* 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.
With hydrogenchloride; sodium chlorite In water; acetonitrile at 0 - 80℃; for 1 h;
Compound 17 (1 g, 6.31 mmol) and CH3CN (20 ml) were added to a 100 ml three-necked flask and stirred at 0°C until dissolved.Further, 5 ml of an aqueous solution of NaClO2 (1.71 g, 18.92 mmol) was added thereto, the mixture was further stirred and mixed, and 5 ml of an aqueous solution of HCl (3.31 ml, 25.23 mmol) was slowly added dropwise.After the addition was completed, the mixture was stirred at 0°C for 0.5 h. The reaction flask was transferred to a silicone oil bath, and the temperature was raised to 80°C and stirred for 0.5 h. The reaction was completed by TLC. The acetonitrile in the reaction solution was spin-dried and diluted with 10 ml of H2O.Adjust pH to 2 with 6N HCl, extract with ethyl acetate/water, dissolve the product in the organic phase, separate the liquid, collect the organic phase, dry with anhydrous Na2SO4, and spin dry the organic solvent.The crude product was obtained, purified by column chromatography, and eluted with petroleum ether:ethyl acetate=2:1 to give compound 21 as a white solid, 1.0 g, yield: 90.8percent.
Reference：
[1] Patent: CN107556289, 2018, A, . Location in patent: Paragraph 0099; 0101; 0102; 0103
2
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
3
[ 167758-87-4 ]
[ 84194-36-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 2, p. 260 - 263
4
[ 112135-96-3 ]
[ 84194-36-5 ]
Reference：
[1] Patent: US4846875, 1989, A,
[2] Patent: US4846882, 1989, A,
5
[ 208186-84-9 ]
[ 84194-36-5 ]
Reference：
[1] Chinese Journal of Chemistry, 2014, vol. 32, # 2, p. 117 - 122
6
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
7
[ 452-73-3 ]
[ 84194-36-5 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 4, p. 526 - 532
8
[ 45767-66-6 ]
[ 84194-36-5 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 4, p. 526 - 532
9
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
10
[ 872-50-4 ]
[ 84194-36-5 ]
[ 127510-96-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 195℃; for 1.5 h; Inert atmosphere
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 °C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73percent yield (6.99 g) as a white solid: mp 92-93 °C; ]H NMR (500 MHz, CDC13) δ 8.18 (dd, 1H, J = 9.0, 5.5 Hz), 7.50 (dd, 1H, J = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 409 - 416
13
[ 84194-36-5 ]
[ 166250-01-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 409 - 416
14
[ 84194-36-5 ]
[ 99329-85-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0 - 20℃; for 2 h;
A stirred solution of 2-chloro-4-fluorobenzaldehyde (1.0g, 6.3 mmol) in cone, sulphuric acid (8ml) at O0C under argon was treated portionwise with potassium nitrate (0.7Og, 6.9 mmol) and maintained at O0C for 30minut.es, before warming to room temperature over 1.5 hrs. The reaction mixture was added to well stirred ice/water (100ml) and then extracted with ethyl acetate. The extract was dried and concentrated to leave the title compound as a pale yellow oil (1.15g, 90percent). 1H NMR δ (CDCI3, 400MHz): 7.50 (1 H, dd), 8.66 (1 H, dd), 10.41 (1 H, s).
With piperdinium acetate; In isopropyl alcohol; at 20℃;
[0178] 1.7 ml of piperidine acetate are added to a solution of 50 g (315 mmol) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> and 36.6 g (315 mmol) of methyl acetoacetate in 150 ml of isopropanol. Stirring at room temperature overnight is followed by dilution with dichloromethane and extraction with water, and the organic phase is dried over sodium sulfate and concentrated. The product is reacted further as a crude cis/trans mixture.
With piperidine; In acetic acid; isopropyl alcohol; at 20℃;
[0190] A solution of 2.44 g (15.4 mmol) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> and 3.19 g (15.4 mmol) of the compound from Example X in 20 ml of isopropanol are mixed with 0.1 ml of piperidine and 0.13 ml of glacial acetic acid. Stirring at room temperature overnight is followed by concentration, and the residue is chromatographed on silica gel with dichloromethane->dichloromethane/methanol (50:1) as mobile phase. The product is employed further as cis/trans mixture. [0191] Yield: 4.5 g (84.0percent of theory)
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
<Reference Example 1>2-chloro-4-[(3-trifluoromethyl)phenylthio]benzaldehyde; [] To a DMF solution (20mL) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (1.15g) and 3-(trifluoromethyl)thiophenol (1.33g), potassium carbonate (2.76g) was added and the mixture was stirred at 120°C for 1 hour while heated. The reaction mixture was poured into water and was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified on a silica gel column chromatography (hexane: ethyl acetate = 10: 1). This gave the desired product as a pale yellow oil (1.96g).
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;
To a DMF solution (20mL) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong>(1.15g) and 3-(trifluoromethyl)thiophenol(1.33g), potassium carbonate (2.76g) was added and the mixture was stirred for 1 hour at 120°C. Subsequently, the reaction mixture was poured into water and was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified on a silica gel column chromatography (hexane: ethyl acetate = 10: 1). This gave the desired product as a pale yellow oil (1.96g).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
potassium carbonate (2.76g) was added to a solution of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (1.15g) and 3-(trifluoromethyl)thiophenol (1.33g) in DMF (20ML) and the mixture was stirred for 1 hour while heated to 120°C. The reaction mixture was poured into water and was extracted with ethyl acetate.. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate.. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1).. In this manner, the desired product (1.96g) was obtained as a pale yellow oil.
2-Chloro-4-fluorobenzaldehyde (5g, 31.5mmol, leq) ANDMETHANESULPHINIC acid sodium salt (3.5g, 34.7mmol, L. leq) were dissolved in dry DMSO (30 ml) and heated to 100°C for 16HRS. The mixture was cooled and poured onto crushed ice (50g). After ice had melted the solid was filtered and dried in a vacuum oven at 50°C for 2 hours to give 2-chloro 4- (methylsulphonyl) benzaldehyde (4.85g, 70percent) as a colourless SOLID. 1H NMR (300 MHz, CDC13) : 6= 10. 52 (1H, s, CHO), 8.16-7. 91 (3H, m, ArH) and 3.10 (3H, s, CH3). GCMS: Rt = 7.63 min, (M+) = 218.
In dimethyl sulfoxide; at 90℃;
2-Chloro-4-methanesulfonyl-benzaldehyde: A suspension of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (24.9 g, 0.16 mol) and dry sodium methanesulfinate (17.9 g, 0.175 mmol) in dry DMSO (60 ml) is stirred at 90 °C overnight. The reaction mixture is allowed to cool to room temperature and then poured onto ice- water (400 ml). The resulting precipitated is collected by filtration and dried under high vacuum to yield the titled compound as a yellow powder.
With tert.-butyl lithium; In diethyl ether; pentane; at -78℃; for 1h;
Step C: A solution of compound 3f (116.2 mg, 0.459 mmol) in 1 ML of ether was cooled to -78° C. To the solution was added t-BuLi (1.70 M in pentane, 0.57 ML) at -78° C. After 1 hour at -78° C., a solution <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (76.4 mg, 0.482 mmol) in 1 ML of ether was added and the mixture was slowly warmed to room temperature.The mixture was quenched with water (5 ML) and layers were separated.The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, filtered through Celite, and concentrated under reduced pressure.The crude was purified by chromatography with 1:2 ether/hexanes to provide 47.6 mg of compound 4f-8 as a pale yellow solid (31.2percent yield). MS ESI (+) m/z 333 and 335 (M+1) detected. 1H-NMR (400 MHz, CDCl3) delta 7.96 (s, 1H), 7.72~7.66 (m, 2H), 7.39~7.34 (m, 2H), 7.13~7.03 (m, 2H), 6.29 (m, 1H), 4.15 (m, 2H), 2.38~2.27 (m, 2H, overlapped with -OH), 0.92 (m, 6H).
2-chloro-4-(N-t-Boc-piperazinyl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In N,N-dimethyl acetamide; at 20 - 140℃;
2-chloro-4-(N-t-Boc-piperazinyl)benzaldehyde: To 5.00 g (31.5 mmol) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> in 75 mL of dry N,N-dimethylacetamide was added 11.7 g (31.5 mmol) of N-Bocpiperazine. The reaction was heated to 140° C. under nitrogen for 3 h, then stirred overnight at room temperature. The solvent was removed in vacuo and the mixture partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated to give an orange solid (14.64 g). The crude material was chromatographed over SiO2 eluting with 10-20percent ethyl acetate in hexanes to give 8.94 g (87percent) of the desired aldehyde as a yellow solid. 1HNMR (DMSO-d6) delta: 10.30 (2, 1H), 7.82 (d, J=10 Hz 1H), 67.77-6.79 (m, 2H), 3.59 (t, J=5 Hz, 4H), 3.39 (t, J=5 Hz, 4H), 1.50 (s, 9H)
4-[3-(3-chloro-4-chloromethylphenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran[ No CAS ]
[ 84194-36-5 ]
2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate; In N,N-dimethyl-formamide;
The 4-[3-(3-chloro-4-chloromethylphenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran used as a starting material was obtained as follows: A mixture of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (0.526 g), 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran (0.726 g), potassium carbonate (0.46 g) and DMF (5 ml) was stirred and heated to 120° C. for 30 minutes. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with brine, dried (Na2 SO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzaldehyde as a gum (1.1 g, 96percent). NMR Spectrum 1.8-2.0 (m, 4H), 3.01 (s, 3H), 3.8-3.9 (m, 4H), 7.1-7.2 (m, 4H), 7.33 (m, 1H), 7.81 (d, 1H), 10.37 (s, 1H).
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 2h;
A stirred solution of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (1.0g, 6.3 mmol) in cone, sulphuric acid (8ml) at O0C under argon was treated portionwise with potassium nitrate (0.7Og, 6.9 mmol) and maintained at O0C for 30minut.es, before warming to room temperature over 1.5 hrs. The reaction mixture was added to well stirred ice/water (100ml) and then extracted with ethyl acetate. The extract was dried and concentrated to leave the title compound as a pale yellow oil (1.15g, 90%). 1H NMR delta (CDCI3, 400MHz): 7.50 (1 H, dd), 8.66 (1 H, dd), 10.41 (1 H, s).
With potassium carbonate; In N,N-dimethyl-formamide; at 30 - 42℃; for 0.5h;
[Reference Example 4] 4-(3-Benzyloxyphenylthio)-2-chlorobenzaldehyde (1) 3-Benzyloxybenzenethiol (13) (75.0 g, 347 mmol) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (55.0 g, 347 mmol) were dissolved in dimethylformamide (DMF) (350 mL) while the solution was being stirred. The solution was then placed in a water bath at 30C and potassium carbonate (62.3 g, 451 mmol) and dimethylformamide (25 mL) were added. This mixture was stirred for 30 min at an internal temperature of 40 to 42C. Tap water (125 mL) was then added and the mixture was cooled in ice water. To the cooled mixture, additional tap water (625mL) was added dropwise for crystallization. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 10% aqueous 2-propanol (188 mL). The moist crystals were dissolved in ethyl acetate (750 mL) and the solution was washed twice with tap water (375 mL x 2). The organic layer was concentrated under reduced pressure and acetone (900 mL) was added to the resulting residue. Purified water (386 mL) was then added dropwise at an internal temperature of 23C. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 50% aqueous acetone (400 mL). The washed crystals were air-dried overnight. Subsequently, the product was dried by blowing an air stream at 45C for 1 hour. This gave 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde (1) as a colorless prism crystals (115 g, 94%). MP 58-59C 400 MHz 1H-NMR (CDCl3) delta; 5.07 (2H, s), 7.04-7.14 (5H, m), 7.31-7.43 (6H, m), 7.75 (1H, d, J = 8.3 Hz), 10.35 (1H, d, J = 0.7 Hz). EI-MS m/z; 354(M+).
PREPARATION 22 [3-Amino-2-(2,6-difluorophenyl)pyridin-4-yl](2-chloro-4-fluoropheny.)methanonea) N-{4-[(2-Chloro-4-fluorophenyl)(hydroxy)methyl]pyridin-3-yl}-2,2-dimethyl- propanamide nBuU (2.5M in hexanes, 56.2 mL, 140.5 mmol) was dropwise added to a solution of the title compound of Preparation 1a (10 g, 56.2 mmol) and N,N,N',N'-tetramethylethylene- diamine (TMEDA) (20.9 mL, 140.5 mmol) in diethyl ether (338 mL) at -78 0C under argon and the resulting mixture was stirred at that temperature for 15 minutes and at -10 0C for 2 hours. Then, the reaction mixture was cooled down to -780C and 2-ch)oro-4-fluorobenzal- dehyde (20 g, 140.5 mmol) in 34 mL of dry tetrahydrofuran was carefully added. After 15 minutes, the cooling bath was removed and the mixture stirred overnight at room temperature. Subsequently, water (100 mL) was added to the flask and it was extracted with ethyl acetate (3 x 200 mL), the organic solution was washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica flash, using dichloromethane/ethyl acetate (7:3) as eluents, to yield the title compound (6.15 g, 33percent) as a solid.
With sodium cyanoborohydride; zinc(II) chloride; In methanol; at 20℃; for 24h;
A mixture of [3-(6-morpholin-4-yl-9-piperidin-4-yl-9H-purin-2-yl)phenyl]methanol (30 mg, 0.076 mmol), NaCNBH3 (25 mg, 0.40 mmol), zinc chloride (20 mg, 0.183 mmol) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (11 mg, 0.11 mmol) in methanol is stirred for 24 hours at room temperature. The mixture is then filtered, dissolved in DMSO (1 mL) and purified by chromatography by HPLC to give 6 mg (16percent yield) of the product. MS (ESI) m/z 538.2.
With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 12h;
Example 36: 1 l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2,3.4,5.10.1 l-hexahvdro-dibenzorb.eipi,41diazepin-l-one (56).; A mixture of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> 54 (4.96 g, 31.3 mmol), 2-bromophenol (5.57 g, 32.2 mmol) and Cs2CO3 (11.3 g, 34.7 mmol) in dry DMF (51 mL) was heated at 75°C under nitrogen. After 12h, the reaction mixture was successively allowed to cool down to room temperature, diluted with water (510 mL) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated to afford 9.74 g (97percent) of the aldehyde 55 as a yellow oil: m/z = 312 (M+H)+.
97%
With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 12h;
Example 5: synthesis of 10-[4-(2-bromo-phenoxy)-2-chloro-phenyl]-7,7-dimethyl- 5,6,7,8,10,1 l-hexahydro-3, 5,1 l-triaza-dibenzora,dlcyclohepten-9-one (13); A mixture of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (11; 4.96 g, 31.3 mmol), 2-bromophenol (5.57 g, 32.2 mmol) and Cs2CO3 (11.3 g, 34.7 mmol) in dry DMF (51 mL) was heated at 75°C under nitrogen. After 12 h, the reaction mixture was successively allowed to cool down to room temperature, diluted with water (510 mL) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated to afford 9.74 g (97 percent) of the aldehyde 12 as a yellow oil: m/z = 312 (M+H)+.
nBuLi (2.5M in hexanes, 56.2 ml_, 140.5 mmol) was dropwise added to a solution of the title compound of Preparation 1a (10 g, 56.2 mmol) and N,N,N',N'-tetramethylethylene- diamine (TMEDA) (20.9 mL, 140.5 mmol) in diethyl ether (338 ml.) at -78 0C under argon and the resulting mixture was stirred at that temperature for 15 minutes and at -10 0C for 2 hours. Then, the reaction mixture was cooled down to -780C and 2-chloro-4-fluorobenzal- dehyde (20 g, 140.5 mmol) in 34 mL of dry tetrahydrofuran was carefully added. After 15 minutes, the cooling bath was removed and the mixture stirred overnight at room temperature. Subsequently, water (100 mL) was added to the flask and it was extracted with ethyl acetate (3 x 200 mL), the organic solution was washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica flash, using dichloromethane/ethyl acetate (7:3) as eluents, to yield the title compound (6.15 g, 33percent) as a solid.
33%
N-{4-[(2-Chloro-4-fluorophenyl)(hydroxy)methyl]pyridin-3-yl}-2,2-dimethyl- propanamide nBuLi (2.5M in hexanes, 56.2 mL, 140.5 mmol) was added dropwise to a solution of the title compound of Preparation 1a (10 g, 56.2 mmol) and N,N,N',N'-tetramethylethylene- diamine (TMEDA) (20.9 mL, 140.5 mmol) in diethyl ether (338 mL) at -78 0C under argon and the resulting mixture was stirred at that temperature for 15 minutes and then at -10 0C for 2 hours. Then, the reaction mixture was cooled to -780C and 2-chloro-4- fluorobenzaldehyde (20 g, 140.5 mmol) in 34 mL of dry tetrahydrofuran was carefully added. After 15 minutes, the cooling bath was removed and the mixture stirred overnight at room temperature. Subsequently, water (100 mL) was added to the flask and it was extracted with ethyl acetate (3 x 200 mL), the organic solution was washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane/ethyl acetate (7:3) as eluent, to yield the title compound (6.15 g, 33percent) as a solid.
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 2h;Cooling with ice;
Reference Example-67 Hydroxylamine hydrochloride (455 mg, 6.35 mmol) was added to a solution of 2-chloro-4-fluorobezaldehyde (943 mg, 5.76 mmol) in ethanol (6 mL) and water (6 mL), and a sodium hydroxide aqueous solution (37percent, 1.1 mL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature for 2 hours. After the reaction was completed, 2N hydrochloric acid was added to the reaction solution to acidify, and the resultant product was extracted with dichloromethane (20 mL*2.10 mL*1). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby 2-chloro-4-fluorobenzaldoxime (794 mg, yield: 79percent) was obtained as a light yellow solid. 1H-NMR (400 MHz, CDCl3): delta6.99 (m, 1H), 7.15 (dd, J=2.5 and 8.5 Hz, 1H), 7.60 (brs, 1H), 7.85 (dq, J=6.3 and 8.5 Hz, 1H), 8.50 (s, 1H). 19F-NMR (376 MHz, CDCl3): delta-108 (s, 1F).
With hydroxylamine hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
General procedure: To the mixture of 4-chlorobenzaldehyde (100 mg, 0.711 mmol) and hydroxylamine hydrochloride (49.4 mg, 0.711 mmol) in an 8-mL vial was added 1.5 mL of DMF, followed by the addition of triethylamine (0.099 mL, 0.711 mmol). The vial was capped and stirred at ambient temperature for 1 h. NCS (0.095 g, 0.711 mmol) was added and the reaction vial was capped and stirred at ambient temperature overnight. Additional 15 mg of NCS was added and the reaction continued for 6 h. A solution of (E)-ethyl 3-(pyrrolidin-1-yl)but-2-enoate (130 mg, 0.711 mmol) and triethylamine (0.059 mL, 0.427 mmol) in ethanol (0.9 mL) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The product was purified by preparative HPLC (0.1percent TFA, MeOH/H2O) to give 148.1 mg.
<strong>[7356-60-7]3-pyridinecarboxamidine hydrochloride</strong> (Schaefer F.C., Peters G. A., et al. J. Org. Chem.; 1961; 26(2); 412-418.) 2.164mmol, 2-chloro-4-fluorobenzaldehyde 2.164mmol, 1,3-cyclohexanedione 2.164mmol and sodium acetate 3.2mmol were reacted in 8ml of anhydrous ethanol under reflexing for 18hr, condensed, to which ethyl acetate, water and 1 N HCl were added and then the layers were separated. The water layer was adjusted with concentrated NaOH solution until the pH to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate and separated by column chromatography to obtain a yellow solid of 0.21g (yield 27%); 1H-NMR (400MHz, CDCl3) 6 2.13-2.17(2H, m, CH2); 2.43-2.51 (2H, m, CH2); 2.63-2.83(2H, m, CH2); 6.06(1H, s, CH); 7.15-7.22 (2H, m, ArH); 7.34-7.38(1H, m, ArH); 8.07-8.09 (1H, m, ArH); 8.70-8.71 (1H, m, ArH); 8.89(1H, m, ArH). MS(HREI) 355.0887 (M+).
3-Pyridinecarboxamidine hydrochloride (Schaefer F.C., Peters G. A., et al. J. Org. Chem.; 1961; 26(2); 412-418.) 2.164mmol, 2-chloro-4-fluorobenzaldehyde 2.164mmol, 5,5-dimethyl-1,3-cyclohexanedione 2.164mmol and sodium acetate 3.2mmol were reacted in 8ml of anhydrous ethanol under refluxing for 18hr, condensed, and ethyl acetate and water and 1 N HCl were added to separate the layers. The water layer was adjusted with concentrated NaOH solution until the pH to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate and separated by column chromatography to obtain a yellow solid of 0.22g (yield 26%); mp 186-187 C. 1H-NMR (400MHz, CDCl3) delta 1.15 (3H, s, CH3); 1.16 (3H, s, CH3); 2.31 (2H, s, CH2); 2.53-2.69 (2H, m, CH2); 6.07(1H, s, CH); 6.94-6.96 (1H, m, ArH); 7.14-7.17 (1 H, m, ArH); 7.23-7.26 (1H, m, ArH); 7.34-7.38(1H, m, ArH) 8.07-8.09(1H, m, ArH); 8.69-8.71 (1H, m, ArH); 8.89(1H, m, ArH). MS(EI) 383.1 (M+).
2-(thiazol-2-yl)-4-(2-chloro-4-fluorophenyl)-7,8-dihydroquinazolin-5(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
<strong>[247037-82-7]2-thiazolecarboxamidine hydrochloride</strong> (Schaefer F.C., Peters G. A., et al.) 2.164mmol, 2-chloro-4-fluorobenzaldehyde 2.164mmol, 1,3-cyclohexanedione 2.164mmol and sodium acetate 3.2mmol were reacted in 8ml anhydrous ethanol under refluxing for 18hr, and condensed, to which ethyl acetate and water and 1 N HCl were added and the layers were separated. The water layer was adjusted with concentrated NaOH solution until pH value to be basic, then ethyl acetate was added again and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow crystal of 0.21 g (yield 27%); 1H-NMR (400MHz, CDCl3-d1) delta 7.86(m, 1H, ArH); 7.73-7.52(m, 1H, ArH); 7.24-7.21 (m, 1H, ArH); 7.15-7.12(m, 1H, ArH); 6.94-6.92(m, 1H, ArH); 6.11 (s, 1H, CH); 2.80-2.47(m, 2H, CH2); 2.14-2.11(m, 2H, CH2). HREI: 361.0450(M+).
2-(thiazol-2-yl)-4-(2-chloro-4-fluorophenyl)-7,7-dimethyl-7,8-dihydroquinazolin-5(1 H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
<strong>[247037-82-7]2-thiazolecarboxamidine hydrochloride</strong> (Schaefer F.C., Peters G. A., et al.) 2.164mmol, 2-chloro-4-fluorobenzaldehyde 2.164mmol, 5,5-dimethyl-1,3-cyclohexanedione 2.164mmoland sodium acetate 3.2mmol were reacted in 8ml of anhydrous ethanol under refluxing for 18hr, condensed, to which ethyl acetate and water and 1N HCl were added, and separated. The water layer was adjusted with concentrated NaOH solution until pH value to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow crystal 0.23g (yield 28%); 1H-NMR (400MHz, CDCl3-d1) delta 7.95-7.85(m, 1H, ArH); 7.64-7.47 (m, 1H, ArH); 7, 34-7.24(m, 1H, ArH); 7.13-7.11(m, 1H, ArH); 6.11 (s, 1H, CH); 2.70-2.52(m, 2H, CH2); 2.43-2.26(m, 2H, CH2); 1.15(s, 6H, CH3). HREI: 389.0765(M+).
To an ice cold suspension of sodium hydride (3.9 g, 0.162 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath. 3, 5-dimethoxybenzylphosphonate ester (18.3 g, 0.063mol,1 eq) diluted in tetrahydrofuran (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to rt and stirred for 30 min. After cooling the solution to 0° C, 2-chloro 4-Fluoro benzaldehyde (10 g, 0.063 mol, 1 eq) in tetrahydrofuran (20 mL) was added and stirred at ice cold temperature for 30 min. and at rt for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-chloro- l-[(.pound.)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-4- fluoro benzene. Yield 9.3 g (50percent).1H NMR (CDCl3, 300 Mz): delta 7.65-7.60 (m, IH), 7.41-7.35 (d, 2H, J = 16 Hz), 7.15-7.11 (m, IH), 6.99-6.95 (m, 2H), 6.68-6.67 (d, 2H, J = 2.2 Hz), 6.42-6.41 (t, IH, J = 2.1 Hz), 3.83 (s, 6H). LCMS: 293 (M+); HPLC: 99.14percent
With potassium carbonate; In water; N,N-dimethyl-formamide;
Reference Example 15 Preparation of 2-Chloro-4-(3-trifluoromethylpyrazolyl)benzaldehyde (Compound XVI) 4.08 g (30.0 mmol) of 3-trifluoromethylpyrazol, 4.75 mmol (30.0 mmol) of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> and 4.14 g (30.0 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue afforded 7.18 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzaldehyde (yield 87.2percent) as a pale yellow powder, after washed with n-hexane.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;
A mixture of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (5.0 g, 31.5 mmol), 3-(trifluoromethyl)pyrazole (4.28 g, 31.5 mmol) and potassium carbonate (6.53 g, 47.3 mmol) in anhydrous N,N-dimethylformamide (40 mL) was stirred for 2 h at 110 °C. The reaction mixture was cooled to 0 °C, poured into ice water (500 mL) and stirred for 15 min. The precipitate formed was filtered and dried under reduced pressure to afford the title compound (8.1 g), which was used without further purification. H NMR delta 10.4 (s, 1H), 8.00 (m, 2H), 7.85 (d, 1H), 7.77 (m, 1H), 6.70 (d, 1H). MS (AP+) 275 amu.
10.2 g
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;
Step A: Preparation of 2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]benzaldehyde A mixture of <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (7.0 g, 44.3 mmol), 3-(trifluoromethyl)- lH-pyrazole (9.03 g, 66.45 mmol) and potassium carbonate (12.2 g, 88.6 mmol) in anhydrous N,N-dimethylformamide (70 mL) was stirred for 2 h at 110 °C. The reaction mixture was cooled to 0 °C, poured into ice water (800 mL) and stirred for 15 min. The precipitate formed was filtered and dried under reduced pressure to afford the title compound (10.2 g), which was used without further purification. H NMR delta 10.4 (s, 1H), 8.00 (m, 2H), 7.85 (d, 1H), 7.77 (m, 1H), 6.70 (d, 1H).
General procedure: N-Pivaloyl-4-chloroaniline (33, 595 mg, 2.81 mmol) was dissolved in THF (50 ml), and the solution was added sec-butyl lithium c-hexane, n-hexane solution (0.99 M, 5.96 ml, 6.18 mmol) at -78 C, and then stirred at 0 C for 2 h. The mixture was added 2-chloro-3-fluoro-benzaldehyde (490 mg, 3.09 mmol) at the same temperature for 30 min. The reaction mixture was poured saturated with NH4Claq and AcOEt. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (n-hexane/AcOEt = 9:1) to give the title compound (676 mg, 65%) as light yellow oil.
General procedure: A solution of glucoBOX (35 mg, 0.052 mmol) and Cu(OAc)2.H2O (10 mg, 0.05 mmol) in ethanol (2 mL) was stirred at room temperature for 1 h. To this blue colored solution, the aldehyde (0.5 mmol) was added and the resulting solution was allowed to stir for 20 min at room temperature. The reaction mixture was cooled to 10 °C and then nitromethane (5 equiv) was added. The resulting mixture was stirred at the same temperature for a specified time (Table 1). The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to afford the pure nitroalkanol.
Example 85Preparation of Derivative 85 According to the Present InventionDerivative 85 having the following formula was prepared as follows. Sodium hydride (404.8 mg, 10.12 mmol, 60percent dispersed oil) was slowly added to benzylalcohol (1 g, 9.2 mmol) dissolved in dried dimethylformamide (30 ml) under nitrogen at room temperature while stirring. Then, the mixture was further stirred at room temperature for 30 minutes. Thereto, <strong>[84194-36-5]4-fluoro-2-chlorobenzaldehyde</strong> (1.46 g, 9.2 mmol) dissolved in dried dimethylformamide was added over 10 minutes and stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, ice water was added thereto, and the reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on a silica gel column (hexane:ethyl acetate=20:1) to afford the intermediate, 4-(benzyloxy)-2-chlorobenzaldehyde (1.64 g, yield: 71.9percent).
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
A 100 mL round-bottom flask was charged with <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (2.50 g, 15.8 mmol, 1.00 equiv), pyrrolidine (2.20 g, 30.9 mmol, 2.00 equiv), potassium carbonate (4.40 g, 31.8 mmol, 2.00 equiv), DMSO (50 mL). The resulting solution was stirred overnight at 100 °C, diluted with 0 (50 mL), extracted with ethyl acetate (3 x 30 mL). The organic layers were combined and washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.40 g (73percent yield) of 2- chloro-4-(pyrrolidin-l-yl)benzaldehyde as a yellow solid. LCMS: (ESI, m/z): 210 [M+H] +.
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93 C; ]H NMR (500 MHz, CDC13) delta 8.18 (dd, 1H, J = 9.0, 5.5 Hz), 7.50 (dd, 1H, J = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
With potassium carbonate; In dimethyl sulfoxide; at 100℃;
D10 2-Chloro-4-[4-chloro-3- benzaldehydeA mixture of 2-chloro-4-fluorobenzaldehyde (500 mg, 3.15 mmol), 4-chloro-3- (trifluoromethyl)phenol (620 mg, 3.15 mmol) and potassium carbonate (1.31 g, 9.46 mmol) in dimethyl sulfoxide (5 mL) was stired at 100 °C overnight, then cooled to rt and diluted with ethyl acetate (30 mL) and water (30 mL). The separated aqueous layer was extracted with ethyl acetate (30 mL) twice. Combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification via ISCO system (petroleum ether/ethyl acetate = 4/1) afforded the title product as a pale white solid (890 mg, 80 percent).
EXAMPLE 251 6-{4-[(2-Chloro-4-fluorophenyl)methyl]-l,4-diazepan-l-yl}-N-(pyridin-4-yl)pyridine-2- carboxamide Intermediate 83 (256mg, 0.86mmol) was dissolved in DCM (15 mL), 2-chloro-4- fluorobenzaldehyde (149 mg, 0.94 mmol) and NaBH(OAc)3 (907 mg, 4.28 mmol) were added and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with DCM (30 mL), washed with sat aq Na2CC>3 (35 mL), dried (MgSC>4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (116 mg, 31percent) as a light yellow gum. HRMS (ESI+) calculated for C23H23C1FN50: 439.157516, found 439.157156. HPLC: Rf 4.40 min, 100percent purity.
116 mg
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
Intermediate 83 (256 mg, 0.86 mmol) was dissolved in DCM (15 mL), <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (149 mg, 0.94 mmol) and NaBH(OAc)3 (907 mg, 4.28 mmol) were added and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with DCM (30 mL), washed with sat aq Na2CO3 (35 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (116 mg, 31percent) as a light yellow gum. HRMS (ESI+) calculated for C23H23ClFN5O: 439.157516, found 439.157156. HPLC: Rf 4.40 min, 100percent purity.
EXAMPLE 203 6-(4-{l-[(2-Chloro-4-fluorophenyl)methyl]piperidin-4-yl}-5,5-dihydrogenio-l,4-diazepan- l-yl)-N-(pyridin-4-yl)pyridine-2-carboxamideIntermediate 175 (200 mg, 0.52 mmol) was dissolved in DCM (30 mL) and 2-chloro-4- fluorobenzaldehyde (166 mg, 1.05 mmol) and NaBH(OAc)3 (554 mg, 2.61 mmol) were added.The reaction mixture was stirred for 18 h, diluted with DCM (30 mL), washed with sat aq Na2CC>3 (30 mL), dried (MgSC^) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (69.7 mg, 25percent) as a pale yellow solid. HRMS (ESI+) calculated for C28H30[2H]2ClFN6O: 524.246666, found 524.245956. HPLC: Rf 3.93 min, 99.3percent purity.
25%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
Intermediate 175 (200 mg, 0.52 mmol) was dissolved in DCM (30 mL) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (166 mg, 1.05 mmol) and NaBH(OAc)3 (554 mg, 2.61 mmol) were added. The reaction mixture was stirred for 18 h, diluted with DCM (30 mL), washed with sat aq Na2CO3 (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (69.7 mg, 25percent) as a pale yellow solid. HRMS (ESI+) calculated for C28H30[2H]2ClFN6O: 524.246666, found 524.245956. HPLC: Rf 3.93 min, 99.3percent purity.
tetrakis(2,2,2-trifluoroacetic acid) 6-[4-(azepan-4-yl)piperazin-1-yl]-N-(pyridin-4-yl)pyridine-2-carboxamide[ No CAS ]
[ 84194-36-5 ]
[ 1373270-82-6 ]
Yield
Reaction Conditions
Operation in experiment
23%
EXAMPLE 2416-(4-{l-[(2-Chloro-4-fluorophenyl)methyl]azepan-4-yl}piperazin-l-yl)-N-(pyridin-4- yl)pyridine-2-carboxamide Intermediate 238 (50.0 mg, 0.53 mmol) was dissolved in DCM (20 mL) and 2-chloro-4- fluorobenzaldehyde (170 mg, 1.05 mmol) and NaBH(OAc)3 (0.56 g, 2.63 mmol) were added.The reaction mixture was stirred for 96 h, diluted with DCM (50 mL), washed with sat aq Na2C(3/4 (75 mL), brine (50 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (0.060 g, 23percent) as a yellow gum. HRMS (ESI+) calculated for C28H32C1FN60: 522.231016, found 522.233146. HPLC: Rf 3.91 min, 100percent purity.
23%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 96h;
Intermediate 238 (50.0 mg, 0.53 mmol) was dissolved in DCM (20 mL) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (170 mg, 1.05 mmol) and NaBH(OAc)3 (0.56 g, 2.63 mmol) were added. The reaction mixture was stirred for 96 h, diluted with DCM (50 mL), washed with sat aq Na2CO3 (75 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (0.060 g, 23percent) as a yellow gum. HRMS (ESI+) calculated for C28H32ClFN6O: 522.231016, found 522.233146. HPLC: Rf 3.91 min, 100percent purity.
With piperidine; acetic acid; In benzene; for 12h;Dean-Stark; Reflux;
A solution of methyl 4-chloroacetoacetate (2.43 mL, 20.0 mmol) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (3.3 g, 20.2 mmol) in benzene (30 mL) was placed into a round-bottomed flask equipped with a Dean-Stark trap. Acetic acid (115 mu?, 2.0 mmol) and piperidine (200 mu?, 2.0 mmol) were added. The mixture was heated at reflux with removal of azeotroped water for 12 h and the resulting mixture was diluted with ether and washed with water and brine. The organic layer was dried over anhydrous Na2S04, and the solvent was removed by rotary evaporation. The product was purified by column chromatography (1: 10 EtOAc/ hexane) to give A (3.8 g, 66percent) as a yellow oil. The NMR data showed the material to be composed of a 2: 1 mixture of isomers. MS (M+H+, m/z) 291.
66%
With piperidine; acetic acid; In benzene; for 12h;Dean-Stark; Reflux;
Compound A. A solution of methyl 4-chloroacetoacetate (2.43 mL, 20.0 mmol) and <strong>[84194-36-5]2-chloro-4-fluorobenzaldehyde</strong> (3.3 g, 20.2 mmol) in benzene (30 mL) was placed into a round-bottomed flask equipped with a Dean-Stark trap. Acetic acid (115 mu, 2.0 mmol) and piperidine (200 mu, 2.0 mmol) were added. The mixture was heated at reflux with removal of azeotroped water for 12 h and the resulting mixture was diluted with ether and washed with water and brine. The organic layer was dried over anhydrous Na2S04, and the solvent was removed by rotary evaporation. The product was purified by column chromatography (1: 10 EtOAc/ hexane) to give A (3.8 g, 66percent) as a yellow oil. The NMR data showed the material to be composed of a 2: 1 mixture of isomers. MS (M+H+, m/z) 291.
To a flame-dried one liter round bottom flask containing 2H-1,2,3-triazole (16.3 g, 236. 5 mmol) in dimethyl formamide (240 ml) was added sodium hydride (60% dispersion in mineral oil, 8.52 g, 355 mmol) in small portions at room temperature. The mixture was stirred for 30 min, or until the gas evolution ceased, and 2-chloro-4-fluorobenzaldehyde (4) (30 g, 189.2 mmol) in dimethyl formamide (240 ml) was added via an addition funnel. This mixture was heated at 80 C for 3 h. The reaction mixture was cooled to room temperature and poured into a flask containing water (1 liter). The aqueous solution was extracted with ethyl acetate (3 x 500 ml), and the combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure to give a off-white solid. This material was dissolved in boiling heptane (4 liter), and cooled to room temperature. The resulting precipitate was collected by filtration (mostly the undesired N-1-regioisomer), and the filtrate was concentrated under reduced pressure to give an off-white residue (mostly the desired N-2 regioisomer). This residue was purified via silica gel column chromatography, eluting with dichloromethane to afford a solid, which was re-dissolved in dichloromethane and washed with 1N sodium hydroxide, brine, dried (magnesium sulfate), and concentrated under reduced pressure to give 14.3 g (36%) of the title compound 5 as a white solid. 1H NMR (CDCl3) delta 10.46 (s, 1 H), 8.06-8.02 (m, 1 H), 8.14-8.10 (m, 1 H), 8.23 (d, J = 1.6 Hz, 1 H), 7.88 (s, 2 H).
To a 1000 L glass-lined reactor was charged 2-chloro-4-fluoro-benzaldehyde (30.8 kg,194 mol) and isopropanol (188.0 kg). To the solution was then added methyl acetoacetate (22.7 kg, 195 mol) followed by piperidine (1.74 kg, 20.4 mol) and acetic acid (1.32 kg, 22.0 mol). The mixture was then heated to 43C - 47 C and stirred under this temperature for 5 hours. To the reaction mixture was then added <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> salt (19.8 kg, 121.Omol)and triethyl amine (20.0 kg, 198.0 mol). The reaction mixture was heated to 80 C - 85 C and stirred for 7 hours.After reaction completion, the reaction mixture was cooled to 20 C - 25 C. To the mixture was then added water (52.0 kg). The resulting suspension was stirred at 20 C - 25 C for 2 hours. The suspension was centrifuged and the collected solid was washed with isopropanollwater (42kg; lOv/3v). The wet solid was dried in vacuum oven to afford 35.05 kg of 4-(2-chloro-4-fluoro- phenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dthydropyrimidine-5-carboxylic acid methyl ester (Example1). The purity was 95.8%, the yield was 79.2 %, and MS mle = 366.2 [M+H] .
79.2%
A 1000 L glass-lined reactor equipped with mechanical stirrer, thermometer and nitrogen bubbler was charged 2-chloro-4-fluoro-benzaldehyde (30.8 kg, 194 mol, compound 11-a) andIPA (188.0 kg). To the solution was then added methyl acetoacetate (22.7 kg, 195 mol, compound 11-b) followed by addition of piperidine (1.74 kg, 20.4 mol) and acetic acid (1.32 kg, 22.0 mol). The reaction mixture was then heated to 43 C-47 C and stirred at such temperature for 5 hours. Then to the reaction mixture was added <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> salt (19.8 kg, 121.0 mol, compound 8-c) followed by addition of triethylamine (20.0 kg, 198.0 mol).The reaction mixture was heated to 80 C - 85 C and stirred for 7 hours. After reaction was completed, the reaction mixture was cooled to 20 C-25 C and then added water (52.0 kg). The resulting suspension was stirred at 20 C-25 C for 2 hours. The solid was collected by centrifuge and washed with isopropanollwater (42 kg, v/v=10/3). The wet solid was dried in vacuum oven to afford Example 11 (35.05 kg, purity: 95.8%, Yield: 79.2%) as yellow solid. MS mle = 366.2[M+H] .
With potassium acetate; In 2,2,2-trifluoroethanol; at 150℃; for 2h;Reflux; Microwave irradiation;
Preparation of Compound B: To a stirred solution of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was either refluxed for 16 hrs or heated at 150 C in microwave oven for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from 1/4 to 1/2) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): delta ppm 9.98 (s, 1H), 7.97 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H), 7.35 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (td, J = 8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H).
With potassium acetate; In 2,2,2-trifluoroethanol; for 16h;Reflux;
To a stirred solution of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from to ) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): 6 ppm 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H).
With potassium acetate; In 2,2,2-trifluoroethanol; for 16h;Reflux;
To a stirred solution of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from 1/4 to 1/2) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): delta ppm 9.98 (s, 1H), 7.97 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H), 7.35 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (td, J = 8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H).
With potassium acetate; In 2,2,2-trifluoroethanol; for 16h;Reflux;
Preparation of Compound B To a stirred solution of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong> (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-4-fluorobenzaldehyde (0.16 g, 1.0 mmol) in trifluoroethanol (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from 1/4 to 1/2) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366.
With sodium acetate; In ethanol; at 80℃; for 16h;Inert atmosphere;
General procedure: To a suspension of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong>(5.4 g, 33 mmol), 2-chloro-4-fluorobenzaldehyde (4.74 g,30 mmol), NaOAc (2.71 g, 33 mmol) in anhydrous EtOH (60 mL)was added tert-butyl 3-oxobutanoate (4.74 g, 33 mmol). The reactionmixture was refluxed at 80 C under N2 atmosphere overnight.Then the mixture was concentrated in vacuo and diluted withEtOAc, washed with water, brine, and the combined organic phasewas dried over Na2SO4, concentrated in vacuo to give a crude product,which was purified by silica gel chromatography (petrolether/ethyl acetate (V/V) = 5/1) to give a yellow solid (6.1 g, 50%).
With formic acid; hydroxylamine hydrochloride; sodium acetate; In water; at 80℃;
General procedure: A mixture of aromatic aldehydes (50mmol) (1-17), hydroxylamine hydrochloride (62.5mmol), sodium acetate (125mmol) were dissolved in the mixture of formic acid and water (60:40) and stirred at 80C until TLC analysis indicated the disappearance of aromatic aldehydes. Then, cooling the reaction system to room temperature and put it into water to obtain the target compounds. Some desired products which were dissolved in the mixture of water and formic acid can be obtained by salting out. Then, solid target compounds were obtained by filtration and recrystallized by alcohol, and then dried under vacuum. While, some target compounds are oily. These oily compounds were obtained by extraction with ethyl acetate and the solvent was removed at the vacuum to afford aryl nitriles (a1-a17).
(R)-(R)-1-ethoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.9%
With sodium acetate; In propan-1-ol; at 80℃; for 12h;
General procedure: Step 1) (R)-(R)-1-ethoxy-1-oxopropan-2-yl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylateMethod 2 To a flask wereadded <strong>[247037-82-7]2-thiazolecarboxamidine hydrochloride</strong> (16.4g, 0.1mol), 2-chloro-4-fluorobenzaldehyde (15.9 g, 0.1 mol), (R)-1-ethoxy-1-oxopropan-2-yl 3-oxobutanoate (20.2 g, 0.1 mol), anhydrous sodium acetate (8.2 g, 0.1 mol) and ethanol (74 g) in turn The mixture was stirred at 78 C for 16 hours. After the reaction, the reaction mixture was cooled to 30, kept at 30 and stirred for 6 hours. The mixture was filtered. The filtrate was washed with ethanol (16.4 g) and water (330 mL) in turn and then dried in vacuo at 60 C for 8 hours to obtain the product as a yellow solid (12.2 g, 27%). [a]25D = -91.47 (c = 0.3083 g/100 mL, MeOH); MS (ESI, pos.ion) m/z: 452.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta 10.05 (s, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.42-7.37 (m,2H), 7.20 (td, 1H), 6.03 (s, 1H), 4.84 (q, 1H), 4.12-4.04 (m, 2H), 2.47 (s, 3H), 1.22 (d, 3H), 1.14 (t,3H).
1.25 g
solution of the compound from step 1-1a (5 g, 24.5 mmol), 2-chloro-4-fluorobenzaldehyde (4.3 g, 27.3 mmol), TsOH (cat) and HOAc (cat) in toluene (60 mL) was stirred at 110 C. overnight. The mixture was concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired product (5.93 g, 70.0%) as yellow solid. ESI MS m/z=343.00 [M+H]+.solution of the compound from step 1-1b (5 g, 14.6 mmol), thiazole-2-carboximidamide HCl salt (2.38 g, 14.6 mmol) and K2CO3 (2.01 g, 14.6 mmol) in DMF (20 mL) was stirred for 2 hours at 80 C. It was diluted with EtOAc and washed with brine, filtered and concentrated. After the residue was purified by silica gel column (ethyl acetate/petroleum ether), the mixture was recrystallized from EtOH at 0 C. to give the desired product as yellow solid (1.25 g, 25.0%). ESI MS m/z=452.05 [M+H]+.
2-chloro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 60℃; for 24h;
Step A. 2-Chloro-4-(3 -methyl-i H-i ,2,4-triazol- 1 -yl)benzaldehydeTo a solution of 2-chloro-4-fluorobenzaldehyde (95 mmol, 15 g) and 3-methyl-1H-i,2,4-triazole(114 mmol, 9.4 g) in CH3CN (300 mL) was added K2C03 (142 mmol, 20 g) and stirred at 60 C.After 24 h, the reaction mixture was added water and extracted with EtOAc. The organic extracts washed with saturated aq. NaC1, dried over Na2SO4, and filtered and concentrated in vacuo. The crude was purified by column chromatography (heptane :EtOAc = 20:80-10:90) to give the title compound. MS (ESI) mlz = 222, 224 (M+H)?H NMR (300 MHz, CDC13) 5 (ppm): 10.45 (1H, s), 8.55 (1H, s), 8.06 (1H, d, J 8.6 Hz), 7.87(1H, d, J= 2.1 Hz), 7.68 (1H, dd, J 8.6, 2.1 Hz), 2.51 (3H, s).
With potassium carbonate; In acetonitrile; at 60℃; for 24h;
To a solution of 2-chloro-4-fluorobenzaldehyde (95 mmol, 15 g) and 3-methyl-lH-l,2,4-triazole (114 mmol, 9.4 g) in CH3CN (300 mL) was added K2C03 (142 mmol, 20 g) and stirred at 60 C. After 24 h, the reaction mixture was added water and extracted with EtOAc. The organic extracts washed with saturated aq. NaCl, dried over Na2S04, filtered and concentrated in vacuo. The crude was purified by column chromatography (heptane: EtOAc = 20:80-10:90) to give the title compound. MS (ESI) m/z = 222, 224 (M+H) 1H NMR (300 MHz, CDC13) delta (ppm): 10.45 (1H, s), 8.55 (1H, s), 8.06 (1H, d, J= 8.6 Hz), 7.87 (1H, d, J= 2.1 Hz), 7.68 (1H, dd, J= 8.6, 2.1 Hz), 2.51 (3H, s).
methyl 1-(3-chloro-4-formylphenyl)-1H-1,2,4-triazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 24h;
Step A. Methyl 1 -(3 -Chloro-4-formylphenyl)- 1 H-i ,2,4-triazole-3 -carboxylate To a solution of 2-chloro-4-fluorobenzaldehyde (25 mmol, 4.0 g) and methyliH-i,2,4-triazole-3-carboxylate (38 mmol, 4.8 g) in NMP (80 mL) was added K3P04 (38 mmol,8.0 g) and stirred at 60 °C. After 24 h, the reaction mixture was added water and extracted withEtOAc. The organic extract was washed with saturated NaC1, dried over Na2SO4, and filteredand concentrated in vacuo. The crude residue was purified by silica-gel column chromatography(heptane:EtOAc = 70:30-30:70) to give the title compound. MS (ESI) mlz = 266, 268 (M+H)
With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 18h;
A mixture of methyl pyridin-2-ylmethyl ketone (98.5mg, 0.73 mmol), 2-chloro-4-fluorobenzaldehyde (116mg, 0.73 mmol), 1,3-thiazole-2-carboxirnidamide HCl salt (100 mg, 0.61 mmol) and KOAc (119.56mg, 1.22 mmol) in CF3CH2OH (10 mL) was stirred for 18 hours at 90 C. After being cooled, it was concentrated and partitioned (EtO Ac-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was purified by Flash-Prep-HPLC (C18, MeCN/H2O) to give the title compound (racemic mixture) as a yellow solid (61.6 mg, 26.2%) ESIMS m/z = 385.10, 387.10 [M+H]+; 1H NMR (400 MHz, Methanol-d4) delta 8.48 (ddd, 1H), 7.95 (d, 1H), 7.75 (d, 1H), 7.71 (td, 1H), 7.59 (dd, 1H), 7.26 - 7.15 (m, 2H), 7.11 (dd, 1H), 7.05 (td, 1H), 6.24 (d, 1H), 2.07 (d, 3H).
With potassium acetate; In 2,2,2-trifluoroethanol; at 80℃; for 14h;
A solution of <strong>[247037-82-7]thiazole-2-carboximidamide hydrochloride</strong> (3.0 g, 18.40 mmol ), allyl 3-oxobutanoate (2.87 g, 20.24 mmol), 2-chloro-4-fluorobenzaldehyde (3.20 g, 20.24 mmol) and KOAc (3.61 g,36.80 mmol) in CF3CH2OH (100 mL) was stirred for 14 hours at 80C. The solution was diluted with EtOAc and washed with brine. The residue was chromatographed (silica, petroleum ether/ethyl acetate) to give the desired compound as yellow solid (5.0 g, 69%). ESIMS m/z = 391.95, 393.95 [M+H] +.
tert-butyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium acetate; In ethanol; at 80℃; for 16h;Inert atmosphere;
To a suspension of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong>(5.4 g, 33 mmol), 2-chloro-4-fluorobenzaldehyde (4.74 g,30 mmol), NaOAc (2.71 g, 33 mmol) in anhydrous EtOH (60 mL)was added tert-butyl 3-oxobutanoate (4.74 g, 33 mmol). The reactionmixture was refluxed at 80 C under N2 atmosphere overnight.Then the mixture was concentrated in vacuo and diluted withEtOAc, washed with water, brine, and the combined organic phasewas dried over Na2SO4, concentrated in vacuo to give a crude product,which was purified by silica gel chromatography (petrolether/ethyl acetate (V/V) = 5/1) to give a yellow solid (6.1 g, 50%). 1H NMR (600 MHz, CDCl3): d 7.82 (d, 1H, J = 4.2 Hz), 7.49 (br s,1H), 7.33 (dd, 1H, J = 13.2 Hz, 9.6 Hz), 7.14 (dd, 1H, J = 12.6 Hz,3.6 Hz), 6.95 (td, 1H, J = 12.6 Hz, 3.6 Hz), 6.12 (s, 1H), 2.54 (s, 3H),1.30 (s, 9H); MS-ESI: (ESI, pos.ion) m/z: 408.1 [M+1]+; HRMS (ESI)calcd for C19H19ClFN3O2S [M+H]+ 408.0871; found 408.0949; HPLCanalysis: retention time = 23.19 min; peak area, 97.67%.
34%
With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 24h;
A mixture of t-butyl 3-oxobutanoate (1.9 g, 12.01 mmol), 2-chloro-4- fluorobenzaldehyde (1.9 g, 11.98 mmol), 1,3-thiazole-2-carboximidamide HCl salt (1.64 g, 10.00 mmol) and KOAc (1.96 g, 19.97 mmol) in CF3CH2OH (50 mL) was stirred for 24 hours at 90C. After concentrated, the residue was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (1.4 g, 34%). ESIMS m/z = 408.0, 410.0 [M+H]+.
With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 24h;
A mixture of ethyl 3-oxobutanoate (7.61 g, 58.47 mmol), 2-chloro-4-fluorobenzaldehyde (7.76 g, 48.94 mmol), 1,3-thiazole-2-carboximidamide HCl salt (8.0 g, 48.78 mmol) and KOAc (9.56 g, 97.41 mmol) in CF3CH2OH (200 mL) was stirred for 24 hours at 90 C. After being cooled, it was concentrated and the residue was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (8.2 g, 44%). ESIMS m/z = 380.2, 382.2 [M+H]+.
With sodium acetate; In ethanol; at 80℃; for 16h;Inert atmosphere;
General procedure: To a suspension of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong>(5.4 g, 33 mmol), 2-chloro-4-fluorobenzaldehyde (4.74 g,30 mmol), NaOAc (2.71 g, 33 mmol) in anhydrous EtOH (60 mL)was added tert-butyl 3-oxobutanoate (4.74 g, 33 mmol). The reactionmixture was refluxed at 80 C under N2 atmosphere overnight.Then the mixture was concentrated in vacuo and diluted withEtOAc, washed with water, brine, and the combined organic phasewas dried over Na2SO4, concentrated in vacuo to give a crude product,which was purified by silica gel chromatography (petrolether/ethyl acetate (V/V) = 5/1) to give a yellow solid (6.1 g, 50%).
6 g
With potassium acetate; In 2,2,2-trifluoroethanol; for 16h;Reflux;
At room temperature, ethyl acetoacetate (4.7 g, 36.0 mmol), <strong>[247037-82-7]thiazole-2-carboximidamide hydrochloride</strong> (5.4 g, 36.0 mmol), 2-chloro-4-fluorobenzaldehyde (5.8 g, 36.0 mmol) and potassium acetate (6.0 g, 60.0 mmol) were added to 2,2,2-trifluoroethanol (100 mL), heated to reflux, and the reaction was performed for 16 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the title compound (6.0 g) was obtained after work-up. ESI-MS (m/z): 380.1 [M + H]+.
4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 24h;
A mixture of 3-oxobutanamide (3 g, 29 mmol), 2-chloro-4-fluorobenzaldehyde (4.9 g, 29 mmol), 1,3-thiazole-2-carboximidamide HCl salt (5 g, 29 mmol) and KOAc (6 g, 58 mmol) in CF3CH2OH (50 mL) was stirred for 24 hours at 90 C. After being cooled, it was concentrated and partitioned (EtO Ac-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (1.2 g, 21%). ESIMS m/z = 350.95, 352.95 [M+H]+.
isopropyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; In ethanol; at 80℃; for 16h;Inert atmosphere;
General procedure: To a suspension of <strong>[247037-82-7]thiazole-2-carboxamidine hydrochloride</strong>(5.4 g, 33 mmol), 2-chloro-4-fluorobenzaldehyde (4.74 g,30 mmol), NaOAc (2.71 g, 33 mmol) in anhydrous EtOH (60 mL)was added tert-butyl 3-oxobutanoate (4.74 g, 33 mmol). The reactionmixture was refluxed at 80 C under N2 atmosphere overnight.Then the mixture was concentrated in vacuo and diluted withEtOAc, washed with water, brine, and the combined organic phasewas dried over Na2SO4, concentrated in vacuo to give a crude product,which was purified by silica gel chromatography (petrolether/ethyl acetate (V/V) = 5/1) to give a yellow solid (6.1 g, 50%).
ethyl 4-(2-chloro-4-fluorophenyl)-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium acetate; In ethanol;Reflux;
Step 3 (Synthesis of Compound 1-7) (0080) Compound 1-4 (4.3 g, 27 mmol) was dissolved in ethanol (20 mL), and compound 1-5 (7.0 g, 27 mmol), compound 1-6 (8.8 g, 54 mmol), sodium acetate (6.6 g, 81 mmol) were added. The temperature of the reaction mixture was slowly raised to reflux, and the reaction was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure and then extracted with EtOAc (500 mL×3). The organic layer was washed with saturated saline solution (1000 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE: EtOAc=10:1) to obtain 5.0 g product 1-7 (yellow solid), yield: 61%. (0081) LCMS (ESI) m/z: 508.0 [M+H+].
ethyl 4-(2-chloro-4-fluorophenyl)-6-(4-ethoxy-4-oxobutyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium acetate; In ethanol;Reflux;
Step 1 (Synthesis of Compound 109-2) (0568) Compound 109-1 (1.34 g, 5.8 mmol) was dissolved in anhydrous ethanol (30 mL), and 2-chloro-4-fluorobenzaldehyde (1.08 g, 5.8 mmol), thiazoledicarboxamidine hydrochloride (0.95 g, 5.8 mmol), sodium acetate (1.1 g, 17.4 mmol) were added. The reaction mixture was slowly warmed to reflux, and the reaction was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure and subsequently extracted with EtOAc (40 mL×3). The organic layer was washed with saturated saline solution (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE: EtOAc=5:1) to obtain 1.5 g compound 109-2, yield: 62%. (0569) LCMS (ESI) m/z: 480.0 [M+H+].
methyl 3-(1-methyl-2-oxopiperidin-4-yl)-3-oxopropanoate[ No CAS ]
[ 84194-36-5 ]
methyl 4-(2-chloro-4-fluorophenyl)-6-(1-methyl-2-oxopiperidin-4-yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; In ethanol; at 80 - 100℃;Inert atmosphere;
General procedure: To a solution of the ketoester of general formula III (1 equivalent) in ethanol was addedthe aldehyde of general formula IV (1 equivalent), the carboxamidine hydrochloride of10 general formula V (1 equivalent) and sodium acetate (1- 1.2 equivalents). The mixturewas brought up to 80 - 100 C and stirred under nitrogen atmosphere overnight. Aftercooled down to room temperature, it was concentrated to dryness. The residue wastaken up in dichloromethane, washed with water, brine, dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure to give a residue,15 which was purified by silica gel column chromatography to afford thedihydropyrimidine product of general formula I. When applicable, the stereoisomers ofthe dihydropyrimidine product of general formula I were isolated and purified usingchiral chromatography.
A solution of ethyl (R)-2-hydroxypropanoate (5 g, 42.3 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (6 g, 42.3 mmol) was stirred for 4 hours at 120 C. The mixture was concentrated under vacuum to give desired product (9 g, crude) as yellow oil, which was used in the next step without further purification. ESI MS m/z=203.25 [M+H]+. Step 1-1b. A solution of the compound from step 1-1a (5 g, 24.5 mmol), 2-chloro-4-fluorobenzaldehyde (4.3 g, 27.3 mmol), TsOH (cat) and HOAc (cat) in toluene (60 mL) was stirred at 110 C. overnight. The mixture was concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired product (5.93g, 70.0%) as yellow solid. ESI MS m/z=343.00 [M+H]+. Step 1-1c. A solution of the compound from step 1-1b (5 g, 14.6 mmol), thiazole-2-carboximidamide HCl salt (2.38 g, 14.6 mmol) and K2CO3 (2.01 g, 14.6 mmol) in DMF (20 mL) was stirred for 2 hours at 80 C. It was diluted with EtOAc and washed with brine, filtered and concentrated. After the residue was purified by silica gel column (ethyl acetate/petroleum ether), the mixture was recrystallized from EtOH at 0 C. to give the desired product as yellow solid (1.25 g, 25.0%). ESI MS m/z=452.05 [M+H]+. Step 1-1d. A solution of the compound from step 1-1c (950 mg, 2.10 mmol), (Boc)2O (915.6 mg, 4.20 mmol) and DMAP (307 mg, 2.51 mmol) in DCM (30 mL) was stirred for 1 hour at rt. (0160) The reaction mixture was concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as yellow solid (1.07 g, 92%). ESI MS m/z=552.30 [M+H]+. Step 1-1e. A solution of the compound from step 1-1d (965 mg, 1.75 mmol) in a solution of NaOH [40 mL, 2M in H2O/MeOH (1:5)] was stirred for 18 hours at rt. After being acidified with aq HCl (4N) to pH 5, the mixture was extracted with DCM. The organic layer was washed with aq. NH4Cl and H2O, dried (Na2SO4) and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as yellow solid (620 mg, 78%). ESI MS m/z=452.15 [M+H]+. Step 1-1f. A solution of the compound from step 1-1e (250 mg, 0.55 mmol) in DCM (10 mL) was treated with NBS (295 mg, 1.66 mmol) for 6 hours at rt. The reaction was quenched by the addition of water (2 mL) and extracted with DCM. The organic layer was dried (Na2SO4), concentrated. The residue was chromatographed (Cis column, MeCN/H2O) to give the title compound as yellow solid (103.5 mg, 33%). ESI MS m/z=566.10, 568.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 8.04 (m, 2H), 7.98 (d, 1H), 7.57 (m, 1H), 7.23 (m, 1H), 6.35 (s, 1H), 4.45 (m, 2H), 1.15 (s, 9H).
ethyl 4-(6-chlorohexoxy)-3-oxo-butanoate[ No CAS ]
[ 84194-36-5 ]
ethyl 4-(2-chloro-4-fluorophenyl)-6-(6-chlorohexoxymethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
692 mg
With sodium ethanolate; at 80℃; for 40h;
A mixture of 2-chloro-4-fluorobenzaldehyde (157 mg, 0.99 mmol), ethyl 4-(6- chlorohexoxy)-3-oxo-butanoate (intermediate 1-5, 452 mg, 0.99 mmol), thiazole-2- carboximidamide hydrochloride (162 mg, 0.99 mmol) and sodium acetate (162 mg, 1.98 mmol) in EtOH (5 mL) was heated at 80 C for 40 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc for three times. The combined organic layer was washed with brine, dried and concentrated to afford ethyl 4-(2-chloro-4-fluoro-phenyl)-6-(6- chlorohexoxymethyl)-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylate (compound 14a, 692 mg) as a yellow oil. MS obsd. (ESI+) [(M+H)+]: 514.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
