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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 446-48-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 386 - 387
2
[ 95-52-3 ]
[ 446-48-0 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 879
[2] Chemische Berichte, 1955, vol. 88, p. 542,548 Anm. 18
[3] Journal of the Chemical Society, 1926, p. 220
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 3814
[5] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 386 - 387
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 1990, vol. 53, # 1-4, p. 43 - 67
[7] Tetrahedron, 2011, vol. 67, # 5, p. 1002 - 1010
[8] European Journal of Organic Chemistry, 2017, vol. 2017, # 5, p. 996 - 1003
3
[ 446-52-6 ]
[ 446-48-0 ]
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 27, p. 5161 - 5164
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 5, p. 996 - 1003
4
[ 446-51-5 ]
[ 446-48-0 ]
Reference：
[1] Journal of the Chemical Society, 1965, vol. 65, p. 1829 - 1843
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 11, p. 1731 - 1735
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 5, p. 996 - 1003
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 415 - 427
5
[ 446-51-5 ]
[ 10035-10-6 ]
[ 71-43-2 ]
[ 446-48-0 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 220
6
[ 95-52-3 ]
[ 7726-95-6 ]
[ 446-48-0 ]
[ 446-51-5 ]
[ 446-52-6 ]
[ 445-29-4 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 220
7
[ 446-48-0 ]
[ 95-52-3 ]
[ 776-35-2 ]
[ 349-38-2 ]
Reference：
[1] Chemical Communications, 1997, # 13, p. 1163 - 1164
8
[ 446-48-0 ]
[ 95-52-3 ]
[ 85-01-8 ]
[ 776-35-2 ]
[ 349-38-2 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 3, p. 402 - 415
With potassium carbonate; hydrazine hydrate In ethanol at 0℃; for 48 h;
With stirring, 190 g (1.0 mol) of 2-fluorobenzyl bromide were added to a mixture of 250 g (5.0 mol) of hydrazine hydrate and 137 g (1.0 mol) of potassium carbonate in 2 l of ethanol. The mixture was stirred at room temperature for 2 d and then concentrated under reduced pressure. The residue was extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated. The crude product was purified by chromatography on silica gel. This gave 109 g (76percent of theory) of the target compound.
With copper(l) iodide; lithium methanolate; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 14 h; Inert atmosphere
2-Fluorobenzyl bromide (3000 mg, 15 mmol), boronic acid pinacol ester (6000 mg, 24 mmol),CuI (320 mg, 1.5 mmol), LiOMe (1200 mg, 32 mmol), PPh3 (540 mg, 2 mmol) and DMF (50 mL) were placed in a 250 mL reaction flask and replaced with nitrogen three times and then reacted for 14 h at room temperature. The reaction solution was poured into 200 mL of water, and the CuI was removed by filtration and washed three times with EA. The filtrate was collected and separated, and the aqueous extracted with EA (150 mL×3). After concentrating the EA layer, the title compound 52b (980 mg, 23percent)
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 528 - 532
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 528 - 532
[3] Patent: CN108341777, 2018, A, . Location in patent: Paragraph 0654-0657
Reference Example 45 (2-fluorobenzyl)methylamine To tetrahydrofuran (5 ml) was added under ice-cooling with stirring 40% aqueous methylamine solution (5 ml) and 2-fluorobenzylbromide (1.00 g, 5.29 mmol) dissolved in tetrahydrofuran (2 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.65 g, yield 87%) as a colorless oil. 1H-NMR (300 MHz, CDCl3); delta(ppm) 2.43 (s, 3H), 3.79 (s, 2H), 7.01-7.12 (m, 2H), 7.21-7.25 (m, 1H), 7.29-7.33 (m, 1H).
With potassium carbonate; hydrazine hydrate; In ethanol; at 0℃; for 48.0h;
With stirring, 190 g (1.0 mol) of 2-fluorobenzyl bromide were added to a mixture of 250 g (5.0 mol) of hydrazine hydrate and 137 g (1.0 mol) of potassium carbonate in 2 l of ethanol. The mixture was stirred at room temperature for 2 d and then concentrated under reduced pressure. The residue was extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated. The crude product was purified by chromatography on silica gel. This gave 109 g (76% of theory) of the target compound.
To a solution of L-amino acid 1 (25.0 mmol) in H2SO4 2N (37.5 ml, aqueous solution), cooled to 0 C., was added a solution of NaNO2 2N (2.57 g, 37.0 mmol) in water (9 ml). The temperature was maintained below 5 C. during the addition, and the mixture was stirred at such a temperature for 24 h. The solution was saturated with (NH4)2SO4, extracted with ether (3x25 ml), dried over Na2SO4 and evaporated under reduced pressure giving 2.72 g (23.0 mmol) of the corresponding ?-hydroxy acid as an oil. A solution of this oily material, p-toluenesulfonic acid monohydrate (0.03 g, 0.16 mmol) and dimethoxypropane (2.8 ml, 23.0 mmol) in methanol (1.15 ml) was heated at 45 C. for 24 h. The reaction mixture was evaporated under reduced pressure providing the corresponding {overscore (?)}hydroxy methyl ester 2 as an oil. This material was dissolved in anhydrous tetrahydrofuran (40 ml) and anhydrous N,N-dimethylformamide (12 ml), under an inert atmosphere, was cooled to 0 C. NaH (0.48 g, 20.0 mmol) was added and the mixture was stirred for 10 min. The corresponding bromide 3 (24.0 mmol) was added dropwise, and the mixture was allowed to reach room temperature. The reaction was monitored by TLC. When the reaction was complete, the reaction mixture was diluted in ether (130 ml) and washed with water (3x50 ml). The remaining organic layer was dried over Na2SO4 and evaporated under reduced pressure, providing the crude product 4, which was purified by flash column chromatography. (S)-Methyl 2-(2-fluorobenzyloxy)-3-methylbutanoate. This compound was prepared from L-valine and 2-fluorobenzyl bromide in 40 % yield: bp 70-72 C. (0.5 mm Hg); IR 1751, 1229 cm-1; 1H-NMR (? ppm, CDCl3) 7.49-6.97 (m, 4H), 4.71 (d, 1H, J=12.1 Hz), 4.49 (d, 1H, J=12.1 Hz), 3.74 (s, 3H), 3.71 (d, 1H, J=5.7 Hz), 2.18-2.00 (m, 1H), 0.96 (d, 3H, J=4.0 Hz), 0.92 (d, 3H, J=4.0 Hz); 13C-NMR (? ppm, CDCl3) 172.8, 163.1, 158.2, 130.3, 130.2, 129.5, 129.4, 124.0, 123.9, 115.3, 114.9, 83.6, 66.1, 66.0, 51.7, 31.6, 18.7, 17.7; [?]D25=-64.9 (c=1.27, CH2Cl2).
Sodium hydride (109 mg, 2.50 mmol) was suspended in N,N-dimethylformamide (10 mL) in a nitrogen atmosphere, and the suspension was cooled to 0C. <strong>[7770-45-8]4-Hydroxy-1-naphthaldehyde</strong> (260 mg, 1.51 mmol) was slowly added, and the mixture was stirred at 0C for 30 minutes. 1-(Bromomethyl)-2-fluorobenzene (270 muL, 2.24 mmol) was further added, and the mixture was stirred at room temperature for two hours. A dilute hydrochloric acid solution (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 2011 to 5/1) to give the target compound (413 mg, yield: 98%) as a yellow solid. 1H-NMR (CDCl3, 400MHz):delta ppm: 5.43 (2H, s), 7.05 (1H, d, J=8.2Hz), 7.14-7.24 (2H, m), 7.39 (1H, m), 7.57-7.62 (2H, m), 7.72 (1H, m), 7.94 (1H, d, J=8.2Hz), 8.39 (1H, d, J=8.6Hz), 9.32 (1H, d, J=8.6Hz), 10.22 (1H, s). MS (EI) m/z: 280.0898 (M+)
Under argon, 12.0 g (83.9 mmol) of <strong>[50264-88-5]3-cyanoindazole</strong> [for the preparation, cf. Salkowski, Chem. Ber. 17 (1984), 508] were dissolved in 100 ml of abs. THF, and 20.6 g (109 mmol) of 2-fluorobenzyl bromide were added. With ice-cooling, 2.55 g (100 mmol) of sodium hydride (95 per cent) were added a little at a time. The mixture was stirred overnight at room temperature and then concentrated to about one quarter of its volume using a rotary evaporator and admixed with H2O and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was distilled off using a rotary evaporator, leaving the product. Yield: 19.5g (93%) Rf value: 0.69 (silica gel; cyclohexane/ethyl acetate 1:1)
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
(a) Cyclopropyl 2-Fluorobenzyl Ketone To a suspension of magnesium powder (7.2 g) in anhydrous diethyl ether (60 ml) was added a solution of 2-fluorobenzylbromide (30 ml) in diethyl ether (30 ml), then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethyl ether (120 ml) over 100 minutes. After stirring for 30 minutes at room temperature the stirred mixture was heated under reflux for 1 hour. After the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid. 1H NMR (CDCl3) deltappm: 0.82-0.98 (2H, m), 1.03-1.17 (2H, m), 1.92-2.06 (1H, m), 3.86 (2H, s), 7.10-7.30 (4H, m); Mass (CI, m/z): 179 (M++1).
With potassium carbonate; In acetone; for 2 - 6h;Heating / reflux;Product distribution / selectivity;
1-r(4-bromophenoxy)methyll-2-fluorobenzene (D25)Procedure 1 : To a solution of 4-bromophenol (502.08g) dissolved in acetone (7322mL) was added K2CO3 (57Og) and then benzylbromide (523g). The mixture was heated under reflux for 2hrs. The reaction mixture was then cooled at 25C, filtered and the filter cake was washed with MTBE (1046mL). The combined filtrate was concentrated to 100OmL and MTBE (4184ml_) were added. The mixture was washed with an aqueous 1 M NaOH solution (1464mL), then with brine (130OmL) and the organic phase was concentrated to dryness. THF (130OmL) was added and the solvent was removed under reduced pressure to afford the title compound (902.1g); 1H NMR (400 MHz, DMSO-d6) delta(ppm): 7.54 (td, 1 H); 7.46 (d, 2H); 7.42 (m, 1 H); 7.23 (m, 2H); 7.01 (d, 2H); 5.13 (s, 2H).D25 was also obtained as follows:Procedure 2: A stirred mixture of 4-bromophenol (19.22g, 111 mmol), orthofluorobenzyl bromide (2Og, 105.8mmol) and potassium carbonate (21.9g, 158.4mmol) in acetone (280ml) was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered, washing the solid with TBME (40ml). The combined filtrate and washings were concentrated under vacuum to a final volume of about 40ml. The resulting solution was diluted with TBME (160ml) and washed with 1M sodium hydroxide and brine, then concentrated under vacuum to an oil which slowly solidified to give the title compound (28.9g). 1 H NMR (300 MHz, CHCI3-cQ. delta(ppm): 5.10 (s, 2H) , 6.86 (m, 2H) , 7.10 (m, 1 H) , 7.17 (m, 1H) , 7.29 (m, 1H) , 7.35 (m, 2H) , 7.38 (m, 1 H) .
With potassium carbonate; In acetone; for 6h;Heating / reflux;Product distribution / selectivity;
A stirred mixture of 4-bromophenol (19.22g, 1 11 mmol), orthofluorobenzyl bromide (2Og, 105.8mmol) and potassium carbonate (21.9g, 158.4mmol) in acetone(280ml) was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered, washing the solid with TBME (40ml). The combined filtrate and washings were concentrated under vacuum to a final volume of about 40ml. The resulting solution was diluted with TBME (160ml) and washed with 1 M sodium hydroxide and brine, then concentrated under vacuum to an oil which slowly solidified to give the title compound (28.9g).1 H NMR (300 MHz, CHCI3-d). delta(ppm): 5.10 (s, 2H) , 6.86 (m, 2H) , 7.10 (m, 1 H) , 7.17 (m, 1 H) , 7.29 (m, 1 H) , 7.35 (m, 2H) , 7.38 (m, 1 H) .
With potassium carbonate; In acetone; for 2h;Heating / reflux;
Description 1 : 1-r(4-Bromophenoxy)methyll-2-fluorobenzene (DPTo a solution of 4-bromophenol (502.08g) dissolved in acetone (7322ml_) was added K2C?3 (57Og) and then benzylbromide (523g). The mixture was heated under reflux for 2hrs. The reaction mixture was then cooled at 25 C, filtered and the filter cake was washed with MTBE (1046ml_). The combined filtrate was concentrated to 100OmL and MTBE (4184mL) were added. The mixture was washed with an aqueous 1 M NaOH solution (1464ml_), then with brine (130OmL) and was concentrated to dryness. THF (130OmL) was added and the solvent was removed under reduced pressure to afford the title compound (902.1g); 1H NMR (400 MHz, DMSO-d6) ?(ppm): 7.54 (td, 1 H); 7.46 (d, 2H); 7.42 (m, 1 H); 7.23 (m, 2H); 7.01 (d, 2H); 5.13 (s, 2H).
With caesium carbonate; In N,N-dimethyl-formamide; at 45℃;
Bocaminophenol(0. 5g,1 eq), 2-fluorobenzyl bromide (0.45g,leq), and cesium carbonate (1.94g, 2.5eq) was dissolved in 30mLdimethylformamide. The reaction was allowed to stir at45 C overnight. The solvent was removed and dissolved in ethyl acetate and water. It was extracted with ethyl acetate three times. The organic layer was washed with IN sodium hydroxide and dried with magnesium sulfate and solvent was removed. It was purified by column chromatography. Yield: 0.44g (58%).
Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78C. Lithium bis(trimethylsilyl) amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluorobenzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil. APCI-MS: m/z 356 [MH+]
75%
Ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.5 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78[deg.] C., and LiHMDS (42.0 mL, 44.5 mmol) was slowly added dropwise thereto. After the solution was stirred at -78C for 30 minutes, o-fluorobenzyl bromide (8.37 g, 44.5 mmol) was slowly added dropwise and allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (250 mL), extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ether = 10:1 to 5:1) as a pale yellow oil 49-f (10.8 g, 75%).
Example- 1; Preparation of l-cyclopropyl-2-(2-fluorophenyI) ethanone (IV); To a suspension of magnesium powder (1.39 gm) in diethyl ether (50 ml) with catalytic amount of methyl iodide was added a solution of 2-fluorobenzylbromide (10 gm) in diethyl ether (30 ml) over period of 45 minutes, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added drop wise to a solution of cyclopropanecarbonitrile (3.2 gm) in diethyl ether (15 ml) over 15 minutes. After stirring for 90 minutes at room temperature the stirred mixture was cooled to 0C and quenched with ammonium chloride solution. The reaction mixture was extracted with ethyl acetate: diethyl ether and washed successively with water, saturated aqueous sodium bicarbonate solution, and diluted hydrochloric acid, dried over anhydrous sodium sulfate, and then organic layer was evaporated under reduced pressure to afford the desired product 6.8 gm (Yield = 72.18%).
Reference Example: Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone; To a suspension of magnesium powder (7.2 g) in anhydrous diethyl ether (60 ml) was added a solution of 2-fluorobenzylbromide (30 ml) in diethyl ether (30 ml), then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethylether (120 ml) over 100 minutes. After stirring for 30 minutes at room temperature the stirred mixture was heated under reflux for 1 hour. After the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfite, and then evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid.
Example-24: Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone:; l-(bromomethyl)-2-fluorobenzene (100 grams) in diethylether (500 ml) was added to a suspension of magnesium metal (14 grams) in diethyl ether (500 ml) under nitrogen atmosphere 25-300C. The reaction mixture was stirred for 30 minutes <n="23"/>at 25-300C and cyclopropyl cyanide (42 grams) in diethyl ether (500 ml) was added. The reaction mixture was heated to reflux temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by 10% sodium carbonate and then with sodium chloride solution. The ethyl acetate layer was distilled off completely under reduced pressure. Yield: 80 grams; Purity: 85% by GC
EXAMPLE 4: PREPARATION OF CYCLOPROPYL-2-FLUOROBENZYL KETONE.Magnesium powder (15.2 g), anhydrous diethyl ether (330 mL) and iodine (0.2 g) are charged into a round bottom flask. A solution of 2-fluoro benzyl bromide (100 g) in diethyl ether (330 mL) is added over a period of 1 hour, 45 minutes and stirred at 30 0C for 1 hour. A solution of cyclopropyl cyanide (46 g) in diethyl ether (330 mL) is added to the above obtained reaction mixture over a period of 1 hour and stirred for 2 hours at 30 0C. The reaction mixture is quenched with saturated ammonium chloride solution (500 mL). The layers are separated. The organic layer is washed with saturated bicarbonate solution (500 mL), saturated aqueous sodium chloride solution (500 mL) and the organic layer is dried over sodium sulfate. The organic solvent is concentrated completely at a temperature of 55 0C to afford 82.6 g of crude product.Purity: 81.9% by HPLC.
After dissolving (exo)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane (CAS 135-97-7) (1.50 g) in N,N-dimethylformamide (20 ml), sodium hydride (60% in oil) (551 mg) was added and the mixture was stirred at 70 C. for 1 hour. The reaction mixture was allowed to cool, and 2-fluorobenzyl bromide (1.53 ml) was added. Stirring was then carried out at 70 C. for 1 hour and then at room temperature overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (722 mg).1H-NMR (400 MHz, CDCl3); delta 1.48-1.55 (m, 2H), 1.68-1.76 (m, 2H), 1.83-1.89 (m, 2H), 1.95-2.04 (m, 2H), 2.32 (s, 3H), 3.16-3.23 (m, 2H), 3.63-3.72 (m, 1H), 4.56 (s, 2H), 6.97-7.03 (m, 1H), 7.08-7.13 (m, 1H), 7.20-7.27 (m, 1H), 7.39-7.43 (m, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;
Step c) 1-(2-Fluorobenzyl)-<strong>[956010-88-1]1H-pyrazolo[3,4-b]pyridine-3-carbonitrile</strong> Under argon, cesium carbonate (437 mg, 1.34 mmol) is added to a solution of <strong>[956010-88-1]1H-pyrazolo[3,4-b]pyridine-3-carbonitrile</strong> (200 mg, 88% pure, 1.22 mmol) and 2-fluorobenzyl bromide (253 mg, 1.34 mmol) in 5 ml of DMF, and the reaction mixture is stirred at RT for 16 h. For work-up, 1.5 ml of 1 N hydrochloric acid and 3 ml of DMSO are added. The resulting solution is purified directly by preparative HPLC (Method 5). This gives 250 mg (81% of theory) of the title compound. 1H-NMR (400 MHz, DMSO-d6): delta=5.88 (s, 2H), 7.16-7.27 (m, 2H), 7.31-7.44 (m, 2H), 7.55 (dd, 1H), 8.51 (dd, 1H), 8.81 (dd, 1H).
Example 8A 2-Amino-3-(2-fluorophenyl)propanenitrile Under argon, a solution of 3.99 g (21.1 mmol) of 1-(bromomethyl)-2-fluorobenzene in 85 ml of dichloromethane is added dropwise to a suspension of 5.00 g (22.7 mmol) of <strong>[70591-20-7]N-(diphenyl-methylene)aminoacetonitrile</strong> and 1.23 g (21.9 mmol) of potassium hydroxide in 85 ml of dichloromethane at 0° C. The mixture is stirred for 20 min and then filtered and concentrated in vacuo. The residue is mixed with 200 ml of diethyl ether and 200 ml of 1 N hydrochloric acid and stirred at RT for 10 h. The aqueous phase is then separated off and made alkaline with conc. sodium hydroxide solution, and the resulting oil is taken up in dichloromethane. The organic phase is dried over sodium sulfate and concentrated. 2.4 g (64percent of theory) of the desired product are obtained as a yellow oil. 1H-NMR (500 MHz, DMSO-d6): delta=2.46 (d, J=7.1 Hz, 2H), 2.97 (d, J=7.6 Hz, 2H), 3.94 (tt, J=7.6, 7.1 Hz, 1H), 7.15-7.21 (m, 2H), 7.29-7.35 (m, 1H), 7.39 (dt, J=7.6, 1.5 Hz, 1H). 13C-NMR (125 MHz, DMSO-d6): delta=33.9 (d, 3JC,F=1.6 Hz), 43.8 (d, 4JC,F=1.2 Hz), 115.1 (d, 2JC,F=21.9 Hz), 122.3, 123.4 (d, 2JC,F=15.5 Hz), 124.3 (d, 4JC,F=3.4 Hz), 129.0 (d, 3JC,F=8.2 Hz), 131.8 (d, 3JC,F=4.4 Hz), 160.6 (d, 1JC,F=244 Hz). HRMS: calc. for C9H9FN2 164.0750; found 164.0749.
Preparation of 3-chloro-5-(3,5-dimethoxyphenyl)-6-(2-fluorophenyl)-4-(2,4,6- trifluorophenyl)pyridazine (Compound 45) Step A: Preparation of l-(3,5-dimethoxyphenyl)-2-(2-fluorophenyl)ethanoneTo a mixture of magnesium turnings (5.7 g, 0.2 mol), iodine (catalytic amount) and 1 ,2-dibromoethane (2 drops) in diethyl ether (150 mL) at reflux was added dropwise a solution of l-(bromomethyl)-2-fluorobenzene (31.45 g, 0.17 mol) in diethyl ether (140 mL) over 105 minutes. The reaction mixture was cooled 10 0C, and a solution of 3,5- dimethoxybenzonitrile (22.51 g, 0.14 mol) in diethyl ether (130 mL) and tetrahydrofuran (80 mL) was added dropwise. The reaction mixture was heated at reflux for 5 h and then allowed to stand at room temperature overnight. The reaction mixture was diluted with hydrochloric acid (1 N, 300 mL), water (75 mL), ethyl acetate (500 mL) and more hydrochloric acid (I N, 200 mL). After stirring for 1 h, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with hexanes to provide the title compound as a solid (31.3 g).1H NMR (CDCl3): delta 7.4-7.3 (m, 2H), 7.17 (s, 2H), 7.17-7.10 (m, 2H), 6.66 (s, IH), 4.28 (s,2H), 3.83 (s, 3H), 3.80 (s, 3H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Example 7A 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine 12.1 g (39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of cesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured onto water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: 97:3 petroleum ether/ethyl acetate) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the desired compound in solid form. The solid was taken up in ethyl acetate and washed with 10% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried and concentrated. LC-MS (method 2): Rt=2.57 min MS (ESIpos): m/z=372 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
61%
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 1) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase:petroleum ether ethyl acetate 97:3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid was taken up in ethyl acetate and washed with 10% strength aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.10430] LC-MS (Method 2): R=2.57 mm10431] MS (ESIpos): mlz=372 (M+H)10432] 1H NMR (400 MHz, DMSO-d6): oe=5.73 (s, 2H),7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Example 6A5-Fluoro-l-(2-fluorobenzyl)-3-iodo-lH-pyrazolo[3,4-b]pyridineIn DMF (2538 ml), 141 g (462.1 1 mmol) of the compound from Example 5A were introduced and then 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and 165.62 g (508.32 mmol) of cesium carbonate were added. The mixture was stirred at RT for two hours. The reaction mixture was then poured into saturated aqueous sodium chloride solution (13 670 ml) and extracted twice with ethyl acetate (5858 ml) The collected organic phases were washed with saturated aqueous sodium chloride solution (3905 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. The resulting solid was dissolved in dichloromethane and washed once with saturated aqueous sodium thiosulphate solution (500 ml) and then with saturated aqueous sodium chloride solution (500 ml). The product was concentrated to dryness and the residue was suspended with diethyl ether, isolated by filtration with suction and dried under a high vacuum. This gave 106.6 g (62% of theory) of the desired compound.LC-MS (Method 1): R, = 2.57 minMS (ESIpos): m/z = 372 (M+H).H NMR (400 MHz, DMSO-d6): delta = 5.73 (s, 2H), 7.13 - 7.26 (m, 3H), 7.33 - 7.41 (m, 1H), 7.94 (dd, 1H), 8.69 - 8.73 (m, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Example 6A 5-Fluoro-1-(2-fluorobenzyl)-3 -iodo- 1H-pyrazolo[3,4-b]pyridine 141 g (462.11 mmol) of the compound from Example 5A were introduced into DMF (2538 ml), and 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and 165.62 g (508.32 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured into saturated aqueous sodium chloride solution (13 670 ml) and extracted twice with ethyl acetate (5858 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (3905 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. The resulting solid was dissolved in dichloromethane and washed once with saturated aqueous sodium thiosulphate solution (500 ml) and then with saturated aqueous sodium chloride solution (500 ml). The product was concentrated to dryness and the residue was suspended in diethyl ether, isolated by filtration with suction and dried under high vacuum. This gave 106.6 g (62% of theory) of the desired compound. 1H NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
106.6 g
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
5-Fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine 141 g (462.11 mmol) of the compound from Example 5A were introduced into DMF (2538 ml), and 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and 165.62 g (508.32 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured into saturated aqueous sodium chloride solution (13 670 ml) and extracted twice with ethyl acetate (5858 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (3905 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. The resulting solid was dissolved in dichloromethane and washed once with saturated aqueous sodium thiosulfate solution (500 ml) and then with saturated aqueous sodium chloride solution (500 ml). The product was concentrated to dryness and the residue was suspended in diethyl ether, isolated by filtration with suction and dried under high vacuum. This gave 106.6 g (62% of theory) of the desired compound. LC-MS (method 1): Rt=2.57 min MS (ESIpos): m/z=372 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
9.0 g
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Example 7A 5-Fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine 12.1 g (approx. 39.65 mmol) of the compound from example 6A was put in DMF (217 ml) and then 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were added. The mixture was stirred for two hours at RT. Then the reaction mixture was added to water (1.17 l) and was extracted twice with ethyl acetate (502 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel (solvent: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated by evaporation. 9.0 g (61% of theor.) of the title compound was obtained as a solid. The solid was taken up in ethyl acetate and washed with 10% aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated by evaporation. LC-MS (method 2): Rt=2.57 min MS (ESIpos): m/z=372 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
106.6 g
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Example 24A 5-Fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine 141 g (462.11 mmol) of the compound from Example 23A were initially charged in DMF (2538 ml), and 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and 165.62 g (508.32 mmol) of cesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured into saturated aqueous sodium chloride solution (13 670 ml) and extracted twice with ethyl acetate (5858 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (3905 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: 97:3 petroleum ether/ethyl acetate) and the product fractions were concentrated. The resulting solid was dissolved in dichloromethane and washed once with saturated aqueous sodium thiosulfate solution (500 ml) and then with saturated aqueous sodium chloride solution (500 ml). The product was concentrated to dryness and the residue was suspended in diethyl ether, isolated by filtration with suction and dried under high vacuum. This gave 106.6 g (62% of theory) of the title compound. LC-MS (method 1): Rt=2.57 min MS (ESIpos): m/z=372 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
12.1 g (about 39.65 mmol) of the compound from Example 19A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured onto water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid was taken up in ethyl acetate and washed with 10% strength aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated. LC-MS (Method 4): Rt=2.57 min MS (ESIpos): m/z=372 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).
With barium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;
Weigh out 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine (10.0 g, 38.0 mmol)In a 500 ml flask,N,N-dimethylformamide (150 mL) was added thereto,Barium carbonate (13.6 g, 41.7 mmol) and 1-(bromomethyl)-2-fluoro-benzene (5.0 mL, 41.5 mmol),The reaction was carried out for 2 hours at room temperature.The reaction solution was poured into a saturated sodium chloride solution (500 mL) and ethyl acetate (50 mL×3).The organic phase was washed with saturated brine (50 mL)Obtained a yellow solid (10.0 g, 70.9%).The crude product was used in the next step without further purification.
With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate; palladium diacetate; In 1,4-dioxane; at 65 - 100℃; for 19h;Inert atmosphere;
General procedure: Procedure1: An oven-dried three-neck round bottom flask was fitted with a condenser. Pd(OAc)2 (145.7 mg, 0.649 mmol), dppf (359.5 mg, 0.649 mmol) bis(pinacolato)diboron (4.120 g, 16.22 mmol) and potassium acetate (1.592 g, 16.22 mmol) were added to the flask. The flask was evacuated and backfilled with argon (this process was repeated a total of 3 times). Benzyl bromide (2.000 g, 11.69 mmol) was added followed by the addition of 1,4-dioxane (30 mL). The reaction mixture was heated to 100 for 4 h and 65 for 15 h and then cooled to room temperature. The reaction mixture was passed through a plug of silica gel eluting with EtOAc and washed with saturated brine (3×50 mL). The organic layers were dried over MgSO4, concentrated in vacuo, and the residue was purified by silica gel flash chromatography.
23%
With copper(l) iodide; lithium methanolate; triphenylphosphine; In N,N-dimethyl-formamide; at 20℃; for 14h;Inert atmosphere;
2-Fluorobenzyl bromide (3000 mg, 15 mmol), boronic acid pinacol ester (6000 mg, 24 mmol),CuI (320 mg, 1.5 mmol), LiOMe (1200 mg, 32 mmol), PPh3 (540 mg, 2 mmol) and DMF (50 mL) were placed in a 250 mL reaction flask and replaced with nitrogen three times and then reacted for 14 h at room temperature. The reaction solution was poured into 200 mL of water, and the CuI was removed by filtration and washed three times with EA. The filtrate was collected and separated, and the aqueous extracted with EA (150 mL×3). After concentrating the EA layer, the title compound 52b (980 mg, 23%)
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 80 - 90℃; for 12h;Inert atmosphere;
Compound WX068-1 (5.00 g, 26.45 mmol, 3.18 mE), bis(pinacolato)diboron (10.08 g, 39.67 mmol), tetrakis (triphenylphosphine) palladium (3.06 g, 2.64 mmol) and potassium carbonate (10.97 g, 79.35 mmol) were dissolved in dioxane (100.00 mE) at room temperature. The reaction mixture was heated to 80-90 C. for 12 hours under nitrogen atmosphere. After the reaction, the mixture was cooled to room temperature, diluted with water (200 mE) and ethylacetate (500 mE). The organic phases were separated,washed with saturated brine (100 mEx2) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was isolated by column chromatography (eluent: petroleum ether/ethyl acetate100/1 - 10/1, volume ratio) to obtain the target product WX068-2. ?H NMR (400 MHz, CDC13) oe: 7.28-6.93 (m, 4H), 2.26 (s, 2H), 1.25 (s, 12H).
General Procedure A; Step 1: Triazole formation:; A mixture of hydrazide A (1.0 eq) and amidine B (1.0 eq) in EtOH (0.05 to 0.3 M depending on solubility) in a sealed vial is heated, e.g., to about 100-1 10C (bath temperature) and monitored by LC/MS analysis. Once complete (reaction time typically 24 h), the reaction mixture is concentrated, azeotroped with toluene and dried in vacuo to afford triazole C as the hydrochloride salt. It is carried on to alkylation step without any further purification.; Step 2: Alkylation:; Triazole C is dissolved in DMF and treated with sodium hydride (e.g., about 60% w/w in mineral oil, about 2.0 eq) and the appropriate benzyl bromide (e.g., about 1.5 eq). The reaction is stirred at room temperature and monitored by LC/MS analysis. Once complete (reaction time typically 30 min), the reaction solution is diluted with ethyl acetate and washed with water (e.g., 4 times) and brine. The organic layer is dried, e.g., over MgS04 or Na2S04, filtered and concentrated. The crude material is purified using Si02 chromatography and an appropriate solvent gradient (ethyl acetate/hexanes or DCM/methanol) to afford products D and E. In all cases, the two regioisomers are readily separable. Structural assignments are based on 1H NMR analysis and confirmed by observed activities in biological assays.; General Procedure B; Amidine formation:; Nitrile F is treated with sodium methoxide (e.g., about 0.5 M in methanol, about 0.5 eq) at room temperature and monitored by LC/MS analysis. Once the starting nitrile is consumed (reaction time was typically 2-7 h), ammonium chloride (e.g., about 1.1 eq) is added and the reaction mixture is stirred for about 16-24h. The reaction mixture is concentrated and dried in vacuo. In some case, the crude amidine is collected by filtration.[00113] The crude amidine is then used as one of the starting compounds in GeneralProcedure A described above without any further purification to yield Compounds D and E.; Example 4: 1-15, 1-18, 1-19, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-55, 1-56, 1-62 and 1-63; Compounds 1-15, 1-18, 1-19, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-55, 1-56, 1-62 and 1-63 were synthesized following General Procedure B described above according to the following conditions.Step 1: Amidine formation: Nitrile F was treated with sodium methoxide (0.5 M in methanol, 0.5 eq) at room temperature and the reaction monitored by LC/MS analysis. Once the starting nitrile was consumed (reaction time was typically 2-7 h), ammonium chloride (1.1 eq) was added and the reaction mixture was stirred for 16-24h. The reaction mixture was concentrated and dried in vacuo resulting in the amidine B. In some case, the crude amidine was collected by filtration. The crude amidine was carried on as described in General Procedure A without any further purification to yield products D and E.; Compound 1-15; Compound 1-15 was synthesized as a light yellow solid (33% over 3 steps) following General Procedure B and using <strong>[1452-16-0]2-cyanothiazole</strong> in step 1. The subsequent steps were performed as described following General Procedure A, using thiazole-2-carboxylic acid hydrazide and 2-fluorobenzyl bromide in the respective steps.1-151-15: ¾ NMR (400 MHz, CDC13) delta 7.97 (d, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 7.26 (n7.16 (app. t, 1H), 7.09-7.02 (m, 2H), 6.22 (s, 2H) ppm. MS: [M+H] = 344.
General procedure: A mixture of <strong>[52562-50-2]5-methyl-1H-indole-3-carbaldehyde</strong> (500 mg, 3.14 mmol) and KOH (263.85 mg, 4.71 mmol) in EtOH (35 mL) was stirred at room temperature when the solid was dissolved. The solvent was evaporated in vacuo, then added acetone (35 mL) and 1-(bromomethyl)-2-fluorobenzene (568 muL, 4.71 mmol). The mixture was stirred at room temperature for 20 min, filtered, the filtrate was concentrated under reduced pressure. The residue was added a little water and put it in the refrigerator overnight. The precipitate was washed with water and vacuum dried to afford 15a (580 mg, 69.0% Yield). 1H NMR (DMSO-d6, 400 MHz): delta 2.40 (s, 3H), 5.57 (s, 2H), 7.10-7.18 (m, 2H), 7.20-7.27 (m, 2H), 7.36 (d, 1H, J = 7.2 Hz), 7.46 (d, 1H, J = 8.0 Hz), 7.93 (s, 1H), 8.34 (s, 1H), 9.91 (s, 1H); MS (ESI), m/z: 266.20 [M - H]-.
Preparation of 1-tert-But I 3-methyI 3-(2-fluorobenzyl)piperidine-l,3-dicarboxyIateIn a flask, lithium bis(trimethylsilyl)amide (LHMDS) (9.24 mL of LO M solution in THF, 9.24 mmol) was added to tetrahydrofuran (20 mL). The reaction mixture was cooled to -78 C, and then a solution of 1-tert-butyl 3 -methyl piperidine-l,3-dicarboxyIate (1.5 g, 6.17 mmol) in tetrahydrofuran (5 mL) was added drop-wise to the reaction mixture at -78 C. The reaction was stirred at -78 C for 30 minutes. Afterwards, 2-fluorobenzylbromide (1.12 mL, 9.24 mmol) was added, and the reaction was stirred for an additional 3 hours at 0 C. Upon reaction completion, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried with sodium sulfate, and concentrated to yield crude product. The crude product was purified using flash chromatography (0 - 60% ethyl acetate in hexane) to give the titled compound (1.41 g)
With potassium carbonate; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, - under nitrogen flow - 22.9 g of 2-Chloro-4-nitrophenol of formula (VI), 25.0 g of 1-(bromomethyl)-2-fluorobenzene of formula (VII) and 230 mL of Acetonitrile are introduced. Stirring is carried out at 20-25 C and 20.1 g of Potassium carbonate are added. The mixture is stirred at 60 C for 2 hours. Upon completing the reaction cooling is carried out and the reaction mixture is poured into 230 mL of purified water pre-cooled at 0-5 C. The precipitation of a yellowish solid is observed. The formed solid is filtered thoroughly draining the mother liquors and washing with 2x46 mL of water/acetonitrile 1:1 mixture pre-cooled at 0-5 C. Washing is then carried out with 46 mL of n-Hexane pre-cooled at 0-5 C. The product is dried in an oven under vacuum for 4-5 hours at 45 C. 33.9 g of product as an almost white solid equivalent to a 91.2% yield are obtained.
91.2%
With potassium carbonate; In acetonitrile; at 60℃; for 2h;Inert atmosphere;
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, -under nitrogen flow-22.9 g of 2-Chloro-4-nitrophenol of formula (VI), 25.0 g of 1-(bromomethyl)-2-fluorobenzene of formula (VII) and 230 mL of Acetonitrile were introduced. Stirring was carried out at 20-25 C. and 20.1 g of potassium carbonate were added. The mixture was stirred at 60 C. for 2 hours. Upon completing the reaction cooling was carried out and the reaction mixture was poured into 230 mL of purified water pre-cooled at 0-5 C. The precipitation of a yellowish solid was observed. The formed solid was filtered thoroughly draining the mother liquors and washing with 2×46 mL of water/acetonitrile 1:1 mixture pre-cooled at 0-5 C. Washing was then carried out with 46 mL of n-Hexane pre-cooled at 0-5 C. The product was dried in an oven under vacuum for 4-5 hours at 45 C. 33.9 g of product as an almost white solid equivalent to a 91.2% yield were obtained.
(R)-N-(2-fluorobenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere;
General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine.
ethyl 1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylate[ No CAS ]
ethyl 1-(2-fluorobenzyl)-3-methyl-1H-pyrazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%; 9%
To <strong>[4027-57-0]ethyl 3-methyl-1H-pyrazole-5-carboxylate</strong> in DMF was added sodium hydride (60 wt% in mineral oil, 1.2 equiv.). After 10 mi 2-fluorobenzyl bromide (1.2 equiv.) was added and the reaction was stirred for 20 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. Purification via silica gel chromatography (10-40% ethyl acetate/hexanes gradient) yielded ethyl1 -(2-fluorobenzyl)-5 -methyl- 1H-pyrazo le-3 -carboxylate (79% yield) and ethyl1 -(2-fluorobenzyl)-3 -methyl- 1H-pyrazo le-5 -carboxylate (9% yield).
79%; 9%
To ethyl 3-methyl-lH-pyrazole-5-carboxylate in DMF was added sodium hydride (60 wt% in mineral oil, 1.2 equiv.). After 10 min, 2-fluorobenzyl bromide (1.2 equiv.) was added and the reaction was stirred for 20 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. Purification via silica gel chromatography (10-40%) ethyl acetate/hexanes gradient) yielded ethyl l-(2-fluorobenzyl)-5-methyl-lH-pyrazole-3-carboxylate (79% yield) and ethyl l -(2-fluorobenzyl)-3-methyl-lH-pyrazole-5-carboxylate (9% yield).
methyl 1-(2-fluorophenylmethyl)-1H-indazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.4%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
2.00 g of methyl 1 H-indazole-3-carboxylate (1 1 .35 mmol, 1 eq.) were dissolved in 20 mL of dry A/,A/-dimethylformamide. 2.36 g of 2-fluorobenzyl bromide (12.49 mmol, 1 .1 eq.) and 4.44 g of cesium carbonate (13.62 mmol, 1 .2 eq.) were added. The mixture was stirred at room temperature overnight under nitrogen atmosphere. Then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography yielding 2.40 g of the titel compound (8.44 mmol, 74.4%). 1H NMR (300 MHz, DMSO-d6) delta [ppm]= 3.87 (s, 3H), 5.81 (s, 2H) 7.05 - 7.26 (m, 3H), 7.28 - 7.41 (m, 2H), 7.43 - 7.55 (m, 1 H), 7.77 - 7.90 (m, 1 H), 8.01 - 8.14 (m, 1 H). LC-MS: retention time: 1 .26 min (method 1 ) MS ES+: 285.2 [M+H]+
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 10h;
Add 400 g (1.63 mol, 1.0 eq) of <strong>[117007-52-0]3-iodo-1H-pyrazolo[3,4-b]pyridine</strong>, 369 g (1.96 mol, 1.2 eq) of o-fluorobenzyl bromide and 450 g (3.27 mol, 1.5 eq) of K2CO3 dissolved in 4L of DMF into a 5L 4-neck flask and react for 10 h at room temperature. Pour the reaction solution into water after thorough reaction as monitored by TLC, stir it to appear a plenty of grey solid, filter and recrystallize PE: EA=5:1 to obtain 411 g of light yellow solid. The yield is 71.16%. [0025] 11 H NMR (400 MHz, CDCl3) delta (ppm): 8.62 (d, 1H), 7.85 (d, 1H), 7.27 (dd, 1H), 7.11 (dd, 1H); 6.96-7.08 m, 3H), 5.82 (s, 2H).
General procedure: To a solution of t-BuOK (1 M sol. in THF, 0.86 mL, 1.3eq) in 5 mL THF dry and 18-crown-6 (0.13 mmol, 35 mg, 0.2 eq), a solution ofcommercially available 4-(1H-indole-4-yl)piperazine-1-carboxylicacid tert-butyl ester (0.66 mmol, 200 mg, 1 eq) in 5 mL of THF dry was addeddropwise at 0 C. After 20 min, benzylbromide derivative or benezenesulfonyl chloride (0.99 mmol, 1.5 eq) was addedand resulted slurry was stirred overnight at room temperature. After that time,THF was evaporated under reduced pressure; the mixture was diluted with (10 mL)EtOAc and extracted with water (10 mL). Organic layer was dried over sodiumsulfate and evaporated. The crude mixture was purified over columnchromatography (Hex/EtOAc 8:2) affording 9-14with 85-95% yield. Next, a mixture of appropriate N1-substituted4-(piperazin-1-yl)-1H-indole 9-14 (0.59 mmol) and 5 mL of 4M HCl solutionin dioxane were stirred at room temperature for 20 min, then dioxane wasremoved under reduced pressure and dried under the vacuum for 1 hour. Theintermediates 15-20 were useddirectly to the next step without further purification.
o-fluorobenzyl (3β)3,23-dihydroxyolean-12-en-28-oate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 18h;
General procedure: A 25 mL one necked round-bottomed flask was charged with a solution of <strong>[465-99-6]hederagenin</strong> (100 mg, 0.23 mmol) in dry DMF (5 mL),and finely grounded potassium carbonate (1 mmol) was added. To this mixture an alkyl bromide (0.46 mmol) was added, and the reaction was stirred for 18 h at 25 C. The reaction mixture was quenched by adding ethyl acetate (20 mL),washed with an aqueous solution of HCl (5%, 50 mL), followed by brine (50 mL) and dried over Na2SO4. The mixture was filtered, the solvent was removed under reduced pressure in a rotary evaporator, and the crude product was obtained as a yellow solid. This solid was purified bysilica gel column chromatography eluting with hexane/ethyl acetate(3:1 v/v) to afford the pure product as a solid. All yields and physical and spectroscopic data for the compounds are included in the Supplementary Material.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 85℃; for 16h;
(2-Chloropyrimidin-5-yl)boronic acid (586 mg, 3.70 mmol) and 1 -(bromomethyl)-2-fluorobenzene (700 mg, 3.70 mmol) were dissolved in Tol (10 mL) and EtOH (2.5 mL). Pd(PPh3)4 (214 mg, 0.19 mmol) was added followed by Na2CO3 (392 mg, 3.70 mmol) in H20 (5 mL). The reaction mixture was heated at 85C for 16 h. The resultant mixture was diluted with EtOAc (25 mL), washed with water and brine, dried over Na2SO4and evaporated. Purification by column chromatography (silica, 0% -> 50% EtOAc in heptane) gave INT7-5 (591 mg, 2.65 mmol, 72%) as white crystals. LCMS: calculated for [M+H]: 223, found: 223.
5-[(2-fluorophenyl)methyl]-N,N-dimethyl-1H-pyrazole-1-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sec.-butyllithium; In tetrahydrofuran; cyclohexane; at -72 - 20℃; for 2h;Inert atmosphere;
A solution of N,N-dimethyl-lH-pyrazole-l -sulfonamide (150 mmol, 1.0 equiv.) in anhydrous THF (250 mL) under nitrogen at -72C was treated with sec-butyllithium (1.4 N in cyclohexane, 170 mmol, 1.1 equiv.) (temperature of the reaction mixture was kept below -60C during the addition). Additional 50 mL of THF was added to facilitate stirring. 2-Fluorobenzyl bromide (170 mmol, 1.1 equiv.) was added dropwise. The mixture was allowed to warm to ambient temperature over 1 hour and stirred for an additional hour. The reaction was cooled on ice and quenched with ice-cold saturated aqueous sodium bicarbonate solution (lOOmL). The mixture was concentrated in vacuo to remove volatile organics, partitioned between water and ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (3 - 40% ethyl acetate/heptane gradient) afforded 5-[(2-fluorophenyl)methyl]-N,N-dimethyl-lH-pyrazole-l-sulfonamide (89%) as a pale yellow oil
ethyl 1-(2-fluorobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate[ No CAS ]
C13H14FN3O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%; 23%
A solution of ethyl 3 -methyl- 1H- 1 ,2,4-triazole-5-carboxylate in anhydrous DMF was treated with sodium hydride (60 wtpercent in mineral oil, 1.2 equiv.) and stirred for 10 min. 2- Fluorobenzyl bromide (1.2 equiv.) was added. After 16 hours, water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (10-50percent ethyl acetate in hexanes gradient) yielded ethyl l-(2-fluorobenzyl)-5-methyl-lH-l,2,4-triazole-3-carboxylate (58percent) and ethyl 1 -(2-fluorobenzyl)-3-methyl- 1H- 1 ,2,4-triazole-5-carboxylate (23percent)
ethyl 1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
To a cold solution of ethyl lH-pyrazole-3-carboxylate (1 equiv.) in THF at 0 °C, was added sodium hydride [60 wtpercent disperion on mineral oil] (1 equiv.). The mixture was stirred at 0 °C for 15 min. To this mixture, was added 2-fluorobenzyl bromide (1 equiv.). The mixture was stirred at rt for 2 h. The mixture was diluted in ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography (0 to 30percent ethyl acetate in hexanes) to give ethyl l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate (1.5 g, 85percent yield) as a clear oil. NMR (500 MHz, CHLOROFORM-d) delta ppm 7.44 (d, 1 H) 7.33 - 7.39 (m, 1 H) 7.19 - 7.26 (m, 1H) 7.08 - 7.18 (m, 2 H) 6.85 (d, 1 H) 5.48 (s, 2 H) 4.43 (q, 2 H) 1.42 (t, 3 H)
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
The 6 - nitro [1, 4] oxazine (10g, 55mmol) dissolved in 100 ml N, in N - dimethyl formamide, adding potassium carbonate (26g, 0.189 muM), system rose to 80 C, dropwise 2 - fluorine phenmethyl bromine (20.8g, 110mmol), canada finishes 80 C reaction 4h, TLC monitoring the disappearance of the raw material point, filtered, filtrate exsolution the caster enters 500 ml ice water, after treats the ice totally melt the filter and collect insoluble, insoluble for 50 ml × 3 water washing, drying to obtain the N - (2 - fluorobenzyl) -6 - nitrobenzene and [1, 4] oxazine.The pure product is a yellow solid 12.6g, yield 80%
(S)-7-[(2-fluorobenzyl)oxy]-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Alkaline conditions;
General procedure: K2CO3 (172.76 mg, 1.25 mmol) and the appropriate substitutedbromine (4-10 mmol) were added, under stirring, to a solution of <strong>[520-33-2]hesperetin</strong>(604 mg, 2 mmol) in anhydrous DMF (15 mL). Another 1 mmolof K2CO3 was intermittently added to the solution to keep the pH as aweak alkaline. The mixture was reacted at room temperature for 4-6 h under atmospheric conditions. The progress of the reaction was monitoredby TLC. The reaction mixture poured into ice cold water thenacidified by dilute hydrochloric acid and extracted with ethyl acetate,then washed three times with saturated aqueous NaCl solution. After drying with anhydrous sodium sulfate, the solution was filtered throughabsorbent cotton. The precipitate obtained by removing the solventunder reduced pressure was purified by column chromatography (SiO2)using trichloromethane/petroleum ether (1:1-5) as eluent. The purifiedprecipitate was recrystallized from dichloromethane/petroleum ether.
5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.6%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;
<strong>[858629-06-8]5-fluoro-3-iodo-1H-indazole</strong> (14.8 g, 56.5 mmol) and cesium carbonate (20.2 g, 62.0mmol) was dissolved m N,N-dimethylformamide (60 mL), then1-(bromomethyl)-2-fluorobenzene (7.15 mL, 59.3 mmol) was added. After the addition, themixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water(100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 2). The combinedorganic layers were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filterd. The filtrate was evaporated to remove the solvent, and thecrude product was recrystallized from isopropanol (10 mL/1 g). The mixture was filtered, and thefilter cake was dried in vacuo at 60 octo give a light yellow solid (13.3 g, 63.6%).MS (ESI, pos.ion) m/z: 371.1 (M+l).
To a stirred solution of <strong>[55919-82-9]5-iodo-1H-indazole</strong> (1.00 g, 4.099 mmol, 1.0 eq) in THF (10 mL) NaH (0.24 g, 4.917 mmol, 1.2 eq) was added at 0 C. under a N2 atmosphere. After 10 min, 1-(bromomethyl)-2-fluorobenzene (0.93 g, 4.917 mmol, 1.2 eq) was added at ambient temperature. The reaction mixture was stirred for 1 h at ambient temperature. After completion of the reaction (monitored by TLC, 20% EtOAc in hexane, Rf-0.6) the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3×20 ml), dried over Na2SO4 and was then concentrated under reduced pressure. The crude product was purified by column chromatography (using 230-400 silica gel) to separate the two isomers. The major isomer was the desired 1-(2-fluorobenzyl)-<strong>[55919-82-9]5-iodo-1H-indazole</strong> which was confirmed by 1H-NMR to afford intermediate C3 (0.57 g, 40%).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;
Hydroxypyridine-2-carbaldehyde (499 mg, 4.05 mmol), 2-fluorobenzyl bromide (500uL) and potassium carbonate (691 mg, 5.00mmol) were combined in a flask under N2 and taken up in dry DMF (10ml_). The reaction was stirred at 60C overnight. The reaction was quenched with water and extracted with EtOAc (2x). The extracts were combined, washed with water (x3) and brine and dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a diethyl ether dichloromethane gradient as eluent to give the desired product (665mg, 71%).
3-(2-fluorobenzyl)thiazolidin-2-ylidenecyanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.6%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 8h;
General procedure: Thiazolidin-2-ylidene-cyanamide (0.317 g, 2.50 mmol) inacetonitrile (20 mL) was dropwise added to a stirred solutionof substituted benzyl bromide (2.5 mmol) and 14 mL NaOHaqueous solution (1 M). The mixture is stirred at room temperaturefor 8-10 h. The soild was collected by filtration,washed with n-hexane and dried in vacuo.
2-(bis(2-fluorobenzyl)amino)ethyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium tert-butylate; at 50℃; for 16h;
General procedure: KOt-Bu (0.5 mmol, 56 mg), 2-oxazoline (0.5 mmol), benzyl bromide (1.0 mmol) and DMC (2 mL) were introduced in a tube, equipped with magnetic stirring bar and the mixture was stirred at 50 C. After 16 h, the progress of the reaction was analyzed by gas chromatography. The solvent was then evaporated under vacuum and the desired product was purified by silica gel chromatography and a mixture of petroleum ether/ethyl acetate as eluent.
tert-butyl ((tert-butoxycarbonyl)oxy)(2-fluorobenzyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 20℃;
Tert-butyl (tert-butoxycarbonyl)oxycarbamate (70 mg) and 1- (bromomethyl) -2-fluorobenzene (56.7 mg) were dissolved in CH 2Cl 2(7 ml) . The mixture was added 1M NaOH (0.33 ml) and tetrabutylammonium bromide(4.83 mg) , and stirred at room temperature for overnight. The resulting mixture was washed with water and dried with Na 2SO 4, concentrated in vacuo and purification by silica gel chromatography to give tert-butyl ( (tert-butoxycarbonyl) oxy) (2-fluorobenzyl) carbamate (82 mg, 80%) . 1HNMR (400 MHz, CDCl 3): delta 7.31-7.37 (m, 4H) , 4.52(s, 2H) , 1.46 (s, 9H) , 1.44 (s, 9H) .
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