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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 1445-73-4 * 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.
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 1826
2
[ 1445-73-4 ]
[ 106-52-5 ]
Yield
Reaction Conditions
Operation in experiment
66%
With tetrakis[3,5-bis(trifluoromethyl)phenyl]boric acid bis(diethyl ether) complex; (bis[(2-dicyclohexylphosphino)ethyl]amine)cobalt(II)(CH2SiMe3); hydrogen In tetrahydrofuran at 25℃; for 65 h;
In a typical experiment, complex 1 (6.1 mg, 10 tmol) and H[BAr’4].(Et2O)2 (10.1 mg, 10 tmol) were dissolved in THF (2.0 mE) in a 100 mE thick-walled glass vessel equipped with a TEFLON stopcock and a stir bar. The substrate (0.5 mmol) to be hydrogenated was then added. The vessel was degassed by freeze-pump-thaw and then hydrogen (1 or 4 atm) was added. The resulting solution was stirred at the desired temperature (25-60° C.) for the indicated reaction time. At the end of the reaction, the solvent was evaporated and the residue was passed through silica gel in a pipette. The solvent was removed under vacuum and the ‘H NMR spectrum of the crude product mixture was recorded in CDC13. Hydrogenation products were then isolated by column chromatography or preparative thin layer chromatography (“TLC”) using n-hexane/ethyl acetate (3:1, v/v) as an eluent. Isolated products were characterized by ‘H NMR and GCMS, with spectra matching those reported in the literature or authentic samples.
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 16, p. 2474 - 2481
[2] Patent: US2015/336862, 2015, A1, . Location in patent: Paragraph 0038; 0054
[3] Patent: US2767190, 1950, ,
[4] Patent: US2776293, 1950, ,
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 1826
[6] Phytochemistry, 1999, vol. 52, # 5, p. 871 - 878
[7] Acta Crystallographica Section C: Crystal Structure Communications, 2003, vol. 59, # 2, p. o60-o61
[8] Organic Letters, 2008, vol. 10, # 20, p. 4697 - 4700
[9] Angewandte Chemie - International Edition, 2012, vol. 51, # 48, p. 12102 - 12106[10] Angew. Chem., 2012, p. 12077
[11] Chemical Communications, 2013, vol. 49, # 86, p. 10151 - 10153
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
5
[ 1445-73-4 ]
[ 41838-46-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonium formate In methanol
Step: 3A-1Synthesis of l-Methyl-piperidin-4-yIamineProcedure:Ammonium formate (2.226g, 0.035348mol) was added to a solution of 1 -Methyl- piperidin-4-one (lg, 0.008837mol) in MeOH and stirred for lOmins. 20percent Pd-C was added to this and the reaction mixture was heated at 60°C for 2hrs. The reaction was monitored by the TLC (10percent methanol in chloroform). The reaction mixture was filtered through celite bed, concentrated to afford lg (100percent yield) of l-Methyl-piperidin-4-ylamine.
1.4 g
With palladium 10% on activated carbon; ammonium formate In methanol; water at 20℃; for 24 h;
Ammonium formate (15.4 g; 240 mmol) and 10percent Pd/C (3.14 g; 29 mmol) are added to a solution of 1-methyl-4-piperidone (3.26 mL; 26.5 mmol) in aqueous methanol (80 mL, CH3OH/H2O 9:1); the mixture is stirred for 24 h. at r.t.;. catalyst removal by filtration over Celite and solvent evaporation to dryness at low pressure give a pale yellow residue of 1-methyl-4-aminopiperidine. Dropwise addition of 37percent HCl (4,6 mL) to a stirred solution of said amine in EtOH (50 mL) separates a white precipitate of 1-methyl-4-aminopiperidine hydrochloride that is filteted 18 hrs later, after cooling for 18 hrs at T = + 4°C. Finally, an aqueous solution of the hydrochloride treated with an excess of 0,1 N NaOH (≈ 10 mL) is extracted with CH2Cl2 (3x10 mL). After the usual work-up, solvent evaporation to dryness yields pure 1-methyl-4-aminopiperidine (1.4 g; 12.4 mmol). 1H-NMR (CDCl3): δ 2.85 (m, 2H); 2.58 (m, 1H); 2.25 (s, 3H); 2.01 (m, 2H); 1.85 (m, 2H); 1.63 (bs, 2H, NH2); 1.47 (m, 2H).
Reference：
[1] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 137
[2] Tetrahedron Letters, 2001, vol. 42, # 25, p. 4257 - 4259
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4390 - 4400
[4] Farmaco, 1998, vol. 53, # 3, p. 233 - 240
[5] Yakugaku Zasshi, 1951, vol. 71, p. 1053,1057[6] Chem.Abstr., 1952, p. 5044
[7] Patent: US2006/183769, 2006, A1, . Location in patent: Page/Page column 7
[8] Patent: EP1366018, 2016, B1, . Location in patent: Paragraph 0112
6
[ 1445-73-4 ]
[ 41838-46-4 ]
Yield
Reaction Conditions
Operation in experiment
88%
With hydrogenchloride; NaCNBH3 In methanol; diethyl ether
a) 4-Amino-1-methylpiperidine 1-Methylpiperidin-4-one (4.22 g, 37 mmol) and an ice cold soln of 1N HCl in Et2 O (37 mL, 37 mmol) were combined. Trituration followed by evaporation of the Et2 O at 23° under a stream of argon afforded the hydrochloride. MeOH (114 mL), anhydrous NH4 OAc (28.7, 373 mmol) and 3A molecular sieves were added. Stirred 10 min and then NaCNBH3 (2.33 g; 37 mmol) was added, and the mixture was stirred for 1 h. Acidified to 2 O. The resulting mixture was made basic with 50percent aq NaOH and extracted with EtOAc, dried (K2 CO3), and distilled (bp=55°-60°, 15 mm) to afford 3.88 g (88percent) of the title compound.
88%
With hydrogenchloride; NaCNBH3 In methanol; diethyl ether
a) 4-Amino-1-methylpiperidine 1-Methylpiperidin-4-one (4.22 g, 37 mmol) and an ice cold soln of 1N HCl in Et2 O (37 mL, 37 mmol) were combined. Trituration followed by evaporation of the Et2 O at 23° under a stream of argon afforded the hydrochloride. MeOH (114 mL), anhydrous NH4 OAc (28.7, 373 mmol) and 3A molecular sieves were added. Stirred 10 min and then NaCNBH3 (2.33 g, 37 mmol) was added, and the mixture was stirred for 1 h. Acidified to 2 O. The resulting mixture was made basic with 50percent aq NaOH and extracted with EtOAc, dried (K2 CO3), and distilled (bp=55°-60°, 15 mm) to afford 3.88 g (88percent) of the title compound.
Reference：
[1] Patent: US5593992, 1997, A,
[2] Patent: US5670527, 1997, A,
7
[ 1445-73-4 ]
[ 74-89-5 ]
[ 73579-08-5 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 3165,3171
[2] Patent: US6423713, 2002, B1,
[3] Patent: US6514977, 2003, B1,
8
[ 1445-73-4 ]
[ 73579-08-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 347 - 352
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 530,534
[2] Journal of Scientific and Industrial Research, 1958, vol. 17 B, p. 31
26
[ 1445-73-4 ]
[ 116480-62-7 ]
[ 5192-03-0 ]
Yield
Reaction Conditions
Operation in experiment
48.9%
With potassium hydroxide In methanol
B. Via 5-amino-1H-indole To a solution of 1.29 gm (20 mMol) potassium hydroxide in 10 mL methanol were added 1.32 gm (10 mMol) 5-amino-lH-indole followed by 2.46 mL (20 mMol) 1-methyl-4-piperidone. The reaction mixture was then heated to reflux for 18 hours. The reaction mixture was cooled to ambient, diluted with 20 ml water and the precipitate collected by filtration. The solid was recrystallized from ethyl acetate:methanol to give 1.11 gm (48.9percent) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyr-idin-4-yl)-1H-indole as a tan solid (m.p.=200-203°C). The tan solid was subjected to flash chromatography, eluding with 100:20:0.5 dichloromethane:methanol:ammonium hydroxide, to give 0.99 gm 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a cream colored solid (m.p.=212-215°C (ethyl acetate:methanol)). MS(m/e): 227(M+) Calculated for C14H17N3: Theory: C, 73.98; H, 7.54; N, 18.49. Found: C, 73.76; H, 7.48; N, 18.22.
Stage #1: With sulfuric acid In 1,4-dioxane at 0 - 60℃; Stage #2: With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water
[0216] 2-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-*]indole (17): Phenyl hydrazine (1.0 g, 9.3 mmols) and l-methyl-piperidin-4-one (1.1 g, 9.3 mmols) were dissolved in 1,4-dioxane (35 mL) and cooled to 0°C. Concentrated sulfuric acid (5 mL) was added dropwise to the reaction at O0C with stirring upon which a precipitate formed. The reaction was then heated to 60°C for one hour after which the precipitate was fully dissolved. The reaction was stirred for an additional hour at 60°C. The reaction was then cooled to room temperature and the pH was adjusted to approximately 12 by the addition of saturated aqueous sodium bicarbonate solution followed by small portions of solid sodium hydroxide. The organic products were extracted with chloroform (3x20 mL) and the combined organic extracts were washed with brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by columnchromatography (0-80percent gradient of ethyl acetate in hexane) afforded the final product (1.6 g, 93percent yield) as a beige solid. 1H NMR (400 MHz, DMSO): δ 10.80 (s, IH), 7.30 (m, 2H), 6.98 (m, 2H), 3.53 (s, 2H), 2.79 (t, J= 5.2 Hz, 2H), 2.71 (t, 2H, J= 5.4 Hz), 2.43 (s, 3H). 13C NMR APT (100 MHz, CDCl3): S 136.2 (up), 132.0 (up), 126.0 (up), 121.0 (down), 119.1 (down), 117.4 (down), 110.7 (down), 108.3 (up), 52.5 (up), 51.8 (up), 45.8 (down), 23.5 (up). ESI-HRMS (m/z): [M+H]+ calcd. for C12H14N2, 187.1230; found, 187.1228
7 g
With hydrogenchloride In water at 55℃; for 48 h;
To a suspension of phenylhydrazine (5.4 g) in 75 mL water was added slowly 4.2 mL of 12 N HCI, followed by addition of 1 -methylpiperidin-4-one (6.7 g). Additional 16 g of 12N HCI was added and the reaction mixture was heated at 55 oC for 2 days. After cooling in a ice-water bath, 10 N NaOH solution was added slowly until pH >12. 20 g of NaCI was added to the mixture and the reaction mixture was extracted with 2 x 100 mL of CH2CI2. The combined extracts were dried over Na2S04, filtered and concentrated. The residue was swished from EtOAc to give 7 g of the title compounds as a light yellow solid.[00111] Step 2 methyl 4-((2-methyl-1 ,2,3,4-tetrahydropyrimido[1 ,6- a]indol-5-yl)thio)benzoate
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 31, p. 10842 - 10846
[2] Patent: WO2011/11186, 2011, A2, . Location in patent: Page/Page column 51
[3] Organic Letters, 2018, vol. 20, # 6, p. 1589 - 1592
[4] Tetrahedron Letters, 2004, vol. 45, # 24, p. 4781 - 4783
[5] Patent: WO2013/78544, 2013, A1, . Location in patent: Paragraph 00109-00110
[6] RSC Advances, 2016, vol. 6, # 60, p. 54918 - 54925
29
[ 1445-73-4 ]
[ 5094-12-2 ]
Reference：
[1] Patent: CN108558905, 2018, A, . Location in patent: Paragraph 0047; 0049-0051
30
[ 1445-73-4 ]
[ 108-42-9 ]
[ 5094-12-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2015, vol. 51, # 5, p. 1257 - 1263
31
[ 1445-73-4 ]
[ 5094-12-2 ]
Reference：
[1] Journal of the Chemical Society, 1945, p. 399,401
32
[ 1445-73-4 ]
[ 591-51-5 ]
[ 4972-68-3 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
[2] Patent: DE872045, 1941, ,
[3] Dansk Tidsskrift for Farmaci, 1943, vol. 17, p. 173,180
[4] Journal of Organic Chemistry, 1947, vol. 12, p. 894,897, 9O2
[5] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
[6] Patent: DE872045, 1941, ,
[7] Dansk Tidsskrift for Farmaci, 1943, vol. 17, p. 173,180
[8] Journal of Organic Chemistry, 1947, vol. 12, p. 894,897, 9O2
[9] Journal of Medicinal Chemistry, 1986, vol. 29, # 3, p. 424 - 427
[10] Antioxidants and Redox Signaling, 2015, vol. 23, # 13, p. 1001 - 1016
33
[ 1445-73-4 ]
[ 108-86-1 ]
[ 4972-68-3 ]
Reference：
[1] Patent: US4132710, 1979, A,
34
[ 1445-73-4 ]
[ 4972-68-3 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
[2] Patent: DE872045, 1941, ,
[3] Dansk Tidsskrift for Farmaci, 1943, vol. 17, p. 173,180
[4] Journal of Organic Chemistry, 1947, vol. 12, p. 894,897, 9O2
[5] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
[6] Patent: DE872045, 1941, ,
[7] Dansk Tidsskrift for Farmaci, 1943, vol. 17, p. 173,180
[8] Journal of Organic Chemistry, 1947, vol. 12, p. 894,897, 9O2
[9] Medicinal Chemistry Research, 2004, vol. 13, # 6-7, p. 518 - 527
35
[ 1445-73-4 ]
[ 71-43-2 ]
[ 106-52-5 ]
[ 4972-68-3 ]
Reference：
[1] Journal of the American Chemical Society, 1950, vol. 72, p. 3134,3135
36
[ 1445-73-4 ]
[ 95533-25-8 ]
Reference：
[1] Patent: EP581538, 1994, A1,
37
[ 1445-73-4 ]
[ 95533-25-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1825 - 1830
38
[ 1445-73-4 ]
[ 541-41-3 ]
[ 29976-53-2 ]
Reference：
[1] Pharmaceutical Chemistry Journal, 1987, vol. 21, # 1, p. 60 - 61
[2] Organic Process Research and Development, 2018, vol. 22, # 1, p. 91 - 96
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 22, p. 8602 - 8609
41
[ 1445-73-4 ]
[ 23007-85-4 ]
Reference：
[1] Antioxidants and Redox Signaling, 2015, vol. 23, # 13, p. 1001 - 1016
42
[ 1445-73-4 ]
[ 74-88-4 ]
[ 26822-37-7 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 0 - 20℃; for 1 h;
Step 1: Preparation of 1,1-dimethyl-4-oxopiperidinium iodide [Show Image] Methyl iodide (1.6 mL, 26.5 mmol) was added into a solution of 1-methyl-piperidin-4-one (2.0 g, 17.6 mmol) in acetone (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with acetone to afford the title compound as an off-white solid (4.0 g, 88 percent). 1H NMR (D2O, 400 MHz): δ 3.38 (t, J=5.8 Hz, 4H), 3.06 (s, 6H), 1.95-2.05 (m, 4H). LCMS (Method D): Mass found (M+ 128.2), Rt (min): 1.19, Area (percent): 95.3 (Max. Chrom.)
88%
at 0 - 20℃; for 1 h;
Step 1: Preparation of 1,1-dimethyl-4-oxopiperidinium iodideMethyl iodide (1.6 mL, 26.5 mmol) was added into a solution of 1-methyl-piperidin-4-one (2.0 g, 17.6 mmol) in acetone (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with acetone to afford the title compound as an off-white solid (4.0 g, 88 percent). 1H NMR (D20, 400 MHz): δ 3.38 (t, J=5.8 Hz, 4H), 3.06 (s, 6H), 1.95-2.05 (m, 4H). LCMS (Method D): Mass found (M+ 128.2), Rt (min): 1.19, Area (percent): 95.3 (Max. Chrom.)
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 22, p. 8602 - 8609
[2] Journal of Organic Chemistry, 2014, vol. 79, # 8, p. 3358 - 3373
[3] Organic Process Research and Development, 2004, vol. 8, # 6, p. 939 - 941
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 32, p. 5968 - 5972
[5] Journal of the American Chemical Society, 2009, vol. 131, # 1, p. 357 - 367
[6] Patent: EP2508526, 2012, A1, . Location in patent: Page/Page column 45
[7] Patent: WO2012/130915, 2012, A1, . Location in patent: Page/Page column 55
[8] Journal of Organic Chemistry, 1945, vol. 10, p. 277,278
[9] Journal of the American Chemical Society, 1949, vol. 71, p. 465
[10] Journal of the Chemical Society, 1949, p. 708,712
[11] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 10, p. 1647 - 1652
[12] Patent: WO2005/90333, 2005, A1, . Location in patent: Page/Page column 135
[13] Patent: CN105985355, 2016, A, . Location in patent: Paragraph 0692; 0693; 0694; 0695
43
[ 1445-73-4 ]
[ 108-20-3 ]
[ 74-88-4 ]
[ 26822-37-7 ]
Reference：
[1] Patent: US6884868, 2005, B1,
44
[ 1445-73-4 ]
[ 74-88-4 ]
[ 26822-37-7 ]
[ 26822-30-0 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1930 - 1933
45
[ 1445-73-4 ]
[ 75-03-6 ]
[ 77542-18-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 20℃; for 4 h;
EXAMPLE 55 Synthesis of (f?)-3-chloro-4-((1 -(1 -phenylethyl)piperidin-4-yl)oxy)-/V-(thiazol-2- yl)benzenesulfonamide 2,2,2-trifluoroacetate Step 1. Preparation of 1-ethyl-1-methyl-4-oxopiperidin-1-ium iodide To a solution of 1-methylpiperidin-4-one (13.8 mL, 120 mmol) in butan-2-one (70 mL) was added iodoethane (10.6 mL, 132 mmol) and the reaction mixture was stirred at ambient temperature for 4 d. The mixture was filtered and the resulting solid was dried in vacuo to afford the title compound as an orange solid (27.8 g, 86percent yield): H NMR (300 MHz, D20) £3.52-3.38 (m, 6H), 3.05 (s, 3H), 2.17-1.99 (m, 4H), 1.34 (t, J = 7.3 Hz, 3H); MS (ES+) m/z 142.2 (M + 1).
Reference：
[1] Green Chemistry, 2017, vol. 19, # 3, p. 614 - 618
[2] ChemMedChem, 2015, vol. 10, # 7, p. 1249 - 1258
[3] Patent: WO2017/201468, 2017, A1, . Location in patent: Page/Page column 163
[4] Organic Process Research and Development, 2012, vol. 16, # 1, p. 109 - 116
[5] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 21, p. 7675 - 7699
With ammonia; In methanol; at 50℃;Schlenk technique;
In a schlenk reactor, a solution of <strong>[14150-94-8]1-methyl-3,5-dinitro-1H-pyridin-2-one</strong> (5.00 g, 25.11mmol) and 1-methyl-4-piperidone (3.13 g, 27.62 mmol) in ammonia (7N in MeOH) (43mL) was stirred overnight at 50 C. After cooling down to rt, the mixture was evaporatedin vacuo, taken-up in DCM and a saturated aqueous solution of NaHCO3 was added. Thelayers were separated and the aqueous layer was extracted with DCM (three times). The combined organic layers were dried over MgSO4, filtered off and evaporated in vacuo togive 2.32 g of intermediate 128 (48% yield, reddish solid) which was used in the next step without further purification.
EXAMPLE 6 5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine Beginning with 0.80 gm (5.4 mMol) of 5-methoxypyrrolo-[3,2-b]pyridine and 1.2 mL (10.1 mMol) 1-methyl-4-piperidone, 1.1 gm (84%) of the title compound were recovered as a yellow solid essentially by the procedure described in Example 5. An analytical sample was recrystallized from methanol. m.p.=202.9 C. (sub.); MS(m/e): 243(M+); Calculated for C14 H17 N3 O: Theory: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.22; H, 7.13; N, 17.47.
With MP-triacetoxyborohydride; In tetrahydrofuran; at 20℃; for 24h;
(R)-3-[(1 -Methyl-piperidin-4-ylamino)-methyl]-pyrrolidine-1 -carboxylic acid tert- butyl ester; To a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (252 mg, 1.26 mmol) and 1- methyl-4-piperidone (0.16 ml_, 1.38 mmol) in THF (10 ml.) MP-(OAc)3BH resin <n="103"/>(Argonaut; 2.33 mmol/g; 1.35 g, 3.15 mmol) was added and the reaction mixture was agitated at room temperature for 24 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (R)-3-[(1-methyl-piperidin-4-ylamino)-methyl]- pyrrolidine-1-carboxylic acid tert-butyl ester (370 mg, 99%) as an orange oil. The product was used without further purification.1H-NMR (400 MHz, CDCI3): delta 1.46 (s, 9H), 1.45-1.58 (m, 1 H), 1.86-2.01 (m, 5H), 2.25 (m, 2H), 2.36 (s, 3H), 2.48-2.74 (m, 3H), 2.97 (m, 2H), 3.28-3.56 (m, 2H), 3.75 (m, 1 H), 4.60 (m, 2H). MS (API-ES, pos) m/z = 298.25 [M+H]+.
With sodium hydroxide; In ethanol; water; at 60℃; for 16.0h;
Reference Example 65 2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6] naphthyridin-7-amine A solution of <strong>[98276-57-4]2,4-diaminobenzaldehyde</strong> (1.00 g, 7.34 mmol), 1-methyl-4-piperidinone (1.08 ml, 8.81 mmol) and 4N aqueous sodium hydroxide solution (11 ml) in ethanol (70 ml) was stirred at 60C for 16 hrs, and the solvent was evaporated under reduced pressure.. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.. The obtained crude product was purified by NH-silica gel chromatography (elute solvent; ethyl acetate) and treated with ethyl acetate - isopropyl ether (1:5) to give the title compound (666 mg) as a powder.1H-NMR (DMSO-d6) delta: 2.37 (3H, s), 2.71 (2H, t, J = 6.0 Hz), 2.96 (2H, t, J = 6.0 Hz), 3.56 (2H, s), 5.58 (2H, br), 6.80 (1H, d, J = 2.1 Hz), 6.87 (1H, dd, J = 2.1, 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.64 (1H, s).
3,3-DimethyM -(1 -methyl-4-piperidinyl)-2,3-dihydro-1 H-indole (D5) To a solution of 3,3-dimethyl-2,3-dihydro-1 /-/-indole (500 mg, 3.4 mmol) in acetic acid (5 ml) under an argon atmosphere was added 1-methyl-4-piperidinone (423 mg, 3.74 mmol) and after 5 minutes NaBH(OAc)3 (1.08 g, 5.1 mmol) was added in one portion. After 0.5 hours the mixture was diluted with water, basified with NaOH (pellets) until pH ca. 10 and extracted with Et2O. The organic phase was separated and dried over MgSO4. The solution was filtered and concentrated to afford 3,3-dimethyl-1-(1-methyl-4-piperidinyl)- 2,3-dihydro-1 H-indole (D5) in 94% yield (780 mg).1H-NMR (CDCI3): delta 1.27 (6H, s), 1.74 (4H, m), 2.04 (2H, dt), 2.30 (3H, s), 2.95 (2H1 d), 3.13 (2H, s), 3.35 (1 H, m), 6.40 (1 H, d, J=7.6 Hz), 6.63 (1 H, t, J=7.6 Hz), 6.98 (1 H, d, J=7.6 Hz), 7.04 (1H, t, J=7.6 Hz). MS: m/z (M+H)+ 245, C16H24N2 requires 244
Example 18 3,5-Bis-(2,6-difluorobenzylidene)-1-methylpiperidin-4-one To a solution of 1.0 g (8.84 mmol) of 1-methylpiperidine-4-one and 2.57 g (18.09 mmol) of 2,6-difluoro benzaldehyde in 90 mL of a 0.25M solution of aqueous NaOH (22.59 mmol) was added 1.16 mL (0.88 mmol) of a 25% w/w aqueous solution of <strong>[112-02-7]cetyltrimethylammonium chloride</strong>. The mixture was allowed to stir vigorously at room temperature for 12 hours, diluted with 100 ml of brine and extracted with three 40 mL portions of methylene chloride. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was slurried in 100 ml of boiling ethyl acetate and the insolubles were removed by rapid suction filtration. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate to provide 3.01 g (94%) of a bright yellow solid.
Preparation 9 5-Methoxy-3-(1-Methyl-1,2,3,6-Tetrahydropyridin-4-yl)indole To a mixture of <strong>[17288-40-3]5-methoxy-4-aza-1H-indole</strong>(7.0 g, 47 mmol) and potassium hydroxide (9.2 g, 165 mmol) in 350 mL of methanol was added 1-methyl-4-piperidone (9.86 mL, 80 mmol) in one portion. The reaction was heated at reflux temperature overnight, and cooled to room temperature. The resulting precipitate was collected, and the filtrate was concentrated to a minimal volume. A second crop of crystals was collected, washed with cold methanol, and combined with the previous crop to afford 9.0 g (79%) of the title compound. MS(m/e): 243 (M+). EA calculated for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.22; H, 7.13; N, 17.47.
3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium methylate; oxalic acid; In methanol;
EXAMPLE 7 3-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole 5-(4-Methoxyphenoxy)indole (as prepared above; 0.411 g, 1.72 mmol) and 1-methyl-piperid-4-one (0.24 mL) were refluxed with sodium methoxide (0.108 g) in MeOH (24 mL) for 16 hr Tlc indicated that reaction was not complete and reflux was therefore continued over a 24 hr period. Over this period further 4-methylpiperidone (4*0.24 mL) and NaOMe (0.108 g) were added. After standing at room temperature for 48 hr, the mixture was diluted with water and the MeOH was evaporated in vacuo. The residual mixture was extracted with EtOAc (3*) and the combined extracts were washed with H2 O and then saturated aqueous NaCl; dried (MgSO4) and evaporated to a yellow solid, which was chromatographed (silica gel; CH2 Cl2 /EtOH), giving the product as a pale yellow solid. This was dissolved in MeOH and treated with oxalic acid (0.15 g). On addition of Et2 O, yellow needles were obtained of: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole oxalate, 0.283 g (39percent), m.p. 157°-65° C. decomp.
5-chloro-2-(4-hydroxy-1-methylpiperidin-4-yl)benzothiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.34 gm (68%)
With n-butyllithium; In tetrahydrofuran; methanol; diethyl ether; hexane;
EXAMPLE 67 5-chloro-2-(4-hydroxy-1-methylpiperidin-4-yl)benzothiophene A solution of 0.300 gm (1.78 mMol) <strong>[20532-33-6]5-chlorobenzothiophene</strong> in 20 mL tetrahydrofuran was cooled to -78 C. To the cooled solution was then added 1.27 mL (1.78 mMol) n-butyllithium (1.2M in tetrahydrofuran) and the reaction mixture stirred for 1 hour after the addition was complete. To this solution was added 0.218 mL (1.78 mMol) 1-methyl-4-piperidone and the reaction mixture was allowed to warm to 0 C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned by the addition of hexane/diethyl ether. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to provide 0.34 gm of a tan solid. This residue was subjected to silica gel chromatography, eluding with chloroform containing 5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 gm (68%) of the title compound as an off-white solid. MS(FD): m/e=281 (M+)
0.34 gm (68%)
With n-butyllithium; In tetrahydrofuran; methanol; diethyl ether; hexane;
EXAMPLE 67 5-chloro-2-(4-hydroxy-1-methylpiperidin-4-yl)benzothiophene A solution of 0.300 gm (1.78 mMol) <strong>[20532-33-6]5-chlorobenzothiophene</strong> in 20 mL tetrahydrofuran was cooled to -78C. To the cooled solution was then added 1.27 mL (1.78 mMol) n-butyllithium (1.2 M in tetrahydrofuran) and the reaction mixture stirred for 1 hour after the addition was complete. To this solution was added 0.218 mL (1.78 mMol) 1-methyl-4-piperidone and the reaction mixture was allowed to warm to 0C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and partitioned by the addition of hexane/diethyl ether. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to provide 0.34 gm of a tan solid. This residue was subjected to silica gel chromatography, eluding with chloroform containing 5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 gm (68%) of the title compound as an off-white solid. MS(FD): m/e=281 (M+)
5,6-dichloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 9 5,6-dichloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole Beginning with 0.136 gm (0.88 mMol) <strong>[121859-57-2]5,6-dichloro-1H-indole</strong> and 0.216 mL (1.75 mMol) 1-methyl-4-piperidone, 0.150 gm (61%) of the title compound were recovered as a white solid. m.p.=255-257 C. MS(FD): m/e=280 (M-1) EA: Calculated for: C14 H14 N2 Cl2: Theory: C, 59.80; H, 5.02; N, 9.96. Found: C, 59.65; H, 4.85; N, 9.91.
EXAMPLE 9 5,6-dichloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole Beginning with 0.136 gm (0.88 mMol) <strong>[121859-57-2]5,6-dichloro-1H-indole</strong> and 0.216 mL (1.75 mMol) 1-methyl-4-piperidone, 0.150 gm (61%) of the title compound were recovered as a white solid. m.p.= 255-257C MS(FD): m/e=280 (M-1) EA: Calculated for: C14H14N2Cl2: Theory: C, 59.80; H, 5.02; N, 9.96. Found: C, 59.65; H, 4.85; N, 9.91.
6-trifluoromethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 7 6-trifluoromethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole Beginning with 1.00 gm (5.4 mMol) <strong>[13544-43-9]6-trifluoromethyl-1H-indole</strong> and 1.33 mL (11.0 mMol) 1-methyl-4-piperidone, 1.34 gm (89%) of the title compound were recovered as colorless crystals. m.p.=279-280 C. (dec.) MS(FD): m/e=280 (M+) EA: Calculated for: C15 H15 N2 F3: Theory: C, 64.28; H, 5.39; N, 9.99. Found: C, 64.52; H, 5.16; N, 10.07.
EXAMPLE 7 6-trifluoromethyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole Beginning with 1.00 gm (5.4 mMol) <strong>[13544-43-9]6-trifluoromethyl-1H-indole</strong> and 1.33 mL (11.0 mMol) 1-methyl-4-piperidone, 1.34 gm (89%) of the title compound were recovered as colorless crystals. m.p.= 279-280C (dec.) MS(FD): m/e=280 (M+) EA: Calculated for: C15H15N2F3: Theory: C, 64.28; H, 5.39; N, 9.99. Found: C, 64.52; H, 5.16; N, 10.07.
2,5-difluoro-4-(1-methyl-4-hydroxy-4-piperidinyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; ammonium chloride; In tetrahydrofuran; hexane; water;
EXAMPLE D 2,5-Difluoro-4-(1-methyl-4-hydroxy-4-piperidinyl)benzoic acid. A solution of 1.19 g (5 mmoles) of <strong>[28314-82-1]4-bromo-2,5-difluorobenzoic acid</strong> in 20 ml of tetrahydrofuran at -75 C. was treated with 4.2 ml of 2.4 M n-butyl lithium in hexane. The mixture was stirred 20 minutes, treated with a solution of 0.58 g (5.1 mmoles) of 1-methyl-4-piperidone in 5 ml tetrahydrofuran, stirred a further 1.5 hours, let warm to -30 C., and treated with a solution of 0.55 g (10.3 mmoles) ammonium chloride in 20 ml water. The product, the title compound, crystallized on standing.
With n-butyllithium; ammonium chloride; In tetrahydrofuran; hexane; water;
Example D 2,5-Difluoro-4-(1-methyl-4-hydroxy-4-piperidinyl)benzoic acid A solution of 1.19 g (5 mmoles) of <strong>[28314-82-1]4-bromo-2,5-difluorobenzoic acid</strong> in 20 ml of tetrahydrofuran at -75 C. was treated with 4.2 ml of 2.4 M n-butyl lithium in hexane. The mixture was stirred 20 minutes, treated with a solution of 0.58 g (5.1 mmoles) of 1-methyl-4-piperidone in 5 ml tetrahydrofuran, stirred a further 1.5 hours, let warm to -30 C., and treated with a solution of 0.55 g (10.3 mmoles) ammonium chloride in 20 ml water. The product, the title compound, crystallized on standing.
4-(4-bromo-2,5-difluorophenyl)-1-methyl-4-piperidinol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; ammonium chloride; In diethyl ether; water;
EXAMPLE A 4-(4-Bromo-2,5-difluorophenyl)-1-methyl-4-piperidinol. A solution of 2.72 g (10 mmoles) of <strong>[327-51-5]1,4-dibromo-2,5-difluorobenzene</strong> in 50 ml of ethyl ether, under an argon atmosphere stirred at -75 C., was treated dropwise with 4.2 ml of 2.5 M n-butyl lithium (hexane solution). The mixture was treated dropwise with a solution of 1.20 g (10.6 mmoles) of N-methyl-4-piperidone in 10 ml of ethyl ether, stirred a further 0.75 hours at -75 C., let warm to -30 C., and poured into a solution of 0.56 g (10.5 mmoles) ammonium chloride in 15 ml of water. The ether layer was washed with two 10 ml portions of water, dried (MgSO4), and evaporated to give 2.85 g of crude product which was purified by chromatography on a column of silica gel and crystallized to give 1.30 g of the title compound; mp 133-135 C.
With n-butyllithium; ammonium chloride; In diethyl ether; water;
Example A 4-(4-Bromo-2,5-difluorophenyl)-1-methyl-4-piperidinol A solution of 2.72 g (10 mmoles) of <strong>[327-51-5]1,4-dibromo-2,5-difluorobenzene</strong> in 50 ml of ethyl ether, under an argon atmosphere stirred at -75 C., was treated dropwise with 4.2 ml of 2.5 M n-butyl lithium (hexane solution). The mixture was treated dropwise with a solution of 1.20 g (10.6 mmoles) of N-methyl-4-piperidone in 10 ml of ethyl ether, stirred a further 0.75 hours at -75 C., let warm to -30 C., and poured into a solution of 0.56 g (10.5 mmoles) ammonium chloride in 15 ml of water. The ether layer was washed with two 10 ml portions of water, dried (MgSO4), and evaporated to give 2.85 g of crude product which was purified by chromatography on a column of silica gel and crystallized to give 1.30 g of the title compound; mp 133-135 C.
1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 g (78%)
With sodium borohydrid; In methanol; cyclohexane; isopropyl alcohol;
EXAMPLE 1 N-(1-Methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate A solution of <strong>[765-39-9]1-aminopyrrole</strong> (4.2 g, 0.05 mol) and 1-methyl-4-piperidine (6.9 g, 0.06 mol) in cyclohexane was refluxed overnight (about 16 hours) over 4 A molecular sieves. After 3 hours, an additional 1 g of 1-methyl-4-piperidone was added. The molecular sieves were filtered off and the cyclohexane removed by evaporation under reduced pressure. The resulting oil was dissolved in isopropanol and 5 g of sodium borohydride added. The mixture was stirred at reflux for three hours, then methanol was added, the heat was removed, and stirring continued until the mixture had cooled to room temperature. The solvent was removed by evaporation under reduced pressure to give a residue to which water was added. This mixture was extracted with dichloromethane, the dichloromethane solution was dried with saturated sodium chloride solution and magnesium sulfate, and the dichloromethane evaporated in vacuo to give 7 g (78%) of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.
1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 g (78%)
With sodium borohydrid; In methanol; cyclohexane; isopropyl alcohol;
EXAMPLE 1 N-(1-Methylpiperidin-4-yl)-N-(1H-pyrrol-1-yl)propanamide maleate A solution of <strong>[765-39-9]1-aminopyrrole</strong> (4.2 g, 0.05 mol) and 1-methyl-4-piperidone (6.9 g, 0.06 mol) in cyclohexane was refluxed overnight (about 16 hours) over 4 A molecular sieves. After 3 hours, an additional 1 g of 1-methyl-4-piperidone was added. The molecular sieves were filtered off and the cyclohexane removed by evaporation under reduced pressure. The resulting oil was dissolved in isopropanol and 5 g of sodium borohydride added. The mixture was stirred at reflux for three hours, then methanol was added, the heat was removed, and stirring continued until the mixture had cooled to room temperature. The solvent was removed by evaporation under reduced pressure to give a residue to which water was added. This mixture was extracted with dichloromethane, the dichloromethane solution was dried with saturated sodium chloride solution and magnesium sulfate, and the dichloromethane evaporated in vacuo to give 7 g (78%) of 1-methyl-4-(1H-pyrrol-1-yl)aminopiperidine.
4-(5-fluoro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
a. Reaction of <strong>[202865-66-5]2-bromo-5-fluorobenzyl alcohol</strong> and 1-methyl-4-piperidone by the method described in Example 16a provides 4-(5-fluoro-alpha-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine.
c. 3.48 g (0.03 mole) of 1-methyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 5.65 g (0.03 mole) of 1-(2-amino-4-methoxy-phenyl) pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 15 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried and recrystallized from ethanol to give 4,5-dihydro-7-methoxy-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 124-125 C. Analysis: Calculated for C17 H21 N3 O; 72.05% C; 7.47% H; 14.83% N. Found: 72.19% C; 7.43% H; 14.90% N.
lithium 1-methyl-4-(1-isoquinolyl)-piperidin-4-olate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water;
EXAMPLE 12 A solution of 11.3 g. of 1-methylpiperidin-4-one in 120 ml. of ether is added dropwise to a stirred isoquinolyl-1-lithium solution, freshly prepared from 20.8 g. of <strong>[1532-71-4]1-<strong>[1532-71-4]bromoisoquinoline</strong></strong> and n-butyllithium in 400 ml. of ether, at 0°, under dry nitrogen. The mixture is stirred for 2 hours more at 0°. Water (50 ml.) and then 100 ml. of 5percent hydrochloric acid are added dropwise to decompose the lithium 1-methyl-4-(1-isoquinolyl)-piperidin-4-olate formed.
A mixture of <strong>[5192-23-4]4-aminoindole</strong> (5 grams, 37.8 mmol) (obtained from preparation 1), 1- methyl piperidine-4-one (5.5 mL, 45.4 mmol), sodium triacetoxyborohydride (16.02 grams, 75.6 mmol) and acetic acid (2.15 mL, 37.8 mmol) in ethylene dichloride (100 mL) was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography. After completion of reaction (5 hours), the reaction mixture was diluted with ice water (500 mL), basified with 10% aqueous sodium hydroxide solution and extracted the mass with ethyl acetate (2 x 250 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained crude product (11.32 grams) was purified by column chromatography using silica-gel (100 - 200 mesh), the eluent system being ethyl acetate and triethyl amine (99:1) to obtain 7.6 grams of the title product. Melting Range: 128.3 - 131C; LR (Cm"1): 1109, 1373, 1519, 2931, 3417; 1H-NMR (ppm): 1.55 - 1.64 (2H, m), 2.14 - 2.20 (4H, m), 2.32 (3H, s), 2.83 - 2.86 (2H, m), 3.48 (IH, m), 3.82 (IH, bs), 6.28 - 6.30 (IH; d, J = 7.6), 6.43 - 6.44 (IH, t), 6.79 - 6.81 (IH, d, J = 8.08 Hz), 7.03 - 7.09 (2H, m), 8.19 (IH, bs); Mass (m/z): 230.4 (M+H)+.
To a suspension of <strong>[62830-55-1]4-iodophenylhydrazine hydrochloride</strong> (2.0 g, 0.0074 mol) in dioxane (30 mL) at RT was added cone. H2SO4 (0.7 mL, 0.0171 mol) dropwise and the reaction mixture was stirred for 5 min. To this was added N-methyl-4-piperidone (0.838 g, 0.0074 mol) and the reaction mixture was stirred at RT for 10 min and heated at 70 0C for 90 min. Reaction monitored by TLC. The solvent was evaporated and pH adjusted to 9-10 by 10percent KOH Solution. The product was extracted with (3x50 rnL) EtOAc. Combined organic layer washed with water and brine and dried over sodium sulfate, concentrated under vacuum and product purified by column chromatography (100-200 mesh silica) in solvent system (0-10percent, DCM/MeOH). Obtained 1.8g of brown solid. 1U NMR (CDCl3, free base) d (ppm) 7.70 (s, IH), 7.38 (d, IH), 7.05 (d, IH), 3.60 (s, 2H), 2.90 (m, 4H), 2.58 (s, 3H).
Example 8A[0405] Sulfuric acid (2 mL) was added to a solution of 4-Ethyl phenyl hydrazine hydrochloride (2.0 g, 11 mmol) in dioxane (30 mL), and allowed to stir for 5 min at RT. N- methylpiperidone (1.7 g, 13 mmol) was added and the mixture was heated at 80 0C for 3 h. After completion of reaction (monitored by TLC), reaction mixture was concentrated to -20 mL under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The mixture was extracted with EtOAc (3x100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound as a brown colored solid (0.35g , 82% yield).
With trifluoroacetic acid; tetramethylammonium triacetoxyborohydride; In dichloromethane; for 0.5h;
To a solution of <strong>[74587-12-5]3-iodo-4-methoxyaniline</strong> (180 mg, 0723 mmol) in DCM (5 mL) 1 -methyl-4-piperidone (0.116 mL, 106 mg, 0.940 mmol), TFA (0.290 mL, 429 mg, 3.760 mmol) and tetramethylammonium triacetoxyborohydride (285 mg, 1.084 mmol) were added in sequence. The reaction is completed in 30 min. The reaction mixture was diluted with DCM, washed with saturated solution of sodium hydrogen carbonate (3 x 5 mL), brine (3 x 5 mL), dried over sodium sulfate and the solvent was removed under vacuum. The solid crude so obtained was purified by flash chromatography (EtOAc/TEA 99/1) to afford a beige solid that was crystallized from diethylether to afford the title compound as a whitish solid (197 mg, 79%).1H NMR (400 MHz, DMSO-de) delta ppm 1.32 (qd, J=11.50, 3.60 Hz, 2 H) 1.82 (d, J=11.96 Hz, 2 H) 1.99 (t, J=11.17 Hz, 2 H) 2.15 (s, 3 H) 2.70 (d, J=11.96 Hz, 2 H) 2.99 - 3.13 (m, 1 H) 3.67 (s, 3 H) 5.14 (d, J=8.54 Hz, 1 H) 6.57 (dd, J=8.79, 2.69 Hz, 1 H) 6.77 (d, J=8.79 Hz, 1 H) 7.01 (d, J=2.81 Hz, 1 H).HRMS m/z calcd for [M + H] 347.0615; found 347.0627.
A mixture of 1 (1 ,23 mmol) and l--methylpiperidin-4-one ( 1.23 mmoi) in POCI3 (2 mL) was heated at 60 C for 6 h. The excess POCI3 was evaporated off the residue was treated with iced 0 and NaHCO, and extracted with CH2C12 (3x25 mL). The organic layer was dried over Na2S04, filtered and evaporated under reduced pressure. Purification by Flash Chromatography (5% MeOH in AcOEt) gave the desired compound (55% of yield). NMR (300 MHz, CDCI3) delta 8.58 (s, 1H), 8.07 (d, LH, J= 8.7 Hz), 7.83 (d, 1H, J= 8.7 Hz), 3.85 (s, 2H), 3.30 (t, 2H, J= 6.0 Hz), 2.89 (t, 2H, J= 6.0 Hz), 2.60 (s, 3H).
55%
With trichlorophosphate; at 60℃; for 6.0h;
10-chloro-2-methyl- 1 ,2,3 ,4-tetrahydrobenzo[] [ 1 ,6]naphthyridine-8-carbonitrile, 4 [00146] A mixture of 1 (1.23 mmol) and l-methylpiperidin-4-one (1.23 mmol) in POCI3 (2 mL) was heated at 60 C for 6 h. The excess POCI3 was evaporated off; the residue was treated with iced H20 and NaHCC>3 and extracted with CH2C12 (3x25 mL). The organic layer was dried over Na2S04, filtered and evaporated under reduced pressure. Purification by Flash Chromatography (5% MeOH in AcOEt) gave the desired compound (55% of yield). lU NMR (300 MHz, CDCI3) delta 8.58 (s, 1H), 8.07 (d, 1H, J= 8.7 Hz), 7.83 (d, 1H, J= 8.7 Hz), 3.85 (s, 2H), 3.30 (t, 2H, J= 6.0 Hz), 2.89 (t, 2H, J= 6.0 Hz), 2.60 (s, 3H).
With sodium methylate; In methanol; at 20℃; for 4h;
General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5% methanol in dichloromethane) or column chromatography (2% methanol in dichloromethane).
With sodium methylate; In methanol; at 20℃; for 4h;
General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5% methanol in dichloromethane) or column chromatography (2% methanol in dichloromethane).
With sodium methylate; In methanol; at 20℃; for 4h;
General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5percent methanol in dichloromethane) or column chromatography (2percent methanol in dichloromethane).
4-(4-cyano-1-methylpiperidin-4-ylamino)-2-fluoro-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With ytterbium(III) triflate; at 80℃; for 12h;Sealed tube;
General procedure: The mixture of compound 22 (336 mg, 2 mmol), correspondingketone 23e28 (4 mmol), trimethylsilylcyanide (0.5 mL, 4 mmol)and ytterbium(III) (62 mg, 0.1 mmol) was stirred in a closed vesselfor 12 h at 80 C (36 h at 90 C for 1-methylpiperidin-4-one). Thecooled mixture was diluted with ethyl acetate, washed with coldwater, dried over Na2SO4 and the solvent was removed underreduced pressure. Purification was performed using column chromatographyon silica gel (hexane/EtOAc 1:1).
(S)-1-benzyl-2-methyl-4-(1-methylpiperidin-4-yl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Step 3: (S)-1-benzyl-2-methyl-4-(1-methylpiperidin-4-yl)piperazine <strong>[511254-92-5](S)-1-Benzyl-2-methylpiperazine</strong> (6.84 g, 36 mmol), 1-methyl-4-piperidone (4.87 g, 43 mmol), and glacial acetic acid (4.32 g, 72 mmol) were successively added to anhydrous ethanol (100 mL). The resultant was stirred for 1 hour, and then cooled to 0C. Sodium triacetoxyborohydride (31.6 g, 150 mmol) was added in portions. The resultant was reacted at room temperature for 6 hours. The solvent was evaporated, and the residue was dissolved by adding ethyl acetate. The resultant was washed by water, dried, concentrated, and purified by silica gel column chromatography to give (S)-1-benzyl-2-methyl-4-(1-methylpiperidin-4-yl)piperazine (7.86 g, 76% yield). MS m/z [ESI]: 288.2 [M+1].
3,5-bis(2-chloro-3-methoxybenzylidene)-1-methylpiperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With sodium hydroxide; In ethanol; at 5 - 27℃;
General procedure: The a,b-unsaturated carbonyl-based cyclohexanone compoundswere synthesized using direct coupling method as reportedpreviously28,37 (Table 2). The ketones were reacted with suitablearomatic aldehyde at molar ratio 1:2 using base-catalyzed claisen-schmidt condensation to synthesize 21 new compounds (3a-3u). Characterization data of only three compounds (3c, 3f, 3o)was reported previously.37 The flow diagram for the synthesis ofa,b-unsaturated carbonyl-based compounds is shown in Scheme 1.The ketone (10 mmol, 1 equiv) and aromatic aldehyde (20 mmol,2 equiv) were mixed in round bottom flask using 25 mL ethanolat 5 C. 40% sodium hydroxide solution (in ethanol) was added tothis solution. The mixture was stirred for 1-24 h at 27 C. The precipitateappearance and color variation indicated product formation.The reaction was monitored using TLC while acidified icewas added to stop it when completed. Recrystallization and/or columnchromatography were used to isolate the compounds. 4.3.13 3,5-Bis-(2-chloro-3-methoxy-benzylidene)-1-methyl-piperidin-4-one (3m) Yield: 67%; Mp: 142-143 C; 1H NMR (500 MHz, CDCl3) delta: 7.89 (s, 2H), 6.97 (t, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.48 (d, J = 8.5 Hz, 2H), 3.76 (s, 6H), 2.74 (s, 4H), 2.12 (s, 3H); 13C NMR (500 MHz, CDCl3) delta: 185.2, 149.6, 148.1, 145.5, 142.6, 135.6, 131.9, 104.2, 98.6, 56.9, 43.5, 16.8; HRMS (ESI) m/z: 419.32 [M+H]+, Microanalysis calculated for C22H21Cl2NO3 (418.31): C, 63.17; H, 5.06; N, 3.35. Found: C, 63.19; H, 5.12; N, 2.3.28.
3,5-bis(2-chloro-3,4-dimethoxybenzylidene)-1-methylpiperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium hydroxide; In ethanol; at 5 - 27℃;
General procedure: The a,b-unsaturated carbonyl-based cyclohexanone compoundswere synthesized using direct coupling method as reportedpreviously28,37 (Table 2). The ketones were reacted with suitablearomatic aldehyde at molar ratio 1:2 using base-catalyzed claisen-schmidt condensation to synthesize 21 new compounds (3a?3u). Characterization data of only three compounds (3c, 3f, 3o)was reported previously.37 The flow diagram for the synthesis ofa,b-unsaturated carbonyl-based compounds is shown in Scheme 1.The ketone (10 mmol, 1 equiv) and aromatic aldehyde (20 mmol,2 equiv) were mixed in round bottom flask using 25 mL ethanolat 5 C. 40percent sodium hydroxide solution (in ethanol) was added tothis solution. The mixture was stirred for 1?24 h at 27 C. The precipitateappearance and color variation indicated product formation.The reaction was monitored using TLC while acidified icewas added to stop it when completed. Recrystallization and/or columnchromatography were used to isolate the compounds. 4.3.14 3,5-Bis-(2-chloro-3,4-dimethoxy-benzylidene)-1-methyl-piperidin-4-one (3n) Yield: 61percent; Mp: 144-145 °C; 1H NMR (500 MHz, CDCl3) delta: 7.87 (s, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 3.82 (s, 12H), 2.78 (s, 4H), 2.14 (s, 3H); 13C NMR (500 MHz, CDCl3) delta: 185.5, 149.7, 147.4, 145.1, 142.2, 135.8, 132.1, 105.7, 98.7, 56.8, 56.5, 41.5, 17.1; HRMS (ESI) m/z: 479.55 [M+H]+, Microanalysis calculated for C24H25Cl2NO5 (478.37): C, 60.26; H, 5.27; N, 2.93. Found: C, 60.52; H, 5.45; N, 2.72.
A stirred solution of <strong>[1000342-71-1]6-bromo-5-azaindole</strong> (4.00 g, 20.3 mmol) in MeOH (100 ml) at ambient temperature was treated with powdered potassium hydroxide (4.55 g, 81.1 mmol). After stirring for 10 minutes, the mixture was treated with N-methyl- piperidinone (4.99 g, 40.6 mmol) and heated at reflux for 72 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc, and the the organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. Trituration of the residue with Et20 afforded the desired product as a white solid (5.21 g, 88%). LCMS (Method C): Rt= 0.30/079 min, m/z [M+H]+ = 292/294
1-(2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With piperidine; octasulfur; In methanol; at 55 - 65℃; for 24h;
General procedure: 3-Acetyl-2-aminothiophene Derivatives; General Procedure Carbonyl compound (0.025 mol) was added to freshly prepared cya-noacetone (0.03 mol) in either MeOH or EtOH (40 mL). Sublimed sul-fur S8 (0.03 mol) and piperidine (0.03 mol) were added and the mix-ture was stirred and heated to 55-65 C for 24 h. Ice was then addedand the formed precipitate was filtered under vacuum and washedwith water. The obtained solid was crystallised from a suitable sol-vent, with the exception of 4g and 4j, which were collected directlywithout further purification.
1-methylpiperidin-4-one (5-chloropyridin-2-yl)hydrazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In ethanol; for 0.5h;Reflux;
General procedure: A solution of the appropriateketone (4.0 mmol) in ethanol (7 ml) was added to asolution of hydrazine 1 (0.574 g, 4.0 mmol) in ethanol(5 ml), and the mixture was refluxed for 30 min. Thesolvent was removed by distillation until constant mass,producing the corresponding hydrazone 5a-p. Theobtained reaction residue was treated with polyphosphoricacid (5 g),12 stirred and heated to 160 (beginning of anexothermic reaction), and maintained at 160-180 untilthe foaming stopped (~5 min). After cooling to ~40, thereaction mixture was suspended in water (30 ml), cooled to0-5C, and adjusted with aqueous 25% NH3 solution to pH9-10. The precipitate that formed was filtered off, washedwith ice water (2×5 ml), methanol (1 ml, cooled to 0),and air-dried, then recrystallized. In the case if oilseparated the reaction mixture was extracted with CH2Cl2(3×20 ml), the extract was dried over anhydrous Na2SO4and evaporated to dryness. The obtained residue wasrecrystallized from methanol or ethyl acetate.
3,5-bis-(3,5,6-trimethylpyrazin-2-ylmethylene)-1-methylpiperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydroxide; In ethanol; at 5 - 27℃;
General procedure: New a, b-unsaturated carbonyl-based compounds (5a-g and 6au)were synthesized using direct coupling technique [40] (Scheme 1). The reaction was carried out using base-catalyzed Claisen-Schmidt condensation reaction, by reacting different types of ketoneswith appropriate aromatic aldehyde at molar ratio 2:1 tosynthesize new compounds (5a-g) and at molar ratio 1:1 for (6a-u).For synthesis of 6a-u first 5a-g intermediates were synthesized andin second step appropriate aldehydes were reacted with intermediates.The detailed method of synthesis has already beenreported by us previously [38,40]. Scheme 1 shows the highlights ofsynthesis of compound 3, 4 and a, b-unsaturated carbonyl-basedcompounds along with oxime derivatives. 15 mL ethanol wastaken in a round bottom flask and aromatic aldehyde (20 mmol, 2equivalent) and specific ketone (10 mmol,1 equivalent) were addedand dissolved using a stirrer for 2-3 min at 5 C. Into the abovesolution, 40% NaOH solution in ethanol was added drop wise andthe mixture was stirred for 1-24 h at 27 C. The color change andprecipitate formation in the reaction mixture showed productformation. TLC was used to monitor the reaction and acidified icewas added to quench the reaction once completed. The isolation ofcompounds was done by recrystallization and/or by using columnchromatography.
2-methyl-2,3,4,5-tetrahydro-1H-benzofuro[3',2':4,5]pyrrolo[3,2-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With iodine; hydrazine; In ethanol; for 2.5h;Reflux;
General procedure: To a stirred solution of 2-bromobenzofuran/2-bromobenzo[b]thiophene (2.53 mmol) in ethanol (5 mL) was added hydrazine(0.08 g, 2.53 mmol), I2 (0.03 g, 10 mol%) and alkanone (2.53 mmol).The reaction mixture was reuxed for 1e3 h. After completion ofthe reaction as monitored by TLC, the reaction mixture wasquenched with a saturated aqueous solution of Na2S2O3. Theorganic and aqueous layers were then separated. The aqueous layerwas extracted with ethyl acetate (3 50 mL). The extract waswashed with water and nally with brine. The organic layer wasdried over anhydrous Na2SO4 and concentrated by rotary evapo-rator. Finally, the residue was puried by recrystallization from ethanol.
5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
To a stirred solution of 5-bromo-1 H-pyrrolo[2,3-c]pyridine (1.0 g, 5.07 mmol) in MeOH (20 mL), powder KOH (1.13 g, 20.28 mmol) was added. The resulting mixture was stirred at rt for 10 minutes. Then, 1 -methy Ipiperidin- 4-one (1.14 g, 10.14 mmol) was added and it was refluxed for 16h . The reaction mixture was quenched with water and extracted with 10% MeOH in DMC. The separated organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford 800 mg (54 %) of the title compound.LC-MS (method 6): Rt = 0.95 min; m/z = 290.20 (M-H+).
To a stirred solution of <strong>[1215387-58-8]5-bromo-1H-pyrrolo[2,3-c]pyridine</strong>-2-carboxylic acid (500 mg, 2.07 mmol, 1.0 equiv) in DMF, dimethyl amine hydrochloride (168 mg, 2.07 mmol, 1.0 equiv), TEA (1.49 g, 10.37 mmol, 5.0 equiv) and T3P (1.97 g, 6.21 mmol, 3.0 equiv) were added at 0C. The reaction mixture was allowed to stir at RT for 16h. The progress of the reaction was monitored by LCMS.. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eiuted at 5% MeOH in DCM in to afford (450 mg, 78%) the title compound. LC-MS (method 16): Rt = 1.75 min; m/z = 270.15 (M+H++2).
With triethylamine; In 2,2,2-trifluoroethanol; at 100℃; for 24h;
General procedure: Ketone (1 eq.)was dissolved in trifluoroethanol (2.0 mL) at roomtemperature. Amino acid (1 eq.) and isocyanide (1 eq.) were addedinto the solution. The, one equivalent of triethyl amine was addedto the reaction and the mixturewas heated at 100 C. After 24 h, thereaction mixture was cooled to room temperature, and the solventwas removed under reduced pressure. Then, the mixture wasredissolved in DCM (0.5 mL) and was directly purified by usingsilica gel column chromatography with 1-5% MeOH in DCM. Theproduct fraction, based on mass spectrometry, was collected, solventwas removed, and the content was dried under reducedpressure to get the desired products.
N-[(2,4-difluorophenyl)methyl]-1-methylpiperidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With ethanol; sodium tris(acetoxy)borohydride; at 20℃; for 2h;
<strong>[72235-52-0]2,4-difluorobenzylamine</strong> (4.0 g, 27.1 mmol) was dissolved in ethanol (30 ml) and N-methyl-4-piperidone (3.16 g, 27.1 mmol) was added followed by sodium (0408) triacetoxyborohydride (54.2 mmol, 11.85 g). The mixture was stirred at room temperature for 2 hours, then partitioned between diethyl ether and 2 M sodium hydroxide (100 ml). The organic phase was collected and extracted with 2M hydrochloric acid (50 ml), then the acidic aqueous phase was made basic with 5 M sodium hydroxide (30 ml) and extracted with diethyl ether. The organic extract was dried and evaporated to give the title compound as a yellow oil (5.96 g, 91 % yield).
91%
With ethanol; sodium tris(acetoxy)borohydride; at 20℃; for 2h;
<strong>[72235-52-0]2,4-difluorobenzylamine</strong> (4.0 g, 27.1 mmol) was dissolved in ethanol (30 ml) and N-methyl-4-piperidone (3.16 g, 27.1 mmol) was added followed by sodium triacetoxyborohydride (54.2 mmol, 11.85 g). The mixture was stirred at room temperature for 2 hours, then partitioned between diethyl ether and 2 M sodium hydroxide (100 ml). The organic phase was collected and extracted with 2M hydrochloric acid (50 ml), then the acidic aqueous phase was made basic with 5 M sodium hydroxide (30 ml) and extracted with diethyl ether. The organic extract was dried and evaporated to give the title compound as a yellow oil (5.96 g, 91 % yield).
(6-bromo-2-methoxy-pyridin-3-yl)-(1-methyl-piperidin-4-yl)-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
[00204] To a solution of 1-methyl-4-piperidone (111 mg, 0.99mmol, 1.0eq) and 3-amino- 6-bromo-2-methoxypyridine (200 mg, 0.99mmol, 1.0eq) in DCM (5 L) was added TFA (83uL, 1.1mmol, 1.1eq). After 1 h, NaBH(OAc)3 (313 mg, 1.5mmol, 1.5eq) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the crude material was purified by silica column chromatography to yield (6-bromo-2-methoxy- pyridin-3-yl)-(1-methyl-piperidin-4-yl)-amine (206 mg, 70 %) as a brown gum. AnalpH2_MeOH_4MIN: Rt: 1.50 min, m/z 300.2/302.2 [M+H]+
(3Z,5E)-1-methyl-3-((4-methylthiophen-2-yl)methylene)-5-((4-methylthiophen-2-yl)methylene)piperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; at 20℃;
General procedure: A mixture of 0.01 mol 1-methylpiperidin-4-one (1) and 0.02 molsubstituted thiophene-carbaldehydes (2) in 15 ml of methanol wasstirred at room temperature for 15 min. With this, 5 mol% NaOH wasadded dropwise. The progression and completion of reaction wasmonitered by TLC. After the reaction completed, the obtained solidobtained was filtered and washed with water. The crude product obtainedwas recrystallized using EtOH and THF in 1:1 ratio. The obtainedproduct (3) was used as starting material for the synthesis of targetcompounds 5a-l.
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