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Structure of 4023-34-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With triethylamine; magnesium chloride In ethyl acetate at 0 - 40℃; for 20 h; Stage #2: at 0 - 20℃; for 20 h;
To ethyl acetate (100 ml) suspension of potassium ethyl malonate (17.0 g, 0.10 mol) were added triethylamine (34.7 ml, 0.25 mol) and magnesium chloride (14.3 g, 0.15 mol) with cooling with ice, and then the resulting mixture was stirred at 40°C for 20 hours. To tetrahydrofuran (50 ml) solution of cyclopropanecarboxylicacid (4.30 g, 50.0 mmol) were added oxalyl chloride (4.36 ml, 50.0 mmol) and a catalytic amount of N,N-dimethylformamide with cooling with ice, and the resulting mixture was stirred as such for 1 hour and then at room temperature for 1 hour. The above-mentioned malonic acid solution was added to this acid chloride solution with cooling with ice, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into 300 ml of aqueous 10 percent citric acid solution, and the mixture was extracted with ethyl acetate (300 ml .x. 3). The organic layer was successively washed with 500 ml of aqueous saturated sodium bicarbonate solution and 300 ml of brine, and dried over sodium sulfate. The solvent was evaporated, and7.26g (93percent) of the entitled compound was obtained as a colorless oil (this was directly used in the next reaction).1H-NMR(400MHz, CDCl3)δ: 0.94-0.99(2H, m), 1.10-1.15(2H, m), 1.28(3H, t, J=7.08Hz), 2.01-2.06(1H, m), 3.57 (2H, s), 4.21(2H, q, J=7.08Hz).
60%
Stage #1: With magnesium chloride In acetonitrile at 25℃; for 0.0833333 h; Stage #2: With triethylamine In acetonitrile at 25℃; for 16 h;
To a solution of ethyl potassium malonate (6.5 g, 38.26 mmol) in acetonitrile was added MgCl2 (4.55 g, 47.8 mmol) and the mixture stirred for 5 min at 25° C. TEA (10.7 mL, 76.54 mmol) was then added, followed by dropwise addition of cyclopropanecarbonyl chloride (2 g, 19.13 mmol) and stirring was continued at 25° C. for 16 h, after which, the mixture was diluted with water, acidified to pH 3 with 6N HCl, extracted with diethylether (3*40 mL), dried over Na2SO4, and concentrated to give 3-Cyclopropyl-3-oxo-propionic acid ethyl ester (1.8 g, 60percent).
With n-butyllithium In tetrahydrofuran; hydrogenchloride; water
a Ethyl 3-cyclopropyl-3-oxopropanoate To a cooled (-70° C.) solution of monoethyl malonate (33.97 g, 257.10 mmol) in THF (639 mL) was added n-BuLi (1.6M in hexanes, 319 mL, 514.19 mmol) and the mixture was stirred under an argon atmosphere for 15 min. The resulting solution was cooled to -65° C. and cyclopropanecarbonyl chloride (15.55 g, 148.77 mmol) was added. The reaction mixture was stirred for 1 h and then allowed to warm up to room temperature. Some drops of water were added and THF was removed. The residue was taken up in 1N HCl/Et2 O and extracted with Et2 O. The organic phase was washed with saturated NaHCO3, dried and concentrated to a residue. This was purified by chromatography on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a yellow oil (14.7 g, 63percent). 1 H-NMR-(CDCl3) δ (TMS): 1.1 (m, 4H), 1.28 (t, J=7.2 Hz, 3H), 2.04 (m, 1H), 3.55 (s, 2H), 4.21 (q, J=7.2 Hz, 2H).
Reference：
[1] Patent: US5827863, 1998, A,
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 4, p. 547 - 558
[3] Patent: US5157040, 1992, A,
Intermediate 3: Synthesis of cvclopropanecarboxamide Ammonia was purged through a well-stirred solution of cyclopropane carbonyl chloride (1 g, 9.61 mmol) in dichloromethane (10 mL) for 2 hours at room temperature. Solvent was removed under vacuum, the residue was taken up in ethyl acetate and filtered The filtrate was concentrated to afford pure cyclopropanecarboxamide as a crystalline solid (0.81 g, 100percent).1H NMR (400 MHz, CHCI3-cf): δ 5.63 - 5.91 (br. s, 2H), 1 .43 (m, 1 H), 0.98 (dd, J=4.42, 2.98 Hz, 2H), 0.79 (dd, J=7.91 , 2.95 Hz, 2H). MS: 85.91 (M+1 ).
100%
With ammonia In dichloromethane; water at 20℃; for 2 h;
Synthesis of cyclopropanecarboxamide Ammonia was purged through a well-stirred solution of cyclopropane carbonyl chloride (1 g, 9.61 mmol) in dichloromethane (10 mL) for 2 hours at room temperature. Solvent was removed under vacuum, the residue was taken up in ethyl acetate and filtered. The filtrate was concentrated to afford pure cyclopropanecarboxamide as a crystalline solid (0.81 g, 100percent). 1H NMR (400 MHz, CHCl3-d): δ 5.63-5.91 (br. s, 2H), 1.43 (m, 1H), 0.98 (dd, J=4.42, 2.98 Hz, 2H), 0.79 (dd, J=7.91, 2.95 Hz, 2H). MS: 85.91 (M+1).
Reference：
[1] Patent: WO2012/160464, 2012, A1, . Location in patent: Page/Page column 59-60
[2] Patent: US2014/155398, 2014, A1, . Location in patent: Paragraph 0365
[3] Chemische Berichte, 1923, vol. 56, p. 2201
[4] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1901, vol. 33, p. 377[5] Chem. Zentralbl., 1901, vol. 72, # II, p. 579
[6] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1905, vol. 37, p. 308[7] Chem. Zentralbl., 1905, vol. 76, # I, p. 1704
[8] Chem. Zentralbl., 1902, vol. 73, # I, p. 913
10
[ 99912-18-2 ]
[ 4023-34-1 ]
[ 6228-73-5 ]
Reference：
[1] Patent: US4673674, 1987, A,
11
[ 108-86-1 ]
[ 4023-34-1 ]
[ 6952-89-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6629 - 6635
Stage #1: With pyridine In chloroform at 10 - 20℃; for 2 h; Stage #2: for 3 h; Heating / reflux
Reference Example 1 Production of methyl 3-cyclopropyl-3-oxopropionate Merdramic acid (50 g; 347 mmols) was dissolved in chloroform (550 ml), and pyridine (56 g; 700 mmols) was added thereto. Subsequently, a solution of cyclopropanecarboxylic acid chloride (40 g; 383 mmols) in chloroform (50 ml) was added dropwise thereto at a temperature of 10°C or lower while cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for further 1 hour under cooling in the ice-bath, then at room temperature for 1 hour. Subsequently, after cooling again using the ice-bath, 1N-HCL aqueous solution (500 ml) was added thereto. The reaction product was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. Then, methanol (500 ml) was added thereto to dissolve the residue, and the solution was heated for 3 hours under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 40 g of methyl 3-cyclopropyl-3-oxopropionate. Yield: 80percent Physical properties: bp. 80°C (10mmHg)
Reference：
[1] Patent: EP1852428, 2007, A1, . Location in patent: Page/Page column 31
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6836 - 6840
14
[ 2033-24-1 ]
[ 4023-34-1 ]
[ 32249-35-7 ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With pyridine In dichloromethane at 0 - 20℃;
a.2 2-te/t-Butvl-4-f4-(3-chloro-propvl)-piperazin-1-vll-6-cvclopropvl-pyrimidine; a.2.1: Methyl-2-cvclopropanovl-acetate; 48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0°C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0°C within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2h. The reaction mixture was concentrated to dryness and the oily residue was purified by destination at 90 °C bath temperature to yield 42.7 g (71,1 percent) of the title compound.MS (ESI) m/z: 143.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.75 (s, 3H), 3.6 (s, 2H), 2.0 (m, 1H), 1.15 (m, 2H),0.95 (m, 2H)
219.1 g (1913 mmol, 1 equiv.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 equiv.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aqueous sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
91%
at 0 - 5℃; for 1.5 h;
Alternative Preparation of (S)-6-Aza-spiro[2.5]octan-4-ol; hydrochloridei) Cyclopropanecarboxylic Acid tert-butyl ester; 219.1 g (1913 mmol, 1 eq.) potassium tert-butylate were suspended in 2.5 L TBME and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-EtOH bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. NaHCO3 solution was added. The aqueous phase was separated and extracted with 500 ml TBME. The organic phases were washed with 500 ml half sat. aq. NaCl solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual TBME).
91%
at 0 - 5℃; for 1.5 h;
i) Cyclopropanecarboxylic acid tert-butyl ester; 219.1 g (1.91 mol, 1 eq.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the title compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
91%
at 0 - 5℃; for 1 h;
i) Cyclopropanecarboxylic acid tert-butyl ester 219.1 g (1.91 mol, 1 eq.) potassium tert-butylate were suspended in 2.5 L tert-butyl methyl ether and cooled to 0-5° C. 200 g (1 eq.) cyclopropanecarbonyl chloride were added over 60 min, maintaining the temperature between 0-5° C. (ice-ethanol bath cooling). In-line FTIR reaction monitoring indicates a feed controlled reaction. The reaction mixture was stirred 30 min at 0-5° C. and 1 L of 5percent aq. sodium hydrogencarbonate solution was added. The aqueous phase was separated and extracted with 500 ml tert-butyl methyl ether. The organic phases were washed with 500 ml half saturated aq. sodium chloride solution, combined and concentrated under reduced pressure (30° C./150 mbar) to provide 271 g of the titled compound (91percent yield corrected for 8percent residual tert-butyl methyl ether).
63.2%
at 0 - 50℃; for 0.5 h;
Example 1Atert-Butyl Cyclopropanecarboxylate 50.99 g (454.4 mmol) of potassium tert-butoxide were dissolved in 454 ml of abs. THF and cooled to 0° C. The solution was stirred vigorously, and 50 g (478.3 mmol) of cyclopropanecarbonyl chloride were added dropwise such that the reaction temperature did not exceed 50° C. (cooling required). After the addition has ended, the resultant suspension was stirred for another 30 min. After cooling, the reaction mixture was, under reduced pressure, concentrated to about one third of the original volume and then added to 2 liters of saturated aqueous ammonium chloride solution. The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the mixture was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure without heating (cold water bath). The residue was distilled at a bath temperature of about 85° C. and 42 mbar. This gave 43.1 g (63.2percent of theory) of the target compound as a clear liquid.GC-MS (Method 1): Rt=1.8 min1H-NMR (400 MHz, DMSO-d6): δ=1.52-1.48 (m, 1H), 1.41 (s, 9H), 0.82-0.72 (m, 4H).
With n-butyllithium In tetrahydrofuran; water; ethyl acetate
EXAMPLE 1 3-Cyclopropyl-3-oxopropanenitrile To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78° C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes. The solution was warmed in a water bath to 0° C. After 15 minutes at 0° C. most of the brown color had faded. The mixture was cooled to -78° C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF. The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5percent HCl solution in water, and was extracted three times with ether. The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30percent ethyl acetate in hexanes to give 6.5 g (54percent yield) of the title compound. The title compound was stored with 1percent w/w BHT in 40 mL CH2 Cl2 at -5° C. Rf 0.12 in 20percent EtOAc/hexane, visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): δ3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
54%
With n-butyllithium In tetrahydrofuran; water; ethyl acetate
EXAMPLE 1 3-Cyclopropyl-3-oxopropanenitrile To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78° C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes. The solution was warmed in a water bath to 0° C. After 15 minutes at 0° C. most of the brown color had faded. The mixture was cooled to -78° C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF. The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5percent HCl solution in water, and was extracted three times with ether. The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30percent ethyl acetate in hexanes to give 6.5 g (54percent yield) of the title compound. The title compound was stored with 1percent w/w BHT in 40 mL CH2 Cl2 at -5° C. Rf 0.12 in 20percent EtOAc/hexane visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): δ3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
Reference：
[1] Patent: US5250521, 1993, A,
[2] Patent: US5260285, 1993, A,
Reference：
[1] Patent: US5804532, 1998, A,
[2] Patent: US5804532, 1998, A,
21
[ 4023-34-1 ]
[ 372-09-8 ]
[ 118431-88-2 ]
Reference：
[1] Patent: EP496631, 1992, A1,
22
[ 6638-79-5 ]
[ 4023-34-1 ]
[ 147356-78-3 ]
Yield
Reaction Conditions
Operation in experiment
72.9%
With triethylamine In dichloromethane at 0 - 20℃;
Example 96. Synthesis of 3-fluoro-2-(4-(3-(5-hydroxy-2-methylpiperidin-l-yl)- -pyrazol-l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)benzonitrile, 1-96 Synthesis of compound 96.2. To a solution of Ν,Ο-dimethylhydroxylamine HCl (10.0g, 95.69 mmol, 1.0 eq) and Et3N (19.36 g, 191.6 mmol, 2.0 eq) in CH2C12 (60 mL) reaction mixture was stirred at 0 °C for 30 min. Compound 96.1 was added at 0 °C. Reaction mixture was stirred at room temperature for 15 h. Upon completion of the reaction, organic layer was washed with water, brine, sat NaHCC solution and 1.0 N HCl, dried over Na2S04 and concentrated under reduced pressure to pressure to obtain crude. Crude was purified by column chromatography to provide 96.2 (9.0 g, 72.9percent).
61%
With triethylamine In dichloromethane at 0℃; for 1 h; Cooling with ice
N,O-dimethyl-hydroxylamine HCl (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2.x.DCM, 1.x.1N HCl, 1.x.NaCl. Distillation: 75° C./20 mbar. One obtained 32.5 g (61percent) of a colorless oil.
61%
With triethylamine In dichloromethane at 0℃; for 1 h;
Cyclopropanecarboxylic acid methoxy-methyl-amide N, O-dimethyl-hydroxylamine HC1 (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2 x DCM, 1 x 1 N HC1, 1 x NaCl. Distillation: 75 °C/20 mbar. One obtained 32.5 g (61 percent) of a colorless oil.
With triethylamine In dichloromethane at 0 - 20℃; for 3 h; Large scale
S1: N-Boc-piperazine (1.82 kg, 9.77 mol) was added to a 20 L four-necked flask with mechanical stirring and a thermometer.Triethylamine (1.48 kg, 14.66 mol), dichloromethane 5.46 Kg, cooled to 0 ° C,Cyclopropylcarbonyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled from 0 ° C to 10 ° C.After the completion of the dropwise addition, the reaction was carried out for 3 hours at 10 ° C to 20 ° C.Add 5kg of water, add sodium carbonate to adjust pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg of water phase, and extract once with dichloromethane.The methylene chloride phases were combined, washed once with 2 kg of 0.05 M diluted hydrochloric acid, and once with 2 kg of water.The dichloromethane was concentrated to remove 2.43 kg of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester, yield 98percent.The nuclear magnetic warp alignment is consistent with the standard map.
73%
With potassium carbonate In dichloromethane at 0 - 20℃;
A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0° C., cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73percent) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
73%
With potassium carbonate In dichloromethane at 0 - 20℃;
Example 17Atert- Butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate[00523] A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 °C,cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4- (cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, yield 73percent) as a white solid. ^-NMR (400 MHz, CDCI3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
Reference：
[1] Patent: CN108341792, 2018, A, . Location in patent: Paragraph 0028; 0033
[2] Patent: US2010/35883, 2010, A1, . Location in patent: Page/Page column 56
[3] Patent: WO2011/130661, 2011, A1, . Location in patent: Page/Page column 102
[4] Patent: US2004/14770, 2004, A1, . Location in patent: Page/Page column 11
With 4-methyl-morpholine In 1,4-dioxane at 50℃; for 4 h; Green chemistry
The intermediate (III) obtained in step E)With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1,4-dioxane,The amidation reaction time was 4 h,The amidation reaction temperature was 50 ° C,The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1,4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature,Adding methylene chloride and water, separating the organic phase with water,Then washed with brine, dried over magnesium sulfate,Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid,That is, Filgotinib, yield 91.2percentThe reaction of this step is the same as in Example 1.
With triethylamine; In dichloromethane; at 0 - 20℃; for 3.0h;Large scale;
S1: N-Boc-piperazine (1.82 kg, 9.77 mol) was added to a 20 L four-necked flask with mechanical stirring and a thermometer.Triethylamine (1.48 kg, 14.66 mol), dichloromethane 5.46 Kg, cooled to 0 C,Cyclopropylcarbonyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled from 0 C to 10 C.After the completion of the dropwise addition, the reaction was carried out for 3 hours at 10 C to 20 C.Add 5kg of water, add sodium carbonate to adjust pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg of water phase, and extract once with dichloromethane.The methylene chloride phases were combined, washed once with 2 kg of 0.05 M diluted hydrochloric acid, and once with 2 kg of water.The dichloromethane was concentrated to remove 2.43 kg of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester, yield 98%.The nuclear magnetic warp alignment is consistent with the standard map.
73%
With potassium carbonate; In dichloromethane; at 0 - 20℃;
A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 C., cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10% citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
73%
With potassium carbonate; In dichloromethane; at 0 - 20℃;
Example 17Atert- Butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate[00523] A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 C,cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10% citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4- (cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, yield 73%) as a white solid. ^-NMR (400 MHz, CDCI3) delta (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
With potassium carbonate; In dichloromethane; at 20℃; for 18.0h;
Cyclopropanoyl chloride (112 muL) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then it was filtered off from inorganics. The organic phase was diluted with Et2O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic layers were dried and concentrated in vacuo to give the title compound (210 mg) as an oil. [0238] T.I.c.: AcOEt, Rf=0.45. [0239] NMR (d6-DMSO): 6 (ppm) 3.64-3.28 (m, 8H); 1.94 (m, 1H); 1.4 (s, 9H); 0.7 (m, 4H). [0240] MS (ES/+): m/z=255 [M+H]+.
With n-butyllithium; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 1 3-Cyclopropyl-3-oxopropanenitrile To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78 C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes. The solution was warmed in a water bath to 0 C. After 15 minutes at 0 C. most of the brown color had faded. The mixture was cooled to -78 C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF. The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5% HCl solution in water, and was extracted three times with ether. The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30% ethyl acetate in hexanes to give 6.5 g (54% yield) of the title compound. The title compound was stored with 1% w/w BHT in 40 mL CH2 Cl2 at -5 C. Rf 0.12 in 20% EtOAc/hexane, visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): delta3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
54%
With n-butyllithium; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 1 3-Cyclopropyl-3-oxopropanenitrile To a mechanically stirred solution of 15.0 g (176 mmol) 2-cyanoacetic acid and 100 mg 1,10-phenanthroline in 500 mL THF at -78 C. was added 141 mL (352 mmol) 2.5M n-butyllithium in hexanes. The solution was warmed in a water bath to 0 C. After 15 minutes at 0 C. most of the brown color had faded. The mixture was cooled to -78 C. and to it was added a solution of 8.0 mL (88 mmol) cyclopropanecarbonyl chloride in 8 mL THF. The mixture was warmed to RT and stirred 15 minutes, was poured into 300 mL 5% HCl solution in water, and was extracted three times with ether. The combined organic material was washed with saturated aqueous sodium bicarbonate then with brine, was dried over magnesium sulfate, was stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 30% ethyl acetate in hexanes to give 6.5 g (54% yield) of the title compound. The title compound was stored with 1% w/w BHT in 40 mL CH2 Cl2 at -5 C. Rf 0.12 in 20% EtOAc/hexane visualized by ninhydrin stain (green tint); 1 H-NMR (300 MHz, CDCl3): delta3.63 (s, 2H), 2.10 (m, 1H), 1.20 (m, 2H), 1.10 (m, 2H).
With dmap; In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane; water;
EXAMPLE 101 Synthesis of 2-cyclopropanecarboxamido-5-Bromo-4-Methyl-3-nitropyridine STR83 A mixture comprising 10 g (43.1 mmol) of <strong>[100367-40-6]2-amino-5-bromo-4-methyl-3-nitropyridine</strong>, 6.3 g of 4-dimethylaminopyridine and xylene (50 ml) was heated at 110 C. in a nitrogen atmosphere. 5 g (47.4 mmol) of cyclopropanecarbonyl chloride was dropwise added thereto, followed by further stirring at 110 C. for 2 hours. The reaction mixture was brought to room temperature, followed by the addition of dichloromethane (200 ml) and water (50 ml). The organic phase was separated and the aqueous phase was further extracted with dichloromethane (50 ml). The organic phases were combined and washed with water (50 ml). The resulting organic phase was dried over anhydrous magnesium sulfate and concentrated to give a crude crystal. It was recrystallized from chloroform/ethyl acetate to give 11.4 g of the title compound (yield 88%). m.p.; 204.7 C. 1 H-NMR (400 MHz, CDCl3); delta(ppm) 0.91~0.96 (2H, m), 1.12~1.16 (2H, m), 1.59~1.71 (1H, m), 2.52 (3H, s), 8.21 (1H, br-s), 8.58 (1H, S) FAB-MS; 300, 302 (MH+)
1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
[ 4965-09-7 ]
Yield
Reaction Conditions
Operation in experiment
Preparation 1-8 1-Cyclopropyl-1,2,3,4-Tetrahydroisoquinoline In accordance with the same procedures as in Preparation 1-1, except that 12.5 ml of phenethylamine (0.1M) and 10 ml of cyclopropane carbonylchloride(0.11M) were used as starting materials, 2.5 g of the title compound was prepared.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;
EXAMPLE 4 Cyanoacetic acid (8.5 g) was dissolved in dry tetrahydrofuran (THF) (250 ml), placed under an inert atmosphere and the solution was cooled using a dry ice-acetone bath. Butyl lithium (80 ml of a 2.5M solution in hexane) was added dropwise over 1 hour. During the addition the internal reaction temperature was maintained below -65 C. The reaction mixture was stirred in the dry ice-acetone bath for 1 hour, the cooling bath removed, and the reaction stirred for an additional hour during which time the internal temperature rose to 15 C. The resultant reaction mixture was cooled to -70 C. and cyclopropanecarbonyl chloride (5.2 g) in THF (50 ml) added dropwise over 20 minutes, while keeping the temperature of the reaction mixture below -65 C. The reaction mixture was thus stirred for 1 hour and then allowed to warm to room temperature overnight. The resultant mixture was acidified by the addition of 2N HCl (200 ml) and then diluted with CH2 Cl2 (500 ml). The layers were separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layers were dried, filtered; the solvents were removed to give 7.5 g of an orange oil. The crude is product was chromatographed on silica gel to afford 4.0 g of 3-cyclopropyl-3-oxopropanonitrile as a pale orange oil, 1 H-NMR (CDCl3): d 0.9-1.3 (m, 4H), 1.9-2.1 (m, 1H), 3.66 (s, 2H).
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;
REFERENCE EXAMPLE 56 Cyanoacetic acid (8.5 g) was dissolved in dry THF (250 ml), placed under an inert atmosphere and the solution was cooled using a dry ice-acetone bath. Butyl lithium (80 ml of a 2.5M solution in hexane) was added dropwise over 1 hour. During the addition the internal reaction temperature was maintained below -65 C. The reaction mixture was stirred in the dry ice-acetone bath for 1 hour, the cooling bath removed, and the reaction stirred for an additional hour during which time the internal temperature rose to 15 C. The resultant reaction mixture was cooled to -70 C. and cyclopropane-carbonyl chloride (5.2 g) in THF (50 ml) added dropwise over 20 min. while keeping the temperature of the reaction mixture below -65 C. The reaction mixture was thus stirred for 1 hour, and then allowed to warm to room temperature overnight. The resultant mixture was acidified by the addition of 2N HCl (200 ml) and then diluted with dichloromethane (500 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried, filtered; the solvents were removed to give 7.5 g of an orange oil. The crude product was chromatographed on silica gel to afford 4.0 g of 3-cyclopropyl-3-oxopropanonitrile as a pale orange oil, NMR (CDCl3): d 0.9-1.3 (m, 4H), 1.9-2.1 (m, 1H), 3.66 (s, 2H).
B. 4-Cyclopropanecarbonylamino-2-nitrobenzoic acid 6 g (0.033 mol) of <strong>[610-36-6]4-amino-2-nitrobenzoic acid</strong> were dissolved in a mixture (100 ml) of THF and water (1:1). The solution was adjusted to pH 8.5 with 2 N NaOH and reacted at room temperature with 3.78 g (0.0363 mol) of cyclopropanecarboxylic acid chloride in 25 ml of THF. The pH value of the reaction solution was kept at 8.0 - 8.5 to the end by further addition of 2 N sodium hydroxide solution. After a reaction time of 3.5 hours, the solvent was next distilled off. The residue was diluted with water and the aqueous solution was extracted by shaking once with ethyl acetate and was finally acidified with 2 N HCl to pH 2.0. The oil which precipitated was isolated by extraction with ethyl acetate. After washing and drying the ethyl acetate phase, the solution was concentrated to dryness. The product was crystallized from ethyl acetate/petroleum ether. Thin layer chromatography: a single product in PEW, SBA and CMA. Yield: 3.0 g (36.4%) C11 H10 N2 O5 (250.2). Calculated: C 52.81; H 4.03; N 11.20; Found: C 51.9; H 4.2; N 11.4.
With sodium hydroxide; potassium carbonate; In tetrahydrofuran; water;
Step A Preparation of 1-cyclopropylmethyl-4-piperidyl-magnesium chloride To an ice-cooled solution of 21.97 g. (0.143 mol) of <strong>[40064-34-4]4-piperidone hydrochloride hydrate</strong> in 80 ml. of water is added dropwise 15.0 g. (0.143 mol) of cyclopropanecarboxylic acid chloride. Simultaneous with the addition of the above acid chloride, 37.53 g. (0.286 mol) of solid potassium carbonate is added in small portions at such a rate that the mixture is basic. When the additions are complete, the solution is stirred 1 hour longer while saturating with solid potassium carbonate. The mixture is extracted with five 100 ml. portions of benzene. The combined benzene phases are dried over magnesium sulfate, filtered, and the benzene removed on a rotary evaporator. The product crystallizes to give 20.78 g. (87%) of 1-(cyclopropanecarbonyl)-4-piperidone, m.p. 69-72. A solution of 20.10 g. (0.120 mol) of 1-(cyclopropanecarbonyl)-4-piperidone in 75 ml. of dry tetrahydrofuran is added dropwise over one hour to a slurry of 9.12 g. (0.240 mol) of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran. The reaction mixture is allowed to warm spontaneously, and then is allowed to stir overnight at room temperature. After cooling the reaction mixture in an ice bath, 40% aqueous sodium hydroxide is added dropwise until a clear, colorless organic phase over a semi-granular, solid aqueous phase is obtained. The organic phase is decanted and the residue is washed with warm tetrahydrofuran. Evaporation of the combined tetrahydrofuran fractions gives 17.81 g. of 1-cyclopropylmethyl-4-piperidinol.
2-cyano-3-cyclopropyl-1-[2-(methylsulphonyl) phenyl] propan-1,3-dione[ No CAS ]
[ 118431-88-2 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;
EXAMPLE 1 Preparation of 2-cyano-3-cyclopropyl-1-[2-(methylsulphonyl) phenyl] propan-1,3-dione, Compound A Cyanoacetic acid (8.5 g) was dissolved in dry THF (250 ml), placed under an inert atmosphere and the solution was cooled using a dry ice-acetone bath. Butyl lithium (80 ml of a 2.5M solution in hexane) was added dropwise over 1 hour. During the addition the internal reaction temperature was maintained below -65 C. The reaction mixture was stirred in the dry ice-acetone bath for 1 hour, the cooling bath removed, and the reaction stirred for an additional hour during which time the internal temperature rose to 15 C. The resultant reaction mixture was cooled to -70 C and cyclopropanecarbonyl chloride (5.2 g) in THF (50 ml) added dropwise over 20 min. while keeping the temperature of the reaction mixture below -65 C. The reaction mixture was thus stirred for 1 hour, and then allowed to warm to room temperature overnight. The resultant mixture was acidified by the addition of 2N HCl (200 ml) and then diluted with CH2Cl2 (500 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, altered; the solvents were removed to give 7.5g of an orange oil. The crude product was chromatographed on silica gel to afford 4.0g of 3-cyclopropyl-3-oxopropanonitrile as a pale orange oil, 1H-nmr (CDCl3): d 0.9-1.3 (m, 4H), 1.9-2.1 (m, 1H), 3.66 (s, 2H).
Reference Example A1: 4-Chloro-2-cyclopropylbenzimidazole 2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine (7.0 mL, 86.9 mmol) were dissolved in DMA (17 mL), cyclopropanecarbonyl chloride (4.0 mL, 43.5) was added and the mixture was stirred at 50C for 3 hr. To the mixture were added methanol (10 mL) and aqueous ammonia (9 mL), and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the precipitated solid was collected by filtration. The solid was suspended in ethanol (38 mL) and water (38 mL), ferrous sulfate 7 hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL) were added, and the mixture was stirred at 50C for 4 hr. The mixture was filtered, and the filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Acetic acid (8 mL) was added to the residue, and the mixture was stirred at 90C for 1 hr. The mixture was concentrated under reduced pressure, neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were added to the residue, and the precipitated solid was collected by filtration to give the title compound (1.20 g, 36%). ESI-MS m/z: 193 (M + H)+; 1H-NMR (CDCl3, delta): 1.11-1.25 (m, 4H), 2.01-2.14 (m, 1H), 7.05-7.55 (m, 3H).
4-chloro-2-cyclopropylbenzimidazole 2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine (7.0 mL, 86.9 mmol) were dissolved in DMA (17 mL), and the solution was added with cyclopropanecarbonylchloride (4.0 mL, 43.5), followed by stirring at 50C for 3 hr. Methanol (10 mL) and aqueous ammonia (9 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the precipitated solid was collected by filtration. The solid was suspended in ethanol (38 mL) and water (38 mL) and the solution was added with ferrous sulfate 7 hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL), followed by stirring at 50C for 4 hr. The reaction mixture was filtrated, and the filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Acetic acid (8 mL) was added to the residue, and the mixture was stirred at 90C for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were added to the residue and the precipitated solid was collected by filtration to give the title compound (1.20 g, 36%). ESI-MS m/z: 193 (M + H)+; 1H-NMR (CDCl3, delta): 1.11-1.25 (m, 4H), 2.01-2.14 (m, 1H), 7.05-7.55 (m, 3H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;
Cyclopropanecarbonyl chloride (23 mul, 0.245 mmol) is added dropwise, under stirring at 00C, to a solution of 8-(3,5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-2-(1-pipehdin-4-yl-1H-pyrazol- <n="141"/>4-yl)-quinoxaline (as obtained in example 98, 120 mg, 0.245 mmol), Et3N (103 mul, 0.734 mmol) in CH2CI2. The cooling bath is then removed and the reaction mixture stirred at RT for an additional 30 min. The mixture is then diluted with de-ionized water and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with CH2CI2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2CI2 and purified by chromatography on a 12 g silica gel column on a Combiflash Companion.(TM). (Isco Inc.) apparatus (gradient CH2CI2/ (CH2CI2: EtOH: NH3 90:9:1.1) from 1 :0 => 1 :9) to afford the title compound as a pale yellow foam. Rt =0.852 min (Acquity UPLC BEH C18, 2.1x50mm, 1.7 micron, detection 215nM, 0.1 min 2percent CH3CN in H2O , 2percent to 100percent CH3CN in H2O in 1.5min, 0.4 min 100percent CH3CN + 0.1percent TFA, flow rate 1.0ml/min); MS: 559 (M+1 )+
Step A. Cvclopropanecarboxylic acid 4-chloro-3-fluoro-benzylamide To a solution of 4-chloro-3-fluorobenzyl amine (232 mg, 1 .5 mmol) in 7 ml. CH2CI2 was added cyclopropane carbonyl chloride (146 mul_, 1.6 mmol).After a few minutes, triethylamine (222 mul_, 1.6 mmol) was added and the resulting mixture was stirred for 18 h. The resulting mixture was washed (H2O), dried (MgSO4) and concentrated. The resulting oil was purified by PTLC to yield the title compound as a white solid.MS (ESI): mass calculated for C11H11CIFNO, 227.66; m/z measured,228.1 [M+H]+1H NMR (CDCI3): 7.36-7.33 (m, 1 H), 7.10-7.07 (m, 1 H), 7.02-7.01 (m,1 H), 5.93 (bs, 1 H), 4.43 (d, J = 6.0, 2H), 1.39-1.34 (m, 1 H), 1 .03-1 .01 (m, 2H), 0.80-0.76 (m, 2H).
With triethylamine; In dichloromethane; at 20℃; for 3h;
A solution of 5-amino-2-methylphenyl boronic acid, pinacol ester (0.5 g, 2.14 mmol), cyclopropanecarbonyl chloride (0.22 ml, 2.35 mmol) and triethylamine (0.89 ml, 6.42 mmol) in DCM (10 ml) is stirred at room temperature for 3 hours. 2M HCl is added and the product is extracted with DCM, and dried (MgSO4). Concentration in vacuo, followed by trituration with EtOH yields the title compound as a pink solid. 1H NMR (400 MHz, d6-DMSO) d 10.1 (1H, s), 7.89 (1H, d), 7.68 (1H, dd), 7.1 (1H, d), 2.4 (3H, s), 1.75 (1H, m), 1.32 (12H, s), 0.78 (4H, m).
2-(cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 15; 5-Amino-2- (cyclopropanecarbonyl-amino)-benzoic acid methyl ester; 5-nitroisatoic anhydride (20.8 g, 0.1 mol) ) was heated to reflux with sodium methoxide (0.5 g, O. Olmol) in methanol (600 mL). After 1 h, the solvent was evaporated under vacuum and the residue dissolved in 1,2-dichloroethane (400 mL), washed with cold water and dried over MgSO4. Cyclopropanecarbonyl chloride (20.9 g, 0.2 mol) was added to the solution and then heated at 80 °C for 4.5 h. The mixture was allowed to cool and water (200 mL) was added under vigorous stirring. After 0.5 h, the stirring was interrupted and the phases separated, the C2H4CI2 layer washed with sodium bicarbonate solution and dried over MgSO4. Evaporation of the solvent afforded 2- (cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester (21.7 g, 0.082 mmol). This material was dissolved in methanol (500 mL) and 10percent Pd/C (2.2 g) was added. The flask was then flushed with H2 and stirred at room temperature and at 1 atm. After 5 h reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the combined filtrate evaporated to dryness to give the pure title compound as a grey solid (18.0 g, 0.077 mol) 1H NMR (CDC13+ CD30D) 8 0.84 (m, 2H), 1.06 (m, 2H), 1.60 (m, 1H), 3.91 (s, 3H), 6.89 (dd, 1H), 7.33 (d, 1H), 8.47 (d, 1H), 10.9 (bs, 1H).
2-chloro-6-(cyclopropylcarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
To a room temperature stirred suspension of 2-chloro-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (50 mg, 0.24 mmol) in dichloromethane (2 ml) under a nitrogen atmosphere was added DIPEA (0.12 ml, 0.73 mmol) followed by cyclopropyl carbonyl chloride (24 mul, 0.27 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 ml) and IM aq. HCl (2 ml). The organic layer was separated and washed with saturated aqueous NaHCCh (15 ml) and brine (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure to provide the title compound (60 mg, 95%) which was used without further purification. LCMS data: Calculated MH+ (237); Found 100% (MH+) m/z 237, Rt = 1.08 mins. NMR data: 1H NMR (250 MHz, CDCl3) delta ppm 7.41 (1 H, d, J=7.5Hz), 7.18 (1 H, d, J=7.5Hz), 4.68 - 4.92 (2 H, m), 3.83 - 4.10 (2 H, m), 2.90 - 3.19 (2 H, m), 1.86 - 1.92 (1 H, m), 0.97 - 1.08 (2 H, m), 0.77 - 0.88 (2 H, m).
With triethylamine; In dichloromethane; at 20℃; for 2h;
Step B: N-(Azetidin-3-ylmethyl)cyclopropanecarboxamideCyclopropanecarbonyl chloride (315 mg, 3.0 mmol) was added into a solution of tert-butyl 3-(aminomethyl)azetidine-1-carboxylat (372 mg, 2.0 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 h, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t for 1 hr. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly.
[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}amine(a) (3 ?)-1 -Cyclopropylcarbonyl)-3-pyrrolidinecarbonitrileA solution of 1 , 1-dimethylethyl (3R)-3-cyano-1-pyrrolidinecarboxylate (138 mmol) in ethanol (200 ml.) was treated with 4N HCI in dioxane (480 mmol) and stirred for 2 h. The mixture was concentrated in vacuo to an oil and then azeotroped with ethanol and chloroform. The residue was dissolved in chloroform (300 ml.) and treated with A/JV-diisopropylethylamine (413 mmol) and cooled over an ice bath. The mixture was treated with cyclopropylcarbonyl chloride (165 mmol) in chloroform (100 ml.) and then the ice bath was removed and the mixture stirred for 2 h. The mixture was washed with 1 N hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-5% MeOH/DCM) gave the titled product (134 mmol, 97 % yield). 1HNMR (400 MHz, CDCI3) delta ppm 0.73 - 0.91 (m, 2 H) 0.96 - 1.10 (m, 2 H) 1 .47 - 1.81 (m, 1 H) 2.08 - 2.52 (m, 2 H) 3.03 - 3.33 (m, 1 H) 3.48 - 4.13 (m, 4 H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Add cyclopropanecarbonyl chloride (1.42 g, 13.68 mmol) slowly to a solution of <strong>[207799-10-8]tert-butyl N-(4-bromo-2-pyridyl)carbamate</strong> (1.24 g, 4.6 mmol), Et3N (1.38 g, 13.68 mmol) in DCM (15 mL) at 0C. After addition, stir the reaction at room temperature for 2 hrs. Pour the reaction mixture to water (50 mL), extract with EtOAc (15 mLx3), combine the organic layers and wash with brine (100 mL). Dry over anhydrous Na2S04; concentrate under reduced pressure to give the crude product (1.55 g) which is used without further purification. MS: (M+l): 241.0
With triethylamine; In dichloromethane; at 0 - 25℃; for 2h;
Add cyclopropanecarbonyl chloride (1.42 g, 13.68 mmol) slowly to a solution of <strong>[207799-10-8]tert-butyl N-(4-bromo-2-pyridyl)carbamate</strong> (1.24 g, 4.6 mmol), Et3N (1.38 g, 13.68 mmol) in DCM (15 mL) at 0 C. After addition, stir the reaction at room temperature for 2 hrs. Pour the reaction mixture to water (50 mL), extract with EtOAc (15 mL*3), combine the organic layers and wash with brine (100 mL). Dry over anhydrous Na2SO4; concentrate under reduced pressure to give the crude product (1.55 g) which is used without further purification. MS: (M+1): 241.0
With triethylamine; In dichloromethane; at 10 - 20℃; for 16h;
Dissolve 2-amino-pyridin-4-ol (5 g, 45.4 mmol) in DCM (30 mL), add Et3N (13.8 g, 136 mmol) and then cyclopropanecarbonyl chloride (14.2 g, 136 mmol) dropwise while keeping the temperature below 10C. After addition, stir the reaction at room temperature for 16 hrs. Remove the solvent under reduced pressure, dissolve the residue in THF (40 mL), adjust pH=12 with IN NaOH solution. Stir the mixture for 3 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:MeOH=9:l) affords the title compound (2.6 g, 32%).
32%
With triethylamine; In dichloromethane; at 10 - 25℃; for 16h;
Dissolve 2-amino-pyridin-4-ol (5 g, 45.4 mmol) in DCM (30 mL), add Et3N (13.8 g, 136 mmol) and then cyclopropanecarbonyl chloride (14.2 g, 136 mmol) dropwise while keeping the temperature below 10 C. After addition, stir the reaction at room temperature for 16 hrs. Remove the solvent under reduced pressure, dissolve the residue in THF (40 mL), adjust pH=12 with 1N NaOH solution. Stir the mixture for 3 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:MeOH=9:1) affords the title compound (2.6 g, 32%).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h;
To 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6- tetrahydropyridine hydrochloride 52 (0.7 g, 2.85 mmol) in acetonitrile (15 mL) was added cyclopropanecarbonyl chloride 53 (0.3 g, 2.87 mmol), followed by N,N-diisopropylethylamine (0.8 mL). The reaction mixture was stirred at room temperature for 3 hours, then passed through a silica gel column (eluting with ethyl acetate and hexanes) to provide crude product in light-colored fractions. The fractions were combined and concentrated. The residue was triturated with a mixture of ethyl acetate and hexanes. The mother liquid was collected and concentrated to provide compound 54 as an orange gel. The compound 54 was used for the subsequent reactions without further purification.
[4-fluoro-2-(trifluoromethyl)phenyl]cyclopropylmethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 500ml-four-necked flask equipped with a Teflon-blade stirrer, reflux condenser, and a dropping funnel was charged with 94. Og 2-bromo-5-fluoro-benzotrifluoride (purity 99%, 0.38mol) and 150g toluene. A solution of isopropylmagnesium chloride in THF (2M, 243g, 0.5mol) was added keeping the temperature between 25 and 30C. After stirring for 60min this solution was added to a mixture of 150g toluene, 61. Og cyclopropanecarbonyl chloride (0.57mol), and 1 .1 g cop- per(l)chloride (0.01 mol) in a 1000ml-four-necked flask equipped with a Teflon-blade stirrer, reflux condenser, and a dropping funnel keeping the temperature between 38 and 42C. After half of the Grignard solution was dosed another 1.1 g of copper(l)chloride were added. When the Grignard addition was completed the mixture was stirred for 2h at 40C. 300g water were added, the solution was stirred for 10min and the phases allowed to separate. The organic phase was washed with a mixture of 250g water and 60g 25%-ammonia solution. After separation of the phases the organic phase was transferred to a rotary evaporator and the solvent was re- moved at 40C and 10mbar to leave 89.9g of a dark brown product (purity: 92.4%, 0.36mol, 93.4% of the theoretical yield).
To a stirred solution of acetonitrile (2.3 g; 56 mmol) in THF (20 mL) was added n-butyl lithium (35 mL; 56 mmol) dropwise at -78C under an argon atmosphere. The reaction mixture was stirred for 30 minutes maintaining the same temperature. A solution of cyclopropanecarbonyl chloride (VII; 3 g; 28 mmol) in THF (10 mL) was added to the reactionmixture and the stirring continued for 1.5 hours at -50C. The reaction mixture was diluted with iN hydrochloric acid and extracted sequentially with ethyl acetate and dichloromethane (3x 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford 3-cyclopropyl-3-oxopropanenitrile as a crude solid (VIII; 3 g). This was used in the next step without further purification.
Step 1 To a solution of <strong>[1681-37-4]3-nitropyridin-4-amine</strong> (LXXV) (500 mg, 3.59 mmol) was in pyridine was added cyclopropanecarbonyl chloride (LXXVI) (413 mg, 3.95 mmol). The reaction mixture was stirred at room temperature for 3 h. The solution was concentrated under vacuum and the residue was dissolved in EtOAc. The EtOAc solution was washed with water, brine, dried over MgSO4 and concentrated to a residue to afford N-(3-nitropyridin-4-yl)cyclopropanecarboxamide (LXXVII) as a light yellow solid (740 mg, 3.57 mmol, 99.5% yield). ESIMS found for C9H9N3O3 m/z 207.7 (M+H).
methyl 5-bromo-6-[(cyclopropylcarbonyl)amino]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; at 0 - 20℃; for 1h;
Methyl 6-amino-5-bromopyridine-2-carboxylate (J&W Pharmlab, 300 mg, 1.3 mmol) was dissolved in pyridine (4.6 mL) and the solution was cooled to 0 C. Then cyclopropanecarbonyl chloride (124 mu,, 1.36 mmol) was slowly added and the resulting reaction mixture was stirred at room temperature for 1 h. Then the reaction was quenched with water and product extracted with EtOAc. The combined organic fractions were washed with 1 M HC1, then with brine and dried with a2S04. After solvent was evaporated, the crude product was used in the next step without further purification. LCMS calc. for CiiHi2BrN203 (M+H)+ m/z = 299.0; found: 299.
5-bromo-2-cyclopropylbenzo[d][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine; at 60℃;Inert atmosphere;
[00469] To a solution of <strong>[20776-48-1]2-amino-6-bromo-benzoic acid</strong> (2 g, 9.3 mmol) in pyridine (20 mL) was added cyclopropanecarbonyl chloride (1.25 mL, 13.9 mmol). The reaction mixture was stirred at 60 C overnight. Cooled to 0 C, and poured into ice-water (100 mL), the resulting suspension was filtered and dried to give 5-bromo-2-cyclopropyl-benzo[d] [l,3]oxazin-4-one (1.75 g, yield: 71%) as white solid. lH NMR (300 HMz, CDC13): delta = 7.68 (d, J= 7.8 Hz, 1H), 7.53 (t, J= 8.1 Hz, 1H), 7.44 (d, J= 7.8 Hz, 1H), 1.95-1.90 (m, 1H), 1.31 -1.27 (m, 2H), 1.16-1.11 (m, 2H).
2-chloro-5-(cyclopropanecarbonylamino)isonicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
[00481] To a stirred solution of (5-amino-2-chloro-isonicotinic acid methyl ester (1.3 g, 7 mmol) in DCM (30 mL) was added Et3N (1.4 g, 14 mmol) and cyclopropanecarbonyl chloride (1.1 g, 10.5 mmol) at 0 C. The mixture was stirred at room temperature overnight. The mixture was evaporated in vacuum. The residue was diluted with water (50 mL). The aqueous phase was extracted with EA (80 mL x2). The extracts were washed with water, dried over anhydrous Na2S04 and filtered. The filtrate was evaporated in vacuum to residue, which was purified by silica gel chromatography (from PE to PE/EA = 10/1) to give (1.0 g, yield: 56 %) of 2-chloro-5-(cyclopropanecarbonyl-amino)-isonicotinic acid methyl ester as yellow solid. 'H NMR (400MHZ, DMSO-i/6): delta = 10.56 (brs, 1H), 8.79 (s, 1H), 7.23 (s, 1H), 3.82 (s, 3H), 1.87- 1.80 (m, 3H), 0.94-0.83 (m, 4H).
N-(4-chloro-5-nitropyridin-2-yl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With triethylamine; In tetrahydrofuran; at 0 - 20℃;
4-chloro-5-nitro-2-amine (1.00g, 5.76mmol) was dissolved in tetrahydrofuran (30mL), cooled to 0 , were added dropwise triethylamine (4.00mL, 28.7mmol) and cyclopropyl chloride (0.55mL, 6.06mmol), warmed to room temperature and stirred overnight.Saturated sodium bicarbonate solution (10 mL) The reaction was quenched with ethyl acetate (200mL × 3) was extracted, the organic phase washed with water (150 mL), saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, separated by column chromatography (eluent: PE / EtOAc (v / v) = 10/1), to give the product 1.20g, yield: 86.0percent.
ethyl 3-[(cyclopropylcarbonyl)amino]-4,4,4-trifluorobut-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With pyridine; In 1,2-dichloro-ethane; at 20℃; for 16h;Reflux;
General procedure: Acid chloride (66.7 mmol) was added in one portion to asolution of the corresponding enamine 17, 21 (60.6 mmol) in 1,2-dichloroethane (200 mL) at RT. Pyridine (8.6 mL, 106 mmol) wasadded thereto also in one portion, and the mixture was stirred atreflux temperature for 16 h. The solvent was evaporated in vacuo,and the residue was partitioned between water (200 mL) and ethylacetate (200 mL). The organic layer was separated and washedsequentially with water (2150 mL), saturated aqueous NaHCO3(100 mL), and brine (100 mL), and dried (MgSO4). Evaporation ofthe extract in vacuo afforded crude compounds 18a-f, 22a-f asoils, which were used in the next step without purification.Analytical samples of the materials were purified by columnchromatography on silica gel eluting with ethyl acetate - hexane(1:3, v/v) mixture.
N-(3-(1H-indol-3-yl)propyl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In dichloromethane; water; at 0 - 25℃; for 1h;
A mixture of 3- (1H-indol-3-yl) propan-1-amine (4.50 g, 25.8 mmol) in aqueous Na2CO3(4.34 g, 51.7 mmol, dissolved in 60 mL of water) and DCM (100 mL) was treated dropwise at 0 with cyclopropanecarbonyl chloride (2.70 g, 25.8 mmol) . The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was then diluted with DCM (300 mL) , washed with brine (3x150 mL) , dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and purified by chromatography on SiO2(0to 20EtOAc/petroleum ether) to provide the title compound (3A-1) . MS (EI) calc?d for C15H19N2O [M+H]+, 243 found, 243.
N-(4-cyanopyridin-2-yl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
2-Amino-4-cyanopyridine (G1) (2.48 g, 20 mmol) was dissolved in dry DCM (240 mL), and a small portion of triethylamine was added to dissolve, and then potassium carbonate (14 g, 5 eq) was added. Stir at room temperature for 10 minutes and stir for 10 minutes in an ice bath. The cyclopropylcarbonyl chloride (5.6 mL, 3 eq) was dissolved in 15 mL of DCM, and the mixture was added dropwise with a sep. funnel, and then DMAP (200 mg, 0.1 eq) was added, and the mixture was allowed to react for 10 hours at room temperature for 16 hours. The reaction was completed by TLC. The potassium carbonate was filtered off with filter paper and celite, and the filter cake was washed with DCM, and the filtrate was directly dried to the next step. Pure product G2 was a white powder with a yield of 92%.
92%
<strong>[42182-27-4]2-amino-4-nitrylpyridine</strong> (6) (2.48 g, 20 mmol) was dissolved in dry DCM (240 mL),Add a small amount of triethylamine to help solubilize,Add potassium carbonate (14g, 5eq),Stir for 10 minutes at room temperature,Stir for 10 minutes in an ice bath.Dissolve cyclopropylformyl chloride (5.6mL, 3eq) in 15mL DCM,Add dropwise to the reaction solution with a separatory funnel,Finally, DMAP (200 mg, 0.1 eq) was added, and the reaction was performed at room temperature for 16 hours after 10 minutes in an ice bath.TLC monitors the completion of the reaction,Use filter paper and diatomaceous earth to filter out potassium carbonate,DCM washed filter cake,The filtrate was spin-dried directly for the next reaction.Pure product 2 was a white powder with a yield of 92%.
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)cyclopropaneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.6%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -10 - 10℃; for 1h;
N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)Pyrimidin-2-yl)benzene-1,2,4-triamine (73 mg, 0.164 mmol)Soluble in anhydrous tetrahydrofuran (5mL),Diisopropylethylamine (32 mg, 0.250 mmol) was added.Acryloyl chloride (21 mg, 0.200 mmol) was added at -10 C.The reaction was stirred at 10 C for 1 h.After the reaction is over,Add water (0.5mL),The reaction solution was concentrated under reduced pressure.The crude solid is washed with dichloromethaneA yellow solid was obtained (62 mg, yield: 73.6%).
With pyridine; In N,N-dimethyl-formamide; at 20 - 30℃; for 8.0h;
Add 16.82 g of <strong>[584-74-7]ethyl 2-fluorophenylacetate</strong> to the three-necked flask and add 100 ml of N,N-dimethylformamide.Stir and dissolve at room temperature, add 0.14 mol of pyridine, and slowly add 9.65 g of cyclopropanecarbonyl chloride at room temperature.After the drop is warmed to 30C, the reaction is stirred for 8 hours, and it is reduced to room temperature and filtered.Slowly add 1ml/L of a mixture of sulfuric acid and acetic acid to the filtrate and add 280ml.After the reaction was completed, the extraction procedure was the same as in Example 1 to obtain 16.30 g of compound (III) in a yield of 91.4%.
To a solution of <strong>[61296-22-8]2-amino-5-bromothiazole monohydrobromide</strong> (la?) (5.2 g, 20.0 mmol, 1.0 eq) in 40 ml of DCM was added 4.2 ml of Et3N. To the resulting mixture was slowly added a solution of cyclopropanecarbonyl chloride (1.83 ml, 2.09 g, 20.0 mmol, 1.0 eq) in 10 ml of DCM at -78 C. After stirring at rt for 30 mm, an additional 0.5 ml of cyclopropanecarbonyl chloride in 5 ml of DCM was added at -78 C and the mixture was then stirred at rt for an additional lh. Sat. aq. Na2CO3 (15 ml) was added with stirring at rt over 15 mm. The organic layers were separated and the aqueous layer was extracted with DCM (1 x 20 ml). The combined organics were washed with brine, dried over Na2504, filtered, and concentrated by rotary evaporation to give a white solid (49b) which was washed with EtOAc, dried under vacuum and then used directly in the next step without purification (3 g, 60%).
1-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a cooled (0 C) suspension of 1a-h20-26 (0.56 mmol) in anhydrousCH2Cl2 (2 mL), 0.72 mmol Et3N and 1.67 mmol of the appropriatechloride were added. The mixture was stirred at 0 C for 2 h and then atroom temperature for an additional 2 h. The solvent was evaporated,cold water was added, and the mixture was neutralized with 0.5 NNaOH. The reaction mixture was extracted with CH2Cl2 (3×15 mL),the solvent was dried over sodium sulfate, evaporated in vacuo, and thefinal compounds were purified by crystallization from ethanol (2a-i,3a,b,e, and 4b) or by column chromatography using cyclohexane/ethylacetate in different ratios: 1:1 (3d), 2:1 (3c and 4a), 3:1 (2l, 4b, 5a and5e), 5:1 (5c), or 6:1 (5b and 5d) as eluents
N-(5-bromo-3-formylpyridin-2- yl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With pyridine; In dichloromethane; for 0.5h;
Cyclopropanecarbonyl chloride (1 mL, 1 1 .02 mmol) was added to a stirred solution of <strong>[206997-15-1]2-amino-5-bromonicotinaldehyde</strong> (1 g, 4.97 mmol) and pyridine (2 mL, 24.73 mmol) in dichloromethane (20 mL) and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness under reduced pressure and placed in vacuo for -15 minutes to give a brown foam. This material was dissolved in tetrahydrofuran (30 mL) and methanol (10 mL) and then 1 N aqueous sodium hydroxide (15 mL, 15.00 mmol) was added dropwise. The mixture was stirred for 10 minutes and the mixture was concentrated under reduced pressure. The remaining material was triturated with water to give a solid which was collected via vacuum filtration, washed with water and dried in vacuo overnight to give N-(5-bromo-3-formylpyridin-2- yl)cyclopropanecarboxamide (1 .21 g, 4.50 mmol, 90 % yield) as a tan solid. 1H NMR (400 MHz, CD3SOCD3) delta 0.80-0.92 (m, 4 H), 1 .98-2.08 (m, 1 H), 8.19 (d, J = 2 Hz, 1 H), 8.76 (d, J = 2 Hz, 1 H), 9.56 (s, 1 H), 1 1 .27 (br s, 1 H); LC-MS (LC-ES) M+H = 269.
N-(6-bromo-3-isoquinolyl)cyclopropanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.7%
With pyridine; dmap; at 20℃; for 3h;
To a stirred suspension of <strong>[891785-28-7]6-bromoisoquinolin-3-amine</strong> (XV) (2.0 g, 8.97 mmol) and DMAP (0.22 g, 1.79 mmol) in pyridine (30 mL) was added cyclopropanecarbonyl chloride (LXV) (0.98 mL, 10.76 mmol) and the mixture was stirred at room temperature for 2 h. Another 0.5 equivalents of cyclopropanecarbonyl chloride was added and stirring continued at room temperature for another 1 h. The reaction went to completion, solvent was concentrated and the residue taken up in EtOAc and washed with water. The organic/aqueous layer was filtered, washed with EtOAc and the solids were dried under high vacuo to obtain 440 mg of the product. The filtrates were transferred to separating funnel, organic layer separated, washed with brine solution, dried over anhydrous Na2SO4 and then concentrated to dryness to obtain N-(6-bromo-3-isoquinolyl)cyclopropanecarboxamide (LXVI) as a brown solid (1.74 g, 5.98 mmol, 66.7% yield). ESIMS found for C13H1lBrN2O m/z 291.0 (M+H).
(1) 2404.5 g of toluene was sequentially added to a 3 L reaction flask.Anhydrous ethanol 96.75g (2.1mol) and solid sodium ethoxide 285.8g (4.2mol),Stirring to 38 C, when the above solids are completely dissolved,To the resulting mixture, 801.5 g (3.5 mol) of the compound of the formula (2) was added dropwise for 3 hours.After the completion of the dropwise addition, the reaction was continued for 2 hours to obtain an ECOC reaction mixture; (2) The ECOC reaction mixture obtained in the step (1) was cooled to 25 C, and 106.2 g (1.05 mol) of triethylamine was added.After the triethylamine was completely dissolved, 439.03 g (4.2 mol) of cyclopropanoyl chloride was added dropwise thereto for 2.5 hours.After the completion of the dropwise addition, the reaction was continued for 1 hour, and then 2,405 g of tap water was added, washed with water, allowed to stand, and layered.The aqueous layer was separated, and the toluene layer was concentrated under a vacuum (-0.095 MPa) to remove about 1300 g of toluene to obtain an ECCOC reaction mixture; (3) 102.5 g (0.45 mol) of benzyltriethylammonium chloride was sequentially added to the ECCOC reaction mixture obtained in the step (2) at 23 C.63.8 g (0.75 mol) of acetone cyanohydrin and 455 g (4.5 mol) of triethylamine were stirred and heated to 60 C, and the reaction was kept for 3 hours.Then, the temperature was lowered to 7 C, 1603 g of tap water was added, stirred, and the layer was allowed to stand. The toluene layer was further added with tap water 200 g, stirred, and the toluene layer was separated and the toluene layer was removed from the solvent to separate the water layer.3007.5 g of petroleum ether was added to the combined aqueous layer, and the temperature was lowered to 18 C, and 30% by weight of hydrochloric acid was added dropwise.Until the pH of the water layer is 2, the layer is allowed to stand, and the obtained aqueous layer is further added with 1000 g of petroleum ether for extraction once.The mixture was allowed to stand for stratification, and the petroleum ether layer was combined, and the combined petroleum layers were slowly cooled to 0 C for 4 hours. The solid was precipitated and filtered to give a 4-cyclopropyl(hydroxy)methylene-3,5-dionecyclohexanecarboxylic acid ethyl ester.The mother liquor obtained after filtration is removed from the solvent for use, and the obtained residue is recorded as mother liquor A4.The obtained wet base is heated and desolvated in the reaction flask to remove the solvent.592 g of a yellow-brown liquid was obtained as ethyl 4-cyclopropyl(hydroxy)methylene-3,5-dionecyclohexanecarboxylate, the purity was 97%, and the yield was 65% by weight.
2-(cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide[ No CAS ]
2-(cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
A 1:3 mixture of 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid and 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid (300 mg, 1.13 mmol) in DCM (5 mL) was treated with COMU (530 mg, 1.24 mmol) and DIPEA (240 m, 1.38 mmol) and the mixture was stirred for 10 minutes at r.t. prior to addition of 2M ethanamine in THF (0.7 mL). The reaction mixture was stirred for a further 30 minutes and was diluted with DCM (20 mL) and washed with water (20 mL) followed by 1 M aqueous hydrochloric acid solution and dried (MgS04), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 50 - 100% EtOAc/heptanes) to afford the 5-isomer title compound intermediate 45 (100 mg, 20%, ~65% purity) as a sticky dark brown oil and the 7- isomer title compound intermediate 46 (150 mg, 45%) as a brown solid. 5-Isomer intermediate 45: LCMS [M+H]+ 293.00, RT 1.04 minutes (Method 11). 7-Isomer intermediate 46: dH (500 MHz, DMSO- d6) 11.09 (s, 1H), 7.91 (t, J 5.5 Hz, 1H), 6.29 (s, 1H), 3.47 (t, J 6.7 Hz, 1H), 3.16 - 3.00 (m, 2H), 2.44 (t, J 5.5 Hz, 2H), 1.97 - 1.83 (m, 3H), 1.74 - 1.67 (m, 1H), 1.63 - 1.51 (m, 1H), 1.03 (t, J 7.2 Hz, 3H), 0.82 - 0.76 (m, 4H).
2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N7-ethyl-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxamide[ No CAS ]
2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-ethyl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
A mixture of intermediates 109 and 110 (30 mg, 0.083 mmol) (6% intermediate 110) was dissolved in DCM (3 mL) then EDCI (24 mg, 0.12 mmol) was added and the reaction mixture was stirred for 20 minutes. 2M Ethyl amine in THF (0.083 mL, 0.16 mmol) was added and the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (20 mL) and washed with water, 1M aqueous hydrochloric acid solution and saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (acidic) to afford the title compound (16 mg, 50%) as a white solid which contained 91% of the 7-isomer title compound example 98 and 9% of the 5-isomer title compound example 99. dH (500 MHz, CD3OD) 3.62 (t, J 6.3 Hz, 1H, 7-isomer), 3.29 - 3.16 (m, 4H), 2.87 - 2.66 (m, 2H, 7-isomer, 4H, 5-isomer), 2.60 - 2.47 (m, 1H, 5-isomer), 2.12 - 1.95 (m, 3H, 7- isomer, 1H, 5-isomer), 1.93 - 1.87 (m, 1H, 5-isomer), 1.85 - 1.67 (m, 2H, 7-isomer, 1H, 5-isomer), (4405) 1.22 - 1.05 (m, 4H), 1.03 - 0.89 (m, 4H), 0.59 - 0.49 (m, 2H), 0.32 - 0.25 (m, 2H). 9% 5-regio isomer present. LCMS [M+H]+ 390.2, RT 2.82 minutes, 90% 7-isomer, 9% 5-isomer (Method 10).
2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid[ No CAS ]
2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
Intermediate 107 and intermediate 108 (20:80 ratio) (600 mg, 1.53 mmol) was dissolved in THF (10 mL) then 2M aqueous lithium hydroxide solution [1310-66-3] (2.3 mL, 4.6 mmol) was added. The reaction mixture was stirred at r.t. for 20 h and the THF was removed in vacuo. The residue was acidified with 1M aqueous hydrochloric acid solution and the resulting solid (75% 5-isomer intermediate 110 and 22 % 7-isomer intermediate 109) was filtered off and dried. The mixture was separated by preparative HPLC to afford the 5-isomer title compound intermediate 110 (218 mg, 49%) and the 7-isomer title compound intermediate 109 (58.5 mg, 12%) with 92% purity containing 6% of the 5-isomer title compound intermediate 110. 5-Isomer title compound intermediate 110: LCMS [M+H]+ 363.1, RT 2.78 minutes, 100% purity (Method 10). 7-Isomer title compound intermediate 109: LCMS [M+H]+ 363.1, RT 2.90 minutes, 92% purity, 6% 5-regiosisomer present (Method 10).
ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate[ No CAS ]
ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of mixture of intermediates 105 and 106 (20:80 ratio) (653 mg, 2.02 mmol) and DIPEA (0.71 mL, 4.05 mmol) in DCM (30 mL) at 0 C was added cyclopropanecarbonyl chloride [4023-34-1] (0.28 mL, 3.08 mmol). The reaction was stirred at r.t. for 2 h before diluting with DCM (50 mL). Water (50 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (2 x 50 mL) and washed with 0.5 M aqueous hydrochloric acid solution (50 mL), saturated sodium hydrogen carbonate solution (50 mL) and brine. The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo to give a pale yellow solid as a mixture of regio-isomers which was purified by flash column chromatography on silica (gradient elution with 55 to 50% EtOAc in heptane) to afford the title compounds as a mixture of 80% 5-isomer intermediate 108, 20% 7- isomer intermediates 107 (600 mg, 76%) as a white solid. LCMS [M+H]+ 391.0, RT 1.40 minutes, 100% purity (Method 6).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Cyclopropanecarbonyl chloride [4023-34-1] (5.44 g, 51.0 mmol) was added to a solution of 2-amino- 4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxylic acid methyl ester [108354-78-5] (10.0 g, 46.4 mmol) and DIPEA (15.0 g, 116 mmol) in DCM (100 mL) and the reaction was stirred at r.t. overnight. The reaction mixture was washed with water and brine, passed through a phase separator and evaporated in vacuo to yield a yellow sticky solid which was dissolved in 1,4-dioxane (100 mL). A solution of lithium hydroxide monohydrate [1310-66-3] (2.92 g, 69.6 mmol) in water (30 mL) was added and the mixture was heated at 70C for ~3 h. The reaction mixture was cooled to r.t. and was left to stand overnight and the 1,4-dioxane was removed in vacuo. The aqueous residue was diluted with water and washed with DCM (2 x). The aqueous phase was acidified to pH <4 by addition of concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water (3 x) and was allowed to air dry to afford the title compound (12.1 g, 99%) as a cream solid. 6H (400 MHz, DMSO -d6) 13.04 (s, 1H), 11.46 (s, 1H), 2.81 - 2.63 (m, 2H), 2.63 - 2.54 (m, 2H), 1.95 (h, J 5.6 Hz, 1H), 1.80 - 1.60 (m, 4H), 1.02 - 0.76 (m, 4H).
O3-tert-butyl O5-ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxylate[ No CAS ]
O3-tert-butyl O7-ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a 79 : 21 solution of intermediate 39 and intermediate 40 (8 g, 24.5 mmol) and DIPEA (8.56 ml, 16.0 mmol) in DCM (300 mL) at 0 C was added cyclopropanecarbonyl chloride (1.08 ml, 49.1 mmol). The reaction was stirred at r.t. for 2 h before diluting with DCM (200 mL). Water (200 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (2 x 100 mL) and washed 0.5 M aqueous hydrochloric acid solution (100 mL), saturated sodium hydrogen carbonate solution (100 mL) and brine. The organic phase was separated, dried (MgSC ), filtered and concentrated in vacuo to give a pale yellow solid as a mixture of regioisomers which was purified by flash column chromatography on silica (gradient elution with 5% to 50% EtOAc in heptane) to afford the solid product as a mixture of regioisomers. The solid was triturated with heptane/Et20 to afford title compound intermediate 41 (7 g, 72%) and the filtrate was concentrated in vacuo to afford the a 40 : 60 mixture of title compound intermediate 41 and title compound intermediate 42 (2 g, 21 %). Intermediate 41: dH (500 MHz, CD3OD) 4.24 - 4.11 (m, 2H), 3.16 (dd, J 17.2, 5.4 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.63 (m, 3H), 2.25 - 2.16 (m, 1H), 1.89 - 1.77 (m, 2H), 1.61 (s, 9H), 1.27 (t, J 7.1 Hz, 3H), 1.05 - 0.94 (m, 4H). LCMS [M+H]+ 394.10, RT 1.63 minutes (Method 6).
2-(cyclopropanecarbonylamino)-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid[ No CAS ]
2-(cyclopropanecarbonylamino)-7-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 1:2 mixture of intermediate 41 and 42 (90%, 2.7 g, 6.18 mmol) was dissolved in 4M hydrochloric acid in 1,4-dioxane (30 mL) and stirred at r.t. for 2 h, followed by 35 C for 6 h, then r.t. for 16 h then 35 C for 3 h. The reaction mixture was concentrated in vacuo and the residue was triturated with Et20 to afford the 5-isomer title compound intermediate 43 (220 mg, 11%) as an off white solid. The filtrate was concentrated in vacuo under reduced pressure to afford a 1:3 mixture of the 5-isomer title compound intermediate 43 and the 7-isomer title compound intermediate 44 (2 g, 88%) as a sticky yellow foam which was utilised without further purification. Title compound intermediate 43: dH (500 MHz, Chloroform-d) 11.27 (s, 1H), 4.25 - 4.12 (m, 2H), 3.24 (dd, J 17.4, 5.4 Hz, 1H), 3.03 - 2.90 (m, 1H), 2.82 - 2.63 (m, 3H), 2.28 - 2.18 (m, 1H), 1.96 - 1.84 (m, 1H), 1.80 - 1.71 (m, 2H), 1.29 (t, J 7.1 Hz, 3H), 1.20 - 1.13 (m, 2H), 1.02 - 0.94 (m, 2H).
ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate[ No CAS ]
ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-(Cvclopropanecarbonylamino-N-ethyl-4.5.6.7-tetrahvdrobenzothiophene-7-carboxamide (1727) A 1:3 mixture of intermediate 43 and intermediate 44 (2 g, 5.45 mmol, 92% purity) was suspended in quinolone [91-22-5] (15 mL) and copper powder [7440-50-8] (520 mg, 8.18 mmol) was added. The mixture was heated to 150 C for 1 h in the microwave and the reaction mixture was diluted with DCM (150 mL) and water (150 mL). The organic phase was washed with 1M aqueous hydrochloric acid solution (2 x 100 mL), followed by saturated aqueous sodium hydrogen carbonate (100 mL), dried (MgSC ), filtered and concentrated in vacuo. Trituration with Et2
2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid[ No CAS ]
2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a 1:3 mixture of ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5- carboxylate and ethyl 2-(cyciopropanecarbonyiamino)-4,5,6,7-tetrahydrobenzothiophene-7- carboxylate (1 g, 3.41 mmol, 85% purity) dissolved in THF (20 mL), 2M aqueous lithium hydroxide solution (6 mL, 12 mmol) was added. The reaction mixture was stirred at r.t. for 20 h and the reaction mixture was concentrated in vacuo and the residue was acidified with 1M aqueous hydrochloric acid solution and the precipitate was filtered to afford a 1:3 mixture of 2- (cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid and 2- (cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid (600 mg, 60%). The mixture was utilised crude.
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