* 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] Patent: WO2005/108355, 2005, A2, . Location in patent: Page/Page column 78-79
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
3
[ 5382-16-1 ]
[ 50-00-0 ]
[ 106-52-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In methanol; water
A mixture of 4-piperidinol (1.16g, 10.07mmol) and 47percent aqueous formaldehyde solution (10 mL) were dissolved in methanol (10 mL), and acidified with concentrated hydrochloricTo pH 2-3, to the system was added 10percent Pd / C (300mg), two days the reaction system was kept under a hydrogen atmosphere. Completion of the reaction, filtered and the filtrate reducedPressure concentrated and the crude product purified by column chromatography (MeOH) to give a white solid (1.59g, 89percent)
Reference：
[1] Patent: CN105367582, 2016, A, . Location in patent: Paragraph 0253; 0254; 0255
[2] Journal of the Chemical Society, 1952, p. 1164,1166
4
[ 695-19-2 ]
[ 106-52-5 ]
Reference：
[1] Yakugaku Zasshi, 1951, vol. 71, p. 1097[2] Chem.Abstr., 1952, p. 5042
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 3701
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 2315 - 2316[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 12, p. 2623 - 2624
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 465
7
[ 25012-72-0 ]
[ 106-52-5 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 1826
8
[ 6315-60-2 ]
[ 106-52-5 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 1826
9
[ 118306-22-2 ]
[ 106-52-5 ]
Reference：
[1] Patent: US4410527, 1983, A,
10
[ 118306-21-1 ]
[ 106-52-5 ]
Reference：
[1] Patent: US4410527, 1983, A,
11
[ 118306-24-4 ]
[ 106-52-5 ]
Reference：
[1] Patent: US4410527, 1983, A,
12
[ 872-50-4 ]
[ 106-52-5 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 2615
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 13, p. 863
13
[ 13880-89-2 ]
[ 106-52-5 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 1164,1166
[2] Journal of the Chemical Society, 1952, p. 1164,1166
14
[ 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
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
2-Nitro-4-trifluoromethyl-phenol (2.07 g,10 mmol), 1-methyl-piperidin-4-ol (1.21 g, 10.5mmol), and triphenylphosphine (2.75 g, 10.5 mmol)were diluted with 30 mL of THF and placed undernitrogen. 'The reaction mixture was cooled to 0C,then DIAD (2.12 g, 10.5 mmol) in 1 mL of THF wasadded dropwise. The reaction mixture was allowed tostir for 12 hours warming to room temperature. Thereaction was diluted with ethyl acetate (150 mL) andsodium carbonate (150 mL of a 10% aq. solution).The organic layer was washed with brine, dried overMgSO4, filtered, and dried under reduced pressure.The product was purified using a Biotage 40M car- tridge, eluting with hexane/ethyl acetate (500 mL1/1), then CH2Cl2/MeOH/NH4OH (98/8/2, 500 mL) toyield a light yellow oil.
With caesium carbonate;palladium diacetate; johnphos; In toluene; at 130℃; for 96h;
a) 6-[(1-Methylpiperidin-4-yl)oxy]pyridine-2-carbonitrile 1-Methylpiperidin-4-ol (1.89 g, 0.0164 mol), <strong>[122918-25-6]6-bromo-2-pyridinecarbonitrile</strong> (3.00 g, 0.0164 mol), Pd(OAc)2 (0.184 g, 0.820 mmol), 2-(di-t-butylphosphino)biphenyl (0.303 g, 1.02 mmol) and Cs(CO3)2 were mixed in 100 mL of toluene. The reaction mixture was stirred under argon and heated to 130 C. in an oil bath for 4 days. The reaction mixture was diluted with EtOAc and washed with water, dried over Na2SO4 and evaporated. The crude product was flash chromatographed on silica gel DCM/MeOH/TEA 95/5/1 to give 1.62 g (45%) of the desired product. 1H NMR (500 MHz, CDCl3) delta 7.67 (m, 1H), 7.29 (d, 1H), 6.95 (d, 1H), 5.12 (m, 1H), 2.74 (m, 2H), 2.40-2.30 (m, 5H, thereof a singlet at 2.35), 2.09 (m, 2H), 1.86 (m, 2H).
With diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 24h;
13 4- (1-Methyl-piperidin-4-YLOXY)-BENZOIC acid methyl ester
To a solution of 1-Methyl-piperidin-4-OL (6.8 g. 59 mmoles), PPH3 (triphenylphosphine, 15.5 g, 59 mmoles) and 4-hydroxy-benzoic acid methyl ester (6 g, 39 mmoles) in THE (150 ml) at 0C, diethyl azodicarboxylate (9.5 ml, 59 mmoles) in THE (30 ml) was slowly added. The reaction mixture was allowed to warm to room temperature over a period of 24 hours. It was then evaporated and the residue redissolved in 5% aqueous citric acid (700 ml). The solution was washed with ethyl acetate (3 x 250 ml), made alkaline with concentrated NH40H (PH-8) and then extracted with dichloromethane (3 x 250 ml). The combined dichloromethane extracts were washed with brine, dried and evaporated to give an oil which was purified by flash chromatography on silica gel using dichloromethane- MEOH (90: 10) as eluent, to give the title compound as a yellow oil (7.4 g, 75%). ESI MS : m/z 250 (MH+); 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.7 (m, 2 H) 2.0 (m, 2 H) 2.2 (m, 5 H) 2.7 (M, 2 H) 3.8 (s, 3 H) 4.5 (m, 1 H) 7.1 (d, J=9. 0 Hz, 2 H) 7.9 (d, J--9. 0 Hz, 2 H).
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20 - 50℃;
66 Example 66; N- [3- (I-METHYL-PIPERIDIN4-YLOXY)-PHENYL]-ACETAMIDE
A suspension of N- (3-HYDROXY-PHENYL)-ACETAMIDE (30.2 g) in anhydrous tetrahydrofuran (600 mL) was treated with 4-HYDROXY-N-METHYLPIPERIDINE (30.54 mL) and triphenylphosphine (68. 18 g); a solution of DIETHYLAZADICARBOXYLATE in anhydrous tetrahydrofuran (THF) (40.94 mL in 60 mL of THF) was added dropwise and the mixture was stirred at room temperature for 2 hours and then heated to 50°C overnight. Further amounts of triphenylphosphine (28.00 g) and diethylazadicarboxylate (14 mL) were added and the heating was continued for additional 24 hours. The solvent was removed under vacuum and the residue was taken up with ethyl acetate (600 mL), and axtracted with 2N hydrochloric acid (3 x 200 mL). The aqueous layer was washed with ethyl acetate and pH was brought to 10 by addition of 20% sodium hydroxide. Extraction with ethyl acetate (4 x 100 mL) was carried out and the combined organic extracts were washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel (eluant dichloromethane/methanol 85: 15 then + 0. 1% triethylamine) to yield 21 g of the desired compound. 'H NMR (400 MHz, DMSO-D6) 8 ppm 1.52-1. 68 (m, 2 H) 1.83-1. 96 (m, 2 H) 2.01 (s, 3 H) 2. 14 (s, 3 H) 2. 46-2.52 (m, 2 H) 2. 52-2.63 (m, 2 H) 4. 18-4.20 (m, 1 H) 6.59 (d, 1 H) 7.05 (d, 1 H) 7.14 (t, 1 H) 7. 26 (s, 1 H) 9.83 (s, 1H).
With sodium hydride; In N,N-dimethyl-formamide; at 20℃;
To a mixture of <strong>[3939-13-7]2-fluoro-nicotinonitrile</strong> (400 mg, 3.3 mmol) and 1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N, N-dimethylformamide (30 mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction was stirred overnight at rt. The mixture was poured into water, and extracted with ethyl acetate (2X). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (8:1 ) to give the title compound (210 mg, 29 %). MS (DCI/NH3) m/z 218 (M+1 )+ 'HNMR (400 MHz, DMSO- d6) 8 ppm 1.73 (m, 2 H) 1.96 (m, 2 H) 2.18 (s, 3 H) 2.22 (m, 2 H) 2.59 (m, 2 H) 5.15 (m, 1 H) 7.15 (dd, J=7.67, 5.22 Hz, 1 H) 8.24 (dd, .I--7.67, 2.15 Hz, I H) 8.44 (dd, .J=4.91 , 1 ,84 Hz, 1 H).
With sodium chloride; In N-methyl-acetamide; ice-water; ethyl acetate; mineral oil;
EXAMPLE 11 5-Chloro-3-(1-methyl-4-piperidyloxy)-1,2-benzisoxazole A solution of 1.53 g (13.3 mmole) of 4-hydroxy-1-methylpiperidine in 25 ml of dimethylformamide was cooled to 5 C. in an atmosphere of nitrogen. 0.58 g (13.3 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to the solution, and then the solution was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5 C., and then 2.50 g (13.3 mmole) of <strong>[16263-53-9]3,5-dichloro-1,2-benzisoxazole</strong> were added to it; the resulting mixture was then stirred at 5 C. for 30 minutes and then at room temperature for 1 hour. At the end of this time, the mixture was poured into 50 ml of ice-water and then extracted twice, each time with 50 ml of ethyl acetate. The ethyl acetate layer was separated and washed with 100 ml of a 10% w/v aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using ethyl acetate as the eluent to afford 2.38 g (yield 67.00%) of the title compound as a colorless powder, melting at 55-56 C. Infrared absorption spectrum (CHCl3) cm-1: 1535, 1470, 1440, 1360, 1310. Nuclear magnetic resonance spectrum (CDCl3) delta ppm: 1.73-3.00 (8H, multiplet); 2.32 (3H, singlet); 4.92 (1H, doubled doublet of doublets, J=13.5, 9.0 & 4.5 Hz); 7.30-7.76 (3H, multiplet).
7-(1-Methyl-4-piperidyloxy)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol; hexane; N,N-dimethyl-formamide;
EXAMPLE 9 7-(1-Methyl-4--piperidyloxy)-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid (Compound No. 13) To a mixture of 530 mg of 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 690 mg of N-methyl-4-piperidinol and 8 ml of DMF was added 320 mg of 60percent sodium hydride while the former was stirred under ice cooling. After the resultant mixture was stirred for 10 minutes at room temperature, 480 mg of acetic acid was added. DMF was distilled off under reduced pressure. To the residue was added 15 ml of n-hexane. The resultant mixture was thoroughly shaken and mixed. The supernatant was discarded. To the resultant precipitate was added 8 ml of ethanol, followed by stirring. A precipitate thus precipitated was collected by filtration, whereby 578 mg of the title compound was obtained. Melting point: 265°-269° C. 1 H-NMR (DMSO-d6) delta: 1.02-1.13(m,2H), 1.22-1.32(m,2H), 1.72-2.87(m,2H), 1.99-2.12(m,2H), 2.20(s,1H), 2.21-2.33(m,2H), 2.55-2.69(m2H), 3.68-3.80(m,1H), 4.70-4.81(m,1H), 7.68(d,1H,J=8Hz), 7.93(d,1H,J=12Hz), 8.62(s,1H).
(+/-)-4-[(4-Fluorophenyl)phenylmethoxy]-1-methylpiperidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In water
(+-)-4-[(4-Fluorophenyl)phenylmethoxy]-1-methylpiperidine hydrochloride
(+-)-4-[(4-Fluorophenyl)phenylmethoxy]-1-methylpiperidine hydrochloride A mixture of 48.6 g of 4-fluorobenzhydryl chloride, 25.3 g of 4-hydroxy-1-methylpiperidine and 18.3 g of potassium carbonate was heated with stirring at 140° C. for 5.5 hours. After cooling, water was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was taken up in ether and the organic layer was extracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The extract was washed with water, dried and concentrated to give 53.3 g of reddish brown liquid, which was converted to the hydrochloride in the usual manner and then recrystallized from a mixture of ethanol and ether to give colorless needles, mp 192°-193° C. Analysis for C19 H22 FNO.HCl.1/4H2 O: Calculated C, 67.05; H, 6.96; N, 4.12 Found C, 67.13; H, 6.89; N, 4.08
With hydrogen bromide; sodium carbonate; In diethyl ether; water; toluene;
REFERENCE EXAMPLE 1 1-Methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide p-Toluenesulfonyl chloride (2.16 g) and 4-hydroxy-1-methylpiperidine (4 g) were added in turn to a solution of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (2.0 g) in dry toluene (200 ml). The mixture was stirred overnight at room temperature and then shaken with 5% sodium carbonate (20 ml) and water (100 ml). The toluene layer was washed with water and dried over anhydrous sodium sulfate. The toluene was distilled off in vacuo and the residue was dissolved in diethyl ether. An ethanolic solution of 47% hydrobromic acid was added to the ether solution. The resulting crystals were collected by filtration and recrystallized from a mixture of ethanol and diethyl ether to give 1-methyl-4-piperidyl 2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (2.8 g), m.p. 179-181 C.
Example 5 5,11-dihydro-11-[[(1-methyl-4-piperidinyl)oxy]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 4.9 g (0.0425 mol) of 1-methyl-4-piperidinol were added dropwise to a mixture consisting of 22.5 ml of a 20% solution of phosgene in toluene, 100 ml of dioxane and 4.75 g (0.045 mol) of anhydrous sodium carbonate, with external cooling with ice. The mixture was stirred for a further 60 minutes at ambient temperature, then 9.0 g (0.0428 mol) of <strong>[885-70-1]5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one</strong> were added to the reaction mixture and the resulting mixture was refluxed for 4 hours. It was then filtered, the filtrate was concentrated by evaporation in vacuo and the crude product obtained was purified by column chromatography on 500 g of silica gel using a mixture of ethyl acetate and methanol (ratio of volumes 10:2) as the eluant. After recrystallization from ethyl acetate, the colorless crystals melted at 247-248 C. and were identical, in their mixed melting point, thin layer chromatogram and IR spectrum, to a product prepared according to Example 4. Yield: 5.8 g (39% of theory).
EXAMPLE I 1-Methyl-4-piperidyl 5-(p-chlorophenyl)-2-furoate Hydrochloride To a stirring solution of 40 g (0.35 mole) of N-methyl-4-piperidol in 400 ml of toluene was added portionwise 84 g (0.35 mole) of <strong>[57753-80-7]5-(p-chlorophenyl)-2-furoyl chloride</strong> with the temperature rising to 50. The resulting mixture was heated at 90 for 1 hour and then stirred at room temperature overnight. The solid was filtered, suspended in H2 O and acidity assured by the addition of a few drops of hydrochloric acid. The insoluble material was filtered. The filtrate was made basic by the addition of concentrated NH4 OH. The resulting solid was filtered and added to 1500 ml of ether with dissolution. The solution was treated with Darco, dried with MgSO4 and filtered. The filtrate was treated with ethereal HCl. A "sticky" solid formed from which the ether was decanted. The semi-solid was triturated in ethanol with a white solid forming which weighed 50 g (40%) after drying.
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.16667h;
14) l-[4-[(l-Methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)phenyl]ethanamineA.4-[(l -Methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)benzonitrile A mixture of 4-hydroxy-iV-methylpiperidine (133 mg, 1.15 mmol) and potassium tert-bu- toxide (150 mg, 1.27 mmol) in tetrahydrofuran (2.5 mL) was stirred under nitrogen for 10 min. <strong>[67515-59-7]4-Fluoro-3-(trifluoromethyl)benzonitrile</strong> (218 mg, 1.15 mmol) was added, and the 5 reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, and the residue was partitioned between a 1 M NaOH solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5) affording 0.18 g (54% yield) of the pure product as a colourless solid. MS (APCI) m/z 285 [M+H]. 1H NMR o (400 MHz, DMSO-D6) delta ppm 1.67-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.16 (s, 3 H), 2.26- 2.31 (m, 2 H), 2.44-2.48 (m, 2 H), 4.78-4.82 (m, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 8.08 (dd, J = 8.8, 2.0 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H).
Step 1 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethylbenzonitrile 6.68 g of potassium t-butoxide was suspended in 40 ml of anhydrous tetrahydrofuran and a solution of 6.85 g of 1-methyl-4-hydroxypiperidine in 20 ml of anhydrous tetrahydrofuran was added dropwise over 35 minutes while stirring under ice-water cooling and further the mixture was stirred for 30 minutes. On the other hand, 7.50 g of <strong>[67515-59-7]4-fluoro-3-trifluoromethylbenzonitrile</strong> was dissolved in 40 ml of anhydrous tetrahydrofuran, the mixture was stirred under cooling in a dry ice/acetone bath, and the solution prepared earlier was added dropwise at the internal temperature of -70C. After adding dropwise, the reaction solution was stirred overnight while naturally heating up to room temperature. The reaction solution was ice-cooled, an aqueous saturated ammonium chloride solution and water were added thereto, and then the solvent was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate twice. The extracts were washed in turn with water and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.31 g of the objective compound as colorless crystals. Melting point: 66-69C
Comparative Example 1; l,l-Dimethyl-4-[(l-phenylcyclopentyl)carbonyl]oxy}piperidinium iodide; Comparative Example IA: l-Methylpiperidin-4-yl 1-phenylcyclopentanecarboxylate; To a stirred solution of 1-phenylcyclopentane carboxylic acid (0.38 g) in dichloromethane (5 mL) was added oxalyl chloride (0.52 mL) and DMF (one drop) at RT. After 2 h, gas evolution had ceased, and the mixture was concentrated in vacuo and redissolved in dichloromethane. JV-Methyl 4-hydroxy piperidine (0.3 g) and triethylamine (0.42 mL) were added, and the mixture was warmed overnight at 40C. The mixture was partitioned between dichloromethane and water, washed with water, and the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to flash <n="55"/>column chromatography, eluting with dichloromethane then 1% and 2% methanol/dichloromethane to leave a white solid (0.385 g).m/z 288 [M+H]+5 1H NMR (399.822 MHz, CDCl3) delta 7.37 (dm, 2H), 7.29 (tm, 2H), 7.21 (tm, IH), 4.77 - 4.69 (m, IH), 2.71 - 2.64 (m, 2H), 2.39 - 2.29 (m, 2H), 2.26 - 2.22 (m, 2H), 2.21 (s, 3H), 1.95 - 1.85 (m, 2H), 1.81 - 1.67 (m, 6H), 1.64 - 1.54 (m, 2H).
4-(N-methylpiperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
To a solution of 1-methyl-piperidin-4-ol (0.4 g, 3.47 mmol) in anhydrous THF (10 ml), cooled at 0-5 oc, NaH (0.14 g,3.4 7 mmol) was added. The mixture was stirred at 0-5 oc for 30 min, then 1-fluoro-4-nitro-2-trifluoromethyl-benzene(0.33 ml, 2.31 mmol) was added. The reaction was stirred at r.t. for 1 h, then poured in water and extracted withEtOAc (2 x 20 ml). The organic phase was washed with brine, dried with Na2S04 and evaporated under vacuum toobtain the title compound (0.65 g, 93%) as yellow oil.30 1H NMR (600 MHz, DMSO-dG) o ppm 1.67-1.79 (m, 2 H) 1.95 (td, J=8.43, 4.03 Hz, 2 H) 2.18 (s, 3 H) 2.27-2.37 (m,2 H) 2.47 (br. s., 2 H) 4.87 (br. s., 1 H) 7.57 (d, J=9.34 Hz, 1 H) 8.38 (d, J=2.75 Hz, 1 H) 8.47 (dd, J=9.34, 2.93 Hz, 1H).
81%
General procedure: NaH (60% disp. in mineral oil) (0.41 g, 10.19 mmol) was added to a solution of N-methyl-4-piperidinol (1.08 g, 9.34 mmol) in DMF (9 mL) at 0 C and the mixture waswarmed to rt for 15 mi 5-chloro-2-fluoronitrobenzene (1.49 g, 8.49 mmol) was added and the mixture was stirred at rt for a further 2 h. The reaction mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Si-PPC, 40 g, mobile phase: DCM/2 Mammonia in MeOH, gradient from 100:0 to 90:10). The desired fraction were collected and evaporated to dryness to give 1.69 g of intermediate 94 (74% yield, yellow oil).
A. To 4-hydroxy-N-methylpiperidine (13.0 g) in DMF was added NaH (4.2 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 hours. 4-fluoro-3-trifluoromethyl-1-nitrobenzene (22 g) was added at -10 C. and the reaction was stirred overnight at ambient temperature. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified on silica gel column (hexane/ethyl acetate.
General procedure: To a solution of 1-methylpiperidin-4-ol (1.15 g, 10 mM) in DMF (10 mL) were added NaH (0.48 g, 12 mM) successively. The mixture was stirred at 0C for 0.5 h, followed by addition of the required 1-fluoro-4-nitro-2-(trifluoromethyl)benzene and heating to reflux for another 5 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100×2 mL) and water (40×2 mL). The organic layer was evaporated, the resulting residue 5a utilized as materials without further purification.
With potassium hydroxide; tetrabutylammomium bromide; In water; toluene; at 60℃; for 17h;
A solution of 1.00 mL (7.27mMol) of1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.71 ml (14.5 mMol) 1-methyl-piperidin-4-ol and 470 mg (1.45 mMol) tetrabutylammonium bromide in 6ml toluene and 6ml 25%KOHaq is stirred at 60 C for 17 h. After cooling the solution, the reaction mixture is diluted with 80 ml H2O and extracted 3x with 60 ml of EtOAc. The combined organic phases are washed twice with 30 mi NaHCO3 solution and 30 ml brine, dried(MgS04), concentrated under reduced pressure and flash chromatographed (MeOH/CH2CI2 1: 19) to give the title compound: MS: [M+1] + = 305.
To a solution of 1-methylpiperidin-4-ol (1.15 g, 10 mM) in DMF (10 mL) was added NaH (0.48 g, 12 mM) successively. The mixture was stirred at 0C for 0.5 h, followed by addition of the required 1-fluoro-4-nitro-2-(trifluoromethyl)benzene and heating to reflux for another 5 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100×2 mL) and water (40×2 mL). The combined organic layers were evaporated, the resulting residue 1c utilized as materials without further purification.
With sodium hydride In toluene; mineral oil at 120℃; for 3.5h;
139
Intermediate 1392-chloro-6-(l-methylpiperidin-4-yloxy)pyridin-4-amine To a 500 mL sealed tube was charge 2,6-dichloro-4-aminopyridine (10 g, 61.3 mmol), sodium hydride (60% in mineral oil, 6.1 g, 153.37 mmol) with l-methyl-4-hydroxypiperidine (25 g,217 mmol). Toluene (50 mL, anhydrous) was added to aid transferring l-methyl-4- hydroxypiperidine. Bubbling in the reaction mixture was observed on addition of the piperidine. When the gas evolution ceased, the reaction mixture was heated at 1200C for 2 h.More sodium hydride (1.4 g, 35 mmol) was added and heating continued at 1200C for another 1.5 h. After cooling to room temperature, water was added and the crude product was extracted with dichloromethane/isopropanol (2:1) three times. The combined organic layers were dried over sodium sulfate. After concentration, the crude was used for the carbonylation.MS (ESP): 227.1 (MH+) for C11H16ClN3O.
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) inDMF (20 mL), at 65 C, was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 1 h, a solution of <strong>[1435-51-4]1,3-dibromo-5-fluorobenzene</strong> (1.26 mL, 10.0 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65 C for 3 days. The mixture was allowed to cool to ambient temperature then poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with water (100 mL) and loaded onto an SCX-2 cartridge, which was then washed with acetonitrile and eluted with 2N ammonia in methanol. Concentration of the basic methanolic fraction in vacuo gave the title compound (1.88 g, 54%). 1H NMR (CDCl3, 400MHz): 7.22 (t, J = 1.6Hz, 1H), 6.98 (d, J = 1.7Hz, 2H), 4.31-4.23 (m, 1H), 2.69-2.59 (m, 2H), 2.37-2.18 (m, 5H), 2.01-1.92 (m, 2H), 1.86- 1.75 (m, 2H). LCMS (Method B): RT = 2.3 min, (M+H)+ = 350.
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) inDMF (20 mL) at 65 C was slowly added a solution of 4-hydroxy-l -methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of <strong>[29578-39-0]3-bromo-5-fluoroanisole</strong> (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65 C for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400MHz): 6.65 (dd, J = 2.2, 1.6Hz, 1H), 6.63 (dd, J = 2.3, 1.6Hz, 1H), 6.37 (dd, J = 2.3, 2.1Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT = 2.1 min, M+H+ = 300.
A solution of <strong>[3684-12-6]2-phenyl-2-(phenylamino)acetic acid</strong> (II) (234 mg, 0.91 mmol) in dioxane, is added with a 4M solution of HCl in dioxane (5 mL) and the reaction is stirred at RT for 1 h; the solvent is evaporated under reduced pressure to obtain a white solid which is dissolved in dry THF (10 mL). DCC (222 mg, 1.12 mmol), HOBt (144 mg, 1.14 mmol) and N-methyl-4-piperidinol (307 mg, 2.71 mmol) are added and the mixture is stirred for 96h at RT under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is partitioned between DCM and water; the organic layer is separated and dried over Na2SO4. The crude compound is purified by preparative LC-MS and the collected fractions are portioned between 2M K2CO3 and EtOAc. The 'organic phase is dried over Na2SO4, filtered and evaporated to dryness to obtain 20.6 mg of the title compound as a white solid (7% yield, racemic mixture).1H NMR (300 MHz, DMSO-d6) ppm: 7.45 - 7.60 (m, 2H), 7.20 - 7.45 (m, 3H), 6.95 - 7.17 (m, 2H), 6.69 (d, 2H), 6.47 - 6.63 (m, IH), 6.23 (d, IH), 5.20 (d, IH), 4.71 (tt, IH), 2.34 - 2.48 (m, IH), 2.11 - 2.25 (m, 2H), 2.09 (s, 3H), 1.94 - 2.08 (m, IH), 1.71 - 1.90 (m, IH), 1.51 - 1.71 (m, 2H), 1.29 - 1.51 (m, IH); LC-MS (ESI POS): 325.2 (MH+).
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
Synthesis of 3-Methoxy-4-(1 -methyl-piperidine-4-yloxy)-benzonitrile (For Example 104)4.432.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1 .57 g 1 -methyl-piperidine-4-o l a n d 7. 1 7 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0C before 6.30 g di-tert- butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0C and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1 -methyl-piperidine-4-ol, 1 .79 g triphenylphosphine and 1 .58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1 N sodium hydroxide (x2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid . The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (x3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (Si02: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound.Yield: 2.48 g (73% of theory)Analysis: HPLC-MS (Method B): Rt: 1 .1 1 min. (M+H)+ = 247
73%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
2.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1.57 g 1-methyl-piperidine-4-ol and 7.17 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0 C. before 6.30 g di-tert-butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0 C. and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1-methyl-piperidine-4-ol, 1.79 g triphenylphosphine and 1.58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1N sodium hydroxide (*2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid. The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (*3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (SiO2: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound. Yield: 2.48 g (73% of theory) Analysis: HPLC-MS (Method B): Rt: 1.11 min. (M+H)+=247
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃;
In a round bottom flask wrapped with foil, methyl 4-hydroxy-3- (trifluoromethyl)benzoate (500mg, 2.13mmol) was dissolved in methylene chloride (lOmL). 4-Hydroxy-l-methyl-piperidine (0.25mL, 2.13mmol), PPh3 (670mg, 2.56mmol), and DIAD (0.50mL, 2.56mmol) were added thereto, and the mixture was stirred at room temperature for 23 hours. DTAD (4.26mmol) and PPh3 (1.12g, 4.26mmol) were added at 0C to the reaction mixture, which was stirred at room temperature for 24 hours. The resulting mixture was concentrated and then purified by silica gel chromatography (Hex/EA=l/l?DCM/MeOH=10/l) to obtain the title compound (512mg, 76%).1H NMR (300MHz, DMSC ¾ delta 8.14 (dd, 1H), 8.08 (d, 1H), 7.43 (d, 1H), 4.77 (m,1H), 4.30(q, 2H), 2.35 (m, 2H), 2.24(m, 2H), 2.19 (s, 3H), 1.93 (m, 2H), 1.73 (m, 2H), 1.27 (t, 3H).
76%
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 47.0h;
In a round bottom flask wrapped with foil, <strong>[115933-50-1]methyl 4-hydroxy-3-(trifluoromethyl)benzoate</strong> (500 mg, 2.13 mmol) was dissolved in methylene chloride (10 mL). 4-Hydroxy-1-methyl-piperidine (0.25 mL, 2.13 mmol), PPh3 (670 mg, 2.56 mmol), and DIAD (0.50 mL, 2.56 mmol) were added thereto, and the mixture was stirred at room temperature for 23 hours. DTAD (4.26 mmol) and PPh3 (1.12 g, 4.26 mmol) were added at 0 C. to the reaction mixture, which was stirred at room temperature for 24 hours. The resulting mixture was concentrated and then purified by silica gel chromatography (Hex/EA=1/1?DCM/MeOH=10/1) to obtain the title compound (512 mg, 76%). 1H NMR (300 MHz, DMSO-d6) delta 8.14 (dd, 1H), 8.08 (d, 1H), 7.43 (d, 1H), 4.77 (m, 1H), 4.30 (q, 2H), 2.35 (m, 2H), 2.24 (m, 2H), 2.19 (s, 3H), 1.93 (m, 2H), 1.73 (m, 2H), 1.27 (t, 3H).
47.4%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃;
The product from Step A (0.5 g, 2.13 mmol) and l-methylpiperidin-4-ol (0.245 mg, 2.13 mmol) were dissolved in dry CH2C12 (15 mL) and the mixture was cooled to 0C and DTAD (0.98 g, 4.26 mmol) and PPh3 (1.1 g, 4.26 mmol) were added. After the addition, the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give the residue, which was purified by silica gel column chromatography (petroleum ether/EtOAc=l : l~CH2Cl2/MeOH=10: 1) to give the target compound (0.32 g, 47.4%) as colorless oil. 1H- MR (400 MHz, DMSO-i) delta 8.17 (dd, J= 8.8, 2.0 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H), 7.46 (d, J= 8.8 Hz, 1H), 4.79 (s, 1H), 3.84 (s, 3H), 2.41 - 2.30 (m, 2H), 2.21 (s, 2.00 - 1.86 (m, 2H), 1.83 - 1.67 (m, 2H), 1.45 - 1.29 (m, 2H)ppm. MS: M/e 318 (M+l)+.
Stage #1: N-methyl-4-hydroxypiperidine; diphenyl-propoxy-acetic acid propyl ester With potassium <i>tert</i>-butylate; tetrabutyl-ammonium chloride at 20℃; for 72h; Inert atmosphere;
Stage #2: With ammonium chloride
Stage #3: With hydrogenchloride In water; acetone
1
Example 1; 7 (1 .23 kg) is treated with N-methyl-4-piperidinol (3 kg) and catalytic amount of potassium t- butoxide (246 g) and tetrabutylammonium chloride (50 g) and stirred under nitrogen for 3 days at room temperature. At the end of 3 days TLC-Thin Layer Chromatography (1 :1 , acetone: chloroform) shows almost 80-90% reaction conversion. Once the TLC is acceptable, , ammonium chloride (400 g) is added to bring the pH to almost neutral. Excess N-methyl-4-pipridinol is recovered under high vacuum at a pressure of about 5 mm. The residue thus obtained is extracted in toluene (4 Lt) and washed with water(2 Lt) 3 times. Toluene was removed under reduced pressure to get crude product 1 .5 kg (almost 100%). Which can be converted to Propiverine hydrochloride by dissolving the residue in acetone(1 :6-7) and charcolizing (1 0% by weight) and treating with hydrochloric acid to get almost white Propiverine HCI 0.9 kg to1 .25 kg which melts at 216-218 °C, with an assay of 99.00-100.00% and HPLC purity of >99.50%. The NMR spectra obtained for the compound is as follows1 H NMR (CDCI3): 12.30 &12.40 (Broad singlet, 1 H), 7.45-7.25 (2 multiplets, 1 0H), 5.14, 5.00 (2 broad multiplets, 1 H),3.23 (triplet, 2H), 2.48 (Doublet, 3H), 1 .62 (quintet, 2H). 0.91 (triplet, 3H), 3.07,3.03,2.45,2.1701 .88 (5 multiplets, 8H)13C NMR (CDCI3): 170.34, 140.80, 128.33, 127.83, 128.17, 86.3,67.03,64.75,48.85, 43.45,26.57,23.18, 10.64.
Intermediate Example Int20.014-(4-bromo-3-methoxyphenoxy)-1 -methylpiperidine To a stirred suspension of sodium hydride (1.76 g; 60% w/w sodium hydride in oil) in DMF (55 mL) was added 1 -methylpiperidin-4-ol (3.37 g) at 0 C. The mixture was stirred at room temperature for 30 minutes. 1 -bromo-4-fluoro-2- methoxybenzene (3.0 g) was added and the mixture was stirred at 100 C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica- gel chromatography gave 3.65 g of the title compound.
Intermediate Example Int20.014-(4-bromo-3-methoxyphenoxy)-1-methylpiperidineTo a stirred suspension of sodium hydride (1.76 g; 60% w/w sodium hydride in oil) in DMF (55 mL) was added 1-methylpiperidin-4-ol (3.37 g) at 0 C. The mixture was stirred at r.t. for 30 min. <strong>[450-88-4]1-bromo-4-fluoro-2-methoxybenzene</strong> (3.0 g) was added and the mixture was stirred at 100 C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 3.65 g of the title compound.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;
To a solution of 100 mg (0.766 mmol) of 4-hydroxy-1-methyl piperidine in 1.5 ml of tetrahydrofuran, 155 mg (1.53 mmol) of di-tert-butyl azocarboxylic acid, 402 mg (1.53 mmol) of triphenylphosphine and 0.170 ml (1.53 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the reaction solution was extracted with 1 N hydrochloric acid. 1 N sodium hydroxide aqueous solution was added to the aqueous layer to make its pH 10 and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to provide 152 mg of the title compound as a white solid (yield: 87percent). 1H-NMR spectrum (400 MHz, CDCl3) delta ppm: 8.22 (2H, s), 4.33 (1H, tt, J=7.5, 3.8 Hz), 2.65-2.57 (2H, m), 2.30-2.22 (5H, m), 2.01-1.93 (2H, m), 1.85-1.75 (2H, m).
1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 120h;
DIAD (930 muIota_, 4.7 mmol) was added to a solution of 3-methyl-4-nitro-1 H-pyrazole (500 mg, 3.93 mmol), /V-methyl-4-piperidinol (453 mg, 3.93 mmol) and triphenylphosphine (1238 mg, 4.7 mmol) in THF (25ml_). The reaction mixture was stirred at rt for 5 days. The mixture was cone, in vacuo before purification by flash chromatography on silica, washing with 50% EtOAc/DCM, followed by 5/45/50 MeOH/EtOAc/DCM mixture. The product was eluted with 2/5/43/50 NEt3/MeOH/EtOAc/DCM mixture to give the title compound as an off-white low melting solid (202 mg, 23%). LCMS (Method 1 ) Rt 2.7 min, ESIMS m/z [M+H]+ 225.3.
With Novozym 435; In n-heptane; at 65℃;Dean-Stark; Enzymatic reaction;
To a 250-mL round bottom flask with a magnetic stir bar was added <strong>[111-82-0]methyl laurate</strong> (25 g, 1 17 mmol), 4-hydroxy-N-methylpiperidine (17.46 g, 152 mmol), heptane (10 mL), and Novozym 435 (2.50 g). A Dean-Stark apparatus was placed onto the flask, and the mixture was heated to 65C. The heptane azeotrope was utilized to remove water by reducing the pressure until the azeotrope distilled overhead into the Dean-Stark trap to return the heptane to the reaction vessel. After 3 hrs, GC analysis indicated 98.7 area% conversion. The reaction was allowed to cool to ambient temperature.Novozym 425 was recovered by filtration. The mixture was taken up in diethyl ether (100 mL) and washed with water (100 mL). The organics were dried with Na2SO4. After filtration, the volatiles were removed under reduced pressure to afford a pale yellow oil that solidified upon standing (32.09 g; 92% yield). 1 H NMR (300 MHz, CDCI3) delta 4.78 (m, 1 H), 2.65 (m, 2H), 2.32-2.22 (m, 7H); 1 .95-1 .85 (m, 3H); 1 .77-1 .57 (m, 4H); 1 .35-1 .23 (m, 17H), 0.88 (t, 3H).[0103] HPLC (150 x 4.6 mm Zorbax SB-C8 column, 75:25 (v:v) (0205) methanol :water (containing 0.1 vol% trifluoroacetic acid) for 10 min, gradient to 100% methanol over 1 min, held at 100% methanol for 9 min, ELSD detection): tR 4.2 min.
4-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-1-methylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a stirred solution of DIAD (35.3 g, 174.8 mmol) in THF (200 mL) was added PPI13 (46 g, 174.8 mmol) portionwise at 0 C and stirred at 0 C for 5 mins. To this mixture was added <strong>[400755-41-1]3-methoxy-4-nitro-1H-pyrazole</strong> (10 g, 69.93 mmol) in THF (300 mL) dropwise at 0C, followed by a solution of 1-methylpyrrolidin-3-ol (12.1 g, 104.9 mmol) in THF (100 mL) at 0C. The mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on Si02 (5-10% MeOH in CH2C12) to afford 4-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-1-methylpiperidine as a pale yellow solid (7g, 41%). 1H NMR (300 MHz, DMSO-J6) delta 8.73 (s, 1H), 4.10-3.98 (m, 1H), 3.94 (s, 3H), 2.90-2.80 (m, 2H), 2.19 (s, 3H), 2.07-1.87 (m, 6H); MS (ESI) m/z 241.2 [M+H]+.
1-methylpiperidin-4-yl 6-hydroxy-2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With toluene-4-sulfonic acid at 160℃; for 3h; Microwave irradiation; Inert atmosphere;
3.2. General Method A (6a-o)
General procedure: The mixture of mollugin (0.35 mmol), alcohol (3.52 mmol), and catalytic p-TsOH (0.035 mmol) in2 mL microwave vial was placed in the cavity of microwave reactor, and then stirred for 3 h at 160 °C.The produced brown mixture was dried under vacuum and subjected to purification (20 g silica gelcartridge, dichloromethane-MeOH) to give the title product.
3-methyl-6-(1-methylpiperidin-4-yloxy)benzo[d]isoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.9%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0℃;
Take <strong>[66033-92-9]3-methyl-6-hydroxybenzo[d]isoxazole</strong> 2.0g, triphenylphosphine 4.2g,N-methyl-4-hydroxypiperidine 1.9g, tetrahydrofuran 40mL was added to the reaction flask and stirred.2.8 g of diethyl azodicarboxylate was dissolved in a small amount of tetrahydrofuran and added dropwise to the reaction flask.The system was browned to black, detected by TLC, and the reaction was completed, and the tetrahydrofuran was distilled off.Add water, extract with ethyl acetate, combine the organic phases, wash with brine,Dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give a brown oil,Column chromatography gave 1.28 g of a white solid, yield 38.9%.
To a solution of compound 62 (486 mg, 4.2 mmol, 1.2 eq) in dimethylacetamide (5 mL) at 0 C under nitrogen was added potassium tert-butoxide (513 mg, 4.6 mmol, 1.3 eq) portion wise, and then the mixture was stirred at 0 C for 1 h. A solution of compound 61 (500 mg, 3.5 mmol, 1.0 eq) in DMA (2 mL) was added drop wise. After addition, the mixture was stirred at RT overnight. The reaction was quenched by water (15 mL) and extracted with EA (5 mL X 3), dried over Na2S04, filtered and concentrated to give a crude residue (700 mg), which was used onto next step without further purification. 1H NMR (300 MHz, CDCl3, contains DMA): delta 8.28-8.22 (m, 2 H), 7.41-7.37 (m, 1 H), 4.55-4.51 (m, 1 H), 2.72-2.70 (m, 2 H), 2.41-2.38 (m, 2 H), 2.35 (s, 3 H), 2.13-2.09 (m, 2 H), 1.98-1.92 (m, 2 H). LCMS: (M+H)+ = 238.1.
To a stirred solution of compound 78 (250 mg, 2.2 mmol, 1 eq) in DMF (5 mL) at 0 C was added NaH (60% in oil, 174 mg, 4.4 mmol, 2 eq) portion wise. After the mixture was stirred at room temperature for 30 mins, a solution of compound 77 (493 mg, 2.4 mmol, 1.1 eq) in DMF (2 mL) was added drop wise at 0 C. After the addition, the reaction was allowed to warm to room temperature and stirred overnight. After LC-MS indicated completion, water (21 mL) was added drop wise at 0 C and the mixture was extracted with EA (6 mL X 3). The combined organic layers was washed with brine (5 mL X 3) and dried over Na2S04, filtered and concentrated to afford the crude product, which was purified by silica gel column to give the desired product as a yellow solid (0.31 g, 50%). *H NMR (300 MHz, CDCb): delta 8.32 (s, 1 H), 7.56 (d, J= 1.5 Hz, 1 H), 7.45 (d, J= 8.1 Hz, 1 H ), 4.50 (s, 2 H), 3.47-3.45 (m, 1 H), 2.74- 2.72 (m, 2 H), 2.32 (s, 3 H), 2.28-2.25 (m, 2 H), 1.96-1.90 (m, 2 H), 1.79-1.72 (m, 2 H). LCMS: (M+H)+ = 285.0, 287.0
5-bromo-3-((1-methylpiperidin-4-yl)oxy)picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
General procedure: A mixture of sodium hydrogen (7.5 mmol), appropriate alcohol(5.0 mmol) in dry THF (100 mL) was cooled at 0 C, then themixture was stirred at room temperature for 30 min. Adding thereaction liquid to the mixture of <strong>[573675-25-9]5-bromo-3-nitropicolinonitrile</strong>(5.0 mmol) in 50 THF (50 mL) dropwise at 0 C then the mixturewas stirred at rt for 3 h. The reaction solution was treated withsaturated NH4Cl and was extracted with EtOAc. The organic layerwas collected, washed with brine, and dried over MgSO4, concentrated.The residue obtained was purified by column chromatography(eluent gradient 10-20% petroleum ether in EtOAc), gave42a-k.
2-((1-methylpiperidin-4-yl)oxy)-5-nitropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
NaH (60percent) oil dispersion, 8 g, 333 mmol) was added to a solution of l-methyl-4- hydroxypiperidine (18 g, 156 mmol) in dry DMF (200 mL) at 6 °C. The solution was stirred at room temperature for 30 min and a solution of <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (25 g, 125 mmol) in dry DMF (50 mL) was then added. The mixture was stirred at room temperature overnight. Water (50 mL) was added and the solution was extracted with EtOAc (3 x 100 mL). The organic layers were combined, concentrated under vacuum, and purified by column chromatography over silica gel (MeOH-dichloromethane gradient from 1percent to 3.3percent). The desired fractions were collected and evaporated to give compound 10a (13 g, 43percent).
N-(but-3-en-1-yl)-4-chloro-N-methyl-3-(trifluoromethyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: N-methyl-4-hydroxypiperidine With alizarin yellow R In acetonitrile for 0.333333h; Inert atmosphere;
Stage #2: 4-chloro-3-trifluoromethylbenzenesulfonyl chloride In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere;
2 Example 2: Synthesis of N-(but-3-en-1-yl)-4-chloro-N-methyl-3-(trifluoromethyl)benzenesulfonamide
Add 20 mg of calcium hydride as a desiccant to a dry 10 ml reaction tube. Nitrogen is introduced to create an oxygen-free environment for the reaction system. Take 1-methylpiperidin-4-ol (138 mg, 1.2 mmol), Alizarin Yellow R (5 mol%) was dissolved in 1.5 ml of acetonitrile and syringed into the reaction tube. After stirring for 20 minutes, p-chlorotrifluoromethylbenzenesulfonyl chloride (279 mg, 1.0 mmol) was dissolved in 1.5 ml of acetonitrile and syringe was introduced into the reaction system. The reaction was carried out for 24 hours under the illumination of a normal temperature 30w LED lamp, and the light was removed. (20ml) quenched with saturated NH4Cl solution, and (20ml × 3 times) and extracted with ethyl acetate, the organic phase retained and washed once with saturated aqueous NaCl solution. The solvent was distilled off under reduced pressure, flash column chromatography to give 252 mg of product, 77% yield.
77%
With calcium hydride; alizarin yellow R In acetonitrile at 20℃; for 24h; Schlenk technique; Inert atmosphere; Irradiation; Green chemistry;
With diisopropyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;
10 Example 10: Preparation of Intermediate (XVIII) (intermediate 16-17) of scheme 6 General procedure 5
General procedure: A mixture of ethyl 4-hydroxybenzoate (1 eq), /V-methyl piperidinol (1 eq), triphenylphosphine (1.1 eq) and DIAD (1.1 eq) in THF (0.2 M) was stirred at RT upon completion. Volatiles were evaporated and the reside was triturated in cyclohexane. The solid was filtered off and the filtrate was evaporated and loaded on a SPE-SCX cartridge. 2M Methanolic ammonia fraction were evaporated to afford title intermediates
1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
1-methyl-4-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 25℃; for 30.5h;
Intermediate C3: l-methyl-4-(3-methyl-4-nitro-lH-pyrazol-l-yl)piperidine.
General procedure: A solution of 3-methyl-4-nitro-lH-pyrazole (5 g, 39.4 mmol) and 1- methylpiperidin-4-ol (4.5 g, 39.4 mmol) in anhydrous THF (60 mL), triphenyl phosphine (154.7 g, 59 mmol) was added under nitrogen atmosphere and the mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (12 mL, 59 mmol) was added drop-wise to the above mixture, over a period of 30 min, and stirring continued at rt for 30 h. THF was removed under reduced pressure and then 3N aqueous HC1 (30 mL) was added. The resulting solution was washed with EtOAc (3 x 20 mL) and aqueous layer was then basified with saturated aqueous potassium carbonate (up to pH = 9). The solution was extracted with 10% methanol in DCM (3 x 20 mL). The combined organic extracts were dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography by silica gel column chromatography (0 to 10 % MeOH/DCM 15 CV’s) to obtain mixture of regioisomers. These two regioisomers were separated by SFC to obtain the desired isomer, l-methyl-4-(3-methyl-4-nitro-lH-pyrazol-l-yl) piperidine (2.0 g, 23 % yield) as white solid. And the other regioisomer, l-methyl-4-(5-methyl-4-nitro-lH-pyrazol-l- yl)piperidine (1.4 g, 15 % yield) was also obtained. NMR (400 MHz, DMSO-d6): d 8.84 (s, 1H), 4.16 (m, 1H), 2.91 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 2.13 (m, 2H), 1.98 (m, 4H); MS (ESI) m/z: 225.4 (M+H+).
4-(3-fluoro-2-nitrophenoxy)-1-methylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.9%
With sodium hydride; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1 g, 6.3 mmol) in DMF (20 mL) was added NaH (225 mg, 9.5 mmol) and 1-methylpiperidin-4-ol (870 mg, 7.55 mmol). The mixture was stirred at RT overnight and then the resulting mixture was quenched with water (30 mL), extracted with DCM (30 mL×3) and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (DCM/MeOH=10/1) to give 4-(3-fluoro-2-nitrophenoxy)-1- methylpiperidine (1.0 g, 62.9%) as a green oil. LC-MS m/z: 255.2 [M+H]+. HPLC Purity (214 nm): 97%; tR = 0.40 min
(2Z,3E)-3-(((1-methylpiperidin-4-yl)oxy)imino)-[2,3'-biindolinylidene]-2'-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: N-methyl-4-hydroxypiperidine With triethylamine; p-toluenesulfonyl chloride In dichloromethane at 0℃; for 0.5h;
Stage #2: indirubin-3'-monoxime With N,N,N',N'-tetramethylguanidine In tetrahydrofuran for 17h; Reflux;
4.1.20. (2Z,3E)-3-(((1-Methylpiperidin-4-yl)oxy)imino)-[2,3'-biindolinylidene]-2'-one (20)
A mixture of compound 64 (0.1 g, 0.87 mmol), p-toluenesulfonylchloride (0.17 g, 0.89 mmol) and TEA (0.2 mL, 1.43 mmol) in DCM(2 mL) was stirred at 0 °C for 0.5 h. The reactionwas quenched withwater, extracted with DCM and dried over anhydrous MgSO4. Thesolvent was removed in vacuo to obtain a green oily product. To thisoil was added compound 15 (0.12 g, 0.44 mmol), 1,1,3,3-tetramethylguanidine (0.16 mL, 1.31 mmol) and THF (1.5 mL), andthe mixturewas stirred at reflux for 17 h. After cooling, the reactionwas quenched with water and extracted with EtOAc. The solventwas removed under reduced pressure, and the residue was dissolvedin DCM. Hexanes were added to the solution, and theresulting suspension was filtered. The solid was purified by flashcolumn chromatography (DCM/MeOH 35/1 then 20/1) to affordthe title compound (0.14 g, 85%). mp 240 °C (dec); 1H NMR(300 MHz, DMSO-d6) δ 11.69 (s, 1H), 10.76 (s, 1H), 8.59 (d, J =7.8 Hz,1H), 8.15 (d, J =7.8 Hz, 1H), 7.48-7.38 (m, 2H), 7.15 (td, J= 7.6,1.1 Hz, 1H), 7.09-7.02 (m, 1H), 6.95 (td, J= 7.8, 1.2 Hz, 1H), 6.91 (d,J =7.8 Hz, 1H), 4.78-4.66 (m, 1H), 2.84-2.67 (m, 2H), 2.63-2.52 (m,1H), 2.34 (s, 3H), 2.26-2.13 (m, 1H), 2.10-1.94 (m, 2H). 13C NMR(150 MHz, DMSO-d6) δ 170.8, 151.5, 145.5, 143.9, 138.7, 132.8, 128.3,126.4, 123.0, 122.3, 121.5, 120.6, 116.1, 111.8, 109.0, 100.1, 51.6, 45.1,29.5. HRMS (ESI) for C22H23N4O2 (M+H)+ calcd 375.1821, found375.1823.
1-(1-methyl-4-piperidyl)-5-nitroindazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.2%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 0 - 25℃; for 16h; Inert atmosphere;
S99.a Step a)
To a mixture of 5-nitro-1H-indazole (2 g, 12.26 mmol) and 1-methylpiperidin-4-ol (2.12 g, 18.39 mmol, 2.15 mL) , PPh3(4.82 g, 18.39 mmol) in THF (20 mL) was added DIAD (1.96 M in toluene) (1.9 M, 9.68 mL) at 0 under N2. The mixture was stirred at 25 for 16 h. The reaction solvent was concentrated to get a residue. The residue was purified by prep-HPLC: column: Welch Xtimate C18 150 *40 mm *10 μm; mobile phase: [water (10 mM NH4HCO3) -ACN] ; B%: 36%-46%, 8 min to give 1-(1-methyl-4-piperidyl)-5-nitro-indazole (900 mg, 3.46 mmol, 28.20%yield, 100%purity) was obtained as a light yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 1.98 -2.05 (m, 3 H) 2.15 -2.27 (m, 2 H) 2.35 -2.51 (m, 5 H) 3.06 (br d, J=12.05 Hz, 2 H) 4.46 (tt, J=11.61, 4.20 Hz, 1 H) 7.53 (d, J=9.29 Hz, 1 H) 8.21 (s, 1 H) 8.25 (dd, J=9.16, 2.13 Hz, 1 H) 8.72 (d, J=2.01 Hz, 1 H) LCMS: (ES) m/z 261.3 (M+H+) .
28.2%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 0 - 25℃; for 16h; Inert atmosphere;
S99.a Step a)
To a mixture of 5-nitro-1H-indazole (2 g, 12.26 mmol) and 1-methylpiperidin-4-ol (2.12 g, 18.39 mmol, 2.15 mL) , PPh3(4.82 g, 18.39 mmol) in THF (20 mL) was added DIAD (1.96 M in toluene) (1.9 M, 9.68 mL) at 0 under N2. The mixture was stirred at 25 for 16 h. The reaction solvent was concentrated to get a residue. The residue was purified by prep-HPLC: column: Welch Xtimate C18 150 *40 mm *10 μm; mobile phase: [water (10 mM NH4HCO3) -ACN] ; B%: 36%-46%, 8 min to give 1-(1-methyl-4-piperidyl)-5-nitro-indazole (900 mg, 3.46 mmol, 28.20%yield, 100%purity) was obtained as a light yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 1.98 -2.05 (m, 3 H) 2.15 -2.27 (m, 2 H) 2.35 -2.51 (m, 5 H) 3.06 (br d, J=12.05 Hz, 2 H) 4.46 (tt, J=11.61, 4.20 Hz, 1 H) 7.53 (d, J=9.29 Hz, 1 H) 8.21 (s, 1 H) 8.25 (dd, J=9.16, 2.13 Hz, 1 H) 8.72 (d, J=2.01 Hz, 1 H) LCMS: (ES) m/z 261.3 (M+H+) .
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
