* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Helvetica Chimica Acta, 1942, vol. 25, p. 1306,1312
4
[ 593-84-0 ]
[ 609-08-5 ]
[ 55477-35-5 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 3397
5
[ 609-08-5 ]
[ 74-88-4 ]
[ 1619-62-1 ]
Yield
Reaction Conditions
Operation in experiment
76.55%
Stage #1: With sodium ethanolate In ethanol at 40℃; for 3 h; Stage #2: at 40 - 80℃; for 21 h;
Sodium ethoxide (163.1g, 2mol) was added to absolute ethanol (950 mL of) and stirred until completely dissolved, diethyl methylmalonate was added dropwise at 40 degrees (174.19g, 1mol), dropwise over 1h to control ,Then continue to heat the reaction at 40 degrees 2h. Then iodomethane at 40 °C (184.5g, 1.3mol),Drop within 1h control. After warming to 80 degrees, holding 20h reflux. Stop heating, vacuum distillation of all ethanol, and then to the residue by adding 800ml of distilled water to dissolve. After the solution was extracted twice with 2 * 800 ml of ethyl acetate,The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered with suction, and the ethyl acetate was concentrated.145.68 g of a light yellow oil was obtained. Crude purity 98.9percent, yield 76.55percent.
Reference：
[1] Patent: CN106957271, 2017, A, . Location in patent: Paragraph 0026; 0034; 0040; 0041
[2] Chemical Communications, 2009, # 42, p. 6406 - 6408
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 45, p. 14262 - 14266[4] Angew. Chem., 2017, vol. 129, # 45, p. 14450 - 14454,5
6
[ 105-53-3 ]
[ 74-88-4 ]
[ 1619-62-1 ]
[ 609-08-5 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1994, vol. 113, # 3, p. 153 - 162
[2] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 155 - 160
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1989, vol. 38, # 6.2, p. 1332[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1989, # 6, p. 1451
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1989, vol. 38, # 6.2, p. 1332[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1989, # 6, p. 1451
Stage #1: With sodium methylate In methanol at 0 - 20℃; for 0.333333 h; Stage #2: for 3 h; Stage #3: With acetic acid In water
Example 41 Synthesis of 2,5-dimethyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0° C. with an ice bath, 9.72 g of sodium methylate (i.e. a solution of concentration c=3 mol.l-) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0° C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up in a minimum amount of water, followed by cooling down to 0° C. then acidifying with pure acetic acid to a pH of between 4 and 5. The white precipitate formed is filtered and rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g (Yield=49percent) of expected product is obtained. TLC: Rf=0.2 (Silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).1H-NMR (DMSOd6): ? 1.68 (s, 3H, OH-CH?C-CH3); 2.18 (s, 3H, N?C-CH3).
Stage #1: With sodium hydride In dimethyl sulfoxide at 20℃; for 1.5 h; Stage #2: at 100℃; for 5 h; Stage #3: With hydrogenchloride; tin In ethanol; water for 2 h; Reflux
Sodium hydride (3.9 g) was suspended in dimethyl sulfoxide (24 mL), and diethyl methyl malonate (16 mL) was added at 0°C, and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was heated to 100°C, and a solution of 2,5-dibromonitrobenzene (15.3 g) in dimethyl sulfoxide (17 mL) was added at 100°C, and then the reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (75 mL), and tin (11.5 g) was added at room temperature. Concentrated hydrochloric acid (45 mL) was added at 0°C, and then the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (4.9 g) as a brown solid. 1H-NMR (400 MHz, CDCl3) δ: 8.48 (1H, brs), 7.17 (1H, dd, J= 7.9, 1.3 Hz), 7.08 (1H, d, J = 7.9 Hz), 7.07 (1H, s), 3.41 (1H, q, J = 7.8 Hz), 1.48 (3H, d, J = 7.8 Hz). ESI-MS found: 226 [M+H]+
General procedure: A mixture of the appropriate aniline (100mmol) and substituted diethyl malonate (102mmol) was heated in a flask equipped with distillation head on a metal bath at 220–230°C for 1h and then at 260–270°C until the distillation of ethanol stopped (3–6h). With the exception of preparation of 1f, l, m, the hot liquid reaction mixture was carefully poured into stirred toluene (50mL), cooled down to room temperature and the precipitate was collected by filtration. In the case of 1f, l, m, the hot reaction mixture solidified and it was cooled down to room temperature. The above precipitate or solidified material was mixed with aqueous sodium hydroxide solution (0.5M, 250mL) and toluene (50mL). The substance that remained undissolved (in the preparation of 1c and 1m) was removed by filtration, purified by recrystallization and identified as propanediamide derivatives (1c′ and 1m′, respectively). The layers of the filtrate were separated and the aqueous layer was washed with toluene (2×40mL). The water layer was treated with decolorizing charcoal, filtered and then acidified with 10percent HCl to Congo red. The precipitated hydroxyquinolone 1 was collected by filtration, washed with water, and if necessary, purified by recrystallization.
Reference：
[1] Tetrahedron, 2013, vol. 69, # 51, p. 10826 - 10835
[2] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 491 - 500
14
[ 609-08-5 ]
[ 87-25-2 ]
[ 1873-59-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 5, p. 591 - 595[2] Khimiya Geterotsiklicheskikh Soedinenii, 1994, # 5, p. 673 - 678
15
[ 64-17-5 ]
[ 140-88-5 ]
[ 6317-49-3 ]
[ 763-69-9 ]
[ 105-37-3 ]
[ 609-08-5 ]
Reference：
[1] Journal of Organometallic Chemistry, 1989, vol. 375, p. 203 - 216
16
[ 67-56-1 ]
[ 609-08-5 ]
[ 3097-74-3 ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: at 20℃; Stage #2: With hydrogenchloride In waterAcidic aqueous solution
Synthesis of 2-Methyl-malonic acid monomethyl ester KOH (386 mg, 6.88 mmol) was added to a solution 2-methyl-malonic acid diethyl ester (1 g, 5.74 mmol) in methanol (7 mL). The resulting mixture was stirred overnight at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 360 mg (47percent) of 2-methyl-malonic acid monomethyl ester
With titanium(IV) isopropylate; N-fluorobis(methanesulfonyl)imide In 1,2-dichloro-ethane at 20℃; for 12 h;
Test tube equipped with a stir bar N- fluoro bis (methanesulfonyl) imide (38.2 mg, 0.2 mmol) and 1,2 g of dichloroethane (1.0 mL), at room temperature, and dissolved.Then, the same solution of 2-methylmalonic acid diethyl (17.4 mg, 0.1 mmol) and tetra -iso- propoxy orthotitanate (0.016 mL, 0.05 mmol) was added and subjected to room temperature, 12 hours .After completion of the reaction, addition of water, dichloromethane extraction (3 times), the combined organic layers washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The resulting crude product was used hexafluorobenzene as internal standardin 19F-NMR measurement, 2-fluoro-2-methyl-diethyl malonate quantitatively the desired product was produced.Then purified by silica gel column chromatography (ethyl acetate / hexane = 10/90 vol / vol) ,to obtain purified 2-fluoro-2-methyl-malonic acid diethyl (7) as a colorless transparent liquid (18.7 mg, 0 .097mmol, 97percent yield).
82%
Stage #1: With sodium hydride In tetrahydrofuran; paraffin oil at 0 - 20℃; for 1.25 h; Stage #2: With N-fluorobenzene sulfonamide In tetrahydrofuran; paraffin oil at 0 - 20℃; for 4.5 h;
To a THF (0.5 M) solution of diethyl methylmalonate (1 eq.) was added sodium hydride (1.4 eq., 60percent (w/w) dispersion in paraffin oil) in four equal portions, three to five minutes apart. The reaction was maintained at 0°C for 15 min, before it was allowed to warm to RT over 30 min. After another 30 min of stirring at RT, the mixture was re-cooled to 0°C and then added N-fluorobenzenesulfonamide (1.1 eq.) in four equal portions. Stirring was continued at 0°C for 30 min and then at RT for 4 h, at which time it was determined to be >95percent complete by lH NMR. The reaction was then diluted with hexanes and vacuum filtered. The filter cake was washed further with hexanes and the product-containing filtrate was concentrated. More hexanes were added to induce further precipitation of the unwanted- by-products and the resulting suspension was filtered again. The filtrate thus obtained was then concentrated in vacuo to furnish a biphasic oil. The upper layer was determined to be paraffin oil and was discarded. The lower layer was the desired product (82percent yield).
18 %Spectr.
With triethylamine pentahydrogen fluoride salt; iodosylbenzene In 1,2-dichloro-ethane at 70℃; for 24 h;
General procedure: PhIO (550 mg, 2.5 mmol), Et3N·5HF (800 mg, 4 mmol), and DCE (1 mL)were placed in a Teflon test tube. After stirring at r.t. for 15 min, the appropriate malonic ester 1 (1 mmol) and DCE (1 mL) were added. The test tube was sealed with a septum rubber and heated at 70 °C for 24 h with stirring. The reaction mixture was neutralized with aq NaHCO3 and the product was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The product was purified by column chromatography on silica gel with hexane–CH2Cl2 as eluent.
Reference：
[1] Patent: JP2016/23178, 2016, A, . Location in patent: Paragraph 0031-0033
[2] Green Chemistry, 2016, vol. 18, # 7, p. 1864 - 1868
[3] Patent: WO2017/49069, 2017, A1, . Location in patent: Paragraph 00160
[4] Journal of the American Chemical Society, 1984, vol. 106, # 2, p. 452 - 454
[5] Canadian Journal of Chemistry, 1965, vol. 43, p. 1700 - 1713
[6] Journal of medicinal chemistry, 1967, vol. 10, # 2, p. 186 - 188
[7] Journal of Organic Chemistry, 1993, vol. 58, # 10, p. 2791 - 2796
[8] Journal of Fluorine Chemistry, 1996, vol. 78, # 2, p. 165 - 166
[9] Synthesis (Germany), 2015, vol. 47, # 20, p. 3241 - 3245
18
[ 145490-75-1 ]
[ 609-08-5 ]
[ 16519-02-1 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With sodium hydride In tetrahydrofuran; paraffin oil at 0 - 20℃; for 0.75 h; Stage #2: at 0 - 20℃; for 4.5 h;
To a THF (0.5 M) solution of diethyl methylmalonate (1 eq.) was added sodium hydride (1.4 eq., 60percent (w/w) dispersion in paraffin oil) in four equal portions, three to five minutes apart. The reaction was maintained at 0°C for 15 mm, before it was allowed to warm to RT over 30 mm. After another 30 mm of stirring at RT, the mixture was re-cooled to 0°C and then added N-fluorobenzenesulfonamide (1.1 eq.) in four equal portions. Stirring was continued at 0°C for 30 mm and then at RT for 4 h, at which time it was determined to be >95percent complete by ‘H NMR. The reaction was then diluted with hexanes and vacuum filtered. The filter cake was washed further with hexanes and the product-containing filtrate was concentrated. More hexanes was added to induce further precipitation of unwanted- by-products and the suspension was filtered again. The filtrate thus obtained was then concentrated in vacuo to furnish a biphasic oil. The upper layer was determined to be paraffin oil and was discarded. The lower layer was the desired product (82percent yield).
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1983, vol. 48, # 1, p. 60 - 70
21
[ 701-45-1 ]
[ 609-08-5 ]
[ 945244-26-8 ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.216667 h; Inert atmosphere Stage #2: at 20℃; for 0.166667 h; Inert atmosphere
Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved in 25 mL of anhydrous DMF. This solution was cooled to 0° C. under an atmosphere of nitrogen. Sodium hydride (1.04 g, 26 mmol, 60percent by weight in mineral oil) was slowly added to the solution. The resulting mixture was allowed to stir for 3 minutes at 0° C., and then at room temperature for 10 minutes. 2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quickly added and the mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and a saturated aqueous solution of sodium chloride. The layers were separated and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organics were concentrated to yield diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g, 99percent) as a pale yellow oil which was used without further purification. Retention time 1.86 min.
With titanium(IV) isopropylate; N-fluorobis(methanesulfonyl)imide; In 1,2-dichloro-ethane; at 20℃; for 12h;
Test tube equipped with a stir bar N- fluoro bis (methanesulfonyl) imide (38.2 mg, 0.2 mmol) and 1,2 g of dichloroethane (1.0 mL), at room temperature, and dissolved.Then, the same solution of 2-methylmalonic acid diethyl (17.4 mg, 0.1 mmol) and tetra -iso- propoxy orthotitanate (0.016 mL, 0.05 mmol) was added and subjected to room temperature, 12 hours .After completion of the reaction, addition of water, dichloromethane extraction (3 times), the combined organic layers washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The resulting crude product was used hexafluorobenzene as internal standard in 19F-NMR measurement, 2-fluoro-2-methyl-diethyl malonate quantitatively the desired product was produced.Then purified by silica gel column chromatography (ethyl acetate / hexane = 10/90 vol / vol) ,to obtain purified 2-fluoro-2-methyl-malonic acid diethyl (7) as a colorless transparent liquid (18.7 mg, 0 .097mmol, 97% yield).
82%
To a THF (0.5 M) solution of diethyl methylmalonate (1 eq.) was added sodium hydride (1.4 eq., 60% (w/w) dispersion in paraffin oil) in four equal portions, three to five minutes apart. The reaction was maintained at 0C for 15 min, before it was allowed to warm to RT over 30 min. After another 30 min of stirring at RT, the mixture was re-cooled to 0C and then added N-fluorobenzenesulfonamide (1.1 eq.) in four equal portions. Stirring was continued at 0C for 30 min and then at RT for 4 h, at which time it was determined to be >95% complete by lH NMR. The reaction was then diluted with hexanes and vacuum filtered. The filter cake was washed further with hexanes and the product-containing filtrate was concentrated. More hexanes were added to induce further precipitation of the unwanted- by-products and the resulting suspension was filtered again. The filtrate thus obtained was then concentrated in vacuo to furnish a biphasic oil. The upper layer was determined to be paraffin oil and was discarded. The lower layer was the desired product (82% yield).
18%Spectr.
With triethylamine pentahydrogen fluoride salt; iodosylbenzene; In 1,2-dichloro-ethane; at 70℃; for 24h;
General procedure: PhIO (550 mg, 2.5 mmol), Et3N·5HF (800 mg, 4 mmol), and DCE (1 mL)were placed in a Teflon test tube. After stirring at r.t. for 15 min, the appropriate malonic ester 1 (1 mmol) and DCE (1 mL) were added. The test tube was sealed with a septum rubber and heated at 70 C for 24 h with stirring. The reaction mixture was neutralized with aq NaHCO3 and the product was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The product was purified by column chromatography on silica gel with hexane-CH2Cl2 as eluent.
In dimethylformamide-toluene; water; toluene; mineral oil;
(d) alpha[3-trifluoromethyl-4-(1-oxoisoindolino)-phenyl]-propionic acid m.p. 181-184 (diethyl ether) or its ethyl ester m.p. 123-125 (diethyl ether). The starting material for the above four compounds is prepared similarly and is illustrated for (d) as follows: 23 g of 50% sodium hydride in mineral oil are washed with hexane and the washings are decanted off. Thereupon 160 ml of dimethylformamide-toluene (1:4) are added following by 83.6 of diethyl alpha-methylmalonate in 200 ml of dimethylformamide-toluene (1:4), which solution is added dropwise while stirring under nitrogen and cooling with ice. After stirring for 30 minutes at room temperature, 100 g of 4-chloro-2-trifluoromethyl-nitrobenzene in 100 ml of toluene are added during one hour and the mixture is stirred overnight at room temperature. Thereupon 200 ml of water are slowly added while cooling, the mixture extracted with diethyl ether, the extract evaporated, the residue distilled and the fraction boiling at 210-230/0.55 mm Hg collected, to yield the diethyl alpha-methyl-alpha-(3-trifluoromethyl-4-nitrophenyl)-malonate. The corresponding 3-(methyl, methoxy and methylmercapto)-analogs are boiling at 110-120/0.2 mm Hg, 155-170 /0.1 mm Hg or 163-165/0.08 mm Hg.
With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃;
General procedure: Dissolving 2,4-difluoronitrobenzene 1a (2.2ml, 20mmol) in DMF solution,A solid NaOH (800 mg, 20 mmol) was added, and diethyl methylmalonate (3.68 ml, 21.6 mmol) was added dropwise to the reaction solution, followed by stirring at room temperature overnight.After the reaction was completed, 120 ml of water was added, extracted with DCM three times, washed with brine three times, and the organic layers were combined and dried over anhydrous sodium sulfate.Spin dry and separate by column chromatography (eluent: PE / EA = 20/1, v / v).A light yellow oily liquid was obtained with a yield of 87%.
diethyl methyl(1'-phenylprop-2'-en-1'-yl)propanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: Diethyl methylmalonate With sodium hydride In tetrahydrofuran
Stage #2: Cinnamyl acetate With triphenyl phosphite; bis(1,5-cyclooctadiene)diiridium(I) dichloride In tetrahydrofuran at 20℃; for 3h;
2-Methyl-2-[(E)-2-phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: Diethyl methylmalonate With sodium hydride In toluene at 20℃; for 1h;
Stage #2: 4,4,5,5-tetramethyl-2-(propa-1,2-dien-1-yl)-1,3,2-dioxaborolane; iodobenzene With tris(para-trifluoromethyl)phenyl phosphine In toluene at 80℃; for 24h;
With tributylphosphine; In acetonitrile; for 17.0h;Heating / reflux;
Example 46: Intermediate 47--Diethyl [ (5-fluoro-lH-indol-3-yl) methyl] (methyl) malonate [0431] A solution of <strong>[343-90-8]5-fluorogramine</strong> (15. 5g, 80. 6MMOL) in acetonitrile (450mL) was treated with diethyl methylmalonate (20. 8mL, 121MMOL) and tributylphosphine at reflux for 17 hours. The cooled reaction is concentrated under reduced pressure and dissolved in ethyl acetate (1. 5L), washed with 1N aqueous HC1 (500ML), saturated aqueous NaCl (500ML), dried over MgS04 and concentrated under reduced pressure to an orange oil. Chromatography ( (3 : 1) hexane-EtOAc) afforded 16. 5g (64%) of desired product as an oil which solidifies on standing to a white solid: mp 76-77 C.
To a solution of Na (1. 39 g) in EtOH (42 mL) were added diethyl methylmalonate (5.00 g) and acetamidine hydrochloride (2.71 g). The mixture was stirred at reflux for 2.5 h and cooled to ambient temperature. The precipitate was collected by filtration, washed with EtOH, and dried at 80C under reduced pressure to give a white solid. To a solution of the above solid in H2O (30 mL) was added conc. HCI (2.5 mL) and the mixture was stirred at 4C for 1 h. The precipitate was collected by filtration, washed with H2O (twice), EtOH (twice), and Et2O (twice), and dried at 80C under reduced pressure to give the title compound (3.02 g). HNMR (300 MHz, DMSO-d6, 8) : 1.69 (s, 3H), 2.19 (s, 3H), 11.42-11. 66 (m, 2H); ESI MS m/z 139 (M--1, 100%).
Synthesis of 2,5-dimethyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0 C. using an ice bath, 9.72 g of sodium methylate (i.e. a solution concentration c=3 mol.l-1) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0 C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up with a minimum quantity of water, cooled down to 0 C. then acidified with pure acetic acid to a pH between 4 and 5. The white precipitate formed is filtered, rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g of expected product is obtained. TLC: Rf=0.2 (silica gel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2). 1H-NMR (DMSO d6): delta 1.68 (s, 3H, OH-CH=C-); 2.18 (s, 3H, N=C-).
102 ml (282 mmoles) of a solution of sodium ethylate at 21% in ethanol is added to a solution of 7.5 g (94 mmoles) of formamidine hydrochloride in 250 ml of ethanol cooled down to 0 C. and the mixture is stirred for 30 minutes; then a solution of 13 ml (94 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and acetic acid in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally with pentane. 7 g (Yield=60%) of expected product is obtained in the form of a beige solid. TLC: Rf=0.20 (silicagel, eluent: ethyl acetate-dichloromethane-methanol 50-40-10) 1H-NMR (DMSO d6): ppm 1.73 (s, 3H, C-); 7.88 (s, N=-N). MS: 127 (MH+); 125 (M-H-).
Example 41 Synthesis of 2,5-dimethyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0 C. with an ice bath, 9.72 g of sodium methylate (i.e. a solution of concentration c=3 mol.l-) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0 C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up in a minimum amount of water, followed by cooling down to 0 C. then acidifying with pure acetic acid to a pH of between 4 and 5. The white precipitate formed is filtered and rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g (Yield=49%) of expected product is obtained. TLC: Rf=0.2 (Silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2).1H-NMR (DMSOd6): ? 1.68 (s, 3H, OH-CH?C-CH3); 2.18 (s, 3H, N?C-CH3).
With hydrogenchloride; sodium ethanolate; In ethanol;
EXAMPLE 11 Synthesis of Compounds 46.1-46.82 2-(4-Chlorophenyl)-5-methylpyrimidine-4,6-diol (42) To ethanol (20 ml) was added sodium ethoxide solution (7.76 ml of a 21% wt solution in ethanol), <strong>[14401-51-5]4-chlorobenzamidine hydrochloride</strong> (1.0 g) and diethylmethylmalonate (0.89 ml). The suspension was stirred at 40 C. in an inert atmosphere for 44 hrs after which time it was cooled to 5 C. and treated dropwise with concentrated hydrochloric acid to a pH of 2. The resulting suspension was filtered and washed with excess water, then ethanol (20 ml) and diethyl ether (20 ml) affording the title compound as a solid (1.71 g). deltaH (d6-DMSO): 1.80 (3H, s), 7.56-7.6 (2H, d), 8.05-8.10 (2H, d); m/z (ES+) 237 (MH)+
With phosphorus tribromide; sodium; lithium chloride In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; dichloromethane; water; dimethyl sulfoxide
6.d (6d)
(6d) 3-methyl-2-oxo-oct-5-ynyl-phosphonic acid-dimethylester 120 g of methyl malonic acid diethylester is dripped into a solution of 15.8 g of sodium in 344 ml of ethyl alcohol at room temperature. After 30 minutes 118 g of 1-bromo-2-pentyne (prepared from pent-2-yne-1-ol with phosphorus tribromide in pyridine) is dripped in and the mixture is heated for 16 h with reflux. Then the reaction mixture is filtered, washed with methylene chloride and vacuum evaporated. The residue is dissolved in 500 ml of methylene chloride, shaken twice each time with 50 ml of water, dried by means of magnesium sulfate and vacuum evaporated. The residue is distilled in a 12 torr vacuum. At 135° C., one obtains 147 g of the alkylated methyl malonic acid ester which is heated in 1.2 liters of dimethylsulfoxide and 11 ml of water with 51.6 g of lithium chloride for 4.5 h at the reflux. Then 4.5 liters of ice water is poured on, the substance is extracted with ether, the organic extract is twice shaken with water, dried over magnesium sulfate and vacuum evaporated. The residue distillation at 84° C. and 12 torr provides 82.5 g of 2-methyl-hept-4-yne acid ethylester in the form of a colorless liquid.
EXAMPLE 6 Preparation of Diethyl 2-fluoro-2-methylmalonate Diethyl 2-methylmalonate (870 mg, 860 muL, 5 mmole) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen. Sodium hydride (250 mg as a 60% oil dispersion, 6 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 15 minutes). The reaction mixture was diluted with toluene (20 mL) and transferred dropwise to a solution of N-fluoro-N-neopentyl-p-toluenesulfonamide (1.295 g, 5 mmole) in anhydrous toluene (10 mL) over 5 minutes. A precipitate formed during addition and the reaction temperature rose from 23 to 36. After stirring an additional 5 minutes under nitrogen, the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid (30 mL), 10% aqueous potassium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL) solutions, and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 1:1 methylene chloride-hexane) yielded diethyl 2-fluoro-2-methylmalonate (512 mg, 53% yield) as a colorless liquid. This material, and additional samples prepared by this procedure, were analyzed and provided the following results: IR (liquid film) gammamax (cm-1) 2940 (m), 1750 (s, ester), 1440 (m), 1370 (m), 1290 (s); 1 H NMR (80 MHz, CDCl3) delta1.33 (t, J=8 Hz, 6H, CH2 CHHD 3), 1.81 (d, J=22.67 Hz, 3H, CH3), 4.30 (q, J=8 Hz, 4H, CH2); 19 F NMR (94.1 MHz, CDCl3) -158.02 (q, J=22 Hz, 1F); HRMS (M--CH2 CH3) calcd. for C6 H8 O3 F: 147.0457; found: 147.0450; LRMS (CI) m/e 193.
With potassium iodide; In N,N-dimethyl-formamide; mineral oil; benzene;
Step 2. Preparation of Diethyl (5-Acetoxypentyl)methylmalonate Sodium hydride (4.8 g., 0.2 mole) as a 50% suspension in mineral oil is washed with petroleum ether under nitrogen to remove the mineral oil, suspended in dry benzene (150 ml.), and the suspension cooled in an ice bath. Diethyl methylmalonate (34.8 g., 0.2 mole) dissolved in sieve dried DMF (150 ml.) is added to the suspension of sodium hydride dropwise. The mixture is allowed to stand overnight at room temperature. Potassium iodide (0.4 g.) and <strong>[13031-39-5]5-acetoxyphenyl chloride</strong> (32.9 g., 0.2 mole) are then added, and the mixture is heated for 24 hours at 125 in an oil bath. The reaction mixture is concentrated in vacuo, diluted with ether (200 ml.), and filtered to remove sodium chloride. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated to yield 39.6 g. (66%) of oily product.
50%
With potassium iodide; In N,N-dimethyl-formamide; mineral oil; benzene;
Step 2. Preparation of Diethyl (5-Acetoxypentyl) methylmalonate Sodium hydride (4.8 g., 0.2 mole) as a 50% suspension in mineral oil is washed with petroleum ether under nitrogen to remove the mineral oil, suspended in dry benzene (150 ml.), and the suspension cooled in an ice bath. Diethyl methylmalonate (34.8 g., 0.2 mole) dissolved in sieve dried DMF (150 ml.) is added to the suspension of sodium hydride dropwise. The mixture is allowed to stand overnight at room temperature. Potassium iodide (0.4 g.) and <strong>[13031-39-5]5-acetoxyphenyl chloride</strong> (32.9., 0.2 mole) are then added, and the mixture is heated for 24 hours at 125 C. in an oil bath. The reaction mixture is concentrated in vacuo, diluted with ether (200 ml.), and filtered to remove sodium chloride. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated to yield 39.6 g. (66%) of oily product.
With potassium hydroxide; thionyl chloride; sodium ethanolate;AlCl3; In ethanol; dichloromethane; water;
4-Bromo-6-fluoro-2-methylindan-1-one To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of <strong>[61150-57-0]2-bromo-1-(bromomethyl)-4-fluorobenzene</strong> in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2*150 ml of cold water, and dried in air. The dibasic acid obtained was then dehcarboxylated by heating it at 160 C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0 C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3*200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%). Anal. calc. for C10H8BrFO: C, 49.41; H, 3.32. Found: C, 49.61; H, 3.30. 1H NMR (CDCl3): delta 7.52 (dd, J=8.1 Hz, J=2.2 Hz, 1H, 7-H), 7.36 (dd, J=7.0 Hz, J=2.2 Hz, 1H, 5-H), 3.32 (dd, J=17.4 Hz, J=7.9 Hz, 1H, 3-H), 2.76-2.84 (m, 1H, 2-H), 2.62 (dd, J=17.4 Hz, J=2.5 Hz, 1H, 3'-H), 1.34 (d, J=7.4 Hz, 3H, 2-Me). 13C NMR (CDCl3): delta 207.3, 162.1 (d, J=252.5 Hz), 148.6, 139.1 (d, J=7.3 Hz), 125.1 (d, J=26.4 Hz), 122.1 (d, J=8.8 Hz), 109.0 (d, J=22.0 Hz), 42.7, 35.2, 16.0.
With potassium hydroxide; thionyl chloride; sodium ethanolate;AlCl3; In ethanol; dichloromethane; water;
4-Chloro-6-fluoro-2-methylindan-1-one To a solution of sodium ethoxide in ethanol obtained from 4.80 g (0.21 mol) of sodium and 120 ml of anhydrous ethanol, a solution of 36.5 g (0.21 mol) of diethyl methylmalonate in 50 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 44.7 g (0.20 mol) of <strong>[45767-66-6]1-(bromomethyl)-2-chloro-4-fluorobenzene</strong> was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then, cooled to room temperature, and a solution of 40 g of potassium hydroxide in 100 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2*200 ml of cold water, and dried in air. The dibasic acid obtained was then decarboxylated by heating it at 160 C. for 2 h. To the viscous oil obtained 40 ml of dichloromethane and 60 ml of SOCl2 were added, and the resulting mixture was refluxed for 2 h. Dichloromethane and the excess of SOCl2 were distilled off, and the residue was dissolved in 50 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 25.3 g (0.19 mol) of AlCl3 in 260 ml of dichloromethane for 1 h at 0 C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3*300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 121-123 C./3 mm Hg. Yield 33.4 g (84%). Anal. calc. for C10H8ClFO: C, 60.47; H, 4.06. Found: C, 60.29; H, 4.21. 1H NMR (CDCl3): delta 7.08 (dd, J=8.4 Hz, J=2.5 Hz, 1H, 7-H), 7.02 (dd, J=7.0 Hz, J=2.5 Hz, 1H, 5-H), 3.13 (ddd, J=17.6 Hz, J=8.0 Hz, J=1.5 Hz, 1H 3-H), 2.53-2.62 (m, 1H, 2-H), 2.43 (ddd, J=17.6 Hz, J=4.0 Hz, J=1.9 Hz, 1H, 3'-H), 1.12 (d, J=7.4 Hz, 3H, 2-Me). 13C NMR (CDCl3): delta 206.3 (d, J=2.9 Hz), 161.7 (d, J=251.8 Hz), 146.1 (d, J=3.0 Hz) 138.8 (d, J=8.1 Hz), 132.9 (d, J=9.6 Hz), 121.5 (d, J=26.5 Hz), 108.0 (d, J=21.3 Hz), 42.1, 32.9, 15.5.
4-bromo-1-butanol (1), 3 g, was treated with 1.5 eq of 3, 4-dihydro-2H-pyran and 0.1 eq of pyridinium para tuloenesulfonate (PPTS) in 135 mL of CH2Cl2. After work-up and purification, 1.45 g (33%) of product 2 was obtained. 1.0 eq of diethylmethylmalonate was deprotonated with 1 eq of NaH and 1.0 eq of bromide 2 was added along with catalytic amount of KI at 50 C. A complete conversion was observed after 10 hours and a 90% yield was obtained. Deprotection of tetrahydo pyran (THP) with PPTS in ethanol at 55 C. went smoothly. After work-up, a quantitative yield of alcohol 4 was obtained and directly used for the mesylation reaction (as above). With the mesylate 5 in hand, the kryptofix reaction was applied as above. Compund 6 was obtained in 68% yield. Compound 6 (233 mg) was treated with 2 N NaOH/EtOH (30 mL/5 mL) at 50 C. to provide NST-ML-F ca. in 99% yield (190 mg). The NMR data of the compound are as follows: 1H NMR (300 MHz, CDCl3) delta 11.89 (bs, 2H), 4.46 (dt, Jt=5.9 Hz, Jd=47.2 Hz, 2H), 1.99-1.92 (m, 2H), 1.82-1.64 (m, 2H), 1.50 (s, 3H), 1.50-1.40 (m, 2H); 13C NMR (75 MHz, CDCl3) delta 178.6, 85.1, 82.9, 54.2, 35.5, 31.0, 30.8, 20.8, 20.7, 20.2; 19F NMR (282 MHz, CDCl3) delta -219.0; MS (EI).
90%
With sodium hydride;potassium iodide; at 50℃; for 10h;
4-bromo-l-butanol (1), 3g, was treated with 1.5 eq of 3, 4-dihydro-2H-pyran and 0.1 eq of pyridinium j>alphar° tuloenesulfonate (PPTS) in 135 mL Of CH2Cl2. After work-up and purification, 1.45 g (33%) of product 2 was obtained. 1.0 eq of diethylmethylmalonate was deprotonated with 1 eq of NaH and 1.0 eq of bromide 2 was added along with catalytic amount of KI at 5O0C. A complete conversion was observed after 10 hours and a 90% yield was obtained. Deprotection of tetrahydo pyran (THP) with PPTS in ethanol at 550C went smoothly. After work-up, a quantitative yield of alcohol 4 was obtained and directly used for the mesylation reaction. With the mesylate 5 in hand, a kryptofix- mediated fluorination was performed. Compound 6 was obtained in 68% yield.
500 mg (2.87 mmol) of 2-methylmalonic acid diethyl ester was dissolved in 25 ml of tetrahydrofuran, and 126 mg (3.15 mmol) of sodium hydride was slowly added to the resulting solution at room temperature. After stirring for 30 minutes, 835mg (3.15 mmol) of <strong>[5544-60-5]1-benzyloxy-4-bromomethyl-benzene</strong> was slowly added thereto. After stirring for 3 hours, ethylacetate was added thereto and the resulting solution was washed with water. An organic layer thus obtained was dried over anhydrous magnesium sulfate and then the residue was purified by column chromatography to obtain 0. 89 g of the title compound in a yield of 75%. NMR : lH-NMR (CDCl3) 6 7. 43-7. 32 (5H, m), 7.04 (2H, d, J=8Hz), 6.87 (2H, d, J=8Hz), 5.03 (2H, s), 4.19 (4H, q, J=8Hz), 3.16 (2H, s), 1.33 (3H, s), 1.25 (6H, t, J=8Hz) Mass (EI) 371 (M++1)
Step 16B : Compound 16b; Diethyl methylmalonate (1.37 mL, 8.7 mmol) was added dropwise to suspension of NaH (60% in oil, 348 mg, 8.7 mol) in THF (20 mL). The generation off : was visible. The mixture was stirred for 0.5 h at room temperature and a solution of 16a (2.16 g, 9.2 mmol) in 10 mL THF and NaI (catalytic amount) was added. The reaction mixture was stirred overnight and then was worked up by adding H20 and extracting with Et2O twice. The combined organic layers were washed with brine, dried overNa2SO4, and concentrated to give a clear oil which was dissolved in 5 mL THF. MeOH (5 mL) and NaOH (2N, 20 mL) were added to the solution and the mixture was heated at 80 C for 4 h. After cooling, the mixture was extracted with Et2O and the aqueous solution was acidified using 6 N HC1. The solution was extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was trituated with hexane to afford 16b as a white solid (885 mg, 3.86 mmol).
To a solution of diethyl methylmalonate (5.19 g) in 100 mL of THF was added NaH (1.2 g, 60%) at 0 C. in portions. The mixture was stirred at 0 C. for 10 min, and to this solution was then added the bromide intermediate (3.84 g) in one portion. The mixture was warmed to 23 C. and stirred for 1 h before the addition of water. The resulting mixture was extracted with ethyl acetate, concentrated and purified by Biotage (5-10% ethyl acetate in hexane) to give the diester containing some diethyl methyl malonate contaminant as a crude oil.
To a solution of sodium ethoxide in ethanol obtained from 4.80 g(0.21 mol) of sodium and 120 ml of anhydrous ethanol, a solution of 36.5 g (0.21 mol) of diethyl methylmalonate in 50 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 44.7 g (0.20 mol) of 1 -(bromomethyl)-2- chloro-4-fluorobenzene was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then, cooled to room temperature, and a solution of 40 g of potassium hydroxide in 100 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2 x 200 ml of cold water, and dried in air. The dibasic acid obtained was then decarboxylated by heating it at 16O0C for 2 h. To the viscous oil obtained 40 ml of dichloromethane and 60 ml of SOCl2 were added, and the resulting mixture was refluxed for 2 h. Dichloromethane and the excess of SOCl2 were distilled off, and the residue was dissolved in 50 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 25.3 g (0.19 mol) Of AlCl3 in 260 ml of dichloromethane for 1 h at O0C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3 x 300 ml of methyl-terZ-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 121-123C/3 mm Hg. Yield 33.4 g (84%).Anal. calc. for C10H8ClFO: C, 60.47; H, 4.06. Found: C, 60.29; H, 4.21.1H NMR (CDCl3): delta 7.08 (dd, J=8.4 Hz, J=2.5 Hz, IH, 7-H), 7.02 (dd, J=7.0 Hz, J=2.5 Hz, IH, 5-H), 3.13 (ddd, J=17.6 Hz, J=8.0 Hz, J=1.5 Hz, IH, 3- H), 2.53-2.62 (m, I H, 2-H), 2.43 (ddd, J=I 7.6 Hz, J=4.0 Hz, J=I .9 Hz, IH, 3'-H), 1.12 (d, J=7.4 Hz, 3H, 2-Me). <n="118"/>13C NMR (CDCl3): delta 206.3 (d, J=2.9 Hz), 161.7 (d, J=251.8 Hz), 146.1 (d, J=3.0 Hz) 138.8 (d, J=8.1 Hz), 132.9 (d, J=9.6 Hz), 121.5 (d, J=26.5 Hz), 108.0 (d, J=21.3 Hz), 42.1, 32.9, 15.5.
Example 14 Synthesis of 2-tert-butyl-5-methyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 80 ml of ethanol is cooled down to 0 C. by an ice bath, 4 g (55.6 mmoles) of sodium ethylate and 3.8 g (27.8 mmoles) of tert-butylcarbamidine hydrochloride are added. The reaction mixture is left to return to ambient temperature, then 5 ml (27.8 mmoles) of diethyl ester methylmalonate is added dropwise. Stirring is maintained at ambient temperature overnight. The ethanol is then condensed under reduced pressure (2 kPa). The crude product obtained is solubilized in a minimum amount of water (approximately 40 ml), then acidified at 0 C. with pure acetic acid until a pH comprised between 4 and 5 is achieved. The white precipitate formed is filtered, rinsed successively with water, ethyl ether and with pentane. Then the white powder obtained is dried over P2O5 under reduced pressure (0.2 kPa). 2.4 g of expected product is obtained. TLC: Rf=0.56 (silica gel, eluent: dichloromethane-methanol 90-10). MS: (MH+)=183, (MH-)=181 1H-NMR (DMSOd6): delta 1.25 (s, 9H, tert-butyl); 1.72 (s, 3H, N=C-CH3).
Example 18 Synthesis of 2-methoxy-4,6-dihydroxy-5-methyl-pyrimidine 13.8 g (200 mmoles) of sodium ethylate is added to a solution of 10 g (58 mmoles) of methoxyformamidine sulphate in 100 ml of ethanol cooled down to 0 C. and the mixture is stirred for 15 minutes; then a solution of 9 ml (52 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 5.9 g of expected product is obtained in the form of a white solid. 1H-NMR (CD3OD): delta 1.85 ppm (s, 3H, C-); 3.95 (s, 3H, C-O). MS: 157 (MH+); 155 (M-H-).
Example 16 Synthesis of 2-methyl-5-cyclopropyl-4,6-dihydroxy-pyrimidine A single-necked flask containing 80 ml of ethanol is cooled down to 0° C. using an ice bath, 4.5 g (66.4 mmoles) of sodium ethylate and 4 g (33.2 mmoles) of cyclopropyl-carbamidine hydrochloride are added. The reaction mixture is left to return to ambient temperature, then 5.7 ml (33.2 mmoles) of diethyl ester methylmalonate is added dropwise. Stirring is maintained at ambient temperature overnight. The ethanol is then condensed under reduced pressure (2 kPa). The crude product obtained is solubilized in a minimum amount of water (approximately 40 ml), then acidified at 0° C. with pure acetic acid until a pH comprised between 4 and 5 is achieved. The white precipitate formed is filtered, rinsed successively with water, ethyl ether and with pentane. Then the white powder obtained is dried over P2O5 under reduced pressure (0.2 kPa). 3 g of expected product is obtained. TLC: Rf=0.36 (silica gel, eluent: dichloromethane-methanol 90-10). MS: (MH+)=167, (MH-)=165 1H-NMR (DMSOd6): delta 0.95 (m, 4H, cyclopropyl); 1.67 (s, 3H, N=C-CH3); 1.83 (m, 1H, cyclopropyl).
Step 1 :To a solution of sodium ethoxide (1.48 L, 3.74 mol, 21 % w/w in EtOH) at RT is added a solution of diethyl methylmalonate 2a (645 mL, 3.72 mol) in anhydrous PhMe (330 mL). The resulting solution is stirred for 30 min and a solution of ethyl 3- aminocrotonate 2b (485 mL, 3.71 mol) in anhydrous PhMe (490 mL) is added. The mixture is stirred at reflux for 39 h, EtOH (1-1.5 L) is removed by vacuum distillation, the mixture is cooled and water (1.6 L) is added. The mixture is stirred at 40C for ~2 h, then is cooled and the phases are separated. The aqueous phase is washed with PhMe (2 x 50 mL) and then adjusted to pH 5-6 with cone. HCl. The solid is filtered and dried to afford dihydroxypyridine 2c.
Compound 1001 was purchased from Okeanos Tech, Beijing, China (Catalog No. OK-J-05025). Compound 1002 was prepared as shown in Scheme 1. Accordingly, as shown in step 1-i, to a suspension of NaH (60percent in mineral oil, 8.47 g, 212 mmol) in DMSO at 00C (260 mL) was slowly added diethyl 2-methylmalonate (29.5 g, 169.4 mmol). The mixture was stirred at 00C for 2 hours and <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (25.0 g, 141.2 mmol) was added. The resulting mixture was warmed to RT and stirred for 12 hours. The reaction mixture was poured into saturated aq. NH4Cl solution and the precipitate was collected by filtration. After washing with water 3 times, the resulting diethyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylmalonate (compound 1003, 44.5 g, 95percent yield) was dried under reduced pressure and used as is in the next reaction.
95%
[0068] Compounds 1001 and 1002 were purchased from Okeanos Tech, Beijing, China(Catalog Nos. OK-J-05024 and OK-J-05025, respectively).[0069] Compound 1004 was prepared as shown in Scheme 1. Accordingly, as shown in step 1-i, to a suspension of NaH (60percent in mineral oil, 8.47 g, 212 mmol) in DMSO at 00C (260 mL) was slowly added diethyl 2-methylmalonate (Compound 1005, 29.5 g, 169.4 mmol). The mixture was stirred at 00C for 2 hours and <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (25.0 g, 141.2 mmol) was added. The resulting mixture was warmed to RT and stirred for 12 hours. The reaction mixture was poured into saturated aq. NH4Cl solution and the precipitate was collected by filtration. After washing with water 3 times, the resulting diethyl 2-(2,6-difluoro-4-nitrophenyl)-2- methylmalonate (Compound 1006 [R = CH3], 44.5 g, 95percent yield) was dried under reduced pressure and used as is in the next reaction.
95%
Compound 1004 was prepared as shown in Scheme 1. Accordingly, as shown in step 1-i, to a suspension of NaH (60percent in mineral oil, 8.47 g, 212 mmol) in DMSO at 00C (260 mL) was slowly added diethyl 2-methylmalonate (compound 1005, 29.5 g, 169.4 mmol). The mixture was stirred at 00C for 2 hours and <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (25 g, 141.2 mmol) was added. The resulting mixture was warmed to RT and stirred for 12 hours. The reaction mixture was poured into saturated aq. NH4Cl solution and the precipitate was collected by filtration. After washing with water 3 times, the resulting diethyl 2-(2,6-difluoro-4-nitrophenyl)-2- methylmalonate (compound 1006 [R = CH3], 44.5 g, 95percent yield) was dried under reduced pressure and used as is in the next reaction.
Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved in 25 mL of anhydrous DMF. This solution was cooled to 0 C. under an atmosphere of nitrogen. Sodium hydride (1.04 g, 26 mmol, 60% by weight in mineral oil) was slowly added to the solution. The resulting mixture was allowed to stir for 3 minutes at 0 C., and then at room temperature for 10 minutes. 2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quickly added and the mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and a saturated aqueous solution of sodium chloride. The layers were separated and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organics were concentrated to yield diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g, 99%) as a pale yellow oil which was used without further purification. Retention time 1.86 min.
With sodium hydride; sodium chloride; In N,N-dimethyl-formamide; mineral oil;
Step a: Diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved in 25 mL of anhydrous DMF. This solution was cooled to 0 C. under an atmosphere of nitrogen. Sodium hydride (1.04 g, 26 mmol, 60% by weight in mineral oil) was slowly added to the solution. The resulting mixture was allowed to stir for 3 minutes at 0 C., and then at room temperature for 10 minutes. 2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quickly added and the mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and a saturated aqueous solution of sodium chloride. The layers were separated and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organics were concentrated to yield diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g, 99%) as a pale yellow oil which was used without further purification. Retention time 1.86 min
Sodium hydride was added to a solution of diethyl-2-methylmalonate (125 mmol) in anhydrous DMF at 0 C under an inert atmosphere. The reaction mixture stirred for 10 minutes followed by addition of 2-bromo-l-fluoro-4-nitrobenzene (113 mmol). The reaction mixture was further stirred at RT and the solvent was evaporated. The residue was dissolved in DCM and partitioned with brine. The DCM layer was separated and dried over sodium sulfate. The solvent was evaporated and the crude solid was used for next step.
With sodium ethanolate; In ethanol; water; at 20℃; for 25h;
EXAMPLE 53 5.22 g of commercially available diethyl(methyl) malonate CH3CH(CO2C2H5)2 and 5 g of sodium ethoxide are added in small portions to 30 ml of anhydrous ethanol cooled to 0 C. A solution of 3.67 g of <strong>[354-08-5]bromodifluoroacetic acid</strong> BrF2CCO2H in 10 ml of ethanol is then added dropwise over a period of one hour. The reaction mixture is left at normal temperature with stirring for 24 hours, and then 3 ml of water are added. After one hour, a CH3C[CF2CO2Na][CO2Na]2 precipitate forms and is extracted after washing in ethanol so as to eliminate the NaBr formed. 2.78 g of this salt are suspended in 15 ml of isopropanol and 2.41 g of aluminum chloride hydrate are added. The NaCl precipitate is filtered off and a solution of the adduct {Hc[CF2CO2-][CO2-]2AlCl}-Na+ of the aluminum complex (IIA1 type) and of sodium chloride is obtained. When treated with NaF in acetonitrile, this adduct gives {HC[C(CH3)2CO2-][CO2-]2AlF}-Na and an NaCl precipitate.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 8h;
Step C: Preparation of Diethyl 2-(1-(pyridin-3-yl)propan-2-yl)malonate. To a suspension of diethyl methyl malonate (1.80 g, 10.2 mmol) in DMF (25 ml) at 0 C. was added sodium hydride (1.25 g, 31.0 mmol, 60%), followed by 3-(chloromethyl)pyridine hydrochloride (2.00 g, 12.2 mmol) and stirred for 8 h at room temperature. The reaction mixture was quenched with acetic acid and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 2.50 g (91.2%) of diethyl 2-(1-(pyridin-3-yl)propan-2-yl)malonate as pale brown oil.
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
22.A
Example 22N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-((pyridin-4-yl)methyl)-propanamideStep A: Preparation of Diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate. To a suspension of diethyl methyl malonate (2.41 g, 13.9 mmol) in DMF (50 ml) at 0° C. was added sodium hydride (1.66 g, 41.6 mmol, 60%), followed by adding the compound 4-chloromethyl pyridine hydrochloride (2.50 g, 15.2 mmol) and stirred for 16 h at room temperature. The reaction mixture was quenched by acetic acid and the product was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.50 g (68.1%) of diethyl 2-(1-(pyridin-4-yl)propan-2-yl)malonate as pale brown oil.
Example 1; An exemplary method for preparation of the compound designated ATT-11T is demonstrated. However, modifications of this method (e.g., similar processes including additional or other steps known in the art such as alkylation, hydration, condensation, as well as other steps), which may result in similar compounds, are also included in embodiments of the invention.The synthetic scheme for ATT-11T according to one embodiment of the invention is illustrated below. As a first step, Boc protection is preformed on a piperidine derivative 1, followed by bromination to obtain compound 3, and condensation with diethyl-methyl malonate, which is produced by methylation of di-ethyl malonate 4. Said condensation results in compound 6A, which is then reduced, to obtain compound 6B. Subsequently, etherification is performed, in order to obtain compound 7. Compound 7 is then Boc-de-protected and condensed with SN-38 (compound 10), to result in compound 11, i.e., the desired product ATT-11T. This synthetic route is further illustrated in the following synthetic scheme:
Sodium hydride (3.9 g) was suspended in dimethyl sulfoxide (24 mL), and diethyl methyl malonate (16 mL) was added at 0C, and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was heated to 100C, and a solution of 2,5-dibromonitrobenzene (15.3 g) in dimethyl sulfoxide (17 mL) was added at 100C, and then the reaction mixture was stirred at 100C for 5 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (75 mL), and tin (11.5 g) was added at room temperature. Concentrated hydrochloric acid (45 mL) was added at 0C, and then the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (4.9 g) as a brown solid. 1H-NMR (400 MHz, CDCl3) delta: 8.48 (1H, brs), 7.17 (1H, dd, J= 7.9, 1.3 Hz), 7.08 (1H, d, J = 7.9 Hz), 7.07 (1H, s), 3.41 (1H, q, J = 7.8 Hz), 1.48 (3H, d, J = 7.8 Hz). ESI-MS found: 226 [M+H]+
General procedure: A mixture of the appropriate aniline (100mmol) and substituted diethyl malonate (102mmol) was heated in a flask equipped with distillation head on a metal bath at 220-230C for 1h and then at 260-270C until the distillation of ethanol stopped (3-6h). With the exception of preparation of 1f, l, m, the hot liquid reaction mixture was carefully poured into stirred toluene (50mL), cooled down to room temperature and the precipitate was collected by filtration. In the case of 1f, l, m, the hot reaction mixture solidified and it was cooled down to room temperature. The above precipitate or solidified material was mixed with aqueous sodium hydroxide solution (0.5M, 250mL) and toluene (50mL). The substance that remained undissolved (in the preparation of 1c and 1m) was removed by filtration, purified by recrystallization and identified as propanediamide derivatives (1c? and 1m?, respectively). The layers of the filtrate were separated and the aqueous layer was washed with toluene (2×40mL). The water layer was treated with decolorizing charcoal, filtered and then acidified with 10% HCl to Congo red. The precipitated hydroxyquinolone 1 was collected by filtration, washed with water, and if necessary, purified by recrystallization.
at 220 - 270℃;
General procedure: Compounds 1-24, 26e-32 and 36-38 were synthesized by a modified literature procedure [13]. A mixture of the appropriate aniline (100 mmol) and substituted diethyl malonate (102-105 mmol) was heated on a metal bath at 220-230 C for 1 hand then at 260-270 C for 3-6 h (the reaction was complete when the distillation of evolving ethanol stopped). After cooling, the solid product was crushed, dissolved in aqueous sodium hydroxide solution (0.5 M, 250 mL) and after filtration the filtrate was washed three times with toluene (40 mL). The aqueous layer was filtered and the product was precipitated from alkaline water layer with concentrated hydrochloric acid. The resulting pure 4-hydroxyquinolin-2(1H)-one product was collected by filtration and washed with water. For the analytical purposes and biological screenings, the crude products were recrystallized from the solvent indicated below.
Sodium hydride was slowly added to a solution of diethyl-2-methylmalonate (125 mmol) in anhydrous DMF at 0 C under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at same temperature, followed by the addition of 2-Bromo-5-nitropyridine (20 g, 99 mmol). The reaction mixture was further stirred for 2 hours at RT. After completion of reaction, the solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain the title compound. Yield: 81%
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride(21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonic acid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product,which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca200-300 mL) was evaporated on a vacuum rotary evaporatorand water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 x 50 mL),ethanol (2 x 50 mL), and acetone (2 x 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
91%
With sodium; In ethanol;Inert atmosphere;
General procedure: Metallic sodium (12.9 g, 0.56 mol) was dissolved in absolute ethanol (300 mL) under argon while being intensively stirred with a mechanical stirrer. The reaction flask was equipped with a reflux condenser with a chlorocalcium tube. After all the sodium was dissolved and the reaction mixture was cooled to room temperature; guanidine hydrochloride (21.02 g, 0.22 mol) was added under intensive stirring, followed by the corresponding monosubstituted malonicacid diester (0.2 mol). The reaction mixture was further intensively stirred due to the production of the solid product, which is so massive that after 2 h it already practically precludes stirring. After another 2 h, absolute ethanol (200 mL) was added and the reaction mixture was refluxed for 1 h while being stirred. Afterward, ethanol (ca 200-300 mL) was evaporated on a vacuum rotary evaporator and water (500 mL) was added to the reaction mixture. After stirring, the product (in the form of sodium salt) was almost dissolved. The obtained mixture was subsequently neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the desired product in the form of a fine solid. This mixture was subsequently heated under reflux for 10 min and then cooled to laboratory temperature. This heating and cooling was repeated twice to get a well-filterable solid product. The solid product was filtered off, washed with water (2 9 50 mL), ethanol (2 9 50 mL), and acetone (2 9 50 mL). The product was dried under high vacuum at 60 C for 2 days. The obtained purity of the product prepared in this manner is sufficient for the following reaction and based on analyses contains only crystalline water.
diethyl 2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-methylmalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 0.166667h;
0O150] Step 1: To a solution of 8..bromo.-6chioroirnidazo[i,2bjpyridazine (1.0 equiv.) and diethyl 2-methylmalonate (1.0 equiv.) in DMF (0.15 M) was added sodium hydride (2.5 equiv.) at it The reaction was stined for 10 mm, then quenched with saturated ammoniurn chloride and extracted twice with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The residue was purified via reverse phase prep-1-IPLC to give cliethyl 2-(6-chloroimidazo[i ,2-bpyridazin-8.yI)-2-rnethylmalonate in 21% yield. LCMS (m/z) (M±H) 326.0, Rt 0.84 miii.
(±)-diethyl 2-methyl-2-(2-nitrophenethyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile Reflux;
Representative procedure for the addition reaction:
General procedure: Toa stirred solution of the nucleophile (active methylene compound or amine, 1.0mmol) in 10 mL of acetonitrile, added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,0.67 mmol) and the appropriate vinylarene (0.67 mmol). The solution was stirredand heated to reflux until the reaction was complete (4-6 h for malonate, 12-18h for amines). The reaction mass was cooled to room temperature andconcentrated under vacuum. The resulting crude product was purified by column chromatography,using increasing concentrations of ether in hexanes, to give the pure compound. The two isomers of 7b were separated by silica gel GF preparative TLC (Analtech, No. 02015)using 10% ether in hexanes
Stage #1: 1-chlorododecane; Diethyl methylmalonate With sodium ethanolate In ethanol at 50 - 60℃; for 5h;
Stage #2: With sodium hydroxide Reflux;
Stage #3: With phosphorus trichloride at 80℃; for 3h;
4 Example 4
1) Take diethyl methylmalonate (52.2 g, 0.3 mol)And chlorododecane (61.2 g, 0.3 mol)Was added to a 1000 mL reaction flask,102 g of a 20% ethanol sodium ethanol solution was added dropwise at room temperature,Drop finished,Slowly warming to 50-60 ,Reaction 3h,Continue to heat up the reaction for 2h,After the reaction, the solvent is recovered (the controlled distillation temperature is not higher than 135 ° C)After cooling, 500 mL of 10% sodium hydroxide solution was added,The reaction solution was poured into 500 mL of 10% hydrochloric acid, 300 ml of diethylbenzene was added, the layers were allowed to stand, the aqueous layer was discarded, the organic phase was subjected to azeotropic dehydration, and the reaction mixture was treated with TLC or GC. When the temperature rose to 175-180 for decarboxylation reaction, no gas production and then re-insulation 1h, low pressure recovery or use of water and azeotropic recovery of diethylbenzene, cooled to room temperature, with methanol recrystallization, 61.8g light yellow solid, melting point For 30-32 ° C.2) The light yellow solid obtained in step 1) is heated to a temperature,Adding 60 mL of phosphorus trichloride,Heated to 80 reaction 3h,Static cooling,Abandoned the lower,The upper layer gave 66.6 g of 2-methyltetradecanoyl chloride.
To a THF (0.5 M) solution of diethyl methylmalonate (1 eq.) was added sodium hydride (1.4 eq., 60% (w/w) dispersion in paraffin oil) in four equal portions, three to five minutes apart. The reaction was maintained at 0C for 15 mm, before it was allowed to warm to RT over 30 mm. After another 30 mm of stirring at RT, the mixture was re-cooled to 0C and then added N-fluorobenzenesulfonamide (1.1 eq.) in four equal portions. Stirring was continued at 0C for 30 mm and then at RT for 4 h, at which time it was determined to be >95% complete by ?H NMR. The reaction was then diluted with hexanes and vacuum filtered. The filter cake was washed further with hexanes and the product-containing filtrate was concentrated. More hexanes was added to induce further precipitation of unwanted- by-products and the suspension was filtered again. The filtrate thus obtained was then concentrated in vacuo to furnish a biphasic oil. The upper layer was determined to be paraffin oil and was discarded. The lower layer was the desired product (82% yield).
diethyl 2-(2,4-difluorobenzyl)-2-methylmalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
To a suspension of 60% sodium hydride (1.4 g, 34.5 mmol) in N,N-dimethylformamide (100 ml) was added diethyl methyl malonate (5.0 g, 28.7 mmol) dropwise at 0oC. The mixture was stirred at 0 oC for 30 min, then 2, 4-difluorobenzyl bromide (6.5 g, 31.6 mmol) in N, N- dimethylformamide (6 ml) was added dropwise. The mixture was stirred from 0 oC to 28 oC for 2.5 h. The reaction was quenched with saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (eluting 3-7% ethyl acetate in petroleum ether) to give diethyl 2-[(2,4-difluorophenyl)methyl]-2- methyl-propanedioate (8.4 g, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 7.14 - 7.09 (m, 1H), 6.80 - 6.74 (m, 2H), 4.23 - 4.17 (m, 4H), 3.25 (s, 2H), 1.34 (s, 3H), 1.26 (t, J = 7.2 Hz 6H).
97%
To a suspension of 60% sodium hydride (1.4 g, 34.5 mmol) in N,N-dimethylformamide (100 mL) was added diethyl methyl malonate (5.0 g, 28.7 mmol) dropwise at 0 C. The mixture was stirred at 0 C for 30 mm, then 2, 4-difluorobenzyl bromide (6.5 g, 31.6 mmol) in N, Ndimethylformamide (6 mL) was added dropwise. The mixture was stirred from 0 C to 28 C for 2.5 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over sodiumsulfate, filtered and concentrated. The residue was purified by flash column chromatography (eluting gradient: 3-7% ethyl acetate in petroleum ether) to give diethyl 2-[(2,4- difluorophenyl)methyl]-2-methyl-propanedioate (8.4 g, 97%) as a colorless oil. ?H NMR (400 MHz, CDC13): oe 7.14 - 7.09 (m, 1H), 6.80 - 6.74 (m, 2H), 4.23 - 4.17 (m, 4H), 3.25 (s, 2H), 1.34 (s, 3H), 1.26 (t, J 7.2 Hz 6H).
2-methyl(4-piperidinyl)malonic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32.78%
With potassium carbonate; In acetonitrile; at 40 - 60℃;
Take 69.6g (0.4mol) of 2-methyl-malonic acid diethyl ester in a three-necked flask, add 55.2g (0.4mol) of anhydrous K2CO3 and stir with 500ml of acetonitrile.Another 4-bromopiperidine hydrobromic acid solution (containing 4-bromopiperidine 160.0g) was added to the reaction mixture, the oil bath heated to 40 ~ 60 ° C for 2-6h, insoluble matter was filtered off,The filtrate was drained and then dissolved in 1000 ml of ethyl acetate, washed with saturated aqueous NaCl (250 ml × 3 times) and the organic layer was dried over anhydrous magnesium sulfate overnight.The pump was depressurized to remove the solvent to obtain 105.1 g of yellowish reddish-brown transparent substance, which was purified by column chromatography to obtain 33.7 g of pure product in a yield of 32.78percent.
A mixture of diethyl malonate and compound 2 is heated to 120 C to react.Return to room temperature every 2 hours, and remove the ethanol produced by the reaction. After 3-4 times, stop the reaction.Recrystallization of acetone to give compound 8-2, directly to the next step;Compound 8-2 and DMAP (4-dimethylaminopyridine) were dissolved in DCM 50 mL.Slowly add 25 mL of DCM dissolved TsCl (p-toluenesulfonyl chloride) within 1 h after cooling to 0 C.After reacting for 24 hours, the reaction was quenched with water and washed three times.Dry Na2SO4, filter, spin dry, column chromatography (PE: EA = 5:1) to obtain a colorless transparent viscous liquid 2.0 g,The yield was 60%.
5 OmL three-necked bottleDiethyl malonate and compound 2,Heat to 12 0 C reaction,Return to room temperature every 2h to reduce the ethanol produced by the reaction, after 3-4 times, stop the reaction, and recrystallize the acetone to obtain the compound 3;
<strong>[632-07-5]2-cyanopropionic acid</strong> was added to ethanol to dissolve, and the molar ratio of <strong>[632-07-5]2-cyanopropionic acid</strong> to ethanol was controlled to be 1:4, and after dissolution, it was transferred to a reaction vessel. Stir and room temperature conditions, slowly add 98% concentrated sulfuric acid to the reactor from the dropping funnel, control the mass ratio of <strong>[632-07-5]2-cyanopropionic acid</strong> to sulfuric acid to 1:1.3, control temperature 60 C, increase the system after the addition The temperature is controlled at 80 C, and the reaction is finished after 4 hours; at 85 C, the ethanol component in the reaction system is distilled off, 12% ammonia water is added dropwise to the system for neutralization, the temperature is controlled at 85 C, and the pH of the feed liquid is adjusted to 7 - 8. The crude organic phase diethyl malonate was separated. The crude methyl malonate was put into a vacuum distillation column to obtain a purity of 99.9% of methyl malonate, and the total yield of the product was 91.2%.
at 20 - 65℃; for 3h;Large scale;
Add 108kg of 2-chloropropionic acid and 138kg of potassium carbonate to the reactor to neutralize to produce potassium 2-chloropropionate,Then gradually add potassium cyanide dropwise for cyanation until it is completely cyanidated, and then acidify with hydrochloric acid to obtain <strong>[632-07-5]2-cyanopropionic acid</strong>;Add <strong>[632-07-5]2-cyanopropionic acid</strong> to ethanol for dissolution, control the molar ratio of <strong>[632-07-5]2-cyanopropionic acid</strong> to ethanol to 1: 4, and transfer to the reaction kettle after dissolution;Stir at room temperature, and add heteropoly acid catalyst to control the mass ratio of <strong>[632-07-5]2-cyanopropionic acid</strong> to heteropoly acid catalyst 2: 1,Control the temperature at 65 , and react for 3h, after which the reaction ends;Ethanol is separated by distillation, neutralized by adding ammonia water, the pH is adjusted to neutral, and the crude diethyl methylmalonate is fractionated;The crude diethyl methylmalonate was put into a rectification tower for vacuum distillation to obtain diethyl methylmalonate.
With sodium methylate; In methanol; for 0.666667h;Reflux;
NaOMe (4.46 g, 82.64 mmol) was added to a solution of diethyl 2- methylmalonate 26 (14.34 g, 82.64 mmol) and <strong>[52313-50-5]pyridine-2-carboxamidine</strong> 23 (10 g, 82.64 mmol) in MeOH (200 ml). The reaction mixture was heated under reflux for 40 mm resulting in the formation of a precipitate. The reaction mixture was diluted with MeOH (100 ml) and EtOAc (200 ml) and the precipitate was triturated and collected by filtration to give 27 (11.57 g, 57 mmol, 69 % yield).
To a solution of Intermediate 1 (3.0 g, 5.30 mmol) and diethyl 2-methylmalonate (1.81 mL, 10.61 mmol) in acetone (26.5 mL) was added K2CO3 (2.20 g, 15.91 mmol). The reaction mixture was stirred overnight at 50 C. before being allowed to cool down, diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, hexane/ethyl acetate) to give the desired compound as a yellow foam (2.21 g, 63%). ESI-MS m/z=660.04, 662.03 [M+H]+. Step 36b. To a solution of the compound from step 36a (1.90 g, 2.88 mmol), <strong>[1206640-82-5]1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.056 g, 4.32 mmol), and silver(I) oxide (2.00 g, 8.65 mmol) in THF (29 mL) was added Pd(PPh3)4 (0.500 g, 0.432 mmol). The reaction mixture was stirred at 70 C. for 18h. It was filtered through celite, rinsed with EtOAc, and concentrated. The crude product was chromatographed (silica, hexane/EtOAc) to give the desired compound as yellow foam (1.28 g, 64%). ESI-MS m/z=696.21, 698.21 [M+H]+. Step 36c. To a solution of the compound from step 36b (1.28 g, 1.839 mmol) in methanol (18 ml) was added sodium borohydride (2.80 g, 73.56 mmol) in 4 evenly divided portions. The reaction mixture was stirred at rt for 3 h before being diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, dichloromethane/methanol) to give the desired compound as yellow gum (751 mg, 67%). ESI-MS m/z=612.18, 614.18 [M+H]+ Step 36d To a solution of the compound from step 36c (751 mg, 1.227 mmol) in dichloromethane (12 ml) at rt was added TFA (3 mL, 38.9 mmol). The reaction mixture was stirred at rt for 1 h before being concentrated. To the residue was added DCM (8 mL), MeOH (4 mL) and NaOH (3 mL, 2M). The mixture was stirred at rt for 18 h before being diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give the desired compound as yellow foam (617 mg, 98%). ESI-MS m/z=512.11, 514.11 [M+H]+. Step 36e. To a solution of the compound from step 36d (617 mg, 1.205 mmol) and Et3N (1.68 mL, 12.05 mmol) in DCM (6 mL) at 0 C. was added mesyl chloride (0.47 mL, 6.03 mmol). The reaction mixture was warmed to rt and stirred for 1 h before being diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, hexane/EtOAc) to give the desired compound as yellow film (625 mg, 91%). ESI-MS m/z=572.08, 574.08 [M+H]+. Step 36f. To a solution of compound from step 36e (350 mg, 0.612 mmol) in DMF (3 mL) was added sodium azide (80 mg, 1.224 mmol). The reaction mixture was heated at 80 C. for 18 h before being allowed to cool down, diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, hexane/ethyl acetate) to give the title compound as a yellow film (30 mg, 10%). ESI-MS m/z=519.10, 521.10 [M+H]+.
With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃;
General procedure: Dissolving 2,4-difluoronitrobenzene 1a (2.2ml, 20mmol) in DMF solution,A solid NaOH (800 mg, 20 mmol) was added, and diethyl methylmalonate (3.68 ml, 21.6 mmol) was added dropwise to the reaction solution, followed by stirring at room temperature overnight.After the reaction was completed, 120 ml of water was added, extracted with DCM three times, washed with brine three times, and the organic layers were combined and dried over anhydrous sodium sulfate.Spin dry and separate by column chromatography (eluent: PE / EA = 20/1, v / v).A light yellow oily liquid was obtained with a yield of 87%.
Stage #1: 2-phenylbenzyl bromide; Diethyl methylmalonate With sodium In ethanol at 130℃; for 3h;
Stage #2: With potassium hydroxide In tetrahydrofuran; water at 100℃; for 4h;
1.3
1.86g (0.081mol) Na was dissolved in 50mL of absolute ethanol, into this solution was dropped a mixture of 14.60mL (0.081mol) diethyl methylmalonate and 20mL of absolute ethanol, after stirring, slowly drip Into a mixed solution of 20.00g (0.081mol) 2-phenylbenzyl bromide and 20mL of absolute ethanol.Dropping for a period of time will produce white precipitation.The mixture was heated to reflux at 100°C for 3h.After cooling to room temperature, KOH aqueous solution (16 g KOH dissolved in 45 mL water) was added, and the mixture was heated to reflux at 100° C. for 4 h.The solid gradually dissolved, and the solution was orange-red or brown-red.After the reaction, the solvent ethanol was removed, water was added to completely dissolve the mixture, the pH=1 was adjusted very carefully with 6M HCl, the yellow precipitate was filtered out and dried.The obtained solid was decarboxylated under vacuum at 130°C to obtain 17.61 g of dark yellow viscous solid.The product was subjected to mass spectrometry.The product is 2-(2-phenylbenzyl)propionic acid.Yield: 91%.
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