* 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.
at 20℃; for 4 h; Molecular sieve; Inert atmosphere
A solution of cyclohexane-1 ,3-dione (500 g, 4459 mmol), 4 A molecular sieves (500 g, 4459 mmol), and p-toluenesulfonic acid (254 g, 1338 mmol) in dry ethylene glycol (2 L) was stirred under nitrogen at room temperature for 4 hours. The reaction mixture was diluted with saturated NaHC03 solution (1 L) to adjust to basic pH, and the basic mixture was extracted with ethyl acetate (3 X 1 L). The combined organic extracts were washed with brine solution (500 ml) and dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (280 g, 1732 mmol, 38.8percent yield) as a yellow liquid. LCMS (m/z) 157.1 (M+H+).
27%
With toluene-4-sulfonic acid In tolueneReflux
The 50g cyclohexan-1,3-diketone, 27.67g 1,2-glycol, 500 ml of toluene and 0.849g a hydrated 4-toluenesulfonic acid, and in the dehydrator boiling reflux 3 to 4 hours. For the mixture 100 ml saturated NaHCO3 solution saturated NaCl solution for washing and washing 2 times, drying and concentrating the rotation evaporator. Then the use of high vacuum the mixture is fractionated (in the 85 °C/1mbar or in 62-75° C/0 . 15mmHg lower distillation product). Yield: 21.9g (the theoretical yield 27percent)
Reference：
[1] Journal of Mass Spectrometry, 1998, vol. 33, # 3, p. 229 - 241
[2] Synthetic Communications, 1999, vol. 29, # 18, p. 3097 - 3106
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 13, p. 1885 - 1892
[4] Journal of the Chemical Society, Chemical Communications, 1993, # 4, p. 364 - 365
[5] Journal of the American Chemical Society, 1986, vol. 108, # 24, p. 7575 - 7579
[6] Patent: WO2017/199199, 2017, A1, . Location in patent: Page/Page column 20; 21
[7] Angewandte Chemie - International Edition, 2016, vol. 55, # 5, p. 1816 - 1819[8] Angew. Chem., 2016, vol. 128, # 5, p. 1848 - 1851,4
[9] Patent: CN101160049, 2016, B, . Location in patent: Paragraph 1130-1133
[10] ChemMedChem, 2013, vol. 8, # 6, p. 967 - 975
[11] Pharmazie, 1983, vol. 38, # 12, p. 851 - 854
[12] Journal of Chemical Crystallography, 1999, vol. 29, # 8, p. 977 - 982
[13] ChemMedChem, 2015, vol. 10, # 1, p. 47 - 51
2
[ 504-02-9 ]
[ 4969-01-1 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3331
Reference：
[1] Journal of Chemical Research, Miniprint, 1995, # 11, p. 2557 - 2568
[2] Organic Letters, 2016, vol. 18, # 5, p. 1178 - 1181
6
[ 107-20-0 ]
[ 504-02-9 ]
[ 16806-93-2 ]
Yield
Reaction Conditions
Operation in experiment
16.5 g
Stage #1: With potassium hydroxide In methanol at 0℃; for 0.5 h;
under argon, cyclohexanedione (20.71 g, 0.18 mol) was dissolved in methanol (100mL) and cooled to 0 °C. To this was added potassium hydroxide (12.2 g, 0.18 mol) and afterstirring 30 minutes at 0 °C the 50percent solution of chloroacetaldehyde in water (26.3 mL, 0.203mol) was added. This was stirred overnight, the resulting solution made acidic with 1 Nhydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water,brine, dried over magnesium sulfate and concentrated to dryness to give the volatile 6,7-S34dihydrobenzofuran-4(5H)-one (16.5 g) clean enough for the next step.
Reference：
[1] Arkivoc, 2011, vol. 2011, # 9, p. 1 - 14
[2] Heterocycles, 2004, vol. 62, p. 807 - 813
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1966 - 1982
[4] Journal of Organic Chemistry, 1988, vol. 53, # 17, p. 4135 - 4137
[5] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 10, p. 2167 - 2169
[6] Tetrahedron, 1996, vol. 52, # 24, p. 8169 - 8180
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2818 - 2841
[8] Chemistry Letters, 2008, vol. 37, # 8, p. 822 - 823
[9] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2853 - 2860
7
[ 107-20-0 ]
[ 504-02-9 ]
[ 150-78-7 ]
[ 16806-93-2 ]
Reference：
[1] Patent: EP101004, 1991, B2,
8
[ 504-02-9 ]
[ 16806-93-2 ]
Reference：
[1] Tetrahedron Letters, 1997, vol. 38, # 32, p. 5671 - 5674
[2] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 1, p. 341 - 343
The 1,3-cyclohexanedione (0 · 03mol) and ammonium acetate (0 · 039mol) added to 100ml three-necked flask, stir hook, the reaction conditions in an oil bath at 110 °C 15min, Remove the oil bath and then naturally cool,During which the reaction liquid is solidified. After cooling to room temperature, ethyl acetate (10 ml) is added, heated to dissolve and cooled to 0 °C., filtered and the filter cake is dried to obtain yellow crystals of 3-amino-2-cyclohexenone (Yield 93.6percent)
90%
With AcONH4 In toluene
Example 5 3-Amino-cyclohex-2-enone A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90percent), which was used directly in the next step without further purification.
90%
With ammonium acetate In toluene for 5 h; Dean-Stark; Reflux
A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90percent), which was used directly in the next step without further purification.
86%
With ammonia In benzene for 4 h; Heating / reflux
To a 1 L two-necked flask charged 200 g (1.78 moL) of 1,3-cyclohexanedione and 600 mL benzene, attached a Dean-Stark apparatus with a condenser and an ammonia inlet. The mixture was heated to reflux and ammonia gas was bubbling into the reaction. The water generated from the reaction was trapped in the Dean-Stark apparatus. The mixture formed two layers and the bottom layer was solidified after refluxing for 4 h. The reaction was then stopped and cooled down to room temperature. The benzene was decanted and the remaining solid was triturated with 300 mL chloroform and filtered to give the desired product as a yellow solid (167.1 g, 1.51 moL, 86percent).1HNMR (400 MHz, CDCl3): 5.23 (s, 1 H), 3.20 (bs, 1 H), 2.37 (m, 2 H), 2.28 (m, 2 H), 1.97 (m, 2 H).
80%
With ammonium acetate In ethanol at 25 - 80℃; for 3 h; Inert atmosphere
S1. At room temperature (25 ° C - 30 ° C), weigh 112g into 2240mL of absolute ethanol, 84.8g of anhydrous ammonium acetate, heated to 80 ° C, reflux for 3h, nitrogen protection.When no raw materials were monitored by S2.TLC, the temperature was lowered to room temperature, and 212 g of anhydrous sodium carbonate was added to react overnight.S3. The reaction mixture was filtered through Celite, and then filtered and evaporated to dryness to give a yellow solid, and the yellow solid was beaten with 100 mL of EA until the impurities were washed.S4. After beating, filter, the filtrate is dissolved in 2240 mL of absolute ethanol, and the solvent is removed by using a 200-300 mesh silica gel column which has been saturated with ethanol.The filtrate by rotary evaporation to give a yellow solid 89g, molar yield 80percent, TLC purity 96percent.
78%
With ammonium acetate In toluene for 2 h; Reflux
Example 1A 3-Aminocyclohex-2-en-1-one A solution of 250 g (2.2 mol) of cyclohexane-1,3-dione and 180.45 g (2.3 mol) of ammonium acetate in 1.3 litres of toluene was heated under reflux for 2 hours using a water separator with reflux condenser. The reaction was then concentrated to dryness. The residue was taken up in 1.3 litres of ethyl acetate and 100 ml of methanol and heated to 110° C. The solution was then filtered while hot and slowly cooled to room temperature. The solution was then stored overnight at about 4° C. in the fridge. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave 66.59 g (0.60 mol) as a first batch of the target product. Under reduced pressure, the recovered filtrate was concentrated to a volume of about 800 ml, seeded with a little crystalline product and then stored at about 4° C. for 12 days. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave a further 13.28 g (0.12 mol) of the target product. Under reduced pressure, the recovered filtrate was concentrated to dryness. The residue was dissolved in 100 ml of a mixture of ethyl acetate and methanol (10:1), applied to silica gel and purified chromatographically on silica gel (mobile phase: ethyl acetate/methanol 10:1). This gave a further 113.79 g (1.02 mol) of the desired product as a yellow solid. In this manner, a total of 193.66 g (1.74 mol, 78percent of theory) of the target product were obtained. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.71-1.84 (m, 2H), 2.01 (t, 2H), 2.25 (t, 2H), 4.91 (s, 1H), 6.39-6.99 (br. s, 2H).
70%
With ammonium acetate In toluene for 4 h; Reflux; Dean-Stark
Cyclohexane-1,3-dione (22.42 g, 200 mmol, 1 eq) was dissolved in 250 ml dry toluene and ammonium acetate (14.42 g, 200 mmol, 1 eq) was added. After refluxing under Dean-Stark conditions for 4 hours, the reaction mixture was evaporated. After recrystallization in ethyl acetate, 7.78 g of pure end product was obtained as a yellow-orange powder.
54%
With ammonium acetate; acetic acid In benzene for 7 h; Reflux
Preparation 1 3-Bromo-7,8-dihydroquinolin-5(6H)-one A mixture of cyclohexane-1,3-dione (30.00 g, 267.6 mmol), ammonium acetate (44.49 g, 535.1 mmol), glacial acetic acid (one drop), and benzene (150 mL) is stirred at reflux under Dean-Stark conditions for 7 h, cooled down to rt, and concentrated at reduced pressure. To the obtained residue EtOH and NaHC03 (2 eq.) are added. The formed precipitate is collected by filtration. The filtrate is concentrated, treated with dioxane and filtered. The solid on filter is washed with dioxane, and the combined filtrates are diluted with EtOAc. The formed solid is collected by filtration and dried to yield 3-aminocyclohex-2-enone (16.04 g, 54percent) as a white solid.
23%
Stage #1: With ammonium acetate In acetic acid; benzene for 7 h; Reflux Stage #2: With sodium hydrogencarbonate In ethanol
Example 983-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 °C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23percent) as yellow solid.[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88percent) as red oil, which is used in the next step without additional purification.[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 °C, and the resulting solution is stirred at 50 °C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 °C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14percent).1H NMR (De-DMSO), δΗ, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 264
99%
With ammonia In ethyl acetate; benzene
EXAMPLE 1 1-Amino cyclohexene-3-one 1,3-Cyclohexane dione (44.5 grams, 0.4 mol) was suspended in benzene (500 ml) in a 1 L flask equipped with mechanical stirrer, gas inlet tube, and Dean-Stark trap with reflux condenser. The mixture was heated to reflux to give a solution and ammonia gas was bubbled through the reaction until the theoretical amount of water had collected in the Dean Stark trap. The reaction mixture was cooled to room temperature and the solid was filtered. The yield was 44 g (99percent) of a tan solid; mp 120°-125° C. The reaction can be monitored by thin layer chromatography on silica gel plates with CHCl3: methanol: acetic acid 90:5:5. If the initial product is not a uniform solid, it can be slurried in hot ethyl acetate, cooled and collected.
Reference：
[1] New Journal of Chemistry, 2005, vol. 29, # 6, p. 769 - 772
[2] Patent: CN107337639, 2017, A, . Location in patent: Paragraph 0120; 0123; 0135; 0144-0146; 0157; 0168; 0179
[3] Synlett, 2009, # 5, p. 818 - 822
[4] Synthetic Communications, 1998, vol. 28, # 7, p. 1197 - 1200
[5] Tetrahedron, 2003, vol. 59, # 43, p. 8589 - 8595
[6] Advanced Synthesis and Catalysis, 2010, vol. 352, # 6, p. 1055 - 1062
[7] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3464 - 3471
[8] Patent: US2011/98311, 2011, A1,
[9] Patent: US2012/309758, 2012, A1,
[10] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0371
[11] Patent: US2008/176308, 2008, A1, . Location in patent: Page/Page column 11
[12] Tetrahedron Letters, 2004, vol. 45, # 25, p. 4911 - 4915
[13] Patent: CN108218770, 2018, A, . Location in patent: Paragraph 0056-0065
[14] Patent: US2014/31391, 2014, A1, . Location in patent: Paragraph 0362; 0363; 0364
[15] Synlett, 2010, # 2, p. 231 - 234
[16] Synlett, 2014, vol. 25, # 10, p. 1443 - 1447
[17] Patent: EP2650284, 2013, A1, . Location in patent: Paragraph 0189
[18] Archives of Pharmacal Research, 2013, vol. 36, # 4, p. 436 - 447
[19] Patent: WO2012/52451, 2012, A1, . Location in patent: Page/Page column 102-103
[20] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2415 - 2425
[21] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 3, p. 685 - 690
[22] Patent: US5206367, 1993, A,
[23] Patent: US4952694, 1990, A,
[24] Patent: WO2009/55437, 2009, A2, . Location in patent: Page/Page column 60; 61
[25] Synthesis, 2009, # 6, p. 985 - 999
[26] Patent: US2012/309758, 2012, A1, . Location in patent: Page/Page column 63
[27] Advanced Synthesis and Catalysis, 2013, vol. 355, # 13, p. 2550 - 2557
[28] Tetrahedron Letters, 2014, vol. 55, # 10, p. 1686 - 1688
[29] Organic and Biomolecular Chemistry, 2014, vol. 12, # 26, p. 4571 - 4575
[30] Heterocycles, 2014, vol. 89, # 6, p. 1427 - 1440
[31] Research on Chemical Intermediates, 2016, vol. 42, # 4, p. 3413 - 3423
[32] Tetrahedron Letters, 2018, vol. 59, # 32, p. 3069 - 3076
With hydrogenchloride; formaldehyd; dimethyl amine In methanol; water
EXAMPLE 1 In a reactor equipped with a stirrer, 300 parts of methanol, 56 parts of 50percent aqueous solution of dimethylamine and 56 parts of 1,3-cyclohexanedione were placed and the temperature of the mixture was raised to 30° C. Thereafter, 53 parts of 37percent aqueous solution of formaldehyde was added dropwise for an hour. After adding, the reaction solution was maintained at 40° C. for 3 hours. The end of the reaction was confirmed by checking the amount of the remaining unreacted material (1,3-cyclohexanedione) by a high performance liquid chromatography. Then, 10 parts of 5percent palladium-carbon was added to the resulting reaction mixture and hydrogen was blown over 15 hours at 30° C. under normal pressure. The end of the reaction was confirmed by checking the amount of the remaining unreacted material (2-dimethylaminomethyl-1,3-cyclohexanedione). After completion of the reaction, the catalyst was removed by filtration at 30° C. and 300 parts of water was added to the reaction mixture and methanol was removed by distillation, after which the residue was adjusted to pH 6 by adding 35percent hydrochloric acid. The resulting precipitate was separated by filtration, washed with water, and was dried at 70° C. to obtain 54.8 parts of a dry cake of 2-methyl-1,3-cyclohexanedione (yield: 87.0percent). The composition analysis of the dry cake by a high performance liquid chromatography revealed that the purity of 2-methyl-1,3-cyclohexanedione was 97.2percent. The melting point of the dry cake was 206°-208° C. (the value described in literature: 207°-209° C.). The FD-mass spectrum of the dry cake had a peak at 126 and the value was the same as the theoretical molecular weight.
Reference：
[1] Patent: US5276198, 1994, A,
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Yield
Reaction Conditions
Operation in experiment
70%
at 120℃;
In order to 1,3-cyclohexanedione, tert-butyl peroxybenzoate is used as a raw material, the reaction steps are as follows:In the reaction flask by adding 1,3-cyclohexanedione (0.11g, 1mmol), tert-butyl peroxybenzoate (0.58g, 3mmol), CuCl (0.01g, 0 . 1mmol) and 2 ml acetic acid, 120 °C reaction;TLC until the complete end tracking of the reaction;After the reaction the crude product by column chromatography (petroleum ether: ethyl acetate = 40:1), to obtain the target product (yield 70percent).
Reference：
[1] Patent: CN105254483, 2016, A, . Location in patent: Paragraph 0045
14
[ 504-02-9 ]
[ 74-88-4 ]
[ 1193-55-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2006, vol. 4, # 18, p. 3498 - 3504
[2] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1870 - 1872
[3] Journal of Organic Chemistry, 1986, vol. 51, # 16, p. 3201 - 3206
[4] Liebigs Annales, 1996, # 12, p. 2155 - 2169
[5] Journal of the American Chemical Society, 2010, vol. 132, # 23, p. 7852 - 7853
[6] Organic Syntheses, 1961, vol. 41, p. 56
[7] Journal of Organic Chemistry, 1943, vol. 8, p. 515
[8] Angewandte Chemie, 1955, vol. 67, p. 769,783
[9] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1952, p. 300,309; engl. Ausg. S. 309, 315
[10] Chemische Berichte, 1952, vol. 85, p. 61,71
[11] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1703,1710; engl. Ausg. S. 1793, 1799
[12] Journal of the Chemical Society, 1953, p. 811,813
[13] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1952, p. 300,309; engl. Ausg. S. 309, 315
[14] Chemische Berichte, 1952, vol. 85, p. 61,71
[15] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1703,1710; engl. Ausg. S. 1793, 1799
[16] Journal of the Chemical Society, 1953, p. 811,813
[17] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 441,443; engl. Ausg. S. 465, 467
[18] Organic Syntheses, 1961, vol. 41, p. 56
[19] Journal of Organic Chemistry, 1943, vol. 8, p. 515
[20] Angewandte Chemie, 1955, vol. 67, p. 769,783
[21] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 3, p. 685 - 690
[22] Angewandte Chemie - International Edition, 2006, vol. 45, # 30, p. 5000 - 5002
15
[ 50-00-0 ]
[ 504-02-9 ]
[ 1193-55-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 19, p. 4400 - 4404
16
[ 504-02-9 ]
[ 13754-86-4 ]
Reference：
[1] Tetrahedron, 2006, vol. 62, # 36, p. 8533 - 8538
[2] Tetrahedron Letters, 1996, vol. 37, # 51, p. 9203 - 9206
[3] Chemistry Letters, 1980, p. 1603 - 1604
[4] Chemistry Letters, 1980, p. 1603 - 1604
[5] Chemistry Letters, 1980, p. 1603 - 1604
[6] Recueil des Travaux Chimiques des Pays-Bas, 1990, vol. 109, # 4, p. 287 - 297
[7] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 1, p. 341 - 343
[8] Patent: US2017/37050, 2017, A1,
General procedure: 1,3-Dicarbonyls (8.9 mmol, 1 equiv.) followed by ammonium acetate (10.6 mmol, 1.2 mmol, 1.2 equiv.) were added to the solution of acrylic acid (10.6 mmol, 1.2 equiv.). The reactant mass was mixed thoroughly with a spatula and heated at 80 °C with stirring under a nitrogen atmosphere for 5 h. After cooling, the reaction mixture was diluted with 10mL distilled water and extracted twice with ethyl acetate (210 mL). The organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure and subjected to column chromatography (ethyl acetate=hexane) to obtain pure products. The characterization data of the compounds are given.
With sodium borohydrid; magnesium chloride In tetrahydrofuran
EXAMPLE 3 A reaction vessel was charged with 510 mg (13.5 mmol) of sodium borohydride, 8 ml of tetrahydrofuran, 209 ml (1.63 mmol) of normal nonane and 650 mg (6.8 mmol) of magnesium chloride, and the contents were stirred at room temperature for 24 hours. To this was added 9.8 ml of tetrahydrofuran solution containing 1.11 g (9.9 mmol) of 1,3-cyclohexanedione, spending 30 minutes. Thereafter, the reaction and after-treatment were carried out in accordance with Example 1. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 97.5percent. The by-products were cyclohexanol (0.2percent) and 2-cyclohexen-1-ol (1.2percent).
95.7%
With sodium borohydrid; magnesium chloride In tetrahydrofuran; water
EXAMPLE 1 A four neck flask equipped with a condenser, a thermometer and a mechanical stirrer was charged with 5.08 g (134.3 mmol) of sodium borohydride, 50 ml of tetrahydrofuran and 492.9 mg (3.84 mmol) of normal nonane as the internal standard for analysis. After further adding 6.15 g (64.6 mmol) of magnesium chloride, the contents were heated to 60° C. and stirred for 1 hour by keeping this temperature. Thereafter, the temperature was decreased to 25° C. and the stirring was continued for 2 hours. A 7.54 g (67.2 mmol) portion of 1,3-cyclohexanedione dissolved in 100 ml of tetrahydrofuran was added dropwise to this mixed solution spending 30 minutes. After completion of the dropwise addition, the mixture was heated to 60° C. and allowed to undergo the reaction for 3 hours by keeping this temperature. After spontaneous cooling of the reaction solution and subsequent cooling to about 0° C., 23 ml of water was added thereto spending 80 minutes. Thereafter, this was returned to room temperature and stirred for 1 hour. The thus obtained-solution was quantitatively analyzed by a gas chromatography and a liquid chromatography to find that 1,3-cyclohexanediol was formed with a yield of 95.7percent.
75.3%
With hydrogenchloride; sodium borohydrid In tetrahydrofuran
EXAMPLE 9 A four neck flask equipped with a condenser, a thermometer and a mechanical stirrer was charged with 237.8 mg (1.85 mmol) of normal nonane and 1.01 g (9 mmol) of 1,3-cyclohexanedione dissolved in 30 ml of tetrahydrofuran. Next, to this was added 679.3 mg (18 mmol) of sodium borohydride. The mixture was heated to 60° C. and stirred for 27 hours. After spontaneous cooling of the reaction solution, 4.5 ml of 1 N hydrochloric acid was added thereto. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 75.3percent. The by-products were cyclohexanol (9.1percent) and 2-cyclohexen-1-ol (5.6percent).
73.8%
With sodium borohydrid; magnesium chloride In tetrahydrofuran
EXAMPLE 2 A reaction vessel was charged with 511.8 mg (13.5 mmol) of sodium borohydride, 8 ml of tetrahydrofuran, 296 mg (2.3 mmol) of normal nonane and 655.4 mg (6.88 mmol) of magnesium chloride, and the contents were stirred at room temperature for 45 minutes. To this was added 10 ml of tetrahydrofuran solution containing 1.11 g (9.9 mmol) of 1,3-cyclohexanedione, spending 30 minutes. Thereafter, the reaction and after-treatment were carried out in accordance with Example 1. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 73.8percent. The by-products were cyclohexanol (0.4percent) and 2-cyclohexen-1-ol (0.9percent).
73.2%
With sodium borohydrid; calcium chloride In tetrahydrofuran
EXAMPLE 6 A reaction vessel was charged with 510 mg (13.5 mmol) of sodium borohydride, 8 ml of tetrahydrofuran, 237.5 mg (1.85 mmol) of normal nonane and 752.8 mg (6.8 mmol) of calcium chloride, and the contents were stirred at room temperature for 24 hours. To this was added 9.8 ml of tetrahydrofuran solution containing 1.11 g (9.9 mmol) of 1,3-cyclohexanedione, spending 30 minutes. Thereafter, the reaction and after-treatment were carried out in accordance with Example 1. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 73.2percent. The by-products were cyclohexanol (3.5percent) and 2-cyclohexen-1-ol (2.2percent).
70.6%
With hydrogenchloride; sodium borohydrid In tetrahydrofuran
EXAMPLE 10 A four neck flask equipped with a condenser, a thermometer and a mechanical stirrer was charged with 115.5 mg (0.9 mmol) of normal nonane and 1.01 g (9 mmol) of 1,3-cyclohexanedione dissolved in 30 ml of tetrahydrofuran. Next, to this was added 170.1 mg (4.5 mmol) of sodium borohydride. The mixture was heated to 60° C. and stirred for 27 hours. After spontaneous cooling of the reaction solution, 4.5 ml of 1 N hydrochloric acid was added thereto. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 70.6percent. The by-products were cyclohexanol (3.3percent) and 2-cyclohexen-1-ol (1.8percent).
70%
With sodium borohydrid In tetrahydrofuran; water
EXAMPLE 5 A reaction vessel was charged with 514 mg (13.6 mmol) of sodium borohydride, 5 ml of tetrahydrofuran, 208.8 mg of normal nonane and 906 mg (6.8 mmol) of aluminum chloride, and the contents were stirred at room temperature for 45 minutes. To this was added dropwise 10 ml of tetrahydrofuran solution containing 1.01 g (9 mmol) of 1,3-cyclohexanedione, spending 30 minutes. After completion of the dropwise addition, the mixture was heated to 60° C. and allowed to undergo the reaction for 25 hours by keeping this temperature. After spontaneous cooling of the reaction solution and subsequent cooling to about 0° C., 2.7 ml of water was added thereto. Thereafter, this was returned to room temperature and stirred for 1 hour. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 70.0percent. The by-products were cyclohexanol (10.7percent) and 2-cyclohexen-1-ol (4.4percent).
66.6%
With sodium borohydrid In tetrahydrofuran; water
EXAMPLE 8 A reaction vessel was charged with 510 mg (13.5 mmol) of sodium borohydride, 8 ml of tetrahydrofuran, 237.5 mg (1.85 mmol) of normal nonane and 918.2 mg (6.8 mmol) of zinc chloride, and the contents were stirred at room temperature for 24 hours. To this was added dropwise 9.8 ml of tetrahydrofuran solution containing 1.11 g (9.9 mmol) of 1,3-cyclohexanedione, spending 30 minutes. After completion of the dropwise addition, the mixture was heated to 60° C. and allowed to undergo the reaction for 8 hours by keeping this temperature. After spontaneous cooling of the reaction solution and subsequent cooling to about 0° C., 2.7 ml of water was added thereto. Thereafter, this was returned to room temperature and stirred for 1 hour. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 66.6percent. The by-products were cyclohexanol (12.5percent) and 2-cyclohexen-1-ol (20.9percent).
65.5%
With sodium borohydrid; magnesium sulfate In tetrahydrofuran
EXAMPLE 4 A reaction vessel was charged with 462.5 mg (12.2 mmol) of sodium borohydride, 8 ml of tetrahydrofuran, 237.5 mg (1.85 mmol) of normal nonane and 737.5 mg (6.13 mmol) of magnesium sulfate, and the contents were stirred at room temperature for 45 minutes. Then, 9.8 ml of tetrahydrofuran solution containing 1.11 g (9.9 mmol) of 1,3-cyclohexanedione was added spending 30 minutes. Thereafter, the reaction and after-treatment were carried out in accordance with Example 1. 1,3-Cyclohexanediol was formed in the reaction solution with a yield of 65.5percent. The by-products were cyclohexanol (14.9percent) and 2-cyclohexen-1-ol (9.5percent).
With triethylamine; 2-hydroxy-2-methylpropanenitrile In dichloromethane at 15℃; Large scale
The obtained 2-nitro-4-methanesulfonylbenzoyl chloride was dissolved in methylene chloride,Cool down to15 ° C, 165 kg of 1,3-cyclohexanedione was charged,In 80 minutes are ticked with 175kg triethylamine esterification condensation; then added15 kg of acetone cyanohydrin,Dropping 160kg of triethylamine for rearrangement reaction, plus hydrochloric acid to adjust the pH to about 1.0, water washing, addWater distillation to recover methylene chloride,And then discharge material, suction filter crude sulphoxylate; hot filter out of the crude sulcotrone into the fineIn the reactor,Stirring at 55 ° C for 40 minutes, after the extraction of the filter, the mother liquor into the methanol distillation distillation distillation to recover methanol,The solid product was dried and the gas stream was pulverized to give a product of mesotrioneThe purity of the obtained meso-ketone product was 97.95percent and the yield was 89.66 percent
88.74%
With triethylamine In dichloromethane at 35 - 40℃;
The obtained 2-nitro-4-methanesulfonylbenzoyl chloride was dissolved in methylene chloride and cooled to 35 to 40 ° C,Put 170kg of 1,3-cyclohexanedione,In 60 ~ 80 minutes evenly added 185kg triethylamine for esterification condensation; then added15 kg of acetone cyanohydrin,Dropping 160 kg of triethylamine for rearrangement reaction,Add hydrochloric acid to adjust the pH of 1 ~ 2, water washing, distillation toRecovery of dichloromethane,And then discharge,Smelting crude saponin;The hot filter will be filtered out of the crude sulphoxyl ketone into the refining reactor,Stirring at 50 to 55 ° C for 20 to 40 minutes,After the extraction filter,The mother liquor was distilled in a methanol distillate to recycle methanol,The solid product was dried,After the air flow cranberrone finished.The purity of the obtained mesotrione was 97.61percentThe rate was 88.74percent.
88%
Stage #1: at 15℃; for 2 h; Stage #2: With 2-hydroxy-2-methylpropanenitrile In dichloromethane at 32℃; for 3 h;
300 g of dichloromethane was introduced into the reaction vessel.Adding 2-nitro-4-methylsulfonylbenzoyl chloride 55g to the reaction kettle1,3-cyclohexanedione 25g,Turn on the agitation,With a negative pressure to -0.07MPa,Slowly warming to 15 ° C, reflux occurs.Keep warm for 2hr,The HCl produced by the reaction is taken out of the reaction system by a negative pressure of the gas, and the exhaust gas is absorbed by the two-stage water. After the reaction of the enol ester, acetone cyanohydrin is added to carry out the rearrangement reaction and the degree of vacuum is adjusted to -0.03 MPa.When the temperature rises to 32 ° C, the reflux starts and the temperature is kept for 3 hr.After the reaction is completed, dichloromethane is distilled off, methanol is added, and the mixture is filtered.The finished product of mesotrione was 62.5 g, the content was 98.3percent, and the yield was 88percent.
Reference：
[1] Patent: CN106565560, 2017, A, . Location in patent: Paragraph 0023-0024
[2] Patent: CN106565556, 2017, A, . Location in patent: Paragraph 0013-0016
[3] Patent: CN108530325, 2018, A, . Location in patent: Paragraph 0023-0029
With potassium iodide; sodium hydroxide; In water; at 20℃; for 12h;Cooling with ice;
Add 1,3-cyclohexanedione (10.0 g, 89.18 mmol) to a 250 mL round bottom flask, dissolve in 60 mL of water, and add 35 mL of 20% sodium hydroxide solution under ice bath.Further, KI (2.9 g, 17.4 mmol) was added, and finally, 16 mL of a 40% aqueous solution of chloroacetaldehyde was slowly added dropwise, and the reaction was carried out at room temperature. After 12 hours, the material was completely reacted by TLC.Adding a mass fraction of 37.5% concentrated hydrochloric acid to pH=4, adding 100 mL of water, extracting with petroleum ether (100 mL×4), combining the organic phases, washing with saturated brine (100 mL×3), and finally using anhydrous sodium sulfate dry,The solvent was evaporated under reduced pressure to give a pale yellow liquid, i.e., 6,7-dihydro-4(5H)-benzofuranone, 10.0 g, yield 82%.
16.5 g
under argon, cyclohexanedione (20.71 g, 0.18 mol) was dissolved in methanol (100mL) and cooled to 0 C. To this was added potassium hydroxide (12.2 g, 0.18 mol) and afterstirring 30 minutes at 0 C the 50% solution of chloroacetaldehyde in water (26.3 mL, 0.203mol) was added. This was stirred overnight, the resulting solution made acidic with 1 Nhydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water,brine, dried over magnesium sulfate and concentrated to dryness to give the volatile 6,7-S34dihydrobenzofuran-4(5H)-one (16.5 g) clean enough for the next step.
In a 200-ml flask connected to a Dean-Stark trap, 2- amino-3-bromo-5-chloropyridine (48.7 mmol, 10.1 g) , 1,3- cyclohexanedione (73.1 mmol, 1.5 eq, 8.20 g), p- toluenesulfonic acid monohydrate (4.87 mmol, 0.1 eq, 926 mg) and toluene (101 ml) were mixed, and the mixture was heated to reflux for 7 hours. After completion of the reaction, the reaction solution was cooled, a 3percent aqueous sodium bicarbonate solution (100 ml) was added, and the mixture was extracted three times with ethyl acetate (100 ml) . The organic layers were combined, washed three times with a 3percent aqueous sodium bicarbonate solution (100 ml) and once with water (100 ml), and then concentrated under reduced pressure. Ethyl acetate (25 ml) was added to the residue, and the mixture was stirred with heating for 1 hour, and then stood to cool and ice-cooled. Precipitated crystals were collected by filtration, washed with cold ethyl acetate, and dried under reduced pressure at 5O0C, to yield the title compound (9.11 g, yield 62percent) .1H-NMR (DMSOd6, TMS, 300 MHz): delta (ppm) : 1.8-2.0 (2H, m) , 2.2-2.3 (2H, m) , 2.6-2.7 (2H, m) , 6.20 (IH, s) , 8.33 (IH, d, J = 4.5 Hz) , 8.41 (IH, d, J = 4.5 Hz), 8.49 (IH, br) .
In a 300-ml flask connected to a Dean-Stark trap, 2- amino-3, 5-dichloropyridine (155 mmol, 25.2 g) , 1,3- cyclohexanedione (194 mmol, 1.25 eq, 21.8 g) , p- toluenesulfonic acid monohydrate (15.5 mmol, 0.1 eq, 2.95 g) and toluene (252 ml) were mixed, and the mixture was heated to reflux for 8 hours. After completion of the reaction, the reaction solution was cooled, a 3percent aqueous sodium bicarbonate solution (250 ml) was added thereto, and the mixture was extracted three times with ethyl acetate (125 ml) . The organic layers were combined, washed with a 3percent aqueous sodium bicarbonate solution (250 ml) , and then concentrated under reduced pressure. Ethyl acetate (250 ml) was added to the concentrate, and the mixture was further concentrated. This operation was performed three times in total, and the amount of the concentration residue was adjusted to about 80 g. The concentrated slurry was stirred with heating for 1 hour, and then stood to cool and ice-cooled. Precipitated crystals were collected by filtration, washed with cold ethyl acetate (20 ml) , and dried under reduced pressure at 50°C, to yield the title compound (19.8 g, yield 50percent).1H-NMR (DMSOd6, TMS, 300 MHz): delta (ppm) : 1.8-2.0 (2H, m) , 2.2-2.3 (2H, m) , 2.6-2.7 (2H, m) , 6.34 (IH, s) , 8.21 (IH, d, J = 4.2 Hz), 8.37 (IH, d, J = 4.1 Hz), 8.63 (IH, br) .
With hydrogenchloride; thionyl chloride; triethylamine; In 1,4-dioxane; N-methyl-acetamide; ethyl acetate; acetonitrile;
Example 1 2-[2-chloro-4- (methylsulfonyl) benzoyl]-1,3-cyclohexanedione 42.5 g of 2-chloro-4-methylsulfonylbenzoic acid were boiled in 160 ml of dioxane with 5 drops of dimethylformamide and 25.1 ml of thionyl chloride until the evolution of gas subsided. The solvent was stripped off with the exclusion of moisture on a rotary evaporator. To the oily residue there were added at 0° C. 19.7 g of 1,3-cyclohexanedione in 250 ml of acetonitrile, and 63.1 ml of triethylamine were then added dropwise at this temperature. Stirring was continued for 15 minutes, 15.3 ml of acetone cyanohydrin were added, and the mixture was allowed to stand overnight. The reaction mixture was concentrated under reduced pressure on a rotary evaporator, the residue was taken up in ethyl acetate/water, and the organic phase was washed with 2N hydrochloric acid. The product was extracted from the organic phase using 5percent K2 CO3 solution, and precipitated at a pH of 2-3 using concentrated hydrochloric acid, with cooling. After filtration with suction and drying, 48.4 g of 2-[2-chloro-4-(methylsulfonyl)benzoyl]-1,3-cyclohexanedione of melting point 141°-142° C. were obtained.
With potassium carbonate; triethylamine; In dichloromethane;
EXAMPLE 1 [This Example describes a procedure for the preparation of the Compound] Triethylamine (3.4 mL, 25 mM) is added dropwise to a stirred solution of 2-nitro-4-trifluromethylbenzoyl chloride (19 mM; itself obtained by reaction of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> with an excess of oxalyl chloride) and cyclohexane-1,3-dione (19 mM) in dichloromethane (100 mL). The mixture is stirred for one hour at ambient temperature and then further triethylamine (57 mM) and acetone cyanohydrin (0.4 mL) is added. Stirring is continued for a further 2.5 hours and then the mixture is washed thoroughly with 2M hydrochloric acid to remove triethylamine. The organic phase is then extracted thoroughly with potassium carbonate (5% w/v). The combined basic extracts are then acidified with 2M hydrochloric acid and extracted with ether. The ether extracts are washed with saturated sodium chloride solution, dried (magnesium sulphate) and the volatile material removed by rotary evaporation in vacuo. There may thus be obtained 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as a solid, m.p. 88-84 C. (recrystallized from ethyl acetate) having a satisfactory microanalysis and infra-red and proton magnetic resonance spectra.
With hydrogenchloride; bunazosin; In 1,4-dioxane; acetonitrile;
EXAMPLE 1 3-Oxo-4-aza-5alpha-androst-1-ene-17-betacarboxylic acid All three neck round bottom flask equipped with a nitrogen inlet, reflux condenser, addition funnel, mechanical stirrer and an immersion thermometer was charged with 180 mL dioxane followed by 18 g of 3-oxo-4-aza-5alpha-androstan-17beta-carboxylic acid portionwise with stirring. To the stirred suspension was added portionwise 13.86 g of DDQ. The flask was evacuated (22" Hg) and flushed with nitrogen three times. To this stirred suspension was added BSTFA via the addition funnel at the rate of 50 mL/minute. The temperature slowly went up form 22 to 25 in a period of thirty minutes as most of the solids dissolved within this period to afford a clear solution. The solution was stirred for 18 hours at 22 after which time formation of the two diastereomeric adducts were observed. To the solution was added 0.54 g cyclohexane-1,3-dione and the reaction mixture was stirred at 22 for an additional three hours to decompose any residual DDQ. The solution was then heated in an oil bath so that a very gentle reflux was maintained. (Bath temperature 120, Internal Temperature 108) After refluxing for 20 hours complete disappearance of the adducts and formation of Delta1 acid were observed. The reaction mixture was cooled to 22 and poured slowly over a period of 2 minutes into a stirred mixture of 300 CH2 Cl2 and 60 mL 1% aqueous sodium bisulfite solution. The flask was rinsed with 50 mL CH2 Cl2. After the mixture was stirred for thirty minutes, 18 mL 6N HCl was added to this mixture and stirred for an additional thirty minutes. The heterogeneous mixture was filtered and the residue was washed with 60 mL 1N HCl followed by 250 mL CH2 Cl2. The filtrated was transferred into a seperatory funnel and allowed to settle. The bottom CH2 Cl2 layer containing the product was separated from the top aqueous layer and the top layer was washed with 60 mL CH2 Cl2. The combined CH2 Cl2 layer was washed with 200 mL 2N HCl. The aqueous layer was washed with 60 mL CH2 Cl2. The two CH2 Cl2 solutions were combined. The liquid chromatography yield at this stage was 16.0 g (88%). The combined CH2 Cl2 solution was then distilled and concentrated to about 120 mL volume. The distillation was continued and acetonitrile was added to the flask at such a rate so that the total volume was maintained at approximately 120 mL. After addition of about 400 mL acetonitrile the distillation head showed a temperature of about 82. Gas chromatography analysis performed on the mother liquor showed the presence of about 2% dioxane. The distillation was discontinued at this point. The suspension was cooled to 20 and aged at 20 for 20 hours with stirring. The crystals were filtered and washed with acetonitrile until the filtrate was colorless. Approximately 100 mL acetonitrile was used for the wash. The wet cake was dried at 60 C. under vacuum (about 1 mm mug) overnight to produce 15.3 g of the Delta1 acid.
With hydrogenchloride; bunazosin; In 1,4-dioxane; dichloromethane; acetonitrile;
EXAMPLE 1 3-Oxo-4-aza-5a-androst-1-ene-17beta-carboxylic acid A 1 l three neck round bottom flask equipped with a nitrogen inlet, reflux condenser, addition funnel, mechanical stirrer and an immersion thermometer was charged with 180 mL dioxane followed by 18 g of 3-oxo-4-aza-5a-androstan-17beta-carboxylic acid portionwise with stirring. To the stirred suspension was added portionwise 13.86 g of DDQ. The flask was evacuated (22' Hg) and flushed with nitrogen three times. To this stirred suspension was added BSTFA via the addition funnel at the rate of 50 mL/minute. The temperature slowly went up from 22 to 25 in a period of thirty minutes as most of the solids dissolved within this period to afford a clear solution. The solution was stirred for 18 hours at 22 after which time formation of the two diastereomeric adducts were observed. To the solution was added 0.54 g cyclohexane-1,3-dione and the reaction mixture was stirred at 22 for an additional three hours to decompose any residual DDQ. The solution was then heated in an oil bath so that a very gentle reflux was maintained. (Bath temperature 120, Internal Temperature 108) After refluxing for 20 hours complete disappearance of the adducts and formation of W1 acid were observed. The reaction mixture was cooled to 22 and poured slowly over a period of 2 minutes into a stirred mixture of 300 mL CH2Cl2 and 60 mL 1% aqueous sodium bisulfite solution. The flask was rinsed with 50 mL CH2Cl2. After the mixture was stirred for thirty minutes, 18 mL 6N HCl was added to this mixture and stirred for an additional thirty minutes. The heterogeneous mixture was filtered and the residue was washed with 60 mL 1N HCl followed by 250 mL CH2Cl2. The filtrated was transferred into a seperatory funnel and allowed to settle. The bottom CH2Cl2 layer containing the product was separated from the top aqueous layer and the top layer was washed with 60 mL CH2Cl2. The combined CH2Cl2 layer was washed with 200 mL 2N HCl. The aqueous layer was washed with 60 mL CH2Cl2. The two CH2Cl2 solutions were combined. The liquid chromatography yield at this stage was 16.0 g (88%). The combined CH2Cl2 solution was then distilled and concentrated to about 120 mL volume. The distillation was continued and acetonitrile was added to the flask at such a rate so that the total volume was maintained at approximately 120 mL. After addition of about 400 mL acetonitrile the distillation head showed a temperature of about 82. Gas chromatography analysis performed on the mother liquor showed the presence of about 2% dioxane. The distillation was discontinued at this point. The suspension was cooled to 20 and aged at 20 for 20 hours with stirring. The crystals were filtered and washed with acetonitrile until the filtrate was colorless. Approximately 100 mL acetonitrile was used for the wash. The wet cake was dried at 60C under vacuum (about 1mm mg) overnight to produce 15.3 g of the W1 acid.
Examples 1 to 13 To 5 ml of water were added 1.12 g (10 mmoles) of 1,3-cyclohexanedione and the each base shown in Table 1, and then 2 ml of 40percent aqueous solution of chloroacetoaldehyde was added thereto. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added about 10 ml of ethyl acetate, and then the reaction mixture was acidified with 0.5 to 1 ml of sulfuric acid and stirred for 30 minutes. The resulting ethyl acetate layer was analyzed by gas-liquid chromatography (hereinafter referred to as 'GLC') (SE30 10percent 1.2 m *3 mmphi glass column, 130°C) using p-dimethoxybenzene as an internal standard. The obtained each result is shown in Table 1. It was proved from the results of the GLC that 4-oxo-4,5,6,7-tetrahydrobenzofuran was produced in a yield shown in Table 1, in each Example.
With thionyl chloride; potassium carbonate; In water; acetonitrile;
EXAMPLE 2 2-(2-Chloro-4-methanesulphonylbenzoyl)-1,3-cyclohexanedione from the acid chloride. 2-Chloro-4-methanesulphonylbenzoyl chloride (5 g) was prepared by the reaction of 2-chloro-4-methanesulphonylbenzoic acid with thionyl chloride. The acid chloride was dissolved in acetonitrile (40 ml). A mixture of 1,3-cyclohexanedione (2.24 g), potassium carbonate (6.9 g) and acetonitrile (40 ml) was stirred at room temperature for 4 hours. To this solution was added the acid chloride solution over 10 min and allowed to stir 1 hour. 1,2,4-Triazole (0.07 g) was then added and the mixture allowed to stir 16 hours at room temperature. The solvent was removed and the residue was dissolved in water and acidified. The product was extracted into dichloromethane and the solvent was dried then evaporated to give the desired product in 83.6percent yield.
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+).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 114℃; for 1.58333h;
A 2 I three-necked round-bottomed flask equipped with a stirring shaft, a thermometer and a condenser is charged with 1.2 I of 1-butanol, 145 g of 3-[1-(tetrahydropyran-2-yl)-1 H- benzimidazol-2-yloxy]benzaldehyde (0.405 mol, B1 ), 62.4 g of 3-amino-2- ethoxycarbonylpyrrole (1 eq., 0.405 mol), 46.8 g of 97% 1 ,3-cyclohexanedione (1 eq., 0.405 mol) and 70.5 ml of N,N-diisopropylethylamine (1 eq.) and this initial charge is taken to reflux (temperature rise time 55 minutes, reflux held for 30 minutes, temperature 1 14C). The mixture is subsequently cooled to AT and concentrated to dryness under reduced pressure, to give 290 g of a brown oil containing ethyl 8-oxo-9-{3-[1-(tetrahydropyran-2-yl)-1 H- benzimidazol-2-yloxy]phenyl}-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate. (LC/MS-A, tr=1 .96 min, MS positive mode m/z=553.33). A similar operation carried out with 35 g of 3-[1-(tetrahydropyran-2-yl)-1 H-benzimidazol-2-yloxy]benzaldehyde (0.098 mol, example B1 ) gives 72 g of a brown oil containing ethyl 8-oxo-9-{3-[1-(tetrahydropyran-2-yl)- 1 H-benzimidazol-2-yloxy]phenyl}-4,5,6J,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3- carboxylate. (LC/MS-A, tr=1 .96 min, MS positive mode m/z=553.35).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 114℃; for 1.41667h;
C1: Ethyl 8-oxo-9-{3-[1-(tetrahydro-pyran-2-yl)-1H-benzimidazol-2-yloxy]phenyl}-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate A 2 l conical flask is charged, with magnetic stirring, with 50 g of <strong>[252932-48-2]3-amino-2-ethoxycarbonylpyrrole</strong> hydrochloride and 0.204 l of 2N sodium hydroxide solution. The mixture is stirred for 15 minutes at ambient temperature (AT), and then extracted with 3×0.3 l of dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue is triturated with n-pentane, filtered and dried under reduced pressure to a constant weight, to give 36.4 g of <strong>[252932-48-2]3-amino-2-ethoxycarbonylpyrrole</strong> in the form of a brown solid.A 2 l three-necked round-bottomed flask equipped with a stirrer shaft, a thermometer and a condenser is charged with 1.2 l of 1-butanol, 145 g of 3-[1-(tetrahydro-pyran-2-yl)-1H-benzimidazol-2-yloxy]benzaldehyde (0.405 mol, B1), 62.4 g of <strong>[252932-48-2]3-amino-2-ethoxycarbonylpyrrole</strong> (1 eq., 0.405 mol), 46.8 g of 1,3-cyclohexanedione in 97% form (1 eq., 0.405 mol) and 70.5 ml of N,N-diisopropylethylamine (1 eq.) and the mixture is taken to reflux (temperature rise time 55 min, reflux maintained for 30 min, temperature 114 C.) The mixture is then cooled to AT and concentrated to dryness under reduced pressure to give 290 g of a brown oil containing ethyl 8-oxo-9-{3-[1-(tetrahydro-pyran-2-yl)-1H-benzimidazol-2-yloxy]phenyl}-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate (LC/MS-A, tr=1.96 min. MS positive mode m/z=553.33). A similar operation carried out with 35 g of 3-[1-(tetrahydro-pyran-2-yl)-1H-benzimidazol-2-yloxy]-benzaldehyde (0.098 mol, example B1) produces 72 g of a brown oil containing ethyl 8-oxo-9-{3-[1-(tetrahydro-pyran-2-yl)-1H-benzimidazol-2-yloxy]phenyl}-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate (LC/MS-A, tr=1.96 min. MS positive mode m/z=553.35).
2-(4-fluoro-3-phenoxybenzylideneamino)-3-(4-methoxyphenyl)benzofuran-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With piperidine; ammonium acetate; In N,N-dimethyl-formamide; at 20℃; for 7h;Reflux;
General procedure: The appropriate beta-nitrostyrene (1 mmol), appropriate aromatic aldehyde (2 mmol), NH4OAc (115 mg, 1.5 mmol), and piperidine (43 mg, 0.5 mmol) were dissolved in DMF (15 mL) at r.t., then to the resultant mixture cyclohexane-1,3-dione or 5-(4-chlorophenyl)cyclohexane-1,3-dione (1 mmol) was added dropwise under stirring and refluxing for 30 min. The reaction mixture was stirred under reflux for ca.7 h, and the completion of reaction was confirmed by TLC (EtOAc-hexanes, 1:10). After the completion of reaction,the reaction mixture was cooled to r.t. Removal of solvent by vacuum distillation, the residues were diluted with CH2Cl2 (20 mL). Subsequently, the resultant solution was washedwith H2O (10 mL) and brine (10 mL), dried over anhydNa2SO4. The crude product was purified by flash chromatography (silica gel; EtOAc-hexanes, 1:20) to give product 4.
With chloro-trimethyl-silane; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 1.5h;
1-((5-Cyanopyridin-2-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea Trimethylsilyl chloride (125 muL, 0.98 mmol) is added to a solution of cyclohexane-1,3-s dione (100 mg, 0.89 mmol), <strong>[206201-64-1]6-formylnicotinonitrile</strong> (118 mg, 0.89 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (182 mg, 0.89 mmol) in a mixture of N,N-dimethyl-formamide (670 muL) and acetonitrile (1.2 mL), and the mixture is stirred at room temperature for 1.5 h. The reaction mixture is cooled to room temperature and poured into a mixture of water and ice. The mixture is filtered, and the precipitate is washed with water and dried under reduced pressure. Yield: 330 mg; ESI mass spectrum [M+H]+=431, Retention time HPLC: 0.63 min (V011_S01).
330 mg
With chloro-trimethyl-silane; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 1.5h;
Trimethylsilyl chloride (125 mu, 0.98 mmol) is added to a solution of cyclohexane-1,3- dione (100 mg, 0.89 mmol), <strong>[206201-64-1]6-formylnicotinonitrile</strong> (118 mg, 0.89 mmol) and l-(3-(trifluoromethyl)phenyl)urea (182 mg, 0.89 mmol) in a mixture of N,N-dimethyl- formamide (670 mu) and acetonitrile (1.2 mL), and the mixture is stirred at room temperature for 1.5 h. The reaction mixture is cooled to room remperature and poured into a mixture of water and ice. The mixture is filtered, and the precipitate is washed with water and dried under reduced pressure. Yield: 330 mg; ESI mass spectrum [M+H] = 431 , Retention time HPLC: 0.63 min (V011 S01).
5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-carbaldehyde[ No CAS ]
[ 504-02-9 ]
[ 252932-48-2 ]
9-[5-(6,7-difluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester[ No CAS ]
9-[5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester[ No CAS ]
8-oxo-9-[5-(4,5,6-trifluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester[ No CAS ]
9-[5-(5-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester[ No CAS ]
9-[5-(1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester trifluoroacetate[ No CAS ]
5-(4,6-difluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-carbaldehyde[ No CAS ]
[ 504-02-9 ]
[ 252932-48-2 ]
9-[5-(4,6-difluoro-1H-benzimidazol-2-ylsulfanyl)furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester[ No CAS ]
2-amino-4-[4-(di-p-tolyl-amino)-phenyl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; In ethanol; for 5h;Reflux;
General procedure: Compounds 1?3 were synthesized according to a reported procedure [11]. A mixture of 1,1-dimethyl-3,5-cyclohexanedione (3,5-cyclohexanedione, 4-hydroxycoumarin) (10 mmol), 4-(di-p-tolyl-amino)-benzaldehyde (10 mmol), malononitrile (10 mmol) and 4-(dimethylamino)pyridine (DMAP) (1 mmol) in ethanol (100 mL) was refluxed for 5 h and then cooled to room temperature. The precipitates were filtered and sequentially washed with ice-cooled water and ethanol and then dried under a vacuum.
2,5-Dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23.62g
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 21h;
At room temperature, the 1,3-Cyclohexanedione (CAS Denn segni: 504-02-9) (13.25g) dissolved in N, N-dimethyl formamide (DMF) (200 ml), and to which potassium butanol joins uncle (13.26g) and (E) - 2-cyano-3-ethoxy-2-acrylic acid ethyl ester (CAS Denn segni: 94-05-3) (20.00g). Stirring the mixture 21 hours. The reaction solution is diluted with ethyl acetate, adding 2mol/L hydrochloric acid aqueous solution, and stirring the mixture. Adding ethyl acetate and water, and the extraction of the organic layer. The extract with saturated aqueous salt solution washing, then drying with anhydrous sodium sulfate, and the solvent is distilled under reduced pressure, to obtain the title compound (23.62g), which has the following physical property value.
23.62 g
With potassium tert-butylate; In N,N-dimethyl-formamide; for 21h;
At room temperature, 1,3-cyclohexanedione (CAS registration No.: 504-02-9) (13.25g) was dissolved in N,Ndimethylformamide (DMF) (200 mL), and tert-butoxy potassium (13.26 g) and ethyl (E)-2-cyano-3-ethoxy-2-propenoate(CAS registration No.: 94-05-3) (20.00 g) were added thereto. The mixture was stirred for 21 hours. The reaction solutionwas diluted with ethyl acetate, 2 N hydrochloric acid aqueous solution was added thereto, and the mixture was stirred.Ethyl acetate and water were further added, and the organic layer was extracted. The extract was washed with a saturatedsaline solution, then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reducedpressure to obtain the title compound (23.62 g) having the following physical property values.TLC: Rf 0.35 (hexane : ethyl acetate = 1:1);1H-NMR (CDCl3): delta 1.37, 2.19, 2.61, 2.92, 4.36, 8.63
Step 1: Ethyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate To a mixture of cyclohexane-1,3-dione (1.0 g, 8.9 mmol) in DMF (10 mL) was added 1 M t-BuOK in THF (8.9 mL, 8.9 mmol) at 0 C. The resulting mixture was stirred for 20 min and added ethyl (E)-2-cyano-3-ethoxyacrylate (1.51 g, 8.9 mmol). The reaction mixture was warmed to rt, stirred for 2 h, quenched with 1N HCl solution, and extracted with EtOAc. The combined organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product. LCMS calcd for C12H13O5 (M+H)+: m/z=237.1. Found: 237.2.
24 g
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 21h;
Example 62 Ethyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate 1,3-cyclohexanedione (CAS registration No:504-02-9) (13 g) was dissolved in N,N-dimethyl formamide (DMF) (200 mL) at room temperature, and tert-butoxy potassium (13 g), ethyl (E)-2-cyano-3-ethoxy-2-propenoate (CAS registration No: 94-05-3) (20 g) were added thereto. The mixture was stirred for 21 hours. The reaction solution was diluted with ethyl acetate, 2 N aqueous solution of hydrochloric acid was added and stirred. Ethyl acetate and waster were further added to the mixture. The organic layer was extracted, and washed with a saturated saline solution, then dried over anhydrous sodium sulfate, and a solvent was removed by evaporation under reduced pressure to obtain the title compound (24 g) having the following physical property values. TLC: Rf 0.35 (hexane : ethyl acetate = 1:1); 1H-NMR (CDCl3): delta 1.37, 2.19, 2.61, 2.92, 4.36, 8.63.
7-fluoro-2,3-dihydro-1H-carbazol-4(9H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
General procedure: To a solution of acetonitrile (10 vol.) in 1,3-cyclohexanedione 5 ( 0.01 mol), added the corresponding phenyl hydrazine hydrochloride 6a-j (0.01 mol) and maintained the reaction mixture at 80-85 C for 6-8 h. After completion of the reaction, acetonitrile was removed under vacuum distillation below 45 C to get respective Schiff's base. To which (10 volumes) Con. hydrochloric acid/sulfuric acid was added and maintained at 90-95 C over a period of 8-10 h. After completion of reaction, quenched the reaction mixture with DM water and adjusted the pH to basic using aqueous 30% sodium carbonate solution. The resulting reaction mixture was extracted with ethyl acetate, separated the organic layer, washed with brine solution and distilled out the organic layer completely to get crude. It was further purified by silica gel column chromatography using 0-5% methanol in chloroform. (Note: In the case of 4-methoxyphenyl hydrazine hydrochloride 6d, schiff's base gets cyclized instantaneously without acid to afford 1d)
9-(3,5-dichloro-4-hydroxyphenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.5%
With N,N'-bis(3-sulfopropyl)triethylenediaminium bis(hydrogensulfate); ammonium acetate; In ethanol; at 80℃; for 4h;
General procedure: The catalyst ionic liquid was prepared according to the literature procedure [28]. To a mixture of 1,3-cyclohexanedione/dimedone (2mmol), arylaldehyde (1mmol), and ammonium acetate (3mmol) in 5mL of anhydrous ethanol, and 0.02g of ionic liquid was added and stirred at 80°C for 4h. After completion of the reaction (TLC monitoring), the mixture was cooled to room temperature. The resulting precipitate was filtered off and washed with ethanol before drying to afford the pure 1,8-acridinedione intermediates in good yields (50?80percent) which were submitted to the following step without further purification [33]. 4.6.1.1 9-(3,5-Dichloro-4-hydroxyphenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4a) Compound 81 4a was prepared using 82 <strong>[2314-36-5]3,5-dichloro-4-hydroxybenzaldehyde</strong> (191mg, 1mmol, 1.0 eq), 83 1,3-cyclohexanedione (224mg, 2mmol, 2.0 eq) and 84 ammonium acetate (231mg, 3mmol, 3.0 eq) according to the general procedure A to give the desired product (240mg, yield 63.5percent) as an off-white solid. 1H NMR (400MHz, DMSO-d6) delta 9.52 (s, 1H), 7.01 (s, 2H), 4.77 (s, 1H), 2.56?2.43 (m, 4H), 2.25?2.17 (m, 4H), 1.96?1.86 (m, 2H), 1.85?1.72 (m, 2H). One NH was not seen.
With poly L-Dopa microspheres; In acetonitrile; for 1.5h;Reflux;
General procedure: In a typical experiment 1.0 mmol pyridine and 1.0 mmol phenacyl bromide were dissolved in 5.0 mL ofacetonitrile and stirred at room temperature for 2 min to form a white sediment powder. Then 1.0 mmol1,3-dicarbonyl compounds, 1.0 mmol aromatic aldehydes, and 0.032 g of PDopa as the catalyst were added andrefl uxed for 4-6 h. After the reaction was completed the mixture was cooled down to room temperature andthe catalyst was removed by simple fi ltration, cleaned by several washings with acetonitrile solvent, and driedfor subsequent uses. The solvent of the fi ltered solution was then evaporated completely and the residual wasdispersed in distilled water, fi ltered, and dried at ambient temperature and pressure and fi nally recrystallizedfrom ethanol solution.
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