* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6331 - 6334
4
[ 93777-26-5 ]
[ 146137-79-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
Reflux
A mixture of 74 (1.82 g, 9 mmol) and copper (I) cyanide (1.4 g, 15.7 mmol) in DMF (14.0 mL) was stirred at reflux overnight. After completion, the reaction mixture was cooled to rt and poured into a solution of water (10 mL) and NH4OH (10 ml) followed by extraction with EtOAc (3 x 25 mL). The organic layer was sequentially washed with brine (2 x 15 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give 757a (0.80 g, 60 percent).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8582 - 8591
[2] Patent: WO2013/56003, 2013, A2, . Location in patent: Page/Page column 63
Stage #1: With sodium hydroxide; dihydrogen peroxide In methanol; water at 20℃; for 2 h; Stage #2: With hydrogenchloride In methanol; water
Example 103A 5-Bromo-2-fluoro-benzoic Acid A mixture of 5-bromo-2-fluorobenzaldehyde (810 mg; 4.0 mmol), 15percent NaOH (aq.) (3 mL), MeOH (5 mL), and 30percent H2O2 (5 mL) was stirred at r.t. for 2 hrs., then acidified with 10percent HCl (aq.). The resulting white solid was collected, rinsed with water, and dried to give the desired product (670 mg; 77percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 39
9
[ 93777-26-5 ]
[ 146328-85-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
With dihydrogen peroxide In methanol
Example 103A 5-Bromo-2-fluoro-benzoic Acid A mixture of 5-bromo-2-fluorobenzaldehyde (810 mg; 4.0 mmol), 15percent NaOH (aq.) (3 mL), MeOH (5 mL), and 30percent H2O2 (5 mL) was stirred at r.t. for 2 hrs., then acidified with 10percent HCl (aq.). The resulting white solid was collected, rinsed with water, and dried to give the desired product (670 mg; 77percent).
Reference：
[1] Patent: US2003/187026, 2003, A1,
10
[ 93777-26-5 ]
[ 146328-87-2 ]
Reference：
[1] Patent: US6384080, 2002, B1,
11
[ 93777-26-5 ]
[ 99725-13-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 0 - 20℃; for 15 h; Inert atmosphere Stage #2: With water; ammonium chloride In ethanol at 0℃;
Preparation Example 4(5-Bromo-2-fluorophenyl)methanolTo a solution of 5-bromo-2-fluorobenzaldehyde (30.0 g, 148 mmol) in EtOH was added sodium borohydride (8.39 g, 222 mmol) at 0 °C. The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0 °C, and quenched with aq. saturated NH4C1 solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated in vacuo to yield the titled compound (30.3 g, quantitative) as a white sold, which was carried on to the next step without further purification.[M-OH"]+ 187.
Reference：
[1] Patent: WO2011/159067, 2011, A2, . Location in patent: Page/Page column 51
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3572 - 3587
[3] Patent: US6034093, 2000, A,
[4] Patent: US5731315, 1998, A,
[5] Patent: WO2004/814, 2003, A1, . Location in patent: Page 49
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3934 - 3948
[7] Patent: WO2015/89809, 2015, A1, . Location in patent: Page/Page column 47; 48
[8] Patent: WO2015/95256, 2015, A1, . Location in patent: Page/Page column 48
12
[ 67-56-1 ]
[ 93777-26-5 ]
[ 99725-13-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0 - 20℃; for 0.583333 h;
Example 5, Step 1To a solution of starting aldehyde 5-1 (3.98 g, 19.6 mmol) in MeOH (20 mL) at 0°C was added sodium borohydride (1.48 g, 39.2 mmol). The reaction was stirred at 0°C for 5 mm then warmed up to RT and allowed to stir for an additional 30 mm. The final mixture was diluted with EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated invacuo to provide 3.92 g (9 8percent) of intermediate 5-2.
With potassium bromate; sulfuric acid In water at 90℃;
Example three: equipped with electric stirring, thermometer, Dropping funnel and condenser tube reactor was added 65percent aqueous sulfuric acid 500ml, Potassium bromate 167 g (1 mol), 124.1 g (1 mol) of o-fluorobenzaldehyde was added dropwise thereto, 90 ° C for 2-3 hours, to the system by adding water 1000ml, Extraction with methyl tert-butyl ether, The organic phase was washed with aqueous sodium sulfite, dried over anhydrous sodium sulfate and concentrated by filtration to remove methyl tert-butyl ether to give a brown-red oil. Vacuum distillation collected 63-65 ° C / 3mmHg fraction 178g, Yield 88percent, content 97percent.
Reference：
[1] Patent: CN105884591, 2016, A, . Location in patent: Paragraph 0008; 0009; 0010; 0011
14
[ 107-31-3 ]
[ 460-00-4 ]
[ 93777-26-5 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 78℃; for 2 h; Stage #2: at -78 - 20℃; for 1.5 h;
To a solution of N,N-diisopropylamine (8.87 mL, 62.9 mmol, 1.1 eq) in dry THF (80 mL) at -78 °C was added n-BuLi (2.5M in hexane, 27.5 mL, 68.5 mmol, 1.2 eq). The resulting mixture was stirred for 30 min then l-bromo-4-fiuoro-benzene (10 g, 57.1 mmol, 1 eq) in dry THF (20 mL) was added. The resultant mixture was stirred at -78 °C for 2h then methyl formate (3.8 g, 62.9 mmol, 1.1 eq) was added and the reaction was stirred a further 30 min at -78 °C. The reaction was allowed to warm to room temperature and stirred a further lh. The reaction was then diluted with water (100 mL), and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SC>4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ethenEtOAc, 20:1) to give the title compound as a yellow oil (6.25 g, 54 percent). 1H NMR (400 MHz, CDCls) δ 10.29 (s, 1H), 7.97 (dd, J = 6.1 , 2.6 Hz, 1H), 7.70 (ddd, J = 8.8, 4.7, 2.6 Hz, 1H), 7.09 (dd, J= 9.6, 8.9 Hz, 1H).
Step 1 : 5-Bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol, 1.0 equiv) and guanidine carbonate (2.68 g, 29.7 mmol, 1.51 equiv) were dissolved in DMA (20 mL) and heated to 140°C & stirred for overnight. After completion of starting material, reaction mixture was poured onto ice cold water. The solid was filtered, washed with diethyl ether and dried to get 6-bromoquinazolin-2- amine (3.0 g, 68percent) as off white solid. LCMS (ES) m/z = 234.0, 236.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 2H), 7.34 (d, J = 8.8 Hz, 1 H), 7.74 - 7.77 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 9.07 (s, 1 H).
60%
at 140℃; for 5 h;
2-Fluoro-5-bromobenzaldehyde (10 g, 49.2 mmol) and bisguanidinium carbonate (13.3 g, 74 mmol) were dissolved in N,N-dimethylacetamide (50 mL). The resulting mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, 120 mL water was added and the reaction mixture was allowed to stir for another 2 h at room temperature. The product was collected by filtration and dried under vacuum to afford 6-bromo-2-quinazolinamine (2) (5.0 g, 60percent).
4 g
at 160℃; for 0.5 h;
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160°C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL χ 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g).
Reference：
[1] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 49
[2] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 506 - 518
[3] Journal of Organic Chemistry, 2006, vol. 71, # 10, p. 3959 - 3962
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 19, p. 5671 - 5686
[5] Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3065 - 3068
[6] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 2, p. 385 - 387
[7] Patent: WO2008/20203, 2008, A1, . Location in patent: Page/Page column 72
[8] Patent: WO2018/102751, 2018, A1, . Location in patent: Paragraph 00208
21
[ 93777-26-5 ]
[ 190273-89-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
With guanidine carbonate In N,N-dimethyl acetamide at 140℃; for 5 h;
Compound 2-Fluoro-5-bromobenzaldehyde (10.0 g, 49.2 mmol)bisguanidiniu carbonate (13.3 g, 74 mmol) were dissolved in N,Ndimethylacetamide(50 mL). The resulting mixture was heated toreflux and stirred for 5 h. After cooling to room temperature,120 mL of water was added and the reaction mixture was allowedto stir for another 2 h at room temperature. The product wascollected by filtration and dried under vacuum to yield 6-Bromo-2-quinazolinamine (12) (5 g, 60percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 275 - 285
22
[ 593-85-1 ]
[ 93777-26-5 ]
[ 190273-89-3 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 150℃; for 5 h;
Guanidine carbonate (2) (4.47 g, 36.9 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (1) (5.00 g, 24.6 mmol) in dimethylacetamide (50 ml). The reaction mixture was heated at 150°C for 5 h. The progress of the reaction was monitored by TLC using AcOEt–hexane, 1:1, as eluent. The reaction mixture was cooled and quenched with ice water, and stirred for 30 min. Then the obtained solid was filtered off, and water was removed by azeotropic distillation with PhMe to get 4.00 g (73percent) of compound 3. Mp 270–272°C. 1H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.04 (2H, s,NH2); 7.37 (1H, d, J = 9.0, H Ar); 7.78 (1H, dd, J = 9.0,J = 2.4, H Ar); 8.05 (1H, d, J = 2.4, H Ar); 9.09 (1H, s,H Ar). Mass spectrum, m/z: 225 [M+H]+.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2015, vol. 51, # 1, p. 60 - 66[2] Khim. Geterotsikl. Soedin., 2015, vol. 51, # 1, p. 60 - 66,7
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 1996 - 2015
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2667 - 2677
[2] Synthesis, 2010, # 24, p. 4287 - 4299
29
[ 93777-26-5 ]
[ 79762-54-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrazine hydrate In dimethyl sulfoxide at 120℃; for 21 h;
To a vigorously stirred solution of 5-bromo-2-fluorobenzaldehyde (40.6 g, 0.2 mol) in DMSO (80 mL) was added N2H4-xH2O (40 mL, 0.8 mol) dropwise over 15 min (slow addition to keep the reaction not too hot). The resulting yellow slurry was heated at 120 0C (oil temp.) for 21 h. The whole mixture was transferred to a 1 L flask and cooled for 10 min in air before quenching with ice (300 mL) and ice- cold H2O (100 mL). The resulting mixture was stirred for 30 min at it. Precipitated formed was collected by suction filtration, rinsed thoroughly with H2O (100 mL x 2), 2 M HCl (100 mL x 2), H2O (100 mL x 2), 0.5 M Na2CO3 (100 mL x 2), H2O (100 mL x 2), dried in air for 1 h and under high vacuum for 2 days to give 6- bromo-lH-indazole (30.05 g, 76percent) as a light yellow solid. MS ESI 196.9 [M + H]+, calcd for [C7H5BrN2 + H]+ 197.0.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[4] Patent: WO2007/126964, 2007, A2,
31
[ 75-16-1 ]
[ 93777-26-5 ]
[ 552331-15-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at 0℃; for 0.5 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; toluene
J. 1-(5-bromo-2-fluorophenyl)ethan-1-ol. To a solution of 5-Bromo-2-fluorobenzaldehyde (10.0 g., 49.26 mmol) in anhydrous ether (60 mL) at 0° C. was added 1.4M methyl magnesium bromide (THF/Tol. solution) (36.9 mL) dropwise. The solution stirred for 30 minutes and quenched with water (50 mL) followed by 1N HCl (10 mL). The organics were separated and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (10.8 g., 100percent). MS (ESI) m/z 218 [M+1]+, 220 [M+2]+.
93%
Stage #1: for 1 h;
[00199] 5-Bromo-2-fluro-phenyl-methanol: 5-Bromo-2-fluorobenzaldehyde(commercially available from Aldrich)( 150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield = 93percent). The product was used directly in the next step without further purification.
93%
at 0℃; for 1 h;
Commercially available 4a (150.0 g,</p> <p id="p0144" num="0144">739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 ml, 812 mmol) was added dropwise via an additional funnel. The reaction mixture was continually stirred for one more hour after the addition. After the reaction was completed, the mixture was slowly poured into 500 ml ice water plus 250 ml saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 ml x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (4b) (150 g, yield = 93percent). The product was used directly for the next step without further purification.
53%
Stage #1: at 0 - 20℃; for 14.5 h; Stage #2: With water In tetrahydrofuran
Methylmagnesium bromide (3M solution in tetrahydrofuran, 18 ml, 54.2 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) under nitrogen at 0° C. over 30 min. The resulting solution was allowed to warm to room temperature over 14 h, upon which TLC analysis showed no remaining starting material, and two new products. The mixture was quenched with water, diluted with ethyl acetate and the organic phase removed and dried over sodium sulfate. This was then concentrated and purified by column chromatography (120 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes). The second fraction was collected as the product, providing the alcohol (5.8 g, 53percent) as an oil; 1H NMR (500 MHz, CDCl3) δ 7.65-7.63 (dd, J=6.5, 2.6 Hz, 1H), 7.36-7.33 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.93-6.89 (dd, J=9.9, 8.7 Hz, 1H), 5.17-5.16 (m, 1H), 1.91-1.90 (m, 1H), 1.51-1.49 (d, J=6.4 Hz, 3H).
46 g
at 0℃; for 0.5 h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0°C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0°C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL χ 3). The combined organic layers were washed with brine (500 mL χ 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 31-2 (46.0 g).
Reference：
[1] Patent: US2008/242694, 2008, A1, . Location in patent: Page/Page column 41
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[3] Patent: WO2009/11880, 2009, A2, . Location in patent: Page/Page column 95
[4] Patent: WO2006/44860, 2006, A2, . Location in patent: Page/Page column 23
[5] Patent: US2006/142307, 2006, A1, . Location in patent: Page/Page column 24
[6] Patent: WO2006/81230, 2006, A2, . Location in patent: Page/Page column 68-69
[7] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 38
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1652 - 1656
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6018 - 6035
[10] Patent: WO2018/102751, 2018, A1, . Location in patent: Paragraph 00260
[11] Patent: WO2007/126964, 2007, A2, . Location in patent: Page/Page column 89
32
[ 676-58-4 ]
[ 93777-26-5 ]
[ 552331-15-4 ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: at 0℃; Stage #2: With water; ammonium chloride In tetrahydrofuran
Acid Preparation 5; 3-Methyl-1 H-indazole-5-carboxvlic acid; To a cooled solution of 3-bromobenzaldehyde (42.5 g, 209 mmol) in THF (300 ml_) at 0 aC was added MeMgCI (17.2 g, 230 mmol) and the mixture was stirred for 2 hours. The reaction mixture was quenched with saturated NH4CI solution (100 ml_) and extracted with diethyl ether (2x250 ml_). The combined organic layers were washed with water (2x100 mL), saturated aqueous NaCI (100 mL), dried over anhydrous Na2SO4 and concentrated to give 1-(5-bromo-2-fluoro-phenyl)-ethanol (17 g, 37percent) as an oil. 1H NMR (CDCI3): δ 7.6-7.7 (d, 1 H), 7.3-7.4 (m, 1 H), 6.8-6.9 (t, 1 H), 5.1-5.2 (m, 1 H), 1.8-1.9 (br, 1 H), 1.46-1.55 (d, 3H).
14.51 g
at -78 - -5℃; for 1 h; Inert atmosphere
Step 1 [0200] 5-Bromo-2-fluorobenzaldehyde (1) (12.98 g) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere, and the solution was cooled in a dry ice-acetone bath. To the solution was added dropwise methylmagnesium chloride (3M in THF, 25.6 ml) at a temperature between −78° C. and −30° C. After completion of addition, the mixture was stirred at a temperature between −10° C. and −5° C. for 1 hour. To the reaction solution were added an aqueous saturated ammonium chloride solution and water, extracted with ethyl acetate and washed subsequently with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford Compound 2 (14.51 g). [0201] 1H-NMR (CDCl3) δ: 1.50 (d, J=6.4 Hz, 3H), 1.91 (d, J=4.2 Hz, 1H), 5.16 (dq, J=4.2, 6.4 Hz, 1H), 6.91 (dd, J=9.9, 8.7 Hz, 1H), 7.31-7.38 (m, 1H), 7.64 (dd, J=6.5, 2.5 Hz, 1H).
Reference：
[1] Patent: WO2009/144554, 2009, A1, . Location in patent: Page/Page column 43
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 935 - 942
[3] Patent: US2013/210839, 2013, A1, . Location in patent: Paragraph 0200; 0201
33
[ 75-16-1 ]
[ 93777-26-5 ]
[ 198477-89-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: at 0℃; for 0.55 h; Stage #2: With Jones reagent In diethyl ether; acetone
To a 0° C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. After 30 min, TLC showed the reaction completed. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL.x.2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87percent) that was used in the next reaction without further purification
87%
at 0℃; for 0.05 h;
To a 0° C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL.x.2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87percent) that was used in the next reaction without further purification.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 10, p. 3263 - 3279
[2] Patent: CN108276396, 2018, A,
45
[ 93777-26-5 ]
[ 95-15-8 ]
[ 1034305-11-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1.5 h; Stage #2: at -78℃; for 2 h;
At -78 ° C,16.6 g (124 mmol) of benzothiophene (compound of formula 2) was dissolved in 200 mL of tetrahydrofuran.Add 78.5 mL (937 mmol) of n-butyllithium,The mixture was stirred at -78 ° C for 1.5 hours.Will be 23.95g (118mmol)5-bromo-2-fluorobenzaldehyde (formula 1 compound) is solubleIn 300 mL of tetrahydrofuran,And mixing it with the above benzothiophene solution,Stirring was continued for 2 hours at -78 °C.Water and diethyl ether were added to the reaction mixture.Separating the organic phase,And dried with magnesium sulfate,It is then filtered and dried under vacuum.The obtained crude product was purified by column chromatography (ethyl acetate-hexane).Obtaining benzo[b]thiophene-2-methanol,Α-(5-bromo-2-fluorophenyl) (compound of formula 3) 35.4 g;Purity 99.5percent; yield 89percent;
84.8%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -24.2 - -13.5℃; Inert atmosphere Stage #2: at -23.5 - -11.8℃; Inert atmosphere Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane; toluene
EXAMPLE; (Example); First step: Synthesis of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol; Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg ) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08percent) in an argon atmosphere at -24.2 to -13.5°C, followed by stirring at -22.1 to -13.5°C for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at -22.1 to -11.8°C, followed by stirring at -23.5 to -16.1°C for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38percent hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0°C for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8percent, purity: 99percent (HPLC)]. 1H-NMR (CDCl3): δ 2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s), 7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd), 7.74 (2H, m)
Reference：
[1] Patent: CN108276396, 2018, A, . Location in patent: Paragraph 0041; 0046; 0047; 0062; 0077
[2] Patent: EP2105442, 2009, A1, . Location in patent: Page/Page column 13
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 10, p. 3263 - 3279
46
[ 141-82-2 ]
[ 93777-26-5 ]
[ 202865-71-2 ]
Yield
Reaction Conditions
Operation in experiment
1.3 g
at 100℃; for 3 h;
5-Bromo-2-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 1.3 g of the titled compound as a white solid. (0164) 1H NMR (400 MHz, CD3OD) 7.89 (d, 1H), 7.74-7.70 (m, 2H), 7.15 (t, 1H), 6.62 (d, 1H)
Step 1 : 5-Bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol, 1.0 equiv) and guanidine carbonate (2.68 g, 29.7 mmol, 1.51 equiv) were dissolved in DMA (20 mL) and heated to 140C & stirred for overnight. After completion of starting material, reaction mixture was poured onto ice cold water. The solid was filtered, washed with diethyl ether and dried to get 6-bromoquinazolin-2- amine (3.0 g, 68%) as off white solid. LCMS (ES) m/z = 234.0, 236.0 [M+H]+. H NMR (400 MHz, DMSO-d6) delta 6.96 (s, 2H), 7.34 (d, J = 8.8 Hz, 1 H), 7.74 - 7.77 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 9.07 (s, 1 H).
60%
In N,N-dimethyl acetamide; at 140℃; for 5h;
2-Fluoro-5-bromobenzaldehyde (10 g, 49.2 mmol) and bisguanidinium carbonate (13.3 g, 74 mmol) were dissolved in N,N-dimethylacetamide (50 mL). The resulting mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, 120 mL water was added and the reaction mixture was allowed to stir for another 2 h at room temperature. The product was collected by filtration and dried under vacuum to afford 6-bromo-2-quinazolinamine (2) (5.0 g, 60%).
In N,N-dimethyl acetamide; at 140℃; for 5h;
2-Fluoro-5-bromo benzaldehyde (1.0 g, 4.9 mmol) and guanidine carbonate (1.3 g, 7.4 mmol, 1.5 equiv) were dissolved in DMA and heated to 140 0C for 5 h. The reaction was treated with H2O and the resulting precipitate was collected by vacuum filtration; m/z 225.
4 g
In N,N-dimethyl acetamide; at 160℃; for 0.5h;
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL chi 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g).
Preparation Example 4(5-Bromo-2-fluorophenyl)methanolTo a solution of 5-bromo-2-fluorobenzaldehyde (30.0 g, 148 mmol) in EtOH was added sodium borohydride (8.39 g, 222 mmol) at 0 C. The resulting mixture was stirred with gradual warming to ambient temperature over 15 h, re-cooled to 0 C, and quenched with aq. saturated NH4C1 solution. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and evaporated in vacuo to yield the titled compound (30.3 g, quantitative) as a white sold, which was carried on to the next step without further purification.[M-OH"]+ 187.
With hydrogenchloride; sodium borohydrid; In tetrahydrofuran; Triethylene glycol dimethyl ether;
A. 5-Bromo-2-fluoro-benzyl alcohol. To a solution of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 mL of THF at 0 C. is added 5 mL of sodium borohydride (2.0 M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0 C. for 25 minutes and then quenched by the addition of 1 N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H2 O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluding with 15% EtOAc/hexanes to afford the title compound (6.00 g, 29.3 mmol). 1 H NMR (CDCl3, 300 MHz) delta7.55 (dd, 1H), 7.36 (m, 1H), 6.89 (t, 1H), 4.71 (d, 2H), 2.11 (bs, 1H). EI MS, [M]+ =204, 206, Br pattern.
With hydrogenchloride; sodium borohydrid; In tetrahydrofuran; Triethylene glycol dimethyl ether;
A. 5-Bromo-2-fluoro-benzyl alcohol To a solution of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 mL of THF at 0 C. is added 5 mL of sodium borohydride (2.0M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0 C. for 25 min and then quenched by the addition of 1N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H2 O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluding with 15% EtOAc/hexanes to afford the title compound (6.00 g, 29.3 mmol). 1 H NMR (CDCl3, 300 MHz) delta7.55 (dd, 1H), 7.36 (m, 1H), 6.89 (t, 1H), 4.71 (d, 2H), 2.11 (bs, 1H). EI MS, [M]+ =204, 206, Br pattern.
With sodium tetrahydroborate; In methanol; at 0 - 25℃;
To a solution of 5-bromo-2-fluoro-benzaldehyde [(L.] Oeq. ) in MeOH (0.2M) at [0C] was added portionwise NaBH4 (2. [0EQ.).] The mixture was stirred at rt for [LH,] poured in HCl (1M) and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over [NA2SO4,] filtered and concentrated to afford the title compound as a white solid.
With sodium tetrahydroborate; In ethanol; at 0℃; for 1h;
To a cold (0 C) solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.2 mmol) in EtOH (100 mL) was added NaBH4 (2.00 g, 54.2 mmol) and the mixture was stirred at 0 C for 1 h. The reaction was quenched with 1 M aq HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to give the crude material. To a ice-cold solution of the crude alcohol in DMF (150 mL) were added imidazole (5.00 mL, 73.8 mmol) and tert-butyl(chloro)diphenylsilane (13.9 mL, 54.1 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 19/1) to give the title compound (15.7 g, 72% yield) as a pale yellow oil.1H NMR (CDCl3) delta: 1.11 (9H, s), 4.77 (2H, s), 6.85 (1H, t, J = 9.0 Hz), 7.29-7.49 (7H, m), 7.65-7.74 (5H, m). MS (FAB) m/z: 443 (M++H), calcd for C23H24BrFOSi: 442.
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 2h;
Step A. 5-Bromo-2-fluoro-phenyl-methanol To a mixture of 5-bromo-2-fluoro-benzaldehyde (25 g, 125 mmol) in THF/MeOH (100 mL / 20 mL) with ice-bath cooling was carefully added NaBH4 (4.75 g, 125 mmol) portionwise and the resulting mixture was stirred at 0 C for 2 hrs. The reaction mixture was added 50 mL of 0 and partitioned with EA. The aqueous phase was extracted with ethyl acetate twice and the combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrate. The residue was purified by short column chromatography on silica gel (PE/EA=8/1) to give the title compound.
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 2h;
Step A. 5-Bromo-2-fluoro-phenyl-methanol To a mixture of 5-bromo-2-fluoro-benzaldehyde (25 g, 125 mmol) in THF/MeOH (100 mL / 20 mL) with ice-bath cooling was carefully added NaBH4 (4.75 g, 125 mmol) portionwise and the resulting mixture was stirred at 0 C for 2 hrs. The reaction mixture was added 50 mL of 0 and partitioned with EA. The aqueous phase was extracted with ethyl acetate twice and the combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrate. The residue was purified by short column chromatography on silica gel (PE/EA=8/1) to give the title compound.
6-[(4-bromo-2-formyl-phenyl)-methyl-amino]-hexanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: 1-methyl-2-azepanone With sodium hydroxide for 8h; Heating;
Stage #2: With hydrogenchloride
Stage #3: 5-bromo-2-fluorobenzaldehyde With sodium carbonate In water; dimethyl sulfoxide Heating; Further stages.;
Stage #1: N-isopropyl-2-pyrrolidone With sodium hydroxide for 8h; Heating;
Stage #2: With hydrogenchloride
Stage #3: 5-bromo-2-fluorobenzaldehyde With sodium carbonate In water; dimethyl sulfoxide Heating; Further stages.;
Stage #1: N-isopropyl-2-pyrrolidone With sodium hydroxide In water for 3.5h;
Stage #2: 5-bromo-2-fluorobenzaldehyde With sodium carbonate In water; dimethyl sulfoxide for 5h; Heating / reflux;
Stage #1: N-n-butyl-2-pyrrolidinone With sodium hydroxide for 8h; Heating;
Stage #2: With hydrogenchloride
Stage #3: 5-bromo-2-fluorobenzaldehyde With sodium carbonate In water; dimethyl sulfoxide Heating; Further stages.;
84%
With sodium carbonate In hydrogenchloride; water; dimethyl sulfoxide
8 Synthesis of 4-(4-bromo-2-formyl-N-butylanilino)-butyric acid
Example 8 Synthesis of 4-(4-bromo-2-formyl-N-butylanilino)-butyric acid A solution of 1-butyl-2-pyrrolidone (3.75 ml) in concentrated hydrochloric acid (7 ml) was refluxed for 24 hours. The pH was adjusted to 6 with 6N aqueous sodium hydroxide. Further added were water (8 ml), sodium carbonate (10.60 g), and a solution of 5-bromo-2-fluorobenzaldehyde (5.10 g) in DMSO (25 ml), followed by stirring at 105°C to 110°C for 5.5 hours. The mixture was cooled to 50°C to 60°C, at which temperature 6N hydrochloric acid was added dropwise to adjust the pH to 6. The aqueous layer was washed with IPE, and the organic layer was extracted with 2N aqueous sodium hydroxide (25 ml). The aqueous layer was adjusted to pH = 1 and extracted with ethyl acetate/THF (4/1, 25 ml * 3), after which the organic layer was washed with a saturated aqueous sodium chloride solution (25 ml * 2). The organic layer was concentrated, and the concentrate was then purified on a silica gel column (n-hexane/ethyl acetate (2/1, then 1/1)) to give 4-(4-bromo-2-formyl-N-butylanilino)butyric acid (7.20 g, 84% yield) as an oil. 1H-NMR (CDCl3, δ, 300 MHz): 0.85 (3H, t, J = 7.3 Hz),1.23-1.28 (2H, m), 1.43-1.48 (2H, m), 1.86 (2H, tt, J = 7.1, 7.3 Hz), 2.34 (2H, t, J = 7.1 Hz), 3.11 (2H, t, J = 7.6 Hz), 3.19 (2H, t, J = 7.3 Hz), 7.06 (1H, d, J = 8.7 Hz), 7.57 (1H, dd, J = 8.7, 2.5 Hz), 7.90 (1H, d, J = 2.5 Hz), 10.22 (1H, s).
7-[benzyl-(4-bromo-2-formyl-phenyl)-amino]-heptanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
Stage #1: benzaldehyde; 7-aminoheptanoic acid With hydrogen In sodium hydroxide at 20℃;
Stage #2: With hydrogenchloride
Stage #3: 5-bromo-2-fluorobenzaldehyde With sodium carbonate Heating; Further stages.;
J. 1-(5-bromo-2-fluorophenyl)ethan-1-ol. To a solution of 5-Bromo-2-fluorobenzaldehyde (10.0 g., 49.26 mmol) in anhydrous ether (60 mL) at 0 C. was added 1.4M methyl magnesium bromide (THF/Tol. solution) (36.9 mL) dropwise. The solution stirred for 30 minutes and quenched with water (50 mL) followed by 1N HCl (10 mL). The organics were separated and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (10.8 g., 100%). MS (ESI) m/z 218 [M+1]+, 220 [M+2]+.
98.51%
In diethyl ether; at 0℃; for 0.25h;
Step-1: Synthesis of 1-(5-bromo-2-fluorophenyl)ethan-1-ol To a stirred solution of 5-bromo-2-fluorobenzaldehyde (5.0 g, 24.63 mmol, 1.0 eq) in diethylether (50 mL) was dropwise added methylmagnesium bromide (12.3 mL, 36.94 mmol, 1.5 eq) at 0 C. The resulting mixture was stirred at 0 C. for 15 min. The progress of reaction was monitored by LCMS. The resection mixture was quenched with saturated solution of NH4Cl (50 mL) extracted with EtOAc (2*50 mL). The combined organic extracts were washed with water (50 mL), with brine (50 mL) dried over Na2SO4 and concentrated under reduced to afford the desired compound 1-(5-bromo-2-fluorophenyl)ethan-1-ol (5.31 g, 98.51%) as yellow liquid. 1H NMR (400 MHz, CDCl3) 7.64 (dd, J=2.41, 6.36 Hz, 1H), 7.35 (ddd, J=2.63, 4.60, 8.55 Hz, 1H), 6.91 (dd, J=8.77, 9.65 Hz, 1H), 5.16 (d, J=5.26 Hz, 1H), 1.88 (brs, 1H), 1.50 (d, J=6.14 Hz, 3H).
93%
[00199] 5-Bromo-2-fluro-phenyl-methanol: 5-Bromo-2-fluorobenzaldehyde(commercially available from Aldrich)( 150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield = 93%). The product was used directly in the next step without further purification.
93%
at 0℃; for 1.0h;
Commercially available 4a (150.0 g,</p> <p id="p0144" num="0144">739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 ml, 812 mmol) was added dropwise via an additional funnel. The reaction mixture was continually stirred for one more hour after the addition. After the reaction was completed, the mixture was slowly poured into 500 ml ice water plus 250 ml saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 ml x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (4b) (150 g, yield = 93%). The product was used directly for the next step without further purification.
53%
Methylmagnesium bromide (3M solution in tetrahydrofuran, 18 ml, 54.2 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) under nitrogen at 0 C. over 30 min. The resulting solution was allowed to warm to room temperature over 14 h, upon which TLC analysis showed no remaining starting material, and two new products. The mixture was quenched with water, diluted with ethyl acetate and the organic phase removed and dried over sodium sulfate. This was then concentrated and purified by column chromatography (120 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 50% hexanes). The second fraction was collected as the product, providing the alcohol (5.8 g, 53%) as an oil; 1H NMR (500 MHz, CDCl3) delta 7.65-7.63 (dd, J=6.5, 2.6 Hz, 1H), 7.36-7.33 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.93-6.89 (dd, J=9.9, 8.7 Hz, 1H), 5.17-5.16 (m, 1H), 1.91-1.90 (m, 1H), 1.51-1.49 (d, J=6.4 Hz, 3H).
Preparation of 5-bromo-3-methyl-1/-/-indazole 104.; Scheme 2 EPO <DP n="70"/>To a solution of 5-bromo-2-fluorobenzaldehydbeta 101 (100 g, 0.492 mol.) in ether (500 ml_), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (i.e., diethyl ether) (173 mL, 0.516 mol.) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-bromo-2-fluoro-phenyl)- ethanol 102 (106 g, 0.484 mol.) which was used in the next step without further purification. To a solution of 1 -(5-bromo-2-f luoro-phenyl)-ethanol 102 (105 g, 0.479 mol.) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol.). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite (i.e., diatomaceous earth) and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) which was used in the next step without further purification.
Example 102A A solution of 5-bromo-2-fluorobenzaldehyde (24.75 g; 122 mmol) in Et2O (125 mL) at 0 C. was treated with 3.0 M MeMgBr in Et2O (43 mL, 129 mmol), stirred for 30 min., carefully diluted with water then acidified with 10% HCl (aq). The aqueous was extracted with Et2O, rinsed successively with 10% HCl (aq), water, and brine, dried (MgSO4), and evaporated to give the desired product (26.6 g; 99%) of sufficient purity to carry on to the next step.
46 g
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL chi 3). The combined organic layers were washed with brine (500 mL chi 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 31-2 (46.0 g).
Step A; To a solution of 5-bromo-2-fluorobenzaldehyde 101 (100 g, 0.492 mol) in ether (500 ml_), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (173 ml_, 0.516 mol) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-Bromo-2-fluoro-phenyl)-ethanol 102 (106 g, 0.484 mol) which was used in the next step without further purification.
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with H4C1 (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL chi 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 2A-2 (46.0 g, crude).
In tetrahydrofuran; at 0℃; for 0.5h;
A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THE (500.0 mL) was cooled to 0C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0C for 0.5 h, quenched with NH4C1 (500 mL) and extracted with ethyl acetate (500 mL >< 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02) to afford compound 2A-2 (46.0 g, crude).
47 Compound 49-2
To N2H4.H2O (85%, 30 mL) was added compound 49-1 (600 mg, 3 mmol), and the reaction solution was heated to 100° C. and stirred for 12 h. To the solution, water (50 mL) and DCM (20 mL) were added and the resulting solution was extracted with DCM (20 mL×2). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give title compound 49-2 (white solid, 400 mg, Yield 96%). LCMS (ESI) m/z: 199 (M+2)
50%
With hydrazine at 100℃;
45%
With hydrazine hydrate In 1,2-dimethoxyethane for 15h; Heating;
39%
With hydrazine at 100℃; for 24h;
16.1
Step 1: 5-bromo-lH-indazoleThe solution of 5-bromo-2-fluorobenzaldehyde (406 mg, 2.0 mmol) in anhydrous hydrazine (10 mL) was heated at 100 °C for 24 hours, then cooled to room temperature. After removal of the residual anhydrous hydrazine under reduced pressure, the residue was separated between EtOAc and water. The organic phase was washed with brine, dried over anhydrous Na2S04, concentrated under reduced pressure and purified with column chromatography (EtOAc : petrol ether = 1 : 3) to give the desired product (154 mg, 39%).1H NMR (CDC13): δ 10.14 (1H, br), 8.03 (1H, d, / = 0.8 Hz), 7.92 (1H, dd, / = 0.8 Hz, / = 1.6 Hz), 7.48 (1H, dd, / = 1.6 Hz, / = 8.8 Hz), 7.40 (1H, d, / = 8.8 Hz).
38%
With hydrazine for 5h; Heating;
38%
With hydrazine
35.A 5-bromo-1H-indazole
Example 35A 5-bromo-1H-indazole A mixture of 5-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol) and 98% hydrazine (20 mL) was heated to reflux for 5 hours, poured over ice, and filtered. The solid was recrystallized from H2O/methanol to provide the desired product (3.7 g, 38%).
38%
With hydrazine for 5h; Heating / reflux;
35.A 5-bromo-1H-indazole
Example 35A 5-bromo-1H-indazole A mixture of 5-bromo-2-fluorobenzaldehyde (10 g, 49.2 mmol) and 98% hydrazine (20 mL) was heated to reflux for 5 hours, poured over ice, and filtered. The solid was recrystallized from H2O/methanol to provide the desired product (3.7 g, 38%).
Multi-step reaction with 2 steps
1: potassium carbonate / 1,2-dimethoxy-ethane / 40 °C
2: hydrazine / 1,2-dimethoxy-ethane / Heating
With hydrazine for 4h; Heating / reflux;
Preparation of 5-bromoindazole 162 ; Scheme 23To 5-bromo-2-fluorobenzaidehyde 161 (2.0 g, 9.85 mmol.) was added hydrazine (10 mL). The reaction mixture was heated under gentle reflux for 4 hours. Excess hydrazine was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromoindazole 162 (1.04 g, 5.28 mmol.).
With hydrazine at 117℃;
Multi-step reaction with 2 steps
1: potassium carbonate / 1,2-dimethoxyethane / 5 h / 40 °C
2: hydrazine hydrate / Reflux
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 40 °C
2: hydrazine hydrate / Reflux
With triethylamine; In dimethyl sulfoxide; at 95℃; for 2h;
(a) Ethyl thioglycolate, Et3N, DMSO, 95 C., 2 h [0304] The substance was obtained according to the general procedure, yielding the title compound as a off-white crystals (75%). [0305] 1H-NMR (400 MHz, DMSO-d6); δ (ppm): 1.33 (t, 3H), 4.36 (dd, 2H), 7.63 (d, 1H), 8.04 (d, 1H), 7.13 (s, 1H), 7.25 (s, 1H)
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 2.5h;
5-Bromo-2-fluorobenzaldehyde (25 g) and potassium carbonate (34 g) were suspended in N,N-dimethylformamide (125 ml), and ethyl thioglycolate (14.2 ml) was added dropwise. After being stirred for 30 minutes at room temperature, this was heated for 2 hours at 80C. It was then poured into ice-cooled aqueous citric acid solution and extracted with ethyl acetate, the organic layer was washed with water and sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The precipitated crystals were filtered out and washed with hexane to obtain ethyl 5-bromo-1-benzothiophen-2-carboxylate (29.2 g) as colorless crystals. 1H-NMR (300MHz, CDC13) 5 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.54 (1H, dd, J = 1.7, 8.7 Hz), 7.73 (1H, d, J = 8.7 Hz), 7.97 (1H, s), 8.01 (1H, d, J = 1.7 Hz)
With sodium carbonate;
Example 218 Synthesis of ethyl 5-bromobenzo[b]thiophene-2-carboxylate. To a solution of 5-bromo-2-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 2-mercaptoacetate (1.2 g, 10 mmol) in EtOH (40 mL) was added Na2CO3 (1.27 g, 12 mmol). The reaction mixture was stirred at reflux for 14 h. Then the mixture was concentrated in vacuo. Water (20 mL) was added and the mixture was extracted with DCM (50 mL*3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc=1/1) to give the ethyl 5-bromobenzo[b]thiophene-2-carboxylate as a yellow solid (2.3 g, yield: 80%). ESI-MS [M+H]+: 284.7, 286.7.
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 15h;
4.1.1. General procedures for the preparation of 2a-2n
General procedure: To a stirred solution of compound 1a-1n (9.90 mmol) in DMF (20 mL) were added methyl thioglycolate (10.9 mmol) and potassium carbonate (39.6 mmol). The resulting mixture was stirred at 60 °C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed under reduced pressure to afford the title compound 2a-2n [31,34].
89%
With triethylamine In dimethyl sulfoxide at 80℃; for 2h; Inert atmosphere;
69%
With triethylamine In N,N-dimethyl-formamide at 60℃; for 12h;
13B methyl 5-bromobenzo[b]thiophene-2-carboxylate (B-113)
To a solution of 5-bromo-2-fluorobenzaldehyde (6.0 g, 30 mmol) and methyl 2- mercaptoacetate (3.8 g, 35mmol) in N, N-dimethyl formamide (50 mL) was added triethylamine (8.97 g, 89 mmol) portionwise at room temperature. The resulting mixture was stirred at 60 °C for 12 hours. On completion, the mixture was poured into ice -water resulting in formation of a solid. The mixture was stirred for 30 min., and the solid was collected by filtration, washed with water and dried in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 7: 1] to give compound B-113 (5.5 g, 69% yield) as a white solid.
69.1%
With sodium hydride
12A Beispiel 12A; 5-Brom-1-benzothiophen-2-carbonsäuremethylester
Ausgehend von 2.99 g (14.7 mmol) [5-BROM-2-FLUORBENZALDEHYD] werden mit 0.88 g (22.1 mmol) Natriumhydrid (60%-ig) und 1.72 g (16.2 mmol) Mercaptoessigsäure- methylester nach der allgemeinen Arbeitsvorschrift A 2.76 g (69.1 % d. Th) der Titel- verbindung erhalten. [H-NMR] (200 MHz, DMSO-d6) : [8] [= 8.] 29 (d, 1H), 8.18 (s, 1H), 8. 08 (d, 1H), 7.69 (dd, 1H), 3. [90] (s, 3H). HPLC (Methode [1)] : Rt = 5.2 min. MS (ESIpos) : m/z = 270 (M+).
49%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 15h;
72a.1
Step 1: Methyl 5-bromobenzo [b] thiophene-2-carboxylate (260a) [0418] To a stirred solution of 259a (2 g, 9.90 mmol) in DMF (20 mL) was added methyl thioglycolate (10.9 MOL, 0. 97 mL) and potassium carbonate (5.47 g, 39.6 MMOL). The resulting mixture was stirred at 60°C for 15 hours. The DMF was removed under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 40 mL). The organic phase was separated and dried with sodium sulfate, the solvent was removed under reduced pressure and the resulting solid was dried under vacuum. This afforded 260a as a white solid (1.3 g, 49% YIELD). H NMR: (DMSO) 8 8.22 (d, J=2.0 Hz, 1H), 8.11 (s, 1H), 8.00 (d, J=8. 0 Hz, 1H), 7.62 (dd, J=8. 6, 2.0 Hz, 1H), 3.88 (s, 3H).
With anhydrous sodium carbonate In methanol
274.A methyl 5-bromo-1-benzothiophene-2-carboxylate
EXAMPLE 274A methyl 5-bromo-1-benzothiophene-2-carboxylate A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methyl thioglycolate (2.64 mL, 29.6 mmol), and Na2CO3 (3.14 g, 29.6 mmol) in methanol was heated to reflux for 1 hour, poured into brine, and extracted with ethyl acetate (3*). The combined extracts were washed with brine and filtered through silica gel to provide the desired product. MS (ESI(-)) m/e 270 (M-H)-.
With anhydrous sodium carbonate In methanol
274.A methyl 5-bromo-1-benzothiophene-2-carboxylate
Example 274A methyl 5-bromo-1-benzothiophene-2-carboxylate A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methyl thioglycolate (2.64 mL, 29.6 mmol), and Na2CO3 (3.14 g, 29.6 mmol) in methanol was heated to reflux for 1 hour, poured into brine, and extracted with ethyl acetate (3*). The combined extracts were washed with brine and filtered through silica gel to provide the desired product. MS (ESI(-)) m/e 270 (M-H)-.
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 15h;
With sodium hydride In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 60℃;
Stage #1: 5-bromo-2-fluorobenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: Methyl thioglycolate In N,N-dimethyl-formamide at 60℃;
5.5. General procedure for the synthesis of intermediates AM4a-m
General procedure: To a solution of 15a-m in DMF, K2CO3 (25 mmol, 3.45 g) wasadded and the mixturewas stirred at room temperature for 30 min.Then 16 was added dropwise. The reactionwas allowed to warm to60 °C and monitored by TLC. The reaction was poured into waterand the mixture was extracted with ethyl acetate three times. Thecombined extracts were dried, concentrated and purified to affordthe intermediate 17a-m. Intermediate AM4a-mwas prepared in a similar manner as thatfor intermediate AM1, using 17a-m instead of 9.
Stage #1: 5-bromo-2-fluorobenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: Methyl thioglycolate In N,N-dimethyl-formamide at 60℃;
5.5. General procedure for the synthesis of intermediates AM4a-m
General procedure: To a solution of 15a-m in DMF, K2CO3 (25 mmol, 3.45 g) wasadded and the mixturewas stirred at room temperature for 30 min.Then 16 was added dropwise. The reactionwas allowed to warm to60 °C and monitored by TLC. The reaction was poured into waterand the mixture was extracted with ethyl acetate three times. Thecombined extracts were dried, concentrated and purified to affordthe intermediate 17a-m. Intermediate AM4a-mwas prepared in a similar manner as thatfor intermediate AM1, using 17a-m instead of 9.
With diethylamino-sulfur trifluoride; In dichloromethane;Heating / reflux;
5-Bromo-2-fluorobenzaldehyde (2 g, 9.8 mmol) in CH2Cl2 (50 ml) was treated at 0C. with (diethylamino)sulfur trifluoride (2 ml, 14.8 mmol). The reaction mixture was refluxed overnight and then quenched with saturated solution of NaHCO3. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethyl acetate 99 : 01) to provide 4-bromo-2-difluoromethyl-1-fluoro-benzene (1.55 g, 70%) as a colorless oil, MS: m/e=226.0 (M+H+).
61%
With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 18.0h;Inert atmosphere;
[143] To a solution of 5-bromo-2-fluoro-benzaldehyde (4.06 g, 20 mmol) in DCM (50 mL) was added DAST (diethylaminosulfur trifluoride) (4.03 g, 25 mmol) and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture was quenched into ice-water and extracted with DCM. The organic layer was dried and concentrated. Yield: 2.74 g (61 %)
With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 1.0h;
Preparation 3:4-BROMO-2-(DIFLUOROMETHYL)-l-FLUOROBENZENE5-bromo-2-fluorobenzaldehyde (2.0 g, 9.85 mmol) and diethylaminosulfur trifluo?de (2.2 ml) was stirred at ambient temperature for 1 hour. Methylene chloride (100 ml) was added and the solution was cooled to 0 0C. Aqueous sodium bicarbonate (10%, 50 ml) was added slowly and the phases were separated. The organic phase was washed with water (50 ml), dried (MgSO4), filtered and evaporated to dryness to yield the crude product (1.79 g). MS m/z (rel. intensity, 70 eV) 226 (M+, 98), 224 (M+, bp), 207 (17), 145 (79), 125 (22).
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-fluoro-phenyl)-acrylamide[ No CAS ]
3-(2-chloro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-iodo-phenyl)-acrylamide[ No CAS ]
3-(3-chloro-2-fluoro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-naphthalen-2-yl-acrylamide[ No CAS ]
3-(5-bromo-2-fluoro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-3-(3,4-dimethoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(1-methyl-1H-indol-3-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-imidazol-1-yl-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-fluoro-4-iodo-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2,4,6-trimethyl-phenyl)-acrylamide[ No CAS ]
2-cyano-3-(2-difluoromethoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-acrylamide[ No CAS ]
3-(2-chloro-6-fluoro-3-methyl-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2,3,6-trichloro-phenyl)-acrylamide[ No CAS ]
2-cyano-3-(3-ethoxy-2-hydroxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
{2-[2-cyano-2-(5-ethyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-vinyl]-phenoxy}-acetic acid[ No CAS ]
2-cyano-3-(3,4-dihydroxy-5-methoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-3,5-dimethoxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-hydroxy-4,6-dimethoxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(3-p-tolyloxy-phenyl)-acrylamide[ No CAS ]
3-(4-benzyloxy-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hexyloxy-phenyl)-acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 0.25 M stock solution of 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2- yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. Benzaldehyde and other heterocyclic aldehydes were individually weighed and were dissolved to 0.25 M using a Tecan Genesis workstation. The Tecan was used to dispense 200 muL of template 1 to each reaction vessel then was used to dispense 400 L of aldehyde stock solutions to individual reaction vessels. The reaction vessels were sealed and were heated at 45-50 C, with agitation, for 18 hours. The reaction vessels were then cooled, unsealed, and 50 L of aminopropyl-functionalized silica gel (Aldrich) was dispensed to each reaction vessel. Activated 4 angstrom molecular sieves (powdered, 50 L) were then dispensed to each reaction. Reaction vessels were then sealed and were heated at 45-50 C with agitation for 3 h. Reactions were then unsealed and were filtered to remove solids. B. Sample solutions were dried in vacuo using a Genevac. Samples were dissolved in 500 pL of DMSO and 500 pL of methanol and purity was determined by LC-MS with using a combination of UV254, UV220, and ELSD detection [purity = (UV254+UV220/2)]. The HPLC conditions were: 4.6 mm x 50 mm C18 column, 10-90% acetonitrile gradient over 5 minutes (mobile phases were H20 with 0.05 % TFA and acetonitrile with 0.035 % TFA), with a flow rate of 3.5 ml/min. Samples which were <80% pure were purified using a mass directed LC-MS purification. Purified samples were concentrated in vacuo then were dissolved in DMSO and were reformatted into 96 well microtiter plates. Samples were tested for purity using LC-MS and quantity was estimated by correlating ELSD response to a standard concentration-ELSD response curve. Samples were then concentrated to dryness and were dissolved in DMSO to a final concentration of 10 uM based on ELSD quantitation. C. The following compounds were prepared in the manner described above in Steps A and B using the appropriate aldehyde in place of benzaldehyde: 2-Cyano-3- (3, 4-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 3- (4-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES) : 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- phenyl ester; MS (ES): 343 (MH+); 2-Cyano-3- (2, 4-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Bromo-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 363 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-phenyl)- acrylamide ; MS (ES): 303 (MH+) ; 3- (4-tert-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 3- (2-Chloro-4-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 2-Cyano-3- (2, 5-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-5- (4-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-iodo-5- methoxy-phenyl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 3-(4-Benzyloxy-3,5-dimethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 419 (MH+) ; 2-Cyano-3- (3, 5-dibromo-2-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES) : 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (4-hexyloxy-phenyl)- acrylamide ; MS (ES): 385 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- 2, 6-dimethoxy-phenyl ester; MS (ES): 403 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-imidazol-1-yi-phenyl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-trifluoromethyl-phenyl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Chloro-3, 4-dimethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- ( 1-methyl-1 H-indol-3-yl)- acrylamide ; MS (ES): 338 (MH+) ; 2-Cyano-3- (2, 6-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 2-Cyano-3-(4-dimethylamino-2-nitro-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-iodo-phe...
With potassium carbonate In N,N-dimethyl-formamide for 6h; Reflux;
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 96h;
35 Reference Example 35
Reference Example 35 A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), pyrrolidine (1.33 ml) and potassium carbonate (2.55 g) in DMF (25 ml) was stirred at 80°C for 4 days. Water was added to the reaction system, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 19 → 1: 9) to give 5-bromo-2-pyrrolidin-1-ylbenzaldehyde (2.50 g) as a yellow oily material. 1H-NMR (300 MHz, CDCl3) δ 1.98-2.02 (4H, m), 3.32-3.37 (4H, m), 6.71 (1H, d, J=9.0 Hz), 7.41 (1H, dd, J=9.0, 2.7 Hz), 7.78 (1H, d, J=2.7 Hz), 10.01 (1H, s). IR (neat) 1667, 1593, 1480, 1462, 1406, 1167, 912, 743 cm-1
With potassium carbonate In N,N-dimethyl-formamide Reflux;
Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h; Sealed tube; Inert atmosphere;
With sodium carbonate In water; dimethyl sulfoxide at 125℃; for 20h;
63 Reference Example 63
Reference Example 63 A mixture of 5-bromo-2-fluorobenzaldehyde (1.35 g), methylpropylamine (0.54 g) and sodium carbonate (0.98 g) in DMSO (10 ml) and water (2.5 ml) was stirred at 125°C for 20 hours. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 49 → 1: 19) to give 5-bromo-2-[methyl(propyl)amino]benzaldehyde (1.43 g) as a yellow oily material. 1H-NMR (200 MHz, CDCl3) δ 0.88 (3H, t, J=7.5 Hz), 1.52-1.71 (2H, m), 2.87 (3H, s), 3.04-3.11 (2H, m), 6.97 (1H, d, J=8.8 Hz), 7.53 (1H, dd, J=8.8, 2.6 Hz), 7.87 (1H, d, J=2.6 Hz), 10.17 (1H, s).
With sodium carbonate In water; dimethyl sulfoxide for 20h; Heating / reflux;
19 Reference Example 19
Reference Example 19 A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), isobutylmethylamine (1.61 g) and sodium carbonate (2.60 g) in DMSO (40 ml) and water (25 ml) was heated under reflux for 20 hours. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane = 1: 29) to give 5-bromo-2-[isobutyl(methyl)amino]benzaldehyde (3.14 g) as a yellow oily material. 1H-NMR (300 MHz, CDCl3) δ 0.90 (6H, d, J=6.6 Hz), 1.89-2.04 (1H, m), 2.89 (3H, s), 2.93 (2H, d, J=7.2 Hz), 6.98 (1H, d, J=8.7 Hz), 7.52 (1H, dd, J=8.7, 2.6 Hz), 7.86 (1H, d, J=2.6 Hz), 10.19 (1H, s). IR (neat) 1684, 1588, 1485, 1389, 1260, 1179, 1154, 1113, 912, 880, 741 cm-1
With sodium carbonate; In water; dimethyl sulfoxide; at 80℃; for 4h;
Reference Example 140 A suspension of 5-bromo-2-fluorobenzaldehyde (2.5 g), <strong>[742100-61-4]3,4-dimethylpyrrolidine hydrochloride</strong> (2.51 g) and sodium carbonate (3.59 g) in DMSO (50 ml) and water (25 ml) was stirred for 4 hours at 80C under a nitrogen atmosphere. After returning to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 ? hexane: ethyl acetate = 6: 1) to give 5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)benzaldehyde (2.84 g) as a brown oily material. 1H-NMR (300 MHz, CDCl3) delta 0.99 (6H, d, J=6.9 Hz), 2.35-2.40 (2H, m), 3.06-3.11 (2H, m), 3.44-3.49 (2H, m), 6.66 (1H, d, J=9.0 Hz), 7.39 (1H, dd, J=9.0, 2.7 Hz), 7.78 (1H, d, J=2.7 Hz), 10.00 (1H, s).
With sodium carbonate; In water; dimethyl sulfoxide; at 75℃; for 5h;
Reference Example 129 A suspension of 5-bromo-2-fluorobenzaldehyde (2.5 g), <strong>[644971-22-2]3-hydroxymethylpyrrolidine hydrochloride</strong> (3.39 g) and sodium carbonate (3.26 g) in DMSO (75 ml) and water (37.5 ml) was heated for 5 hours at 75C under a nitrogen atmosphere. After returning to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 ? hexane: ethyl acetate = 1: 4) to give 5-bromo-2-[3-(hydroxymethyl)pyrrolidin-1-yl]benzaldehyde (2.9 g) as a yellow oily material. 1H-NMR (300 MHz, CDCl3) delta 1.77-1.89 (1H, m), 2.09-2.19 (1H, m), 2.51-2.60 (1H, m), 3.26-3.50 (4H, m), 3.65-3.78 (2H, m), 6.73 (1H, d, J=9.0 Hz), 7.45 (1H, dd, J=9.0, 2.7 Hz), 7.79 (1H, d, J=2.7 Hz), 10.01 (1H, s).
With sodium carbonate; In water; dimethyl sulfoxide; at 90℃; for 4h;
Reference Example 174 A suspension of 5-bromo-2-fluorobenzaldehyde (300 mg), ethyl pyrrolidin-3-yl acetate hydrochloride (401 mg) and sodium carbonate (330 mg) in DMSO (10 ml) and water (5 ml) was stirred for 4 hours at 90C under a nitrogen atmosphere. After returning to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 ? hexane: ethyl acetate = 3: 1) to give 5-bromo-2-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]benzaldehyde (455 mg) as a yellow oily material. 1H-NMR (300 MHz, CDCl3) delta 1.27 (3H, t, J=6.9 Hz), 1.69-1.79 (1H, m), 2.15-2.30 (1H, m), 2.46-2.49 (2H, m), 2.65-2.80 (1H, m), 3.15-3.21 (1H, m), 3.30-3.60 (3H, m), 4.12-4.19 (2H, m), 6.71 (1H, d, J=9.0 Hz), 7.43 (1H, dd, J=9.0, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz), 9.99 (1H, s).
With sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 8h;
To a solution of 5-bromo-2-fluorobenzaldehyde (15 g, 73.8 mmol) in DMSO (150 ml.) and water (40 ml.) were added 2-methylpyrrolidine (9.8 ml_, 96 mmol) and sodium carbonate (15.7 g, 148 mmol). The resulting mixture was heated at 1100C for 8 hours. The reaction mixture was cooled at RT, diluted with water (1000 ml.) and extracted with MTBE (2x100 ml_). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a yellow oil (17 g, 85%). 1H NMR (DMSO-d6, 400 MHz) delta 9.94 (1 H, s), 7.75 (1 H, s), 7.51 (1 H, d), 6.93 (1 H, d), 3.92 (1 H, m), 3.68 (1 H, m), 2.97 (1 H, t), 2.49- 2.18 (1 H, m), 1.88 (1 H, m), 1.57-1.68 (2H, m), 1.10 (3H, d).
With sodium carbonate; In water; dimethyl sulfoxide; at 100℃; for 12h;
Reference Example 52 A mixture of 5-bromo-2-fluorobenzaldehyde (2.50 g), 2-methylpyrrolidine (1.63 ml) and sodium carbonate (2.6 g) in DMSO (25 ml) and water (5 ml) was stirred at 100C for 12 hours. Water was added to the reaction system, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate: hexane 1: 19 ? 1: 9) to give 5-bromo-2-(2-methylpyrrolidin-1-yl)benzaldehyde (2.76 g) as a yellow oily material. 1H-NMR (200 MHz, CDCl3) delta 1.20 (3H, d, J=5.8 Hz), 1.63-1.82 (2H, m), 1.88-2.03 (1H, m), 2.08-2.32 (1H, m), 3.03-3.13 (1H, m), 3.69-3.96 (2H, m), 6.81 (1H, d, J=9.2 Hz), 7.44 (1H, dd, J=9.0, 2.6 Hz), 7.82 (1H, d, J=2.6 Hz), 10.04 (1H, s). IR (neat) 1674, 1590, 1474, 1402, 1175, 912, 741 cm-1Reference Example 53
Stage #1: (R)-3-aminoquinuclinine; 5-bromo-2-fluorobenzaldehyde With sodium triacetoxyborohydride; acetic acid; triethylamine In 1,2-dichloro-ethane at 20℃; for 4.5h;
Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane
77.1
Sodium triacetoxyborohydride (1.6 g, 7.53 mmol) and enough acetic acid to bring the pH to 5 were added to a solution of 5-bromo-2-fluorobenzaldehyde (510 mg, 2.51 mmol), (R)-(-)-l-aza- bicyclo[2.2.2]oct-3i?-ylamine (1.0 g, 5.02 mmol) and triethylamine (508 mg, 5.02 mmol) in 8 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 4.5 h, and then it was quenched by the careful addition of 1 M sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 816 mg of product.
a a
a 4-bromo-2-phenoxybenzaldehyde The title compound was prepared in a 46% yield from 5-bromo-2-fluoro-benzaldehyde and phenol in a manner similar to that described for the preparation of 5-bromo-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ10.32 (s, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 7.46 (t, 2H), 7.27 (t, 1H), 7.18 (d, 2H), 6.90 (d, 1H) RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6*250 mm; 25%-100% acetonitrile-0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.08 min.
With hydrogenchloride; iron(III) chloride; In water; N,N-dimethyl-formamide;
Step A 5-Cyano-2-fluorobenzaldehyde To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190 ° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65 ° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10percent sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product: 1H NMR (CDCl3) delta 10.34 (m, 1H), 8.21 (m, 1H), 7.90 (m, 1H), 7.35 (m, 1H).
With hydrogenchloride; iron(III) chloride; In water; N,N-dimethyl-formamide;
Step A 5-Cyano-2-fluorobenzaldehyde To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10percent sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product: 1H NMR (CDCl3) delta 10.34 (m, 1H), 8.21 (m, 1H), 7.90 (m, 1H), 7.35 (m, 1H).
PREPARATION 88(1) To a solution of 5-bromo-2-fluorobenzaldehyde (10 g) in dimethylformamide (60 mL) were added zinc cyanide (6.92 g) and tetrakis(triphenylphosphine)palladium(O) (2.28 g), and the mixture was stirred at 80° C. for 6 hours. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluding with a mixture of hexane and ethyl acetate (3:1) to give 5-cyano-2-fluorobenzaldehyde (5.3 g) as a solid substance. NMR (DMSO-d6, delta): 7.35 (1H, t, J=9 Hz), 7.91 (1H, m), 8.22 (1H, dd, J=2, 7 Hz), 10.36 (1H, s); Mass m/z: 150 (M++1).
With diethylaminosulfur trifluoride; In dichloromethane;
4-Bromo-2-difluoromethyl-1-fluoro-benzene 5-Bromo-2-fluorobenzaldehyde (2 g, 9.85 mmol) was dissolved in CH2Cl2 (50 ml). The reaction mixture was put under an argon atmosphere and cooled to 0 C. Diethylaminosulfur trifluoride (2.04 ml, 14.78 mmol) was added dropwise. The mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with a saturated aqueous NaHCO3 solution. The layers were separated and the aqueous one was extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the solvent evaporated. The brown oil was chromatographed (silica, elution hexane/AcOEt) to afford the title compound (1.55 g, 70%) as a colorless oil. MS: m/e=226.0 (M+H+).
With hydrogenchloride; potassium carbonate; magnesium; triphenylphosphine; In tetrahydrofuran;
Referential Example 2 Production of 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde Under an argon atmosphere, magnesium (1.25 g, 51.5 mmol) was suspended in 100 ml of tetrahydrofuran, which was then refluxed. Under reflux, 50 ml of a tetrahydrofuran solution of bromophenetole (10 g, 50 mmol) was dropped and refluxed for 2 hours. After cooling to -11 C., a solution of trimethoxyborane (5.6 ml, 50 mmol) in 50 ml of tetrahydrofuran was dropped at -11 to -8 C. Stirring was conducted at -10 C. for 1 hour. At room temperature, palladium (II) acetate (64 mg, 0.285 mmol) and subsequently triphenylphosphine (299 mg, 1.14 mmol) were added and stirred at room temperature for 30 minutes. 5-Bromo-2-fluorobenzaldehyde (5.79 g, 28.5 mmol) and subsequently 30 ml of an aqueous solution of potassium carbonate (20.7 g, 150 mmol) were added at room temperature and heated under reflux for 5 hours. After cooling to room temperature, 170 ml of a 2N hydrochloric acid was dropped at 20 to 30 C. After phase separation had occurred, the water layer was extracted with 80 ml of toluene.
ethyl 6-bromo-2H-thiochromene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With hydrogenchloride; potassium carbonate In N,N-dimethyl-formamide
R.237 REFERENCE EXAMPLE 237
REFERENCE EXAMPLE 237 To a solution of 5-bromo-2-fluorobenzaldehyde (0.49 g, 2.62 mmol) and ethyl 3-mercaptopropionate (0.37 ml, 2.88 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.90 g, 6.55 mmol), and the mixture was stirred at room temperature for 1 hour and then at 70° C. for 15 hours. The mixture was poured into ice-water, and made pH 4 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography [hexane:ethyl acetate (5:1)] to give ethyl 6-bromo-2H-thiochromene-3-carboxylate (0.45 g, 58%) as yellow powder, a part of which was recrystallized from ethanol to give pale yellow needles. m.p. 87° C.; 1 H-NMR (CDCl3) δ: 7.47 (1H, br s), 7.26-7.38 (2H, m), 7.14 (1H, d, J=8.0), 4.31 (2H, q, J=7.4), 3.73 (2H, d, J=1.2), 1.36 (3H, d, J=7.4). Anal. Calcd for C12 H11 BrO2 S: C; 48.17, H; 3.71. Found: C; 48.07, H; 3.77.
With hydrogenchloride; hexamethylenetetramine; acetic acid; In water;
5-Bromo-2-fluorobenzaldehyde A mixture of 79.5 g (0.296 mol) of <strong>[99725-12-9]4-bromo-2-bromomethyl-1-fluorobenzene</strong> (prepared according to G. E. Stokker, A. W. Alberts et al., J. Med. Chem., 1986, 29, 170), 126 ml of acetic acid, 82.7 g (0.59 mol) of hexamethylenetetramine and 126 ml of water is heated for 2 hours at reflux. The mixture is cooled to 90 C., 99.5 ml of concentrated hydrochloric acid are added and the mixture is heated for 30 min at reflux. Cooling, extraction with ether, washing with water, washing with an aqueous NaHCO3 solution, washing with water, drying over Na2 SO4, filtration and evaporation under vacuum are carried out. The residue is purified by chromatography on silica (eluent: 10/1 hexane/ethyl acetate). Yd.: 23.6 g (39%) 1 H N.M.R. (CDCl3): 6.8 to 8.1 (3H, m), 10.3 (1H, s).
Step 26.1: 2-Amino-6-bromo-quinazoline In a 250 mL reaction tube 9.30 g (45.4 mmol) 5-bromo-2-fluorobenzaldehyde and 12.40 g (68.1 mmol) guanidine carbonate are dissolved in 130 mL N, N-dimethylacetamide. After bubbling the solution with nitrogen for 1 h, the tube is sealed and heated at 140 C. for 3 h. After cooling the reaction is diluted with 50 mL of a saturated NaHCO3 solution and 300 mL water and stirred for 0.5 h. The resulting precipitate is collected, washed first with 50 mL water followed by 50 mL ether, and air dried to give 4.0 g (17.7 mmol) of the titled compound: HPLC tR=5.6 min; MS-ES+: (M+H)+=225.
In ISOPROPYLAMIDE; at 140℃; for 5h;
Method 10 6-Bromoquinazolin-2-amine; 2-Fluoro-5-bromobenzaldehyde (1.0 g, 4.9 mmol) and guanidine carbonate (1.3 g, 7.4 mmol, 1.5 equiv) were dissolved in DMA and heated to 140 0C for 5 h. The reaction was treated with H2O and the resulting precipitate was collected by vacuum filtration; m/z 225.
In ISOPROPYLAMIDE; at 18 - 140℃;
As shown in Scheme 14, guamdine carbonate (5.4 g, 0.03 mol) was added to the DMA (75 mL) solution of 3-bromo-6-fluoro-benzaldehyde (4.06g, 0.02 mol) at room temperature. The solution was heated to 140 0C overnight, and the solvent was removed in vacuo. The residue was worked up with AcOEt/ H2O. The organic layer was dried, and the residue was recrystahzed with CH2Cl2/Me0H to obtain 6-bromo-2-qumazohnamine. To this bromide intermediate (100 mg, 0.448mmol), Pd(OAc)2 (10 mg) and P(O-tol)3 (29 mg) were added to a Et3N (2 mL) solution of the acrylamide (252 mg, 0.896 mmol) under nitrogen. The solution was degassed for 5 mm and heated to 100 0C for 12 h. The reaction mixture was diluted with 20 mL AcOEt, filtered, washed with H2O and dried in vacuo. The residue was purified by RPHPLC. This intermediate (70 mg) m a solution of MeOH, a few drops Of CH2Cl2, two drops of TFA and 10 mg Pd(OH)2 was hydrogenated for 16 h at room temperature. The product was obtained after filtration and dried in vacuo. A water (2 mL) solution of eerie ammonium nitrate (195 mg) was added to this intermediate (59 mg) in acetone (2 mL) at room temperature and stirred for 2 h. The solution was diluted with AcOEt (10 mL) and washed with water (5 mL). The organic layer was dried and purified by RPHPLC to obtain the desired product. 1H NMR (DMSO-d6, 500 MHz) delta 8.99 (s, 1H), 8.50 (d, 1H), 7.58 (m, 3H), 7.32 (d, 1H), 7.18 (d, 1H), 6.73 (s, 1H), 2.91 (t, 2H), 2.74 (t, 2H); LCMS m/z 337 (M++1)
With hydrogenchloride; sodium carbonate; In hexane; water; dimethyl sulfoxide;
Example 1 Synthesis of 4-(4-bromo-2-formyl-N-methylanilino)-butyric acid To a suspension of 5-bromo-2-fluorobenzaldehyde (20.3 g) and <strong>[6976-17-6]4-methylaminobutyric acid hydrochloride</strong> (18.4 g) in DMSO/water(100 ml/100 ml) was slowly add sodium carbonate (25.4 g), followed by stirring at 105°C to 110°C for 3.5 hours. The mixture was cooled to 50°C to 60°C, atwhich temperature 6N hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was extracted with ethyl acetate (200 ml + 100 ml), and the organic layer was washed with a saturated aqueous sodium chloride solution (40 ml * 2) and water (40ml). The organic layer was concentrated, and the concentrate was then dissolved in IPE (50 ml), to which n-hexane (50 ml) was added dropwise. The precipitates were filtered out and washed with IPE/n-hexane (16 ml/4 ml). The filter cake was dried under reduced pressure at room temperature for 4 hours to give 4-(4-bromo-2-formyl-N-methylanilino)butyric acid (25.9 g, 86percent yield) as yellow crystals. 1H-NMR (CDCl3, delta, 300 MHz): 1.95 (2H, tt, J = 6.5, 7.4 Hz), 2.38 (2H, t, J = 6.5 Hz), 2.88 (3H, s), 3.17 (2H, t, J = 7.4 Hz), 7.01 (1H, d, J = 8.7 Hz), 7.55 (1H, dd, J = 8.7, 2.5 Hz), 7.87 (1H, d, J = 2.5 Hz), 10.16 (1H, s).
With caesium carbonate In N,N-dimethyl acetamide at 100℃;
2.1; 7
5-Bromo-2- (2-methoxy-4-methyl-phenoxy) -benzaldehyde A suspension of 5-bromo-2-fluoro-benzaldehyde (1.470 g, 7.240 mmol), 2-methoxy-4-methyl-phenol (1.000 g, 7.240 mmol) and cesium carbonate (2.83Og, 8.690 mmol) in DMA (10 mL) was stirred EPO at 1000C overnight. The reaction mixture was poured into water (20 mL) and extracted with ether (30 mL x 3) . The organic layer was washed with water (30 mL) , dried over anhydrous sodium sulfate, filtered and evaporated. The solid residue was triturated in hexane and dried in vacuum, giving the product (1.270 g, 55%) as white powder. M.P.: 89 - 90 0C; Ci5H13BrO3 (320.00) : GC-MS (EI +) m/e: 320.
To a 0 C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. After 30 min, TLC showed the reaction completed. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL×2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87%) that was used in the next reaction without further purification
87%
In diethyl ether; at 0℃; for 0.05h;
To a 0 C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL×2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87%) that was used in the next reaction without further purification.
Compound 471 : 1 -(1 H-benzo[d]imidazol-6-yl)-5-(5-bromo-2-fluorophenyl)-3-hydroxy- 4-methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5ml_ of dry EtOH and 3-bromo-5-fluoro- benzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2-oxal- propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHCIs/MeOH gradient. The purified carboxylic acid ethyl EPO <DP n="192"/>ester derivative was suspended in 1 OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried.Yield: 0.403g (51 %);1H-NMR 400 MHz, CD3OD, 1.78 (s, 3H, CH3), 6.00 (s, 1 H, CH-N), 6.99 -7.10 (m, 1 H, aro), 7.36 - 7.44 (m, 1 H, aro) 7.69 -781 (3H, aro, benzimid), 8.10 (s, 1 H, benzimid),9.28 (s, 1 H, benzimid); MS m/z 404.3 (M+H)+, HPLC (254 nm): purity 97 % molecular weight (g/mol): 402.21Ki hQC (nM): 33.16
With potassium carbonate In N,N-dimethyl acetamide at 170℃; for 1h;
35a
EXAMPLE 35a; Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester; To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N,N-dimethylacetamide (30 mL) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170° C. for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc: hexanes=1:8 then 1:4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%).
95%
With potassium carbonate In N,N-dimethyl acetamide at 170℃; for 1h;
50.a Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester
EXAMPLE 50a Preparation of intermediate 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N,N-dimethylacetamide (30 mL) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170° C. for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc: hexanes=1:8 then 1:4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%). Similar transformations have been described by Marsh, G. et al in Eur. J. Org. Chem. 2003, 2566-2576. The procedures were used with little modification.
With hydrazine hydrate; In dimethyl sulfoxide; at 120℃; for 21h;
To a vigorously stirred solution of 5-bromo-2-fluorobenzaldehyde (40.6 g, 0.2 mol) in DMSO (80 mL) was added N2H4-xH2O (40 mL, 0.8 mol) dropwise over 15 min (slow addition to keep the reaction not too hot). The resulting yellow slurry was heated at 120 0C (oil temp.) for 21 h. The whole mixture was transferred to a 1 L flask and cooled for 10 min in air before quenching with ice (300 mL) and ice- cold H2O (100 mL). The resulting mixture was stirred for 30 min at it. Precipitated formed was collected by suction filtration, rinsed thoroughly with H2O (100 mL x 2), 2 M HCl (100 mL x 2), H2O (100 mL x 2), 0.5 M Na2CO3 (100 mL x 2), H2O (100 mL x 2), dried in air for 1 h and under high vacuum for 2 days to give 6- bromo-lH-indazole (30.05 g, 76%) as a light yellow solid. MS ESI 196.9 [M + H]+, calcd for [C7H5BrN2 + H]+ 197.0.
At -78 C,16.6 g (124 mmol) of benzothiophene (compound of formula 2) was dissolved in 200 mL of tetrahydrofuran.Add 78.5 mL (937 mmol) of n-butyllithium,The mixture was stirred at -78 C for 1.5 hours.Will be 23.95g (118mmol)5-bromo-2-fluorobenzaldehyde (formula 1 compound) is solubleIn 300 mL of tetrahydrofuran,And mixing it with the above benzothiophene solution,Stirring was continued for 2 hours at -78 C.Water and diethyl ether were added to the reaction mixture.Separating the organic phase,And dried with magnesium sulfate,It is then filtered and dried under vacuum.The obtained crude product was purified by column chromatography (ethyl acetate-hexane).Obtaining benzo[b]thiophene-2-methanol,Alpha-(5-bromo-2-fluorophenyl) (compound of formula 3) 35.4 g;Purity 99.5%; yield 89%;
84.8%
EXAMPLE; (Example); First step: Synthesis of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol; Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg ) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08%) in an argon atmosphere at -24.2 to -13.5C, followed by stirring at -22.1 to -13.5C for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at -22.1 to -11.8C, followed by stirring at -23.5 to -16.1C for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0C for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8%, purity: 99% (HPLC)]. 1H-NMR (CDCl3): delta 2.74 (1H, d), 6.35 (1H, d), 6.93 (1H, dd), 7.14 (1H, s), 7.27-7.38 (2H, m), 7.39 (1H, m), 7.68 (1H, dd), 7.74 (2H, m)
General procedure: To a cold (-78 C) solution of 50 (16.6 g, 124 mmol) in THF (200 mL) was added n-BuLi (1.60 M in hexane; 78.5 mL, 124 mmol) and the mixture was stirred at -78 C for 1.5 h. To the reaction mixture was added a solution of 64 (29.0 g, 118 mmol) in THF (300 mL) and the mixture was stirred at -78 C for 2 h. To the reaction mixture was added H2O and Et2O and the organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (EtOAc-hexane) to give alcohol as a pale yellow oil. To a cold (-20 C) solution of this oil (43.3 g, 114 mmol) in CH2Cl2 (800 mL) was added Et3SiH (36.5 mL, 229 mmol) and BF3·OEt2 (15.2 mL, 120 mmol) and the mixture was stirred at -20 C for 30 min. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and the organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (EtOAc-hexane) to give the title compound (66) (35.6 g, 86%) as a pale yellow oil.
Acid Preparation 5; 3-Methyl-1 H-indazole-5-carboxvlic acid; To a cooled solution of 3-bromobenzaldehyde (42.5 g, 209 mmol) in THF (300 ml_) at 0 aC was added MeMgCI (17.2 g, 230 mmol) and the mixture was stirred for 2 hours. The reaction mixture was quenched with saturated NH4CI solution (100 ml_) and extracted with diethyl ether (2x250 ml_). The combined organic layers were washed with water (2x100 mL), saturated aqueous NaCI (100 mL), dried over anhydrous Na2SO4 and concentrated to give 1-(5-bromo-2-fluoro-phenyl)-ethanol (17 g, 37%) as an oil. 1H NMR (CDCI3): delta 7.6-7.7 (d, 1 H), 7.3-7.4 (m, 1 H), 6.8-6.9 (t, 1 H), 5.1-5.2 (m, 1 H), 1.8-1.9 (br, 1 H), 1.46-1.55 (d, 3H).
14.51 g
In tetrahydrofuran; at -78 - -5℃; for 1.0h;Inert atmosphere;
Step 1 [0200] 5-Bromo-2-fluorobenzaldehyde (1) (12.98 g) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere, and the solution was cooled in a dry ice-acetone bath. To the solution was added dropwise methylmagnesium chloride (3M in THF, 25.6 ml) at a temperature between -78 C. and -30 C. After completion of addition, the mixture was stirred at a temperature between -10 C. and -5 C. for 1 hour. To the reaction solution were added an aqueous saturated ammonium chloride solution and water, extracted with ethyl acetate and washed subsequently with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford Compound 2 (14.51 g). [0201] 1H-NMR (CDCl3) delta: 1.50 (d, J=6.4 Hz, 3H), 1.91 (d, J=4.2 Hz, 1H), 5.16 (dq, J=4.2, 6.4 Hz, 1H), 6.91 (dd, J=9.9, 8.7 Hz, 1H), 7.31-7.38 (m, 1H), 7.64 (dd, J=6.5, 2.5 Hz, 1H).
Step 2: Synthesis of (5-bromo-2-fluorophenyl)(4-ethoxyphenyl)methanol:To a stirred solution of Mg (9.5 g) in dry tetrahydrafuran (50 ml), 1-bromo- 4-ethoxybenzene (step 1, 53.4 g) in tetrahydrafuran (150 ml) was added under N2 atmosphere at room temperature slowly by drop wise and stirred for about 1 hour. Then 5-bromo-2-fluorobenzaldehyde (11 ml) was added slowly to the above reaction mixture and the reaction mixture was allowed to stir for over night. After completion of the reaction (monitored by TLC), the reaction mixture was poured into saturated NH4C1 solution at 0 C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane to afford the title compound as liquid (24 g). Yield: 85.7 ; NMR (CDC13, 300 MHz): delta 7.745- 7.71 (m, 1H), 7.37- 7.27 (m, 3H), 6.91- 6.84 (m, 3H), 6.02 (d, J = 3.3 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.20 (d, J = 3.3 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 20 - 100℃; for 1h;Microwave irradiation;
To a solution of 5-bromo-2-fluorobenzaldehyde (200 mg, 0.99 mmol) in DMF (5 mL) and H20 (1 mL) are added l,5-dimethyl-lH-pyrazole-4-boronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (113 mg, 0.099 mmol) and K2C03 (204 mg, 1.5 mmol) at room temperature. The solution is heated to 100 C for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H20 (10 mL) and is extracted with EtOAc (3 x 10 mL). The combined organic layer is dried with MgS04 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography with 20% EtOAc in Hepthane as the eluent to afford 5-(l,5-dimethyl-lH-pyrazol-4-yl)-2-fluoro-benzaldehyde (160 mg, 74%).
A mixture of 74 (1.82 g, 9 mmol) and copper (I) cyanide (1.4 g, 15.7 mmol) in DMF (14.0 mL) was stirred at reflux overnight. After completion, the reaction mixture was cooled to rt and poured into a solution of water (10 mL) and NH4OH (10 ml) followed by extraction with EtOAc (3 x 25 mL). The organic layer was sequentially washed with brine (2 x 15 mL), dried over anhydrous Na2S04, and concentrated in vacuo to give 757a (0.80 g, 60 percent).
Guanidine carbonate (2) (4.47 g, 36.9 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (1) (5.00 g, 24.6 mmol) in dimethylacetamide (50 ml). The reaction mixture was heated at 150C for 5 h. The progress of the reaction was monitored by TLC using AcOEt-hexane, 1:1, as eluent. The reaction mixture was cooled and quenched with ice water, and stirred for 30 min. Then the obtained solid was filtered off, and water was removed by azeotropic distillation with PhMe to get 4.00 g (73%) of compound 3. Mp 270-272C. 1H NMR spectrum (300 MHz), delta, ppm (J, Hz): 7.04 (2H, s,NH2); 7.37 (1H, d, J = 9.0, H Ar); 7.78 (1H, dd, J = 9.0,J = 2.4, H Ar); 8.05 (1H, d, J = 2.4, H Ar); 9.09 (1H, s,H Ar). Mass spectrum, m/z: 225 [M+H]+.
48%
With caesium carbonate; diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150 - 160℃; for 3h;
Barium carbonate (281 g, 1.56 mol),A mixed solution of DIEA (540 mL, 3.12 mol) and NMP (1 L) was heated to 150-160 C under stirring.A solution of 5-bromo-2-fluorobenzaldehyde (250 g, 1.20 mol) in NMP (100 ml) was slowly added dropwise.After 3 hours of reaction, the temperature was lowered to 100 C.Add ice (2kg) and water (4L),A yellow-brown solid precipitated and stirring was continued for 30 minutes.Filter under reduced pressure,Wash with water (1L) and ethanol (1L),The resulting filter cake was transferred to a 5 L flask.Add ethanol (2L) and stir for 2 hours.Then filtered, followed by ethanol (0.5 L),Wash with toluene/ethanol (1:1, 0.5 L) and toluene (0.5 L).Compound 3 was obtained as a pale yellow solid (168 g, 48%).
With sodium tetrahydroborate; at 0 - 20℃; for 0.583333h;
Example 5, Step 1To a solution of starting aldehyde 5-1 (3.98 g, 19.6 mmol) in MeOH (20 mL) at 0C was added sodium borohydride (1.48 g, 39.2 mmol). The reaction was stirred at 0C for 5 mm then warmed up to RT and allowed to stir for an additional 30 mm. The final mixture was diluted with EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated invacuo to provide 3.92 g (9 8%) of intermediate 5-2.
4'-(benzyloxy)-4-fluoro-2',6'-dimethylbiphenyl-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.4%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; toluene; at 100 - 120℃; for 2.5h;Microwave irradiation;
4-(Benzyloxy)-2,6-dimethylphenyl)boronic acid 12b (256 mg, 1 mmol), 2-fluoro-5-bromo-benzaldehyde (203 mg, 1 mmol), 2 M aqueous sodium carbonate solution (1 mL, 2 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (37 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 3 mL of the mixture solvent of ethylene glycol dimethyl ether and toluene (V/V = 1:2). The reaction mixture was heated at 100 C for 2 hours, and then at 120C for 0.5 hours under micarowave condition. The resulting mixture was added with 10 mL of water and extracted with ethyl acetate (10 mL*3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4'-(benzyloxy)-4-fluoro-2',6'-dimethylbiphenyl-3-carbaldehyde 18a (390 mg, yield 58.4%) as a colorless oil. MS m/z (ESI): 335.2 [M+1]
58.4%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; toluene; at 100 - 150℃; for 2.5h;Microwave irradiation; Inert atmosphere;
(4-(Benzyloxy)-2,6-dimethylphenyl)boronic acid 12b (256 mg, 1 mmol), 2-fluoro-5-bromo-benzaldehyde (203 mg, 1 mmol), 2M aqueous sodium carbonate solution (1 mL, 2 mmol), 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (37 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 3 mL of a mixture of the solvents ethylene glycol dimethyl ether and toluene (V/V=1:2). The reaction mixture was heated at 100 C. for 2 hours, and then at 120 C. for 0.5 hours under microwave conditions. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4?-(benzyloxy)-4-fluoro-2?,6?-dimethylbiphenyl-3-carbaldehyde 18a (390 mg, yield 58.4%) as a colorless slime. MS m/z (ESI): 335.2 [M+1]
5-Bromo-2-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100 C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 1.3 g of the titled compound as a white solid. (0164) 1H NMR (400 MHz, CD3OD) 7.89 (d, 1H), 7.74-7.70 (m, 2H), 7.15 (t, 1H), 6.62 (d, 1H)
Stage #1: 4-methoxy-benzaldehyde; 7-aminoheptanoic acid With palladium on activated charcoal; sodium hydroxide In methanol; water for 24h; Inert atmosphere;
Stage #2: 5-bromo-2-fluorobenzaldehyde With sodium carbonate In methanol; water; dimethyl sulfoxide at 135℃; Inert atmosphere;
R.39 Reference Example 39
Reference Example 39 To a solution of 4-methoxybenzaldehyde (20.0 g) and 7-aminoheptanoic acid (18.8 g) in methanol (240 ml) were added an aqueous 1N sodium hydroxide solution (138 ml) and palladium carbon (10%, 4.0 g) and then the mixture was stirred under hydrogen atmosphere for a day. After filtering off insolubles, the mixture was neutralized with 6N hydrochloric acid (23 ml) at 0° C. and the solvent was distilled off under reduced pressure. To the resulting residue were added DMSO (160 ml), water (107 ml) and sodium carbonate (36.5 g), after which a solution of 5-bromo-2-fluorobenzaldehyde (23.3 g) in DMSO (50 ml) was added dropwise at 135° C. under nitrogen atmosphere. After stirring with heating as such overnight, the reaction mixture was cooled to 0° C., to which water was added, and it was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water twice and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→ethyl acetate) to give 7-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)heptanoic acid (41.5 g) as a brown oily material. 1H-NMR (200 MHz, CDCl3) δ 1.15-1.65 (8H, m), 2.31 (2H, t, J=7.8 Hz), 3.05 (2H, t, J=7.4 Hz), 3.78 (3H, s), 4.22 (2H, s), 6.81 (2H, d, J=8.8 Hz), 6.98 (1H, d, J=8.8 Hz), 7.06 (2H, d, J=8.8 Hz), 7.54 (1H, dd, J=8.8, 2.2 Hz), 7.89 (1H, s, J=2.2 Hz), 10.30 (1H, s).
With guanidine carbonate; In N,N-dimethyl acetamide; at 140℃; for 5h;
Compound 2-Fluoro-5-bromobenzaldehyde (10.0 g, 49.2 mmol)bisguanidiniu carbonate (13.3 g, 74 mmol) were dissolved in N,Ndimethylacetamide(50 mL). The resulting mixture was heated toreflux and stirred for 5 h. After cooling to room temperature,120 mL of water was added and the reaction mixture was allowedto stir for another 2 h at room temperature. The product wascollected by filtration and dried under vacuum to yield 6-Bromo-2-quinazolinamine (12) (5 g, 60%).
3-bromo-9-methoxyindolo[1,2-a]quinoline-7-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 5h;Inert atmosphere;
General procedure: To a suspension of 2-methylindole-3-carboxaldehyde (7a) (200 mg, 1.26 mmol) and Cs2CO3 (1.34 g, 3.80 mmol) in N,N-dimethylformamide (4 mL) was added 2-fluorobenzaldehyde (210 muL, 1.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 140 C until the indole substrate was all consumed (monitored by TLC), and then allowed to cool down to room temperature. The resulting mixture was filtered and washed with ethyl acetate (80 mL). The filtrate was washed with water (3 X 80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes = 1:3) to afford the desired indolo[1,2-a]quinoline.
With caesium carbonate; In N,N-dimethyl acetamide; at 80℃; for 1.5h;Inert atmosphere;
A mixture of Example 15a (10.6 g, 0.05 mol), Example 4a (6.5 g, 0.05 mol), and Cs2CO3 (16.3 g, 0.05 mol) in DMA (100 mL) was heated at 80C with stirring for 1.5 hours under N2 atmosphere. Then, the reaction solution was poured into water (500 mL). After extraction with EtOAc (200 mL*2),The combined organic phase was washed with brine, dried over Na2 SO4, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 15b (14.6 g, yield 93%) as a white solid. MS [M+1] = 313.
(E)-3-(3-(5-bromo-2-fluorophenyl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.33%
With piperidine; In chloroform; at 60℃; for 12h;Inert atmosphere;
<strong>[520-45-6]Dehydroacetic acid</strong> (500 mg, 2.97 mmol),O-bromobenzaldehyde (603.66 mg, 2.97 mmol) was dissolved in CHCl3 (4 ml).Piperidine (2d) was added dropwise,Nitrogen protection, reaction at 60 C for 12 h.Post-processing is the same as in Embodiment 1,A yellow solid was obtained, 287 mg (yield: 27.33%).
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL chi 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g, crude).
In N,N-dimethyl acetamide; at 160℃; for 0.5h;
To a solution of 5-bromo-2-fluoro-benzaldehyde (20.0 g, 98.5 mmol) in DMA (700 mL) was added guanidine-carbonic acid (26.6 g, 147.7 mmol). The mixture was stirred at 160C for 0.5 h, cooled to rt and concentrated. The residue was diluted with H20 (300 mL) and extracted with ethyl acetate (200 mL < 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was washed with DCM (300 mL) to get compound 1A-2 (4.0 g, crude).
ethyl 2,6-bis(5-bromo-2-fluorophenyl)-1-(diethoxyphosphoryl)-4-((diethoxyphosphoryl)amino)-1,2,5,6-tetrahydropyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With ammonium cerium (IV) nitrate In acetonitrile at 20℃; for 12h; Green chemistry;
General procedure for synthesis of tetrahydropyridines (4a-j)
General procedure: CAN (5 mol %) was added to a mixture of diethylphosphoramidate (2 mmol), aldehyde (2 mmol) and ethyl acetoacetate (1 mmol) in acetonitrile. The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction(monitored by TLC), distilled water (15 mL) was added to the reaction mixture and stirring was continued till a free flowing solid was obtained. It was filtered and then washed successively with water and n-hexane. The crude product was purified by recrystallization from ethanol. The boiling ethanol was saturated with the crude product and then the solution and solid mixture was filtered when it was hot to remove the undissolved solid. The hot filtrate was cooled to room temperature. Analytically pure crystalline product was obtained. Similar experimental procedure was adopted for the synthesis of all the tetrahydropyridine derivatives.
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