* 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.
The aldehyde (3.5g) and conc. HCI (20MUT) were combined and stirred overnight at 40°C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NAHCO3 AND brine, dried over anhydrous MGS04, filtered and concentrated in vacuo to give 1.76g of product (55percent)
55%
at 40℃;
The aldehyde (3.5 g) and cone. HC1 (20 ml) were combined and stirred overnight at 40 C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1.76 g of product (55percent)
55%
for 40 h;
The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirred overnight at 40 C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1.76 g of product (55percent)
55%
With hydrogenchloride In water at 40℃;
PREPARATIVE EXAMPLE 34.1; The aldehyde (3.5g) and conc. HCI (20ml) were combined and stirred overnight at 40°C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 1.76g of product (55percent)
55%
With hydrogenchloride In water at 40℃;
The aldehyde (3.5g) and conc. HCl(20ml) were combined and stirred overnight at 40°C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 1.76g of product (55percent)
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 1, p. 129 - 133
[2] Patent: WO2004/33440, 2004, A1, . Location in patent: Page 238
[3] Patent: US2004/147559, 2004, A1, . Location in patent: Page 121
[4] Patent: US2004/106794, 2004, A1, . Location in patent: Page 122
[5] Patent: WO2005/66147, 2005, A1, . Location in patent: Page/Page column 207
[6] Patent: WO2005/68460, 2005, A1, . Location in patent: Page/Page column 202
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3471 - 3488
2
[ 1137088-24-4 ]
[ 21508-19-0 ]
Reference：
[1] Australian Journal of Chemistry, 2010, vol. 63, # 12, p. 1619 - 1626
3
[ 98-01-1 ]
[ 21508-19-0 ]
Reference：
[1] Journal of Organic Chemistry, 1945, vol. 10, p. 541
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3471 - 3488
4
[ 98-01-1 ]
[ 21508-19-0 ]
[ 2689-65-8 ]
Reference：
[1] Synthesis, 1995, # 3, p. 248 - 250
[2] Synthesis, 1995, # 3, p. 248 - 250
5
[ 24078-79-3 ]
[ 21508-19-0 ]
Reference：
[1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1366,1369[2] Chem.Abstr., 1960, p. 24633
6
[ 613-75-2 ]
[ 21508-19-0 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1931, vol. 50, p. 833,835
7
[ 618-30-4 ]
[ 21508-19-0 ]
Reference：
[1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1366,1369[2] Chem.Abstr., 1960, p. 24633
8
[ 75-15-0 ]
[ 7791-25-5 ]
[ 613-75-2 ]
[ 21508-19-0 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1931, vol. 50, p. 833,835
9
[ 21508-19-0 ]
[ 618-30-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydroxide; ammonia; water; silver nitrate In methanol at 20℃; for 0.5 h;
Example 7: Synthesis of N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo [3.3.0] octane trifluoroacetate Example 7 relates to the synthesis of 5-chlorofuran-2- yl(hexahydropyrrolo[3,4-c]pyrrol-2-yl)methanone trifluoroacetate (or N-(5- chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane trofluoroacetate), which was prepared according to the following techniques, illustrative of the coupling reaction used to make heteroaromatic amides of 3,7-diazabicyclo[3.3.0]octane: S-Chlorofuran-l-carboxylic acid; Aqueous sodium hydroxide (80 mL of 10percent) was added to a solution of silver nitrate (8.0 g, 47 mmol) in water (20 mL). This suspension was stirred and slowly treated with 30percent aqueous ammonium hydroxide until it became clear. A solution of S-chlorofuran^-carboxaldehyde (3.0 g, 23 mmol) (Aldrich Chemical) in methanol (5 mL) was added, and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was filtered, and the filtrate was washed with ether (100 mL). The aqueous filtrate was then made acidic (~pH 3) by the addition of cold 20percent sulfuric acid. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried (anhydrous sodium sulfate) and concentrated under vacuum to give 3.2 g (95percent yield) of white solid (mp 178- 1790C). This reaction was easily scalable and was run multiple times at >10 g scale.
In tetrahydrofuran; diethyl ether; at 0℃; for 0.416667h;
Step 1: l-(5-Chloro-2-furyl)ethanol To a RBF was added <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (0.74 g, 5.7 mmol) and THF (35 mL). The resulting reaction mixture was cooled to 0C and methylmagnesium bromide (3.0 M solution in ether; 3.5 mL, 10.50 mmol) was added dropwise. The mixture was then stirred at 0C for 25 min and the reaction was quenched by addition of a saturated solution of H4CI. The mixture was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over MgSC>4, and concentrated to give l-(5- chloro-2-furyl)ethanol (0.82 g, 99%). H NMR (CDC13) delta 6.13 (dd, J= 3.3, 0.7 Hz, 1H), 6.01 (d, J= 3.3 Hz, 1H), 4.71 (q, J= 6.4 Hz, 1H), 2.56 (s, 1H), 1.42 (d, J= 6.6 Hz, 3H).
The aldehyde (3.5g) and conc. HCI (20MUT) were combined and stirred overnight at 40C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NAHCO3 AND brine, dried over anhydrous MGS04, filtered and concentrated in vacuo to give 1.76g of product (55%)
55%
With hydrogenchloride; at 40℃;
The aldehyde (3.5 g) and cone. HC1 (20 ml) were combined and stirred overnight at 40 C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1.76 g of product (55%)
55%
With hydrogenchloride; for 40h;
The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirred overnight at 40 C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1.76 g of product (55%)
55%
With hydrogenchloride; In water; at 40℃;
PREPARATIVE EXAMPLE 34.1; The aldehyde (3.5g) and conc. HCI (20ml) were combined and stirred overnight at 40C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 1.76g of product (55%)
55%
With hydrogenchloride; In water; at 40℃;
The aldehyde (3.5g) and conc. HCl(20ml) were combined and stirred overnight at 40C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCO3 and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 1.76g of product (55%)
2-(5-chloro-furan-2-yl)-2-trimethylsiloxyethanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With zinc diiodide;
EXAMPLE 4 2-(5-Chloro-2-furyl)-2-trimethylsiloxyethanenitrile <strong>[21508-19-0]5-Chloro-2-furaldehyde</strong> (2.7 g., 21 mmoles) was dissolved in 30 ml. of ether. Trimethylsilylcarbonitrile (6.3 ml., 50 mmoles) and zinc iodide (about 50 mg.) were added and the mixture stirred for 1.5 hours at room temperature, at which time tlc (hexane:ethyl acetate 8:1) indicated complete reaction. Concentration to dryness afforded 2-(5-chloro-2-furyl)-2-trimethylsiloxyethanenitrile as an oil (5.5 g.; pnmr/CDCl3 /delta: 0.3 (s, 9H); 5.4 (s, 1H); 6.1 (d, 1H); 6.5 (d, 1H).
PREPARATION 4 5-Chloro-2-furaldehyde 2-(5-Chloro-2-furyl)-1,3-dioxolane (4.8 g.) was dissolved in 20 ml. of ether. 6 N Hydrochloric acid (10 ml.) was added and the two-phase mixture stirred for 1 hour at room temperature. The ether phase was separated, washed with water and evaporated to yield 5-chloro-2-furaldehyde as an oil (2.8 g.).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃;
Example 10: Synthesis of N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo [3.3.1] nonane trifluoroacetateExample 10 relates to the synthesis of (3,7-diazabicyclo[3.3.1]non-3-yl)-5- chlorofuran-2-ylmethanone trifluoroacetate (or N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo[3.3.1]nonane trifluoroacetate), which was prepared by a process similar to that described in Example 9, according to the following techniques:; 5-Chlorofuran-2-carboxylic acid (0.96 g, 6.5 mmol) was combined with triethylamine (21 mmol, 2.9 mL) in dry dichloromethane (10 niL), and HBTU (2.47 g, 65.1 mmol) was added. A solution of 3,7-diazabicyclo[3.3.1]-3-carboxylic acid tert-butyl ester (1.5 g, 66 mmol) in dichloromethane (5 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was treated with 10% aqueous sodium hydroxide and extracted with chloroform (2 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with an ethyl acetate in hexane gradient, to give the tert- butoxycarbonyl-protected product, as a viscous oil. This material was dissolved in a mixture of trifluoroacetic acid (20 mL) and dichloromethane (20 mL), and the mixture was stirred at ambient temperature for Ih. The volatiles were removed by rotary evaporation, followed by high vacuum treatment, to give 1.38 g (57.5% yield) of viscous yellow oil (1H NMR (dVmethanol, 300 MHz) 2.00 (bs, 2H), 2.15 (bs, 2H), 3.15-3.35 (m, 6H), 4.25 (m, 2H), 6.53 (d, IH) and 7.10 (d, IH). MS m/z 255 (M+H)).
Manufacturing Example 62-1-1 4-((5-Chloro-furan-2-yl)-hydroxy-methyl)-benzonitrile ; To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at -78 C., which was stirred for 1 hour at 0 C. The reaction mixture was cooled to -78 C., <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0 C. Following 30 minutes of stirring at 0 C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
Manufacturing Example 16-1: 4-((5-Chloro-furan-2-yl)-hydroxy-methyl)-benzonitrile To a solution of THF (40 mL) and 4-iodobenzonitrile (2.0 g) was added isopropylmagnesium chloride (2M, 6.1 mL) dropwise at -78C under a nitrogen atmosphere, which was stirred for 1 hour and 10 minutes at 0C. After cooling to 78C, <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (1.4 g) was added dropwise thereto, which was stirred for 15 minutes at room temperature. A saturated aqueous ammonium chloride solution was added at room temperature, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate = 1:1) to obtain the titled compound(2.4 g). 1H-NMR spectrum (DMSO-d6) delta (ppm): 5.78 (1 H, d, J = 4.9 Hz), 6.28 (1 H, d, J = 3.3 Hz), 6.37 (1 H, d, J = 4.9 Hz), 6.39 (1 H, d, J = 3.3 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz).
To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 mL) was added dropwise isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 mL, 11-22 mmol) at -78 C., which was stirred for 1 hour at 0 C. The reaction mixture was cooled to -78 C., <strong>[21508-19-0]5-chloro-2-furaldehyde</strong> (2.2 g, 17 mmol) was added at that temperature, and the temperature was gradually raised to 0 C. Following 30 minutes of stirring at 0 C., saturated aqueous ammonium chloride solution, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to the residue, which was then filtered with NH silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g) as a crude product. This compound was used in the subsequent reaction without further purification.
S-(fluoromethyl) (4aS,4bR,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a,8,8-tetramethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]-indeno[1,2-d][1,3]dioxole-6b-carbothioate[ No CAS ]
[ 1185142-75-9 ]
S-(fluoromethyl) (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-8-(5-chloro-2-furyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carbothioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
perchloric acid; In dichloromethane; for 0.25h;
In a 4 mL vial intermediate 4 (50 mg, 0.1 mmol) was suspended in 2 mL of DCM. Perchloric acid (0.050 mL, 0.23 mmol) was added, the vial was capped and shaken for 5 <n="61"/>min. 5-Chlorofuran carbaldehyde (19 mg, 0.15 mmol) was added to the mixture and the vial was shaken for another 15 min. Saturated aq. NaHCO3 was added to neutralise the acid and the product was extracted with DCM. The organic phase was washed with water, dried over solium sulfate, filtered and the solvent was removed in vacuo. The crude product was puried by HPLC (MeCN-water 40-100% MeCN in 20 min) to afford 10 mg ( 17 %) of the desired product as an off-white solid. The product was isolated as 2:1 mixture of S-(R)- and 8-(S)- diastereomers according to 1H-NMR spectroscopy.1H-NMR (400 MHz, CD3CN) delta 7.20 - 7.17 (IH, m), 6.63 (IH, d), 6.43 (IH, m), 6.42 (IH, d), 6.35 (IH, m), 6,30 (IH, d), 6.28 (IH, d), 6.26 (IH, s), 6.24 (IH, s), 5.89 - 5.82 (IH, m), 5.71 (IH, s), 5.57 - 5.53 (IH, m), 5.36 (IH, d), 5.04 (IH, d), 4.36 (IH, m), 3.44 (IH, m), remaining proton signals appear between 2.65 - 0.99 ppm; APCI-MS: m/z 559.2 [MH+].
A MIXTURE OF TERT-BUTYL DIMETHYLCARBAMATE (7.2 g) AND N, N, N ; N-TETRAMETHYLETHYLENE- diamine (12.7 ML) in THF (210 mL) is cooled TO-70 C. SEC-BUTYL lithium (1.4 M in cyclohexane, 43.7 ML) is added dropwise, maintaining the reaction temperature below - 65 C. The mixture is allowed to stir for 1.5 h at-70 C. A solution of 5-chloro-2- furaldehyde (5.0 g) in THF (20 mL) is added dropwise, maintaining the reaction temperature below-65 C. The mixture is allowed to stir for 1 h at-70 C. The mixture is allowed to WARM TO 0 C and is then quenched with sat. aq. NH4C1 solution (125 ML) while cooled by an ice bath. The mixture is diluted with diethyl ether (300 ML). The aqueous layer is extracted with diethyl ether (2 x 100 mL). The combined organic layers are washed with sat. aq. NH4C1 (2 x 50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated. The resulting oil is dissolved in THE (115 mL) and sodium hydride (60% dispersion in mineral oil, 3.1 g) is added. The mixture is allowed to stir at room temperature for 18 h. With an ice bath cooling the reaction mixture is quenched with sat. aq. NILCl solution (100 mL). The mixture is diluted with diethyl ether (200 mL). The organic layer is washed with sat. aq. NH4CL (100 mL) followed by brine (100 mL), dried (MgSO4), and concentrated in vacuo. The crude product is purified by column chromatography (EtOAc/heptane, 1/1) to afford 1.9 g of the title compound as an amber oil. Physical characteristics. 1H NMR (400 MHz, DMSO-D6) B 6.80, 6.55, 5. 56, 3.81, 3.69, 2. 81.
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