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With dipyridinium dichromate In dichloromethane at 0 - 20℃; for 48 h;
A solution of pyridinium dichromate (55.4 g, 147 mmol) in DCM (100 mL) was brought to 0° C. and a solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.8 g, 49.1 mmol) in DCM (30 mL) was added. The reaction was allowed to warmed to room temperature and stirred for 48 h. The mixture was filtered through Celite, washed with DCM and concentrated to afford 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (11 g, 51 mmol, 100percent yield) as a light yellow solid. LC/MS (ESI+) m/z=218 (M+H
70.2%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane; acetonitrile at 20℃;
l -(5 jrorao~2~flero-3-pyrtdyl)tHiiaoe: To a solution of the above compound (3.15 g, 14.32 mmol, L0 eq.) in DCM (95.5 m'L) and MeCN (9.5 mL) was added 4-meihyiroor}?hohne N-oxide (6.71 g, 57.26 mmol, 4.0 eq.) followed by tetrapropylammonium perrumenate (251.54 mg, 0.72 mmol, 0.5 eq.). The reaction mixture was stirred at rt until completion by TLC. The mixture was filtered through a pad of Celtic which, was washed with DCM. Solvents were removed under reduced pressure. The crude residue was purified using flash chromatography (0-30percent EtOAc/hexanes) to provide the title compound (2) as a white crystalline solid (2.19 g, 70.2percent yield). TLC (25percent EiQAe/hexanes): f - 0.58; H NMR (400 MHz, CDCIj) 3 8.46-8.43 (m, 2H), 2.70 (d, J - 4.7 Hz, 3H).
63%
With dipyridinium dichromate In dichloromethane at 0 - 20℃;
Step 3:76 77To a mixture of PDC (365 g, 0.97 mol) and CH2CI2 (2000 mL) was added compound 76 (85 g, 0.39 mol) at O0C. After the addition, the reaction mixture was warmed up to room temperature and stirred overnight. TLC (petroleum ether/EtOAc 10:1) indicated the reaction was complete. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give crude compound 77, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 50:1 ) to yield pure compound 77 (56 g, 63percent) as a yellow solid.
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - -65℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere
Preparative Example 7 Step 1: l-(5-bromo-2-fluoropyridin-3-yl)ethanone To a solution of diisopropylamine (46.3 g, 458.4 mmol) in tetrahydrofuran (lOOOmL) was added butyllithium (176 mL, 440 mmol, 2.5 M) at -78 °C under nitrogen. After addition, the reaction mixture was stirred for 30 min at -78 °C. 5-bromo-2-fluoropyridine (86.7 g, 442.3 mmol) was added (keeping the temperature under -65 °C). After addition, the mixture was stirred for 1 h. N-methoxy- N-methylacetamide (50 g, 485.4 mmol) was added and stirred at -78 °C for 1 h. The reaction mixture was quenched with water (lOOOmL), extracted with ethyl acetate (3 x 500 mL), washed with brine, dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0.5percent ethyl acetate in petroleum ether) affording 1- (5-bromo-2-fluoropyridin-3-yl)ethanone (43 g, 44.6 percent): H NMR (400 MHz, Chloroform-d): δ 8.46- 8.42 (m, 2H), 2.70 (s, 3H).
With dipyridinium dichromate; In dichloromethane; at 0 - 20℃; for 48h;
A solution of pyridinium dichromate (55.4 g, 147 mmol) in DCM (100 mL) was brought to 0 C. and a solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.8 g, 49.1 mmol) in DCM (30 mL) was added. The reaction was allowed to warmed to room temperature and stirred for 48 h. The mixture was filtered through Celite, washed with DCM and concentrated to afford 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (11 g, 51 mmol, 100% yield) as a light yellow solid. LC/MS (ESI+) m/z=218 (M+H
70.2%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 20℃; under 760.051 Torr;
l -(5 jrorao~2~flero-3-pyrtdyl)tHiiaoe: To a solution of the above compound (3.15 g, 14.32 mmol, L0 eq.) in DCM (95.5 m'L) and MeCN (9.5 mL) was added 4-meihyiroor}?hohne N-oxide (6.71 g, 57.26 mmol, 4.0 eq.) followed by tetrapropylammonium perrumenate (251.54 mg, 0.72 mmol, 0.5 eq.). The reaction mixture was stirred at rt until completion by TLC. The mixture was filtered through a pad of Celtic which, was washed with DCM. Solvents were removed under reduced pressure. The crude residue was purified using flash chromatography (0-30% EtOAc/hexanes) to provide the title compound (2) as a white crystalline solid (2.19 g, 70.2% yield). TLC (25% EiQAe/hexanes): f - 0.58; H NMR (400 MHz, CDCIj) 3 8.46-8.43 (m, 2H), 2.70 (d, J - 4.7 Hz, 3H).
63%
With dipyridinium dichromate; In dichloromethane; at 0 - 20℃;
Step 3:76 77To a mixture of PDC (365 g, 0.97 mol) and CH2CI2 (2000 mL) was added compound 76 (85 g, 0.39 mol) at O0C. After the addition, the reaction mixture was warmed up to room temperature and stirred overnight. TLC (petroleum ether/EtOAc 10:1) indicated the reaction was complete. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give crude compound 77, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 50:1 ) to yield pure compound 77 (56 g, 63%) as a yellow solid.
With dipyridinium dichromate;
Step 3. 1-(5-bromo-2-fluoropyridin-3-yl)ethanone To a solution of pyridinium dichromate (98 g, 262 mmol) in DCM (200 mL) at 0 C. was added a solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (19.19 g, 87 mmol) in DCM (100 mL). After addition, the mixture was then stirred at RT 72 hr. Pyridinium dichromate (15 g) was added and the mixture was stirred at RT for an additional 12 h. Then, the mixture was filtered through celite and the solid was washed with DCM (3*200 mL). The combined filtrates were concentrated and the residue was dissolved in DCM (10 mL). The mixture was then purified by silica gel chromatography, eluent 0%-100% EtOAc/hexane, to give 11.0 g of the title compound as a white solid. MS (ESI, positive ion) m/z: 218, 219.9 (M+H)
With dipyridinium dichromate; In dichloromethane;
Step 2: 1-(5-Bromo-2-fluoropyridin-3-yl)ethanone To a solution of pyridinium dichromate (55.4 g, 147 mmol) in dichloromethane (100 mL) at 0 C. was added of 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.80 g, 49.1 mmol) in dichloromethane (30 mL). The reaction was allowed to warm up to RT and stirred for two days. The mixture was filtered through Celite, washed with DCM, and concentrated to afford the title intermediate (11 g) as a light yellow solid.
5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.7%
With hydrazine hydrate; In ethanol;Reflux;
Step 2: 5-bromo-3-methyl-lH-pyrazolo[3,4-b]pyridine To a solution of l-(5-bromo-2-fluoropyridin-3-yl)ethanone (43 g, 197.2 mmol) in ethanol (500 niL) was added hydrazine monohydrate (34.8 g, 591.6 mmol, 85 %) at RT. After addition, the reaction mixture was refluxed overnight. The reaction mixture was cooled to RT and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 5% to 17% ethyl acetate in petroleum ether) affording 5-bromo-3-methyl-lH-pyrazolo[3,4-b]pyridine (35g, 83.7%): NMR (400 MHz, DMSO-d6): delta 13.42 (s, 1H), 8.51 (m, 2H), 2.54 (s, 3H).
76%
With hydrazine; In ethanol; at 20℃;Heating / reflux;Product distribution / selectivity;
Step 4:77 78To a solution of compound 77 (40 g, 0.184 mol) in ethanol (300 mL) was added NH2NH2 (27.6 g, 0.553 mol) at room temperature. After the addition, the reaction mixture was refluxed overnight. TLC (petroleum ether/EtOAc 3:1 ) indicated the complete consumption of compound 77. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo to give crude product, which was purified by column chromatography (silica gel, petroleum ether/EtOAc from 10:1 to 3:1 ) to yield 78 (30 g, 76%) as a white solid.
Step 3: (R)-5-Amino-3-(5-bromo-2-fluoropyridin-3-yl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide In an analogous sequence of reactions to those described for Example 7, steps 1-4, <strong>[1111637-74-1]1-(5-bromo-2-fluoropyridin-3-yl)ethanone</strong> (11 g, 50 5 mmol) was converted to the title compound in 20% yield. LC/MS (ESI+) m/z=364, 366 (M+H; 2 bromine isotopes).
(R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Step 4. (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide To a solution of <strong>[1111637-74-1]1-(5-bromo-2-fluoropyridin-3-yl)ethanone</strong> (10.93 g, 50.1 mmol) in THF (100 ml) was added (R)-(+)-2-methyl-2-propanesulfinamide (12.15 g, 100 mmol) and titanium (IV)-ethoxide (20.75 mL, 100 mmol). The resulting mixture was then heated at reflux for 1 h. The mixture was cooled to RT and brine (300 mL) was added. The mixture was stirred at RT for 15 min, then filtered and the solid was washed with DCM (2*100 mL). The organic layer was collected and the aqueous layer was dried over MgSO4 and concentrated. The residue was then dissolved in DCM (10 mL) and purified by silica gel chromatography, eluent 0%-100% EtOAc/hexane, to give 14.9 g of the title compound as a yellow solid. MS (ESI, positive ion) m/z: 321, 323 (M+H).
(R,Z)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In tetrahydrofuran; ethyl acetate;
Step 1: (R,Z)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (5b) A mixture of <strong>[1111637-74-1]1-(5-bromo-2-fluoropyridin-3-yl)ethanone</strong> (5a, synthesized according to procedures described in WO2009016460; 11 g, 50.5 mmol), (R)-2-methylpropane-2-sulfinamide (Ak Scientific, 12.23 g, 101 mmol) and titanium (IV) ethoxide (Aldrich, 26.1 ml, 126 mmol) in THF (100 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, and brine (200 mL) was added. The suspension was vigorously stirred for 10 min. The suspension was filtered through a pad of silica gel and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient 0-20% EtOAc/hexanes) to afford the title compound as a bright yellow oil (16 g, 49.8 mmol, 99% yield). MS m/z=320.8 [M+H]+; Calculated for C11H14BrFN2OS: 320.0
With titanium(IV) tetraethanolate; In tetrahydrofuran; for 2h;Reflux;
A mixture of <strong>[1111637-74-1]1-(5-bromo-2-fluoropyridin-3-yl)ethanone</strong> (11 g, 51 mmol), (R)-2-methylpropane-2-sulfinamide (12.2 g, 101 mmol) and titanium (IV) ethoxide (26.1 mL, 126 mmol) in THF (100 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, brine was added and the mixture was stirred for 10 min. The suspension was filtered through silica gel. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0-20% EtOAc/hexanes) gave (R,Z)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (16 g, 50 mmol, 99% yield) as a bright yellow oil. LC/MS (ESI) m/z=321 (M+H).
99%
With titanium(IV) tetraethanolate; In tetrahydrofuran; for 2h;Reflux;
A mixture of 1 -(5-bromo-2-fluoropyridin-3- yl)ethanone (prepared according to procedures described in WO2009016460; 11.0 g, 50.5 mmol), (R)-2-methylpropane-2-sulfinamide (AK Scientific, 12.2 g, 101.0 mmol) and titanium(IV) ethoxide (Aldrich, 26.1 mL, 126.0 mmol) in THF (100 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, and brine (200 mL) was added. The suspension was vigorously stirred for 10 min. The suspension was filtered through a pad of silica gel and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient 0-20% EtOAc/hexanes) to afford (R,Z)-N-(1 -(5-bromo-2- fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (214A) as a bright yellow oil (16 g, 49.8 mmol, 99% yield). MS m/z= 320.8 [M+H]+.
99%
With titanium(IV) tetraethanolate; In tetrahydrofuran; for 2h;Reflux;
Preparation of (ii^-iV-il-iS-bromo-Z-fluoropyridin-S-y ethylideneJ-Z-methylpropane- 2-sulfinamide (25A). A mixture of l-(5-bromo-2-fluoropyridin-3-yl)ethanone (prepared according to procedures described in WO2009016460; 11.0 g, 50.5 mmol), (i?)-2-methylpropane-2- sulfinamide (AK Scientific, 12.2 g, 101 mmol) and titanium(IV) ethoxide (Aldrich, 26.1 mL, 126.0 mmol) in THF (100 mL) was heated at reflux for 2 hours. The mixture was cooled to room temperature, and brine (200 mL) was added. The suspension was vigorously stirred for 10 minutes. The suspension was then filtered through a pad of silica gel and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient 0-20% EtOAc/hexanes) to afford (i?,Z)-N-(l-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (25A) as a bright yellow oil ( 16 g, 99% yield). MS m/z = 320.8 (M+H).
With trimethylsilyl trifluoromethanesulfonate; triethylamine; In toluene; acetonitrile;
Step 1: 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (12a) A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (200 mg, 0.92 mmol) and triethylamine (140 mul, 1.01 mmol) in toluene (2 mL) was treated with trimethylsilyl trifluoromethanesulfonate (182 mul, 1.01 mmol) under nitrogen atmosphere. The reaction mixture was heated to 80 C. for 2 h, the upper toluene phase was isolated (e.g. by decanting) and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in acetonitrile (2 mL) and added to a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-(2.2.2)octane bis(tetrafluoroborate) (325 mg, 0.92 mmol) in acetonitrile (2 mL) at room temperature. After 1 h, the solvent was removed under reduced pressure. The residue was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure to obtain 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.72 mmol, 79% yield, 90% purity) as a light yellow solid. This material was used in the next step without purification. MS m/z=237.9 [M+H]+. Calculated for C7H4BrF2NO: 236.01.
With titanium(IV) tetraethanolate; In tetrahydrofuran; for 12h;Reflux; Inert atmosphere;
Step 2 A mixture of F-3 (13.0 g, 59.6 mmol), (R)-(+)-2-methyl-2-propanesulfi namide (14.5 g, 1 19 mmol), titanium (IV) ethoxide (31.0 g, 136 mmol), and 100 mL THF was heated at reflux under nitrogen for 12 h. The mixture was cooled and poured into ice water (300 mL) and EtOAc (300 mL) and stirred for 1 h. The mixture was filtered through Celite and the layers were separated. The organic layer was washed with brine, dried (Na2S04), filtered and concentrated to provide F-4 which was used without further purification. MS for F-4: m/e = 321 and 323 (M+l).
Preparative Example 7 Step 1: l-(5-bromo-2-fluoropyridin-3-yl)ethanone To a solution of diisopropylamine (46.3 g, 458.4 mmol) in tetrahydrofuran (lOOOmL) was added butyllithium (176 mL, 440 mmol, 2.5 M) at -78 C under nitrogen. After addition, the reaction mixture was stirred for 30 min at -78 C. 5-bromo-2-fluoropyridine (86.7 g, 442.3 mmol) was added (keeping the temperature under -65 C). After addition, the mixture was stirred for 1 h. N-methoxy- N-methylacetamide (50 g, 485.4 mmol) was added and stirred at -78 C for 1 h. The reaction mixture was quenched with water (lOOOmL), extracted with ethyl acetate (3 x 500 mL), washed with brine, dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0.5% ethyl acetate in petroleum ether) affording 1- (5-bromo-2-fluoropyridin-3-yl)ethanone (43 g, 44.6 %): H NMR (400 MHz, Chloroform-d): delta 8.46- 8.42 (m, 2H), 2.70 (s, 3H).
Step 1 To a solution of diisopropylamine (16.2 mL, 114 mmol) in 25 mL THF at -78 C was added dropwise n-butyllithium (2.5 M in hexanes, 45.5 mL) and the mixture stirred 1 h at -78 C following complete addition. The resulting solution was added dropwise over 50 min. to a stirred solution of F-1 in 75 mL THF at -78 C and the mixture stirred 1 h at -78 C. A solution of F-2 in 20 mL THF was then added and the mixture was allowed to warm slowly to rt, stirring 12 h. The reaction mixture was quenched with 1.0 N HCl and diluted with EtOAc. The organic layer was separated and washed sequentially with water and brine, dried (Na2S04), filtered and concentrated. The resulting residue was purified by flash chiOmatography (220 g Si02; 0 to 20 % EtOAc in hexanes) to provide F-3. MS for F-3: m/e = 218 and 220 (M+l).
With titanium(IV) tetraethanolate; In tetrahydrofuran;Reflux;
General procedure: The requisite methyl ketone (1equiv), (R)-2-methylpropane-2-sulfinamide (1.5equiv), and Ti(OEt)4 (technical grade, 20% Ti, ?2equiv) in THF (1M), were stirred at reflux for 24-48h. The reaction mixture was cooled to RT and then added to an equal volume of ice water. EtOAc was added and the mixture was stirred vigorously for 15 min after which it was filtered through a pad of Celite. The filter cake was washed with EtOAc. The filtrate was then washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography or triturated with ether to provide the (R)-tert-butanesulfinyl ketimine.
5-bromo-1,3-dimethylpyrazolo[3,4-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.4%
In butan-1-ol; at 150℃; under 760.051 Torr; for 0.75h;Microwave irradiation;
A solutioa of the above compouad (160.0 mg, 0.73 mmol, .0 eq.) and meftjyihydrazme ( 193.2 uL, 3.67 mmol, 3,0 eq.) in l-butaaol (2,5 niL) was heated to 1.50 C in a microwave reactor for 45 mm. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified using flash chromatography (0-40% EtOAc/hexanes) to provide the title compound (3) as a pale yellow solid (150 nig, 90,4% yield). ES-M.S M?l f : 228.2.
(S)-methyl 4-(5-bromo-2-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate[ No CAS ]
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