (ppm)=6.92 (br d, 1H), 3.72 (m, 2H), 3.03 (m, 1H), 3.25 (m, 2H), 2.27 (s, 3H), 1.83 (m, 2H), 1.44 (m, 2H), 1.38 (s, 9H).
44%
With palladium diacetate; sodium t-butanolate; CyJohnPhos; In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation;
Palladium (II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17.4 mg, 0.048 mmol) were stirred under nitrogen at room temperature in dioxane (1.7 mL) for 10 minutes. Sodium tert-butylat (44 mg, 0.33 mmol), Boc-4-aminopiperidine (61.3 mg, 0.3 mmol), and 5- chloro-3-methyl-[l,2,4]-thiadiazole (44.4 mg; 0.33 mmol) were added and the reaction was heated to 150 C for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from n-heptane/EtOAc 9:1 to 1 :1 (v/v) as eluent. The title compound was obtained as a yellow solid (39 mg, 44%).MS ISP (m/e): 299.2 (43) [(M+H)+], 243.2 (100) [(M-isobutene+H)+].1H NMR (DMSO-D6, 300 MHz): (ppm) = 6.92 (br d, 1H), 3.72 (m, 2H), 3.03 (m, 1H), 3.25 (m, 2H), 2.27 (s, 3H), 1.83 (m, 2H), 1.44 (m, 2H), 1.38 (s, 9H).
With potassium carbonate; In tetrahydrofuran; at 20℃; for 1.0h;
<strong>[942199-56-6]2-Chloro-5-cyanobenzene-1-sulfonyl chloride</strong> (8.00 g) was dissolved in 100 ml THF and N-BOC-4-aminopiperidine (5.79 g) was added. Slowly 6 equiv. of K2CO3 was added and the mixture stirred 1 hour at room temperature. 3,5-dichlorophenol (11.06 g) and 18-Crown-6 (4.66 g) were added and the reaction stirred 4 days at reflux (75° C.). The mixture was cooled and vacuum filtered, the filtrate concentrated in vacuo, redissolved in methylene chloride, partitioned with water and the aqueous layer extracted three times with methlyene chloride. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over MgSO4. The filtrate was concentrated in vacuo, triturated with methylene chloride/diisopropyl ether and vacuum filtered to afford a yellow powder. The powder was recrystallized in MeOH to afford the product as a white powder (14.50 g, 87.3percent).
With triethylamine; In 1,4-dioxane; at 100 - 120℃; for 4h;Microwave irradiation;
EXAMPLE 6. TERT-BUTYL 1-(4-BROMOTHIAZOL-2-YL)PIPERIDIN-4-YLCARBAMATE (XJB02- 032)[0113] A mixture of <strong>[4175-77-3]<strong>[4175-77-3]2,4-dibromothiazol</strong>e</strong> (500 mg, 2.06 mmol), tert-butyl piperidin-4- ylcarbamate (495 mg, 2.47 mmol) in 1,4-dioxane (5.00 mL) and TEA (2.50 mL) was heated in mu\\.yen. at 100 °C for 1 h and at 120 °C for another 3 h. 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 0-10percent MeOH in CH2C12 to give 654 mg (88percent) product as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 6.41 (s, 1 H), 4.46 (br. s., 1 H), 3.92 (dt, 7=13.4, 3.3 Hz, 2 H), 3.70 (br. s., 1 H), 3.13 (ddd, 7=13.4, 11.6, 3.1 Hz, 2 H), 1.88 - 2.19 (m, 2 H), 1.40 - 1.54 (m, 11 H); LCMS RT = 6.137 min, m/z 362.0 [M+H+]; HRMS (ESI) m/z calcd for Ci3H2i79BrN302S [M+H+] 362.0538.
0.5 g (2.8 mmol) of <strong>[60211-57-6]3,5-dichlorobenzyl alcohol</strong> and 0.55 g (3.4 mmol) of 1,1' carbonyldiimidazole (CDI) are dissolved in 10 ml of CH2Cl2 and stirred at RT for 3 h. 0.56 g (2.8 mmol) of 6 are then added and stirred at RT for 18 h. The mixture is washed with water. The organic phase is then dried over sodium sulfate, filtered off, and the solvent is evaporated in vacuo. The residue is purified by means of preparative HPLC, giving 1.0 g (88%) of 7 as white crystals.
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 24h;
To a solution of <strong>[450-83-9]4-fluoro-2-methoxybenzaldehyde</strong> (292 mg, 1.89 mmol) in DMSO (3 mL) were added potassium carbonate (392 mg, 2.84 mmol) and tert-butyl piperidin-4-yl carbamate (378 mg, 1.89 mmol). The reaction mass was stirred at 80 C for 24 h. The reaction mass was quenched with water and was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to afford the title product (410 mg, 64%). 1H NMR (300 MHz, DMSO-d6): delta 10.02 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.86 (br s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 3.97-3.92 (m, 2H), 3.87 (s, 3H), 3.51 (br s, 1H), 3.32 (s, 2H), 3.03-2.95 (t. J =11.7 Hz, 2H), 1.81-1.77 (m, 2H), 1.38 (s, 9H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20.0℃; for 1.0h;Inert atmosphere;
Diisopropylethylamine (1.74 ml, 9.98 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.25 g, 1.25 mmol) in DCM (5 ml) at room temperature.To this mixture was added <strong>[64835-30-9]3-chloro-4-nitrobenzene sulfonyl chloride</strong> (0.32 g, 1.25 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour.After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated.The resulting residue was purified by flash column chromatography (elution: percent EtOAc: percent Heptane) to give the title compound (0.44 g, 84percent yield) as a white solid. deltaH (500 MHz, DMSO) 7.97-8.12 (m, 3H) 6.93 (d, J=7.72 Hz, 1H) 3.64 (d, J=12.77 Hz, 2H) 3.43 (d, J=3.94 Hz, 2H) 2.88-3.00 (m, 2H) 1.78 (d, J=10.40 Hz, 2H) 1.25-1.46 (m, 11H). Tr=2.22 min, m/z (ES+) (M+Na)+ 442.
A mixture of the crude product of <strong>[265108-36-9]4,4-difluorocyclohexane-1-carbaldehyde</strong> obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0 C., tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3 mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at mom temperature for eight hours. Brine was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.15-2.20 (17H, m), 1.44 (9H, s), 2.70-2.85 (2H, br), 3.38-3.53 (1H, br), 4.37-4.50 (1H, br).
650 mg
(Example 2c) tert-Butyl N-{1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl}carbomate A mixture of the crude product of <strong>[265108-36-9]4,4-difluorocyclohexane-1-carbaldehyde</strong> obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0C, tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at room temperature for eight hours. Brine was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.15-2.20 (17H, m), 1.44 (9H, s), 2.70-2.85 (2H, br), 3.38-3.53 (1H, br), 4.37-4.50 (1H, br).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 48h;
a) tert-butyl 1-f5-carbamoylpyridin-2-yl)piperidin-4-ylcarbamate To a stirred solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (200 mg, 1.28 mmol) in CH3CN (5 ml) was added 4-N-Boc-piperidinamine (270 mg, 1.34 mmol) and DIPEA (530 mg, 3.83 mmol). The reaction mixture was stirred at reflux for 48 h. The solid was collected by filtration and washed with CH3CN. After drying in vacuo, the title compound was obtained as a white solid (400 mg, 98%). [LCMS RtA =1.71 min, [M+H]+ = 321 ].
98%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 48h;Reflux;
a) tert-butyl 1-(5-carbamoylpyridin-2-yl)piperidin-4-ylcarbamate To a stirred solution of <strong>[6271-78-9]6-chloronicotinamide</strong> (200 mg, 1.28 mmol) in CH3CN (5 ml) was added 4-N-Boc-piperidinamine (270 mg, 1.34 mmol) and DIPEA (530 mg, 3.83 mmol). The reaction mixture was stirred at reflux for 48 h. The solid was collected by filtration and washed with CH3CN. After drying in vacuo, the title compound was obtained as a white solid (400 mg, 98%). [LCMS RtA=1.71 min, [M+H]+=321].
With sodium hydrogencarbonate; 1,1'-carbonyldiimidazole; In ethyl acetate; N,N-dimethyl-formamide;
Step 1: 3,5-Dichlorobenzyl 4-(tert-butoxycarbonylamino)piperidine-1-carboxylate A mixture comprising tert-butyl piperidin-4-ylcarbamate (5 g, 24.97 mmol), <strong>[60211-57-6]3,5-dichlorobenzyl alcohol</strong> (4.42 g, 24.97 mmol) and carbonyldiimidazole (4.05 g, 24.97 mmol) in DMF (83 ml) was heated at 50 C. with stirring for 3 days. The resulting mixture was concentrated under reduced pressure. The crude material was redissolved in EtOAc and washed with 1M HCl, a saturated solution of sodium bicarbonate and brine.
With potassium carbonate; In acetonitrile; at 20℃; for 4h;
4-N-Boc-aminopiperidine (0.96 g, 4.78 mmol) was added lot wise to a well stirred suspension of 2-bromo-5-nitro thiazole (1 g, 4.78 mmol) and potassium carbonate (0.79 g, 5.74 mmol) in acetonitrile (15 mL). The reaction mixture was then stirred at room temperature for about 4 h (monitored by TLC & LCMS for completion), and solvent evaporated under reduced pressure. The residue was further diluted with water (10 mL) and ethyl acetate (20 mL) and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2 * 15 mL) and the combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure and the residue purified by column chromatography using hexane/ethylacetate as eluent to give the desired product 2 (1.32 g, 84percent) as yellow solid. 1H NMR (DMSO-d6): deltaH 1.39 (s, 9H), 1.44-4.03 (m, 9H), 8.38 (s, 1H), 13C NMR (DMSO-d6): deltac 171.9, 154.8, 147.6, 135.7, 77.8, 47.1, 46.1, 30.7, 28.2. ESI-MS m/z 329.1 (M+H)+. Anal. Calcd for C13H20N4O4S: C, 47.55; H, 6.14; N, 17.06. Found: C, 47.52; H, 6.11; N, 17.09.
Intermediate XIV.1 a solution of methyl 4-hydroxymethyl-pyridine-2- carboxylate (3 g; 17.95 mmol) and triethylamine (5.0 mL; 35.89 mmol) in 50 mL DCM is added slowly methanesulfonyl chloride (1 .9 mL; 25.1 mmol). The reaction is stirred 1 h at r.t.. The mixture is extracted with water, separated and the organic layer is dried with MgS04, filtered and evaporated. Boc-4-aminopiperidine (3.59 g; 17.95 mmol), triethylamine (5.0 mL; 35.9 mmol) and ACN 50 mL are added and the mixture is stirred 2h at 85C. The reaction is cooled to r.t. and the precipitate formed is filtered off and dried in vacuo at 50C. C18H27 3O4 ESI Mass spectrum: m/z = 350 [M+H]+; m/z = 394[M+HCOO]"
tert-butyl (1-((3-(trifluoromethyl)benzoyl)glycyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 24h;Molecular sieve;
To 1 equivalent of tert-butyl piperidin-4-ylcarbamate (4) dissolved in DCM was added 1 equivalent of <strong>[17794-48-8]N-(3-(trifluoromethyl)benzoyl)glycine</strong>, 1 equivalent of PyBroP, 0.8 equivalents of 4-dimethylaminopyridine, 3 equivalents of N,N-diisopropylethylamine and molecular sieves 4 . The reaction mixture was stirred for 24 h at room temperature. The product was extracted with DCM/ 1 M NaOH. The organic layer was washed with brine, dried over MgSO4 and evaporated. The intermediate was purified by column chromatography (50/50 EtOAc in DCM). 1H NMR (400 MHz, CDCl3) delta: 8.13 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 (br s, 1H), 4.65-4.50 (m, 2H), 4.70 (dd, J = 22.4, 3.6, Hz, 2H), 3.82-3.72 (m, 2H), 3.23-3.15 (m, 1H), 2.88 (t, J = 12.0 Hz, 1H), 2.15-2.00 (m, 2H), 1.47 (s, 9H), 1.41-1.30 (m, 2H)
tert-butyl 1-(6-chloro-5-cyanopyridin-2-yl)piperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In ethanol; for 4h;Reflux;
To a solution of 2,6- dichloronicotinonitrile 1 (346 mg, 2.0 mmol) in ethanol (10 mL) was added tert-butyl piperidin- 4-ylcarbamate 2 (400 mg, 2.0 mmol) and K2C03 (552 mg, 4.0 mmol). The mixture was heated to reflux stirred for 4 h. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 20: 1 to 5: 1 PE/EA to afford the title compound as a white solid (470 mg, 70%). MS (ESI, method A): m/z = 337.2 [M + H].+
tert-butyl (1-(6-chloropyridazin-4-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20 - 80℃; for 4h;Inert atmosphere;
To a stirred solution of 3, 5-dichioropyridazine (1.2 g, 8.05 mmol) in NMP (12 mL) under argon atmosphere were added tert-butyl piperidin-4-yl-carbamate (1.6 g, 8.05 mmol), and DIPEA (1.4 mL, 8.05 mmol). The mixture was purged under argon for 20 mm at RT then stirred at 80 C for 4 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-Butyl (1 -(6-chloropyridazin-4-yl) piperidin4-yl) carbamate (2.3 g) as a thick black liquid was used without further purification. ?H-NMR (CDC13, 400 MHz): oe 8.72 (s, 1H), 6.67 (s, 1H), 4.59 (br s, 1H), 3.91-3.82 (m, 2H), 3.80-3.71 (m, 1H), 3.09-3.05 (m, 2H), 2.35-2.39 (m, 2H), 2.13-2.11 (m, 2H), 1.45 (s, 9H); LC-MS:313.4 (M+1); (column; X-Bridge C-18 (50 x 3.0 mm, 3.5 pt); RT 3.58 mm. 5 mM NH4OAc:ACN; 0.80 mL/min); TLC: 60% EtOAc:hexanes (R1: 0.3).
tert-butyl (1-(2-methoxypyridin-4-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 90℃; for 16h;Inert atmosphere;
To a stirred solution of tert-Butyl piperidin-4-ylcarbamate (1.2 g, 6.38 mmol) in toluene (80 mL) under argon atmosphere were added <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.3 g, 6.38 mmol), sodium tert-Butoxide (1.8 g, 19.14 mmol) and Xantphos (220 mg, 0.06 mmol)l. The mixture was purged under argon for 20 mm, then Pd2(dba)3 (73 mg, 0.12 mmol) added. The reaction mixture was stirred at 90 C for 16 h. After consumption of the starting material (monitored by TLC), the reaction was diluted with water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 30% EtOAc:hexanes to afford tert-Butyl (1-(2-methoxypyridin-4-yl) piperidin-4-yl) carbamate (1 g, 53%) as an off-white solid. ?H-NMR (DMSO-d6, 500 MHz):oe 7.77-7.75 (m, 1H), 6.83-6.82 (m, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 3.80-3.75 (m, 5H), 3.47 (s, 1H), 2.86 (t, 2H), 1.75-1.73 (m, 2H), 1.38-1.30 (m, 11H); LC-MS: 308.3 (M+1); (column; XBridge C-18 (50 x 3.0 mm, 3.5 pt); RT 3.14 mm. 0.05% aq TFA: ACN; 0.80 mL/min); TLC:45% EtOAc:hexanes (Rf 0.3).
53%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 90℃; for 16h;Inert atmosphere;
[0171] To a stirred solution of tert-butyl piperidin-4-ylcarbamate (1.2 g, 6.38 mmol) in toluene (80 mL) was added <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.3 g, 6.38 mmol), sodium tert- butoxide (1.8 g, 19.14 mmol) and Xantphos (220 mg, 0.06 mmol). The mixture was purged under an argon atmosphere for 20 min, then Pd2(dba)3 (73 mg, 0.12 mmol) was added. The reaction mixture was heated to 90 C and stirred for 16 h. After consumption of the starting materials (monitored by TLC), the mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 30% EtOAc:hexanes to afford tert-butyl (l-(2-methoxypyridin-4-yl) piperidin-4-yl) carbamate (1 g, 53%) as an off-white solid. 1H-NMR (DMSO-< 5, 500 MHz): delta 7.77-7.75 (m, 1H), 6.83-6.82 (m, 1H), 6.52 (d, 1H), 6.08 (s, 1H), 3.80-3.75 (m, 5H), 3.47 (s, 1H), 2.86 (t, 2H), 1.75-1.73 (m, 2H), 1.38-1.30 (m, 11H); LC-MS: 308.3 (M+l); (column; X- Bridge C-18 (50 3.0 mm, 3.5 mu); RT 3.14 min. 0.05% aq TFA: ACN; 0.80 mL/min); TLC: 45% EtOAc:hexanes (Rf. 0.3).
tert-butyl (1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of Ao; Step 9: Dissolve 4-(N-Boc-amino)piperidine (1 eq) dry DCM and added DIPEA (3 eq) stirred the reaction mixture for 10 minutes at 15 C, added 4- ethoxy-3 -(1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5- yl)benzene- 1 -sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 30 C. Aftercompletion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ao as a white solid; yield 90%.?H NMR (400 MHz, CDC13) 6 10.85 (s, 1H), 8.82 (d, J= 1.9 Hz, 111), 7.84 (dd,J= 8.7,1.8 Hz, 111), 7.16 (d, J= 8.8 Hz, 111), 4.39 (q J= 6.9 Hz, 211), 4.28 (s, 311), 3.74 (br s,2H), 3.42 (m, 1H), 2.94 (t, J= 7.5 Hz, 211), 2.52 (br s, 2H), 2.00 (d, J 11.2 Hz, 211),1.85 (m, 211), 1.66 (t, J= 6.9 Hz, 311), 1. 53 (m, 211), 1.41 (s, 9H), 1.03 (t, J= 7.3 Hz,311). MASS: ESI [M + H] : 575.26 Elemental anal. calcd. for C27H38N606S; C, 56.43; H, 6.66; N, 14.62; 0, 16.70; S, 5.58; found C, 56.45; H, 6.56; N, 14.67; 0, 16.75; S,5.56.
75%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
tert-butyl (1-(6-methoxypyrimidin-4-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130.0℃; for 16.0h;Inert atmosphere;
[0188] To a stirred solution of 4-iodo-6-methoxypyrimidine (500 mg, 2.12 mmol) in (0423) NMP (5 mL) was added diisopropylethylamine (383 mg, 2.96 mmol) and tert-butyl piperidin- (0424) 4-ylcarbamate (550 mg, 2.75 mmol) and purged with argon for 15 min. The reaction mixture was heated to 130 C and stirred for 16 h. After consumption of the starting materials (0425) (monitored by TLC), the mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 10-30% EtOAc:hexanes to afford tert-butyl (l-(6-methoxypyrimidin- (0426) 4-yl) piperidin-4-yl) carbamate (400 mg, 61%) as an off-white solid. 1H-NMR (DMSO-< 5, 500 MHz): delta 8.22 (s, 1H), 6.84-6.82 (m, 1H), 6.06 (s, 1H), 4.24-4.21 (m, 2H), 3.81 (s, 3H), 3.51 (br s, 1H), 2.94 (t, 2H), 1.75-1.73 (m, 2H), 1.38 (s, 9H), 1.30-1.22 (m, 2H); LC-MS: 308.9 (M+1); (column; X-Select CSH C-18 (50 3.0 mm, 3.5 mupiiota); RT 2.45 min 0.05% Aq TFA: ACN; 0.80 mL/min); UPLC (column; Acquity BEH C-18 50 X 2.1 mm, 1.7 mupiiota); RT 1.67 min. ACN: 0.025% Aq TFA; 0.5 mL/min; TLC: 30% EtOAc:hexanes (Rf. 0.2).
methyl 2-(4-(tert-butoxycarbonylamino)piperidin-1-ylsulfonyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 25℃;
Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (440 mg, 2.20 mmol, 1.00 equiv), dichloromethane (20 mL) and triethylamine (1 mL). To the resulting mixture was then added <strong>[56146-83-9]methyl 2-(chlorosulfonyl)acetate</strong> (400 mg, 2.32 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at 25 C. The resulting mixture was the washed with water (2*20 mL), dried over anhydrous sodium sulfate and the solids filtered out. The filtrate was then concentrated under vacuum to yield methyl 2-(4-[[(tert-butoxy)carbonyl]amino]piperidine-1-sulfonyl)acetate as a yellow solid.
(1-(6-cyano-pyridazin-3-yl)piperidin-4-yl)-carbamic acid tert-butylester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine; In ethanol; at 20℃;
To 4-yl amino-carboxylate (1.40g, 6.99mmol) and 6-chloro-pyridazin-3-carbonitrile (967.4mg, 6.93mmol) in ethanol(20mL) was added triethylamine (976.2mg, 9.65mmol) solution. The reaction was stirred overnight at room temperature, and then concentrated under reduced pressure. IncomeThe residue was mixed solvent of ethanol and water (10mL / 1mL) beating 0.5 hours, filtered to give the title compound as a light brown solid (2.13g,100% yield).
100%
With triethylamine; In ethanol; at 20℃;
To a solution of tert- butyl piperidin-4-yl carbamate (1.40 g, 6.99 mmol) and 6- chloropyridazine-3-carbonitrile (967.4 mg, 6.93 mmol) in EtOH (20 mL) was added Et3N (976.2 mg, 9.65 mmol). The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was stirred with a mixture of EtOH and water (10 mL/l mL) for 0.5 hour and filtered to give the title compound as a pale brown solid (2.13 g, yield 100%).MS (ESI, pos. ion) m/z: 304.2 [M+H]+;1H NMR (400 MHz, DMSO-^e) d (ppm): 7.83 (d, J= 9.7 Hz, 1H), 7.36 (d, J= 9.7 Hz, 1H), 6.89 (d, J= 7.3 Hz, 1H), 4.40 (d, J= 13.4 Hz, 2H), 3.67 - 3.56 (m, 1H), 3.24 - 3.12 (m, 2H), 1.84 (d, J= 10.1 Hz, 2H), 1.39 (s, 9H), 1.35 - 1.31 (m, 2H).
100%
With triethylamine; In ethanol; at 20℃;
To tert-butyl piperidin-4-ylcarbamate (1.40 g, 6.99 mmol)And <strong>[35857-89-7]6-chloropyridazine-3-carbonitrile</strong> (967.4 mg, 6.93 mmol)In ethanol (20mL) solutionTriethylamine (976.2 mg, 9.65 mmol).The reaction system was stirred at room temperature overnight.After the reaction,Concentrate under reduced pressure.The residue obtained was a mixed solvent of ethanol and water (10 mL / 1 mL)Beating for 0.5 hours, filtering,The title compound was obtained as a light brown solid (2.13 g, yield 100%).
(1) To a solution of the compound 1 (2.0 g) in chloroform (5 mL) were added the compound 2 (1.24 g) and aceticacid (0.63 mL), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, and then extracted 3 times with chloroform. The resultingorganic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The resulting residue was purified by silica gel column chromatography (eluent: chloroform-methanol; gradient:100:0-95:5), and dried to give the compound 3 (900 mg) as a brown solid.MS (APCI) 296 [M+H]+
tert-butyl N-[1-(5-bromo-1H-indazole-3-carbonyl)-4-piperidyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
Step 1-Preparation of tert-butyl N-[1-(5-bromo-1H-indazole-3-carbonyl)-4-piperidyl]carbamate, 30 A solution of <strong>[1077-94-7]5-bromo-1H-indazole-3-carboxylic acid</strong> 29 (1 g, 4.15 mmol) and HBTU (2.36 g, 6.22 mmol) were allowed to stir in dimethylformamide (20 ml) at room temperature for 40 minutes. Tert-butyl N-(4-piperidyl)carbamate (1.08 g, 5.39 mmol) and N,N-diisopropylethylamine (1.08 ml, 6.22 mmol) were added and the reaction was allowed to stir at room temperature for 18 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford tert-butyl N-[1-(5-bromo-1H-indazole-3-carbonyl)-4-piperidyl]carbamate 30 (0.80 g, 46%).
[1-(2-bromo-4-cyanophenyl)-piperidin-4-yl]carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate; In acetonitrile;Reflux;
General procedure: A mixture of the protected 4-(N-Boc-amino)piperidine (1.2 equiv), the corresponding fluorinated derivatives (Ia-d) (1.0 equiv), K2CO3 (1.5 equiv) and acetonitrile (30mL) was heated at reflux for 24h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50mL) and washed with water (3×30mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by gradient elution glass-column chromatography on silica gel using DCM/MeOH (v/v) as an eluent or gradient elution automated flash chromatography eluting with DCM/MeOH (v/v).
[1-(2-chloro-4-cyanophenyl)-piperidin-4-yl]carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; In acetonitrile;Reflux;
General procedure: A mixture of the protected 4-(N-Boc-amino)piperidine (1.2 equiv), the corresponding fluorinated derivatives (Ia-d) (1.0 equiv), K2CO3 (1.5 equiv) and acetonitrile (30mL) was heated at reflux for 24h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50mL) and washed with water (3×30mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by gradient elution glass-column chromatography on silica gel using DCM/MeOH (v/v) as an eluent or gradient elution automated flash chromatography eluting with DCM/MeOH (v/v).
[1-(4-cyano-2-trifluoromethyl-phenyl)-piperidin-4-yl]carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium carbonate; In acetonitrile;Reflux;
General procedure: A mixture of the protected 4-(N-Boc-amino)piperidine (1.2 equiv), the corresponding fluorinated derivatives (Ia-d) (1.0 equiv), K2CO3 (1.5 equiv) and acetonitrile (30mL) was heated at reflux for 24h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (50mL) and washed with water (3×30mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by gradient elution glass-column chromatography on silica gel using DCM/MeOH (v/v) as an eluent or gradient elution automated flash chromatography eluting with DCM/MeOH (v/v).
tert-butyl (1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 7h;Inert atmosphere;
General procedure: Solid K2CO3 (2 equiv) was added to a solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (1 equiv) and amine (1 equiv) in DMF(20 mL), and the resulting solution was stirred at 110 °C for 7 h.The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (ethyl acetate: hexane= 4:1) to yield pure product
tert-butyl 1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32.6%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 16h;
Step 1: tert-butyl 1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylcarbamate A mixture of <strong>[64115-88-4]1-bromo-2-(trifluoromethoxy)benzene</strong> (2.40 g, 9.96 mmol), tert-butyl N-(4-piperidyl)carbamate (1.99 g, 9.96 mmol), Pd2(dba)3 (546 mg, 597 umol), BINAP (744 mg, 1.20 mmol), t-BuONa (6.47 g, 69 mmol) in toluene (50 mL) was stirred at 90 C. for 16 h. Cooled to rt, filtered and concentrated, eluted with EtOAc (50 mL), washed with H2O (100 mL), then extracted with EtOAc (100 mL*3), washed with brine (50 mL*2), dried, concentrated to afford methyl 5-formyl-2,4-dimethylbenzoate (1.6 g, 32.6%) as brown gum. ESI-MS (EI+, m/z): 361 [M+H]+.
tert-butyl N-[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 17h;
Step 1: tert-Butyl 1-(2-cyano-6-fluorophenyl)piperidin-4-ylcarbamate A mixture of <strong>[425379-16-4]2-bromo-3-fluoro-benzonitrile</strong> (3.00 g, 15.00 mmol), tert-butyl N-(4-piperidyl)carbamate (3.61 g, 18.00 mmol), Pd2(dba)3 (1.37 g, 1.50 mmol), BINAP (932.95 mg, 1.50 mmol) and tBuONa (2.16 g, 22.50 mmol) in toluene (50.00 mL) was charged with N2 for three times, then stirred at 90 C. for 17 h. The reaction mixture was cooled down to rt and concentrated to give a residue which was purified by a flash column (10% to 22% of EtOAc in PE) to afford tert-butyl N-[1-(2-cyano-6-fluoro-phenyl)-4-piperidyl]carbamate (4.00 g, 83% yield) as a yellow solid. MS (EI+, m/z): 320.1 [M+H]+.
tert-butyl N-[1-(2-cyano-4-fluoro-phenyl)-4-piperidyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;
tert-Butyl N-(4-piperidyl)carbamate (10 g, 49.9 mmol), <strong>[64248-64-2]2,5-difluorobenzonitrile</strong> (7.29 g, 52.4 mmol) and K2CO3 (8.28 g, 59.9 mmol) were suspended in DMF (100 ml) then the reaction was heated to 110 C. for 18 hours. The reaction was cooled then partitioned between water (200 ml) and (3:1) EtOAc/Hept (200 ml). The organics were separated, the aqueous layer extracted with (3:1) EtOAc/Hept (100 ml). The organics were combined, washed with brine (200 ml), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified via flash column chromatography using gradients of 0 to 100% EtOAc in heptane, followed by 0 to 100% MeOH in EtOAc. The fractions containing product were combined and concentrated in vacuo to afford the title compound as a white powdery solid (7.29 g, 44%). 1H NMR (500 MHz, DMSO-d6) delta 7.69 (dd, J=8.4, 3.1 Hz, 1H), 7.48 (td, J=8.7, 3.1 Hz, 1H), 7.21 (dd, J=9.2, 4.7 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 3.39 (s, 1H), 2.80 (t, J=10.8 Hz, 2H), 1.84 (d, J=10.6 Hz, 2H), 1.56 (qd, J=12.1, 3.9 Hz, 2H), 1.39 (s, 9H). LCMS Method 1-Tr=1.23 min (ES+) (M+H+) 320.0.
tert-butyl N-[1-(2-cyano-6-fluorophenyl)piperidin-4-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;
2,3-Difluorobenzonitrile (1.25 g, 8.99 mmol) and K2CO3 (1.49 g, 10.78 mmol) were suspended in DMF (10 ml) then tert-butyl N-(piperidin-4-yl)carbamate (1.8 g, 8.99 mmol) was added and the mixture was heated at 110 C. for 16 hours. The cooled reaction was diluted with water (40 ml) and extracted with DCM (3×30 ml) then the combined organics were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography eluting with a gradient of 10% to 100% EtOAc in heptane to yield the title compound (2.12 g, 74%). 1H NMR (500 MHz, Chloroform-d) delta 7.34 (d, J=7.7 Hz, 1H), 7.20 (ddd, J=12.2, 8.2, 1.4 Hz, 1H), 7.04-6.97 (m, 1H), 4.51 (s, 1H), 3.65 (s, 1H), 3.38 (d, J=12.2 Hz, 2H), 3.25 (t, J=11.8 Hz, 2H), 2.04 (d, J=10.2 Hz, 2H), 1.69-1.58 (m, 2H), 1.46 (s, 9H). LCMS Method 1-Tr=1.28 min (ES+) (M+H+) 320.1.
tert-butyl N-[1-(3-formyl-2-methoxypyridin-4-yl)piperidin-4-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.666667h;
A mixture of <strong>[1008451-58-8]4-chloro-3-formyl-2-methoxypyridine</strong> (0.43 g, 2.51 mmol), 4- Boc-aminopiperidine (0.7 g, 3.5 mmol), and DIEA (1.0 mL, 2.5 eq.) in ACN (14 mL) was stirred at 100 C for 40 min. After removal of the volatile solvent, the residue was purified by column chromatography to afford the title compound (0.84 g, 100%). MS (M+H)+: 336.5.
tert-butyl N-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With triethylamine; In N,N-dimethyl-formamide; at 40℃; for 1h;
into a 40-mL round-bottom flask, was placed 2,4-dichloropyridine-3- carbaldehyde (2.0 g, 11.36 mmol, 1.00 equiv), tert-butyl N-(piperidin-4-yl)carbamate (2.3 g, 11.48 mmol, 1.00 equiv), TEA (3.5 g, 34.59 mmol, 3.00 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1 h at 40C and then quenched with 50 mL water. The crude product was extracted out by 3x20 mL of ethyl acetate and ethyl acetate layer was washed with 4x20 mL of brine, then dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated and purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1 :3) to afford 3.2 g (83%) of the title compound as a yellow solid. MS (M+H)+= 340.1/342.1.
With triethylamine;
Step 2-1, Preparation of tert-butyl N-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate into a 40-mL round-bottom flask, was placed <strong>[134031-24-6]2,4-dichloropyridine-3-carbaldehyde</strong> (2.0 g, 11.36 mmol, 1.0 equiv), tert-butyl N-(piperidin-4-yl)carbamate (2.3 g, 11.48 mmol, 1.0 equiv), TEA (3.5 g, 34.59 mmol, 3.0 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1 h at 40 C. and then quenched with 50 mL water. The crude product was extracted out by 3*20 mL of ethyl acetate and ethyl acetate layer was washed with 4*20 mL of brine, then dried over anhydrous sodium sulfate.
tert-butyl N-[1-(2-amino-5-bromopyridin-4-yl)piperidin-4-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 16h;
A mixture of <strong>[944401-69-8]2-amino-5-bromo-4-fluoropyridine</strong> (0.15 g, 0.78 mmol), 4-Boc aminopiperidine (0.31 g, 2.0 eq.), and DIEA (0.33 mL, 2.5 eq.) in DMSO (3 mL) was stirred at 120 C for 16h. The reaction was cooled to rt, and diluted with H20 to form solid. The solid were collected, washed with H20 and -10% AcOH in H20, and dried to afford the title compound (0.23 g, 79 %). MS (M+H)+ = 371.1.
tert-butyl {1-[(2-amino-1,3-thiazol-4-yl)methyl]piperidin-4-yl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 16h;Reflux;
A suspension of <strong>[59608-97-8]4-(chloromethyl)thiazol-2-amine hydrochloride</strong> (50 mg, 0.27 mmol) in THF (2 mL) was treated with 4- (N-Boc amino)-piperidine (76 mg, 0.378 mmol) and DIPEA (0.185 mL, 1.08 mmol) and stirred 16 h under reflux. The volatiles were removed under vacuum. The residue was partitioned between DCM (10 mL) and water (5 mL). The organic layer was dried over Na2S04, filtered and evaporated. The crude was purified over silica gel (DCM:MeOH:7N NH3 in MeOH = 9:0.5:0.5) to give 70 mg of title compound (84percent). 1H NMR (500 MHz, DMSO-d6) delta ppm 1.28 - 1.36 (m, 2 H) 1.36 (s, 9 H) 1.58 - 1.71 (m, 2 H) 1.86 - 2.02 (m, 2 H) 2.72 - 2.86 (m, 2 H) 3.08 - 3.27 (m, 3 H) 6.25 (br. s., 1 H) 6.75 (d, J=7.78 Hz, 1 H) 6.81 (br. s., 2 H). HRMS (ESI+): calcd. for C^sN^S [M + H]+ 313.1693; found 313.17.
tert-butyl N-[1-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.42 g
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 72h;
Tert-butyl N-(4-piperidyl)carbamate (895.3 mg, 4.47 mmol) and 4,5-dichloro-7H-pyrrolo[2,3- djpyrimidine (1080 mg, 5.36 mmol) were dissolved in NMP (8 ml) and DIPEA (2.33 ml, 13.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature 3 days. The mixture was dissolved in water and extracted with EtOAc (3 x l5mL). Combined organic layers were dried and concentrated to afford the cmde product which was recrystallized with acetonitrile to afford tert-butyl N-(5 -chloro-7H-pyrrolo [2,3 -djpyrimidin-4-yl)carbamate(1.42 g). LCMS: MW (calcd): 351.15; MS (ES, m/z): 352.22 (M+H).
methyl 2‐{4‐[(tert‐butoxycarbonyl)amino]piperidin‐1‐yl}pyrimidine‐5‐carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.1%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 3h;Inert atmosphere;
4-(N-Boc-amino)piperidine 9.3 g was added to a 250 mL three-necked flask.N,N-dimethylacetamide 100mL,N,N-diisopropylethylamine 7.5 g,<strong>[287714-35-6]2-chloropyrimidine-5-carboxylic acid methyl ester</strong> 4.0 g,Stir at room temperature for 3 h under nitrogen.The end of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1).200 mL of water was added and extracted with dichloromethane (100 mL x 3), and the organic phases were combined.The organic phase was washed successively with 5% dilute hydrochloric acid (100 mL×3) and saturated sodium chloride (100 mL×3).The organic phase was dried over anhydrous sodium sulfate for 2 h, filtered, and evaporated, evaporated, evaporated.A white solid was obtained in 6.8 g, yield: 87.1%.
methyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃;Inert atmosphere;
Example 70 Synthesis of (S)-3-(4-aminopiperidin-1-yl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)isonicotinamide 2,2,2-trifluoroacetate Compound 120a. To a stirred solution of <strong>[59786-31-1]methyl 3-bromoisonicotinate</strong> (0.200 gm, 0.925 mmol, 1.0 equiv) & tert-butyl piperidin-4-ylcarbamate (0.185 gm, 0.925 mmol, 1.0 equiv) and CS2CO3 (0.601 gm, 1.85 mmol, 2.0 equiv) in Dioxan (5 mL). The resulting mixture was purged with nitrogen for 10 min followed by addition of Pd2(dba)3 (0.042 gm, 0.046 mmol, 0.05 equiv) and xantphos (0.053 gm, 0.092 mmol, 0.1 equiv), again purged with nitrogen for 10 min. The reaction mixture was heated at 120 C. for overnight. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (2*50 mL). The combined organic layers were washed with water (30 mL), with brine (30 mL), dried over Na2SO4, concentrated to afford the crude which was purified by column chromatography to obtain methyl 3-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)isonicotinate (0.120 g, 38% Yield) as an yellow semi solid.
tert-butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl acetamide; at 120℃;
tert- Butyl piperidin-4-ylcarbamate (commercial, 500 mg, 3.22 mmol) was dissolved in DMA (10 ml_) and <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (552 mg, 3.22 mmol) was added followed by potassium carbonate (2.23 g, 16.1 mmol). The suspension was heated to 120C and stirred overnight before cooling and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and subsequently dried (anh. MgS04) and concentrated in vacuo to give the crude product (1.1 g, 78%) as an orange solid which was taken on as such into the next step. LCMS (Method B): RT = 1.45 min, m/z = 352 [M+H]+.
tert-butyl (1-(4-(2-methoxyethoxy)phenyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25.8%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In toluene; at 120℃; for 3h;Inert atmosphere;
A mixture of tert-butyl piperidin-4-ylcarbamate (2.3 g, 10 mmol) , 1-bromo-4- (2-methoxyethoxy) benzene (2 g, 10 mmol) , Pd 2 (dba) 3 (0.905 g, 1 mmol) , X-phos (0.952 g, 2 mmol) and Cs 2CO 3 (6.52 g, 20 mmol) in toluene (30 mL) was stirred at 120 for 3 hours under N 2. The reaction was concentrated to give the residue, which was treated with EtOAc/H 2O (50 mL/20 mL) . The organic layer was separated, washed with brine, dried over Na 2SO 4, concentrated and purified by column chromatography (petroleum ether/EtOAc=8: 13: 1) to give the target compound (0.9 g, 25.8%) as yellow oil. MS: M/e 351 (M+1) +.
methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.6%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 4h;
General procedure: To a solution of compound11(2mmol) in acetonitrile (5mL) was added substituted amine (2.2mmol) and DIEA (3mmol) at room temperature. The reaction mixture was refluxed for 4h and then the solvent was evaporated in vacuo. The resultant residue was diluted with ethyl acetate (20mL), washed with water and brine (3×20mL), dried over Na2SO4. The mixture was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography with ether/ethylacetate (1/3) to afford 12.
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