* 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 Organic Chemistry, 2018, vol. 83, # 24, p. 15558 - 15568
2
[ 14774-37-9 ]
[ 50675-18-8 ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 4℃; Stage #2: With sodium hypochlorite; chlorine In dichloromethane; water at 4 - 20℃; for 17.4 h;
To 5.00 g (43.0 mmol) of (tetrahydro-pyran-yl)-methanol in DCM (50 mL) are added 67 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy (0.43 mmol), a solution of 9.04 g (108 mmol) NaHCO3 in water (70 mL) and 512 mg (4.30 mmol) of potassium bromide at 20° C. The suspension is cooled in an ice bath to 4° C. Then a solution of 23.5 mL sodium hypochlorite (10-15percent free chlorine; 47.4 mmol) is added in 35 min. The suspension is stirred for 30 min at 4-9° C. and further 45 min to reach 17° C. 4.80 mL sodium hypochlorite (10-15percent free chlorine) is added within 15 min. The reaction is stirred for 16 h at RT. The suspension is filtered and the layers are separated. The aq. layer is washed with 50 mL DCM, the combined organic layers are washed with 50 mL water. The solvent is removed under reduced pressure to afford 3.00 g of tetrahydro-pyran-4-carbaldehyde. Yield: 61percent; ESI-MS: 113 [M+H]-
61%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 4 - 20℃; for 18.0833 h;
To 5.00 g (43.0 mmol) of (tetrahydro-pyran-yl)-methanol in DCM (50 mL) are added 67 mg of 2,2,6,6-tetramethyl-1 -piperidinyloxy (0.43 mmol), a solution of 9.04 g (108 mmol) NaHC03 in water (70 mL) and 512 mg (4.30 mmol) of potassium bromide at 20 °C. The suspension is cooled in an ice bath to 4 °C. Then a solution of 23.5 mL sodium hypochlorite (10-15percent free chlorine; 47.4 mmol) is added in 35 min. The suspension is stirred for 30 min at 4-9 °C and further 45 min to reach 17 °C. 4.80 mL sodium hypochlorite (10-15percent free chlorine) is added within 15 min. The reaction is stirred for 16 h at RT. The suspension is filtered and the layers are separated. The aq. layer is washed with 50 mL DCM, the combined organic layers are washed with 50 mL water. The solvent is removed under reduced pressure to afford 3.00 g of tetrahydro-pyran-4-carbaldehyde. Yield: 61 percent; ESI-MS: 1 13 [M+H]"
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 16, p. 6928 - 6931
[2] Patent: US8865744, 2014, B1, . Location in patent: Page/Page column 24
[3] Patent: WO2014/184327, 2014, A1, . Location in patent: Page/Page column 26
[4] Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 865 - 893
[5] Chemistry - A European Journal, 2008, vol. 14, # 26, p. 7951 - 7960
[6] Patent: US2005/70712, 2005, A1, . Location in patent: Page/Page column 40
[7] Patent: US2005/171131, 2005, A1, . Location in patent: Page/Page column 39
[8] Patent: WO2010/96371, 2010, A2, . Location in patent: Page/Page column 156-157
[9] Patent: WO2015/10078, 2015, A2, . Location in patent: Paragraph 0576; 0577
[10] Patent: WO2015/200650, 2015, A1, . Location in patent: Paragraph 0613; 0616-0617
[11] Organic and Biomolecular Chemistry, 2016, vol. 14, # 41, p. 9716 - 9719
[12] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5871 - 5876
[13] Patent: CN108314680, 2018, A, . Location in patent: Paragraph 0691; 0692; 0696-0698
3
[ 110238-91-0 ]
[ 50675-18-8 ]
Reference：
[1] Patent: WO2006/74003, 2006, A2, . Location in patent: Page/Page column 161
[2] Journal of the American Chemical Society, 2012, vol. 134, # 16, p. 6928 - 6931
[3] Patent: WO2014/49133, 2014, A1, . Location in patent: Page/Page column 49-50
[4] Patent: US8865744, 2014, B1,
[5] Patent: WO2014/184327, 2014, A1,
[6] Patent: WO2015/10078, 2015, A2,
[7] Patent: WO2015/200650, 2015, A1,
4
[ 101765-10-0 ]
[ 50675-18-8 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 7035 - 7044
[2] Patent: WO2010/46194, 2010, A1, . Location in patent: Page/Page column 45
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1903 - 1907
[4] Patent: WO2008/110307, 2008, A1, . Location in patent: Page/Page column 37
5
[ 4295-99-2 ]
[ 50675-18-8 ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: With diisobutylaluminium hydride In toluene at -78℃; for 1 h; Stage #2: With water; ammonium chloride In toluene
Reference Example 2: Tetrahydropyran-4-carbaldehyde. To a solution of tetrahydro pyran-4-carbonitrile (1.0 g, 9.0 mmol) in toluene (10 mL) was added diisobutylaluminium hydride solution (DIBAL-H, 10.8 mL, 10.8 mrnol,10 IM in toluene) at -78°C. The reaction was stirred at -780C for 1 hour then allowed to warm to r.t. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tetrahydropyran-4-carb aldehyde (530 mg, 52 percent).
Multi-step reaction with 3 steps
1: 0.930 g / Jones reagent / acetone; H2O / 1 h
2: thionyl chloride / 0.75 h / Heating
3: 0.890 g / aluminium chloride / 1 h / 75 °C
2-cycloheptylcarbonylamino-2-(tetrahydropyran-4-yl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; lithium bromide;bis(triphenylphosphine)palladium dibromide; In 1-methyl-pyrrolidin-2-one; at 120℃; under 41927.6 Torr; for 10.0h;
To a solution of 4-formyltetrahydropyran (1.14 g), cycloheptylcarboxyamide (1.41 g) in N-methylpyrrolidone (8 ml) were added lithium bromide (304 mg), conc. sulfic acid (10 mg) and dibromobis(triphenylphosphine) palladium (II) (20 mg) and the mixture was stirred at 120C for 10 hours in an autoclave under atmosphere of carbon monoxide at a pressure of 57 kg/cm2. The reaction mixture was extracted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was neutralized with conc. hydrochloric acid and extracted with ethyl acetate twice, washed with diisopropyl ether to give 2-cycloheptylcarbonyl amino-2-(tetrahydropyran-4-yl)acetic acid (2.33 g). TLC:Rf0.60 (methylene chloride:methanol=10:1).
1-ethyl-6-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine; at 110℃; for 48h;
EXAMPLE 104; A mixture of benzoylacetonitrile (365 mg), tetrahydropyran-4-carbaldehyde (287 mg), 5-amino-1-methylpyrazole (289 mg) in pyridine (7.3 ml) was stirred for 2 days at 110 C. The solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography to give pure 1-ethyl-6-phenyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (359 mg). 1H-NMR (CDCl3) delta 1.56 (3H, t, J=6.6 Hz), 1.94 (2H, d, J=12.2 Hz), 2.25-2.42 (2H, m), 3.62-3.79 (3H, m), 4.16-4.24 (2H, m), 4.62 (2H, q, J=6.6 Hz), 7.51-7.58 (3H, m), 7.85-7.93 (2H, m), 8.35 (1H, s)
Step 1: A flask was charged with compound 14.1 (200 mg, 100 mol %), tetrahydro-pyran-4-carbaldehyde (100 mol %), and dichloroethane. To this was added NaBH(OAc)3 (150 mol %) and the resulting slurry was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was re-suspended in EtOAc and H2O. The organic layer was washed sequentially with saturated sodium bicarbonate, H2O, and brine. The organic layers were combined, dried over Na2SO4, and concentrated to give (5-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester (compound 33.1) as an oil which was used in the next step without further purification.
methyl 5-oxo-6-((tetrahydro-2H-pyran-4-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine In methanol at 65℃;
21
Preparation 21; methyl 5-oxo-6-((tetrahydro-2H-pyran-4-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2- carboxylate; A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.9 mmol), tetrahydro-pyran-4-carbaldehyde (3.2 mmol), and piperidine (3.2 mmol) in 6 mL of methanol was heated to 65 0C overnight. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel, eluting with ethyl acetate in hexane from 10% to 40%, to give 430 mg of the desired product. ES-MS m/z 301 (M+H).
With diisobutylaluminium hydride; In toluene; at -5 - 25℃;Inert atmosphere;
[0169] Dry toluene (500 g) was charged into a dried reactor under nitrogen and <strong>[4295-99-2]tetrahydropyran-4-carbonitrile</strong> 5 (100 g, 0.90 mol) was added. The resulting solution was cooled to -5C to 5C and a solution of DIBAL-H in toluene (1.0M, 800 g, 1.0 mol) was added dropwise at -5C to 5C and the resulting reaction mxture was stirred at this temperature for 1-2 hrs. The reaction mixture was then warmed to 20-25C and stirred at this temperature for 1-2 hrs. Subsequently the reaction mixture was cooled to -5C - 5C and quenched by the dropwise addition of a solution of AcOH (195 g) in toluene (180 g) at -5 - 5C (caution: exothermic, gas release). A 25% solution of sodium tartrate tetrahydrate (1000 g) was added slowly at -5C - 5C (caution:exothermic, gas release). The reaction mixture was allowed to warm to 20-25C and stirred at this temperature for 8-16 hrs. The layers were separated and the aqueous layer was extracted twice with EtOAc (900 mL each) at 20-25C. The two EtOAc extracts were combined with the original organic phase and the combined organic phases were evaporated in vacuo to about 100-200 g to yield the product 6. The product was generally isolated in 50-80% yield.
52%
Reference Example 2: Tetrahydropyran-4-carbaldehyde. To a solution of tetrahydro pyran-4-carbonitrile (1.0 g, 9.0 mmol) in toluene (10 mL) was added diisobutylaluminium hydride solution (DIBAL-H, 10.8 mL, 10.8 mrnol,10 IM in toluene) at -78C. The reaction was stirred at -780C for 1 hour then allowed to warm to r.t. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tetrahydropyran-4-carb aldehyde (530 mg, 52 %).
Stage #1: 4-Aminomethylpiperidine With ethyl trifluoroacetate, In isopropyl alcohol at -10 - 0℃;
Stage #2: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde In isopropyl alcohol at 0℃; Reflux;
Stage #3: With sodium tris(acetoxy)borohydride In isopropyl alcohol at 10 - 20℃;
1; 2
4-(aminomethyl)-piperidine (2) (11.5 g) is dissolved in isopropanol and cooled to between -100C and -5°C; 15.5 g of ethyl trifluoroacetate is then added in portions, maintaining the internal temperature at under 0°C. When the addition has been completed, the reaction mixture is left under stirring at O0C for 1 hour. 11.6 g of 4-formyl-tetrahydropyran and further isopropanol are then added rapidly, still at 0-50C.The reaction mixture is reflux heated, and part of the solvent is then distilled. After cooling to 100C, 23.4 g of sodium triacetoxy boro hydride is added in portions, maintaining the temperature at under 200C. The reaction mixture is maintained under stirring at ambient temperature for 2 hours; 52.2 g of 32% NaOH solution and 14 g of water are then added. The reaction mixture is reflux heated for 2 hours and evaporated at low pressure, eliminating part of the distillate. The mixture is cooled to ambient temperature, and more water and methylene chloride are added. After extraction with methylene chloride the combined organic phases are washed with 2M NaOH and partly evaporated at low pressure. The solution of (11) thus obtained (content of (11) amounting to a theoretical value of 21.4 g) is normally used "as is" in the subsequent preparation of compound (12).A sample of product (11) obtained by evaporation until dry has been characterised as reported below.MS (ESI, positive ions), m/z: 213 [M+H]+; (CAD MS/MS), m/z: 196.991H-NMR (CDCl3, 200 MHz): δ (ppm) 0.98-1.36 (m, 6H), 1.49-1.95 (m, 6H), 2.04-2.21 (m, 2 H), 2.44-2.61 (m, 2 H), 2.73-2.93 (m, 2 H), 3.22-3.45 (m, 2 H), 3.83-4.01 (m, 2 H).
Stage #1: 4-Aminomethylpiperidine With ethyl trifluoroacetate, In isopropyl alcohol at -10 - 0℃; for 1h;
Stage #2: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde In isopropyl alcohol at 0℃; Reflux;
Stage #3: With sodium tris(acetoxy)borohydride In isopropyl alcohol at 10 - 20℃; for 2h;
1 C-(1 -(tetrahydropyran-4-ylmethyl)-piperidin-4-yl)-methylamine (11)
4-(aminomethyl)-piperidine (2) (11.5 g) is dissolved inisopropanol and cooled to between -10° C. and -5° C.; 15.5of ethyl trifluoroacetate is then added in portions, maintaining the internal temperature at under 0° C. When the additionhas been completed, the reaction mixture is left under stirring0° C. for 1 hour. 11.6 g of 4-formyl-tetrahydropyran andfurther isopropanol are then added rapidly, still at 0-5° C.The reaction mixture is reflux heated, and part of the solvent is then distilled. After cooling to 10°C., 23.4 g of sodiumtriacetoxy borohydride is added in portions, maintaining thetemperature at under 20° C. The reaction mixture is maintained under stirring at ambient temperature for 2 hours; 52.2of 32% NaOH solution and 14 g of water are then added.The reaction mixture is reflux heated for 2 hours and evaporated at low pressure, eliminating part of the distillate.The mixture is cooled to ambient temperature, and morewater and methylene chloride are added. After extraction withmethylene chloride the combined organic phases are washedwith 2M NaOH and partly evaporated at low pressure. Thesolution of (11) thus obtained (content of (11) amounting to atheoretical value of 21.4 g) is normally used “as is” in thesubsequent preparation of compound (12).A sample of product (11) obtained by evaporation until dryhas been characterised as reported below. MS (ESI, positive ions), mlz: 213 [M+H] (CADMS/MS), mlz: 196.99‘H-NMR (CDC13, 200 MHz): ö (ppm) 0.98-1.36 (m, 6H),1.49-1.95 (m, 6H), 2.04-2.21 (m, 2 H), 2.44-2.61 (m, 2 H),2.73-2.93 (m, 2 H), 3.22-3.45 (m, 2 H), 3.83-4.01 (m, 2 H).
With hydrogen;20% palladium hydroxide on carbon; In ethanol; at 100℃; under 20686.5 Torr; for 27.5h;
A high pressure vessel on the HEL 100 system containing compound 12 (2.5 g; 24.244 mmol) and tetrahydro-pyran-4-carbaldehyde (5.05 mL; 48.487 mmol) is added palladium hydroxide, 20% on carbon, wet (3.405 g; 10 mol%; 2.424 mmol) and 50 mL of ethanol. The reaction is subjected to 400 psi H2 at 50 C for 40 h. After this time, the reaction is cooled to room temperature and filtered through Celite. The CeIi te is rinsed with methanol and water.The combined filtrates are concentrated and slurried in dichloromethane, then filtered to afford compound 13 as a white solid (3.95g; 81%), LC-MS (LC Method h): retention time 0.32 min, m/z 202 [M+H]+
70%
With hydrogen; palladium(II) hydroxide; In methanol; at 50℃; under 20679.6 Torr; for 18h;
To 0.90 g (8.76 mmol) of 2-amino-2-methyl-propionic in 10 mL MeOH is added at RT1.00 g (8.76 mmol) of tetrahydro-pyran-4-carbaldehyde. After 25 min Pd(OH)2 (310 mg, w=20%) is added. The reaction is stirred at 50 C. and 2757 kPa hydrogen pressure for 18 h. 10 mL of acetonitrile and 20 mL of water are added, filtered through celite to remove the catalyst and washed with water. The solvent is removed under reduced pressure to give 1.62 g of crude product, which is recrystallized from MeOH and water to afford 1.24 g of 2-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield: 70%; ESI-MS: 202 [M+H]+
70%
To 0.90 g (8.76 mmol) of 2-amino-2-methyl-propionic in 10 mL MeOH is added at RT 1 .00 g (8.76 mmol) of tetrahydro-pyran-4-carbaldehyde. After 25 min Pd(OH)2 (310 mg, w=20%) is added. The reaction is stirred at 50 C and 2757 kPa hydrogen pressure for 18 h. 10 mL of acetonitrile and 20 mL of water are added, filtered through celite to remove the catalyst and washed with water. The solvent is removed under reduced pressure to give 1.62 g of crude product, which is recrystallized from MeOH and water to afford 1.24 g of 2-methyl-2- [(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield: 70%; ESI-MS: 202 [M+H]+
Stage #1: 3-methoxycyclopent-2-enone With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1h; Inert atmosphere;
Stage #2: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃; for 18.5h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; n-heptane; ethylbenzene
1
A solution of S-methoxy-cyclopent^-enone (18.8 g, 0.17 mol) in THF (200 ml) was added drop wise over 30 minutes (using an addition funnel) to a solution of lithium diisopropylamide solution (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 103 ml, 0.18 mol) in THF (150 ml) at -78 0C, under nitrogen and allowed to stir at this temperature for 30 minutes. Tetrahydropyranyl-4-carbaldehyde (21 g, 0.18 mol) was then added drop wise and the reaction stirred at -78 0C for 30 minutes, before being allowed to warm to room temperature overnight (18 h). The reaction was then quenched by the addition of 1 M hydrochloric acid (500 ml) and extracted with ethyl acetate (3 x 500 ml). The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 250 ml). The combined organics were evaporated and the crude product was purified using column chromatography (EtOAc: hexane, 3:7 to 100% EtOAc) to give 5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3- methoxy-cyclopent-2-enone (20.8 g).
With titanium(IV) tetraethanolate In tetrahydrofuran at 60℃; for 0.5h; Inert atmosphere;
20 (R) -2-methyl-N- [(E) -tetrahydro-2H-pyran-4-ylmethylene] -2-propanesulfinamide
A 100 mL round-bottom flask was charged with tetrahydro-2H-pyran-4-carbaldehyde (5000 mg, 43.81mmol), (R) -2-methylpropane-2-sulfinamide (5309.27 mg, 43.81mmol), Ti (OEt) 4 (13.5mL, 65.71mmol) and THF (25mL). The reaction was heated at 60 °C for 30min under N 2 protection to give a yellow solution. TLC (PE/EA= 3/1, Rf =0.4) showed a new spot was detected. H 2O (3 mL) was added dropwise and it was stirred at 20 °C for 5mins, then it was filtrated through a pad of celite and the filtrate concentrated in vacuum to give thc title compound (8700 mg, 40.03 1mmol, 91.383% yield) as white solid. LC-MS Method1 0.745 min, MS (m/z) 218.1 (M + H +).
91.383%
With titanium(IV) tetraethanolate In tetrahydrofuran at 60℃; for 0.5h; Inert atmosphere;
20 (R) -2-methyl-N- [(E) -tetrahydro-2H-pyran-4-ylmethylene] -2-propanesulfinamide
A 100 mL round-bottom flask was charged with tetrahydro-2H-pyran-4-carbaldehyde (5000 mg, 43.81mmol), (R) -2-methylpropane-2-sulfinamide (5309.27 mg, 43.81mmol), Ti (OEt) 4 (13.5mL, 65.71mmol) and THF (25mL). The reaction was heated at 60 °C for 30min under N 2 protection to give a yellow solution. TLC (PE/EA= 3/1, Rf =0.4) showed a new spot was detected. H 2O (3 mL) was added dropwise and it was stirred at 20 °C for 5mins, then it was filtrated through a pad of celite and the filtrate concentrated in vacuum to give thc title compound (8700 mg, 40.03 1mmol, 91.383% yield) as white solid. LC-MS Method1 0.745 min, MS (m/z) 218.1 (M + H +).
90%
With magnesium sulfate; toluene-4-sulfonic acid In 1,2-dichloro-ethane at 20℃; for 12h;
19.1; 20.1 Step 1: (R, E) -2 - methyl - N - (tetrahydro - 2H - pyran -4 - yl) methylene) propane -2 - sulfonamide
The tetrahydro - 2H - pyran -4 - formaldehyde (1.8 g, 15.8 mmol), (R)-2 - methyl propane -2 - sulfonamide (0.9 g, 7.4 mmol) and magnesium sulfate (4.7 g, 39.2 mmol) dissolved in 1, 2 - dichloroethane (180 ml) in, then adding to the methyl benzene sulfonic acid (0.2 g, 0.8 mmol). The reaction liquid stirring at room temperature 12 hours, then the dichloromethane is used for washing the filter and diatomaceous earth pad (100 ml * 3). The filtrate and the washing liquid combined, concentrated. The residue fast chromatography for separation and purification (dichloromethane/methanol=50:1), the title compound as a colorless oily matter obtained (1.6 g, 90%).
With pyridinium p-toluenesulfonate; magnesium sulfate In dichloromethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfmamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Rt = 0.58 min.
With pyridin-2-yl tosylate; magnesium sulfate In 1,1-dichloroethane at 20℃; for 18h;
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Rt = 0.58 min.
With pyridinium p-toluenesulfonate; magnesium sulfate In 1,2-dichloro-ethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2-methylpropane-2- sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.
With pyridinium p-toluenesulfonate; magnesium sulfate In 1,2-dichloro-ethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.
With pyridinium p-toluenesulfonate; magnesium sulfate In dichloromethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 ml_) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.
With pyridinium p-toluenesulfonate; magnesium sulfate In 1,2-dichloro-ethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Rt = 0.58 min.
With pyridin-2-yl tosylate; magnesium sulfate In 1,2-dichloro-ethane at 20℃; for 18h;
Synthesis of (S)-1-(tetrahvdro-2H-pyran-4-yl)ethanamineStep 1 : Preparation of (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4- yl)methylene)propane-2-sulfinamideA mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1.062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.110 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran- 4-yl)methylene)propane-2-sulfinamide (1.9 g). LCMS (m/z): 218.1 [M+H]+; Retention time = 0.58 min.
With pyridinium p-toluenesulfonate; magnesium sulfate In 1,2-dichloro-ethane at 20℃; for 18h;
1
A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.0 g, 17.52 mmol), (R)-2- methylpropane-2-sulfinamide (1 .062 g, 8.76 mmol), pyridine 4-methylbenzenesulfonate (0.1 10 g, 0.438 mmol) and magnesium sulfate (5.27 g, 43.8 mmol) in dichloroethane (13 mL) was stirred at room temperature for 18 hrs. The solids were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography [silica gel] providing (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4- yl)methylene)propane-2-sulfinamide (1 .9 g). LCMS (m/z): 218.1 [M+H]+; Rt = 0.58 min.
Stage #1: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde; methylmagnesium bromide In diethyl ether at 0 - 20℃;
Stage #2: With water; ammonium chloride In diethyl ether
10.1
Example 10.2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [l-(tetrahydro-pyran-4-yl)- ethyl] -amide Step 1To a solution of tetrahydropyran-4-carbaldehyde (5.00 g, 43.8 mmol) in Et20 (100 mL) at 0°C was added dropwise methyl magnesium bromide (3.0 M in Et20, 18.9 mL, 56.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with 50% sat NH4C1 and extracted with EtOAc. The organic extracts were washed with saturated aqueous NaCl, dried over MgS04 and evaporated to give 4.34 g of l-(tetrahydropyran-4-yl)-ethanol as a colorless oil.
Stage #1: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde; methylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 1h; Cooling with ice;
Stage #2: With ammonium chloride In tetrahydrofuran; diethyl ether; water
Intermediate 25l-(Tetrahydro-2H-pyran-4-yl)ethanol[0229] Tetrahydro-2H-pyran-4-carbaldehyde (500mg, 4.38mmol) was placed in a vial with anhydrous THF (5mL) and cooled on ice. Methylmagnesium bromide (3M in diethyl ether) (2.19mL, 6.57mmol) was slowly added (exothermic). A white precipitate formed. The reaction mixture was stirred at room temperature for 1 hour and quenched with saturated ammonium chloride (3mL) (slowly at first - exothermic) and water (3mL). The supernatant organic phase was passed through a phase separator filled with dry MgS04 (5-10g). The aqueous phase was re- extracted with diethyl ether (lOmL) and this was also passed through the MgS04 filled phase separator. The solvent was removed in vacuo to provide the title compound as a mixture of isomers. ]H NMR (400MHz, DMSO- ) δ 4.35 (1H, d), 3.87 (2H, m), 3.32 (1H, m), 3.21 (2H, m), 1.65 (1H, m), 1.42 (1H, m), 1.33 (1H, m), 1.20 (2H, m), 1.01 (3H, d).
1.4 g
In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2h; Inert atmosphere;
1.3 Step 3: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)ethanol:
Step 3: Synthesis of l-(tetrahydro-2H-pyran-4-yl)ethanol: To a stirred solution of tetrahydro-2H-pyran-4-carbaldehyde (2.4 g, 21.05 mmol) in dry THF (50 mL) at 0 °C under nitrogen atmosphere, methyl magensium bromide (3M in diethyl ether, 10.5 mL, 31.57 mmol) was added. The resulting reaction mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. Upon completion the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1.4 g, 51%).
1.4 g
In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2h; Inert atmosphere;
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 20h;
To a solution of 5-Amino-3-bromo-2-chloropyridine (3.00 g, 14.46 mmol) in DCM (90 ml) was add tetrahydro-2H-pyran-4-carbaldehyde (1.981 g, 17.35 mmol), acetic acid (0.828 ml, 14.46 mmol) and sodium triacetoxyborohydride (4.60 g, 21.69 mmol). The resulting slightly cloudy reddish solution was stirred at room temperature for about 2 hours. Additional sodium triacetoxyborohydride (-1.3 g) was added and the reaction was stirred for about 18 hours. The reddish mixture was then concentrated, redissolved in EtOAc, and washed with water, NaHCC , and brine. The organic extracts were combined, dried over Na2S04, filtered through silica plug, and the filtrate was concentrated in vacuo to give a yellow solid (4.3 g, 14.07 mmol, 97 % yield). LC/MS: 306.9 (MH+), retention time = 0.85 min
[01753] Step 1 : Synthesis of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl) methyl) amino) benzoate[01754] To a stirred solution of methyl 3-amino-5-chloro-2-methyl benzoate (2.0 g, 10 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (1 .71 g, 15 mmol) in methanol (20 mL), acetic acid ( 1 .2 g, 20 mmol) was added and the reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.1 1 g, 25.1 mmol) was added at 0C and the reaction stirred overnight at room temperature. On completion, the solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound ( 1 .8 g, 60%).
Stage #1: 3-bromo-1-ethanesulfanylbenzene With n-butyllithium In cyclohexane at -78℃; for 0.166667h; Inert atmosphere;
Stage #2: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde In cyclohexane at -78 - 20℃; for 1h;
aw.1
Step 1: (3-(ethylthio)Phenyl)rtetrahvdro-2H-Dyran-4-yl>rnethartolTo a solution of 1 -Bromo-3'(ethylthio)benzene (720.9 mg, 3.32 mmol) in dry THF (5mL) under N2 at -78°C was added 1.9M n-BuLi in cyclohexane (2 mL, 3.80 mmol) drop-wise. The reaction was stirred at this temperature for 10 mins before addition of 4- formyltetrahydropyran (350 μ, 3.36 mmol) drop-wise. The cooling bath was removed and the reaction allowed to achieve ambient temperature over 1 hour. TLC (1 :9 EtOAc/hexanes) showed the reaction complete. The reaction was quenched with sat.NH4CI and extracted with EtjO. The extracts were combined, dried over MgS04l filtered and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 15-30% EtOAc hexanes to afford (3- (ethylthio)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (719.1 mg. 2.85 mmol, 86%)
2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
2-(Tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole A mixture of sodium acetate trihydrate (27.2 g, 200 mmol) and 3,3-dibromo-1,1,1-trifluoroacetone (26.98 g, 100 mmol) in water (75 ml) was heated under reflux for 1 h. The mixture was then cooled to rt and was slowly added to a solution of tetrahydro-2H-pyran-4-carbaldehyde (90 mmol, 10.27 g) and concentrated ammonium hydroxide solution (50 mL) in MeOH (150 mL). The mixture was stirred at rt for 18 hand was then evaporated under reduced pressure. The aqueous residue was extracted with EtOAc (150 mL*3) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give the crude as an oil. The oil was then triturated in water with a trace of MeOH to afford the title compound as crystalline solids (19.8 g, 90%). LCMS: m/z=221 [M+H]+.
2-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
A mixture of sodium acetate trihydrate (27.2 g, 200 mmol) and 3,3-dibromo-1,1,1-trifluoropropan-2-one (26.98 g, 100 mmol) in water (75 ml) was heated under reflux for 1 h. The mixture was then cooled to r.t. and was slowly added to a solution of tetrahydro-2H-pyran-4-carbaldehyde (90 mmol, 10.27 g) and concentrated ammonium hydroxide solution (50 mL) in MeOH (150 mL). The mixture was stirred at r.t. for 18 h and was then evaporated under reduced pressure. The aqueous residue was extracted with EtOAc (150 mL x 3) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give an oil. The oil was then triturated in water with a trace of MeOH to afford the titled compound as a crystalline solid (19.8 g, yield 90%). LC-MS (m/z) = 221 [M + H]+.
80%
[0170] Water (730 g) was loaded into the main reactor Rl under nitrogen followed by sodium acetate (159 g, 1.94 mol) and l,l-dibromo-3,3,3-trifluoroacetone (260 g, 0.96 mol) was added dropwise while keeping the reaction temperature between 20- 30C. The reaction mixture was then warmed to 80-85C and stirred at this temperature for 1-2 hrs after which it was cooled to 20-25C. Compound 6 (100 g, 0.88 mol) was loaded into the secondary reactor R2 followed by MeOH (1150 g) and a 25% aqueous solution of ammonia (614 g, 4.38 mol) was added slowly while keeping the temperature in the range 15-30C. The mixture in Rl was then added dropwise to R2 over 2 hrs at 15-30C. The reaction was then stirred at 25-30C for 18-24 hrs. The reaction was then evaporated in vacuo at a temperature below 45C to around 500-800 g after which it was cooled to 25-30C and MTBE (100 g) was charged with stirring followed by heptanes (180 g); the reaction mixture was stirred at 20-30C for 2-3 hrs after which it was filtered. The filter was washed with water (320 g) and heptanes (120 g). At this point an HPLC analysis was performed to verify that the purity of 7 was greater than 96%. The filter cake was dried in vacuo at 40-45C for 8-24 hrs. At this point a Karl-Fischer titration showed that the water content was less than 0.5%. Compound 7 was generally isolated in 50-80%. Purity was greater than 96%.
With potassium carbonate In methanol; diethyl ether at 0 - 20℃; for 3h; Inert atmosphere;
3-Ethynyl-1,1-difluorocyclobutane (22)
General procedure: To a solution of 3,3-difluorocyclobutanecarbaldehyde (1.86 g, 15.5 mmol, 28.4 wt% in diethyl ether) and Ohira Bestmann Reagent (3.02 mL, 20.1 mmol) in methanol (21 mL) at 0 °C was added potassium carbonate (8.56 g, 61.9 mmol). After 2 h at 0 °C, the ice bath was removed and stirring continued for 1 h. The reaction was poured into water (~60 mL) and diluted with ~150 mL pentane. The layers were separated. The organics were washed with water 2X, dried over magnesium sulfate, and filtered. The resulting colorless solution was concentrated by distillation using a short path distillation head, fitted with a 12 cm vigreux column. The bulk of the material distilled at 36 °C. Toward the end of the distillation, the temperature began to drop, and heating was discontinued. 2.025 g remained in the boiling flask (title compound + pentane). 1H-NMR shows purity to be 43.5 wt% (881 mg, 49% yield).
400 mg
With potassium carbonate In methanol at 20℃; for 8h;
50.50.2 50.2 4-Ethynyltetrahydro-2H-pyran
50.2 4-Ethynyltetrahydro-2H-pyran A 50 mL single-necked flask was charged with tetrahydro-2H-pyran-4-carbaldehyde (433 mg), potassium carbonate (1050 mg) and methanol (10.8 mL). The reaction system was stirred at room temperature. Ohira-Bestmann reagent (948 mg) was added to the reaction solution. The reaction solution was stirred at room temperature for 8 h. A sample was taken, and TLC detection showed that the raw materials disappeared and the reaction was complete. The reaction solution was filtered through celite, and the filtrate was dried by rotary evaporation under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (eluent: PE : EA = 10 : 0 to 10 : 1) to obtain 400 mg of 4-ethynyltetrahydro-2H-pyran.
6'-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)spiro[cyclopropane-1,3'-indolin]-2'-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
Stage #1: 6'-bromospiro[cyclopropane-1,3'-indoline]-2'-one With potassium hydride In tetrahydrofuran at -30℃; for 0.333333h;
Stage #2: With tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 0.5h;
Stage #3: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde In tetrahydrofuran; pentane at -78 - 20℃; for 16h;
52.52a 6'-(Hvdroxy(tetrahvdro-2H-pyran-4-yl)methyl)spiro[cyclopropane-1 ,3'-indolinl-2'-one
6'-Bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (1.1 g, 4.67 mmol) in dry THF (40 mL) was added drop wise at -30°C to a suspension of KH (30% in mineral oil, 0.61 g, 4.58 mmol) in dry THF (15 mL). The reaction mixture was stirred at this temperature for 20 min and then cooled to -78°C. tert-Butyllithium (2 M in pentane, 5.8 mL, 10.50 mmol) was added and stirring was continued at - 78°C for 30 min. A solution of pyran-4-aldehyde (1.6 g, 14.01 mmol) in dry THF (10 mL) was added via a dropping funnel and the reaction mixture was slowly warmed to RT over 16 h. After quenching with saturated NH4CI solution at 0°C, the mixture was extracted first with EtOAc (3 x 100 mL) and then with DCM/MeOH (98:2, 30 mL). The combined organic layers were dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; DCM with 5% MeOH]. Brown solid. Yield: 0.43 g (33%). HPLC (method 1 ): Rt = 2.25 min, m/z [M+H]+ = 274.3 (MW calc. 273.33)
N-(3,4-dimethylphenyl)-4-(tetrahydro-2H-pyran-4-yl)-2,3,3a,4,5,9b-hexahydrofuran[3,2-c]quinolone-8-sulfonamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: 3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde; 4-amino-N-(3,4-dimethylphenyl)benzenesulfonamide With scandium tris(trifluoromethanesulfonate) In acetonitrile at 20℃; for 1h; Molecular sieve; Inert atmosphere;
Stage #2: 2,3-dihydro-2H-furan In acetonitrile at 20℃; Inert atmosphere;
Preparation of N -(3,4-dimethylphenyl)-4-(tetrahydro-2H-pyran-4-yl)- 2,3,3a,4,5,9b-hexahydrofuran[3,2-c]quinolone-8-sulfonamine (69L58).
Compound 4-ammo-N-(3,4-dimethylphenyl)benzenesulfonarnide (2) (0.55 g, 1.99 mmol), tertahydro-2//-pyran-4-carbaldehyde (0.23 g, 1.99 mmol), Sc(OTf)3 (0.20 g, 0.40 mmol) and 4A molecular sieves (1 g) were mixed together and dissolved in anhydrous CH3CN (10 mL) at room temperature under argon. The reaction mixture was stirred for one hour at room temperature. 2,3-Dihydrofuran (0.28 g, 4.00 mmol) was then added via a syringe. The resulted mixture was stirred at room temperature under argon overnight. The reaction was quenched by adding 50 mL of water at room temperature and neutralized by adding NaHCO3. The solution was extracted with ethyl acetate (3x50 mL). The extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to dryness. The solid residue was purified by column chromatography (silica gel, CHzCb/Acetone = 17/3 v/v) to give a white solid product (0.76 g, 86.4% yield). (98% trans-isomer) : 1H NMR (400 MHz,, DMSO-d6) d 9.65 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.24 (dd, J1 - 8.4 Hz, J2 - 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.77 (dd, J; = 8.4 Hz, J2 = 2.0 Hz, 1Hj, 6.69 (d, J = 8.4 Hz, 1H), 6.08 (s, 1H), 4.94 (d, J = 7 6 Hz, 1H), 3.91-3 88 (m, 2H), 3.70-3.67 (m, 1H), 3.48-3.45 (m, 1H), 3.30-3.17 (m, 2H), 2.09 (s, 6H), 2.00-1.84 (m, 1H), 1.83-1.80 (m, 1H), 1.65-1.54 (m, 3H), 1.29-1.18 (m, 2H). HRMS (ESI) calcd for C24H31N2O4S: 443.2005 [M + H]+, found 443.2204.
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