* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium In ethanol for 0.5 h; Stage #2: at 15℃; for 6.5 h; Reflux
Step a): Sodium metal (23 gram, 1 mole) was dissolved in dry ethanol (500 ml) with stirring. To this 160 gram (1 mole) of diethyl malonate (compound [2]) was added in 30 minutes. The reaction mixture was cooled to 15 °C and ethyl chloroacetate (compound [1], 117 gm, 0.095 mole) was then added drop wise in 30 minutes. On completion of addition the reaction mass was refluxed for 6 hours and then poured in 2 liters of water. The organic materials were extracted with dichloromethane (three times with 500 ml). Next, the organic extracts were dried over sodium sulfate, filtered and evaporated to give an oily substance which was then vacuum distilled to give 220 gm (89 percent of the theoretical maximum yield) of triethyl ethane-1 ,1 ,2-tricarboxylate, compound[3].
87.2%
With dmap; tetrabutylammomium bromide; sodium carbonate; sodium iodide In acetic acid butyl ester at 20 - 120℃;
In 1000ml reaction flask installed with a stirrer, thermometer,pressure-equalizing dropping funnel, a trap and a condenser, at room temperature, the solventbutyl acetate was added 500ml, open stirring, was added diethyl malonate 100g,and the acid bindingagent sodium carbonate 133g, sodium iodide catalyst 7. 0g, phase transfercatalyst is tetrabutylammonium bromide 6. 5g, DMAP and 5g PEG400, heated slowlyAfter the addition is complete, the temperature raise to 20 ° C ~ 120 ° C , ethyl chloroacetate was added dropwise start83. 5g, control the dropwise addition time 1.5 hours, the reaction was kept 1hour, slowly warming to 20 ~120 ° C incubation the reaction, water produced asthe reaction proceeds, through manifold conduct watershed, the reaction waskept under reflux for 9 to 13 hours until dry produce inside the trap duringthe reaction system transparent white color;Sampling and analysis, qualified after the GC control,cooling down to about 1 (TC, saturated aqueous ammonium chloride was slowlyadded dropwise and adjusted ΡΗ = 7, then adding water-soluble clear, standinglayer, aqueous layer was separated organic layer was collected .[0030] 100ml aqueous layer was added a saturatedsodium chloride solution, extracted twice with 100ml butyl acetate, standingstratified layer of water, organic layer was collected, and the combinedorganic layer solvent removal under reduced pressure to give the product.Decompression melting off the end of the degree of vacuum control -0. 098Mpa,vacuum distillation final temperature of about 120 ~130 ° C, when the condenser no condensed liquid stream under reduced pressure to end off the solvent, togive a colorless or pale yellow liquid product 135.6g, the yield is about87.2percent.
73.1%
Stage #1: at 0 - 20℃; for 0.5 h; Stage #2: at 20℃; for 4 h; Reflux
Intermediate A8:Intermediate A6 was synthesized according to the scheme as foliowir reflux, overnightStep A: triethyl ethane-1 , 1 ,2-tricarboxylateTo a solution of anhydrous ethanol (1000 mL) was added sodium (23.0 g, 1 mo.) in pieces. After ail the sodium dissolved, the reaction mixture was cooled to 0 °C with an ice bath, diethyl ma.onafe (180.2 g, 1 rrto.) was added dropwise, the reaction was allowed to warm to room temperature after stirred for 0.5 h, ethyl 2-chloroacetate (122.6 g, 1 mo.) was added and stirred for another 1 h, then heated to reflux for 3 h and cooled to room temperature. Most of ethanol was removed under reduced pressure and the residue was poured into ice-water. The aqueous phase was extracted with ethyl acetate, and the organic extracts were combined, washed by brine, dried over anhydrous sodium sulfate, and evaporated to afford the product ethane-1 ,1 ,2-tricarboxylate as a pale-yellow oil (180.0 g, yield 73.1 percent), which was used for the next step without purification.
Reference：
[1] Patent: WO2013/29767, 2013, A1, . Location in patent: Page/Page column 16; 17
[2] Patent: CN105566111, 2016, A, . Location in patent: Paragraph 0029-30
[3] Liebigs Annalen der Chemie, 1983, # 1, p. 112 - 136
[4] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 45-46
[5] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 38
[6] Journal of Organic Chemistry, 1962, vol. 27, p. 1975 - 1978
[7] Patent: WO2016/115434, 2016, A1, . Location in patent: Page/Page column 220
2
[ 105-36-2 ]
[ 105-53-3 ]
[ 7459-46-3 ]
Yield
Reaction Conditions
Operation in experiment
93.8%
With tetrabutylammomium bromide; sodium carbonate; sodium iodide In toluene at 20 - 120℃;
In 1000ml reaction flask installed with a stirrer, athermometer, a pressure-equalizing dropping funnel, a glass trap and condenser,At room temperature, the solvent toluene 500ml, openstirring, diethyl malonate100g, acid binding agent sodium bicarbonate 105g, sodium iodide catalyst8. 5g, phase transfer catalyst is tetrabutylammonium bromide 8. 0g, feedingafter the completion of the slow heating, the temperature raise to 20 ° C ~ 115° C, the dropwise addition of ethyl bromoacetate 104. 5g, dropping time control in 1.0 hours,the reaction incubated 1.5 hours, slowly warming to 20 ~ 120 ° C (TC thermalreaction, as the reaction to produce water, carried through the watershed trap,reflux heat for 8 to 12 hours until dry produce inside the trap during thereaction system color transparent white; sampling analysis, after passing thecontrol, cooling down to about 10 ° C, and acetic acid was slowly addeddropwise, regulating ΡΗ = 7, suction filtered, the inorganic salt was filteredoff, the filtrate was collected. the inorganic salt was washed with 50ml X 2with hot toluene, The filtrate was collected and the combined filtrate underreduced pressure solvent removal under reduced pressure to end off the solventcontrol the degree of vacuum -0.098Mpa, vacuum distillation final temperatureof about 120 ~ 130 ° C, vacuum degassing solvent condenser end when there is no condensed liquid stream to give a colorless or pale yellow liquid product 145.1g, the yield is about 93.8percent.
88%
Stage #1: With potassium carbonate In acetone at 55℃; for 1 h; Stage #2: at 55℃; for 10 h;
Triethyl 1,1,2-ethanetricarboxylateAdd 7L of acetone to the 10L reaction bottle.Add 1.6 kg of potassium carbonate (11.68 mol, 1.5 eq),Turn on the agitation,1.247 kg (7.78 mol, 1.0 eq) of diethyl malonate was added dropwise.The system has a slight warming phenomenon.After the addition, the temperature was raised to 55 ° C for 1 h.111.6 g (0.778 mol, 0.1 eq) of sodium iodide was added.After the addition, 1 kg (5.99 mol, 0.77 eq) of ethyl bromoacetate was added dropwise.After the addition is completed,The reaction was carried out at 55 ° C for 10 h.The GC detected that the ethyl bromoacetate reaction was completed.Stop the reaction.The reaction system is cooled to room temperature.Filter to remove insoluble solids,The reaction solution was concentrated to remove the solvent.Pour the concentrate into the water,5percent dilute sulfuric acid is adjusted to weakly acidic,EA extracts the aqueous phase twice,Combine the organic phase water backwash twice,Concentrated to dry a yellow transparent liquid.Vacuum distillation (-0.1Mpa),Collect 80 ° C fractions,Colorless transparent liquid 0.88kg,The yield was 88percent.
20%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; Stage #2: at 0 - 20℃; for 16.33 h;
Synthesis of compound 3.1. To a suspension of sodium hydride (60percent in mineral oil, 5 g, 0.125 mol) in THF (200 ml) at 0° C. was added diethyl malonate (20 g, 0.125 mol) dropwise. To the reaction mixture was added ethyl bromoacetate (16.4 g, 0.097 mol) maintaining the temperature at 0° C. for 20 minutes. The reaction mixture was allowed to stir at RT for 16 hr and then quenched with saturated ammonium chloride solution (100 ml) at 0° C. The reaction mixture was extracted with ethyl acetate (3.x.100 ml). The combined organic extracts were dried (Na2SO4), concentrated under vacuum and purified with fractional distillation to afford compound 2 (6 g, 20percent) as a white liquid. 1H NMR (200 MHz, CDCl3) δ 4.3-4.2 (m, 6H), 3.83 (t, J=7.2 Hz, 1H) 2.95 (d, J=7.2 Hz, 2H), 1.2-1.4 (m, 9). MS m/z 247 [M+1]+.
Reference：
[1] Patent: CN105566111, 2016, A, . Location in patent: Paragraph 0031
[2] Patent: CN108586248, 2018, A, . Location in patent: Paragraph 0017; 0018; 0019; 0022; 0025
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 5.1, p. 955 - 961[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 5, p. 1073 - 1079
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 3, p. 365 - 368
[6] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 17
[7] Archiv der Pharmazie, 1991, vol. 324, # 4, p. 243 - 247
[8] Patent: US2010/120801, 2010, A1, . Location in patent: Page/Page column 60-61
[9] Patent: WO2009/139834, 2009, A1, . Location in patent: Page/Page column 96
[10] Patent: CN107698541, 2018, A, . Location in patent: Paragraph 0007; 0008
3
[ 105-36-2 ]
[ 7459-46-3 ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2.5 h; Stage #2: at 0 - 20℃; for 3 h;
A suspension of NaH (60percent, 90 g, 3.75 mol) in dry THF (7.5 L) was cooled to 0 °C and to this was added a solution of diethylmalonate (500 g, 3.12 mol) over a period of 1 h. The reaction mixture was slowly allowed to warm to RT and stirred for another 1.5h at RT. The reaction mixture was then cooled to 0 °C and added a solution of ethylbromoacetate (307 mL, 2.79 mol) slowly for 30 min and finally stirred at RT for 2.5h. The reaction mixture is poured into a mixture of 1.5 N HCI (250 mL) and ice (5 kg), extracted with CH2CI2 (4x5 L), dried and concentrated under vacuum to give crude product. The crude was purified by column chromatography over silica gel (4percent ethyl acetate in pet. ether) to give the title compound (496 g, 64percent). TLC: Pet. ether/EtOAc, 4: 1, Rf=0. 4
The enolate 4i (4 mmol, 172.2 mg) was added to a 50 ml reaction flask,Hexafluoroisopropanol (2 ml), ethanol / hexafluoroisopropanol volume ratio V / V: CH3CH2OH / (CF3) 2CH2OH = 4/1,System sealed, heated at 90 under the conditions of heating,TLC (DCM / MeOH = 100/1). The monitoring reaction was completed,In addition to solvent and excess ethanol,Flash column chromatography (eluent: DCM / MeOH = 150/1) Was added to compound 5d (colorless oily liquid) in 69percent yield.
Reference：
[1] Patent: CN107162967, 2017, A, . Location in patent: Paragraph 0102; 0103; 0104
Reference：
[1] Journal of Organometallic Chemistry, 1985, vol. 287, p. C18 - C22
9
[ 996-82-7 ]
[ 105-39-5 ]
[ 7459-46-3 ]
Reference：
[1] Synthesis, 1981, vol. No.10, p. 826 - 828
[2] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 38
[3] Chemische Berichte, 1879, vol. 12, p. 752
[4] Journal of the Chemical Society, 1906, vol. 89, p. 1643
10
[ 95-92-1 ]
[ 123-25-1 ]
[ 7459-46-3 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1968, vol. <C>, p. 893 - 900
11
[ 10359-15-6 ]
[ 64-17-5 ]
[ 7459-46-3 ]
Reference：
[1] Annales de Chimie (Cachan, France), 1892, vol. <6>27, p. 247
[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1877, vol. 9, p. 278[3] Chemische Berichte, 1876, vol. 9, p. 1604
[4] Annales de Chimie (Cachan, France), 1889, vol. <6>18, p. 284[5] Bulletin de la Societe Chimique de France, 1889, vol. <3>1, p. 300
12
[ 996-82-7 ]
[ 105-36-2 ]
[ 7459-46-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 38
[2] Chemische Berichte, 1879, vol. 12, p. 752
[3] Journal of the Chemical Society, 1906, vol. 89, p. 1643
13
[ 42126-21-6 ]
[ 7459-46-3 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 797[2] Justus Liebigs Annalen der Chemie, 1895, vol. 285, p. 2
14
[ 56-23-5 ]
[ 15219-34-8 ]
[ 78209-71-9 ]
[ 7459-46-3 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 297,300
15
[ 17920-23-9 ]
[ 7459-46-3 ]
Reference：
[1] Patent: CN107162967, 2017, A,
16
[ 996-82-7 ]
[ 141-52-6 ]
[ 105-39-5 ]
[ 7459-46-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 38
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2h;
To a solution of 1.8 g of <strong>[72587-15-6]2-chloro-3-nitro-5-(trifluoromethyl)pyridine</strong> in 8 mL of tetrahydrofuran, 2.0 mL of triethyl 1,1,2-ethanetricarboxylate and 0.63 g of 60% sodium hydroxide were added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g of triethyl 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylate as a brown oily substance. 1H-NMR (CDCl3) delta: 1.20-1.28 (9H, m), 3.57 (2H, s), 4.10 (2H, q, J = 7.2 Hz), 4.25 (4H, q, J = 7.2 Hz), 8.64-8.67 (1H, m), 8.96-8.99 (1H, m)
(4,6-dihydroxy-pyrimidin-5-yl)-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Step 1- Synthesis of Compound HB; To a solution of sodium metal (2.38 g, 2.12 eq) in MeOH (45 mL) was added formamidine HCl (4.1 g, 1.02 eq) and the resulting mixture was allowed to stir at room temperature for 1 hour. Triethyl 1.1,2-ethane tricarboxylate (HA, 1 1 mL) was then added slowly to the reaction mixture and stirring was continued at room temperature under a nitrogen atmosphere for an additional 19 hours. The reaction mixture was concentrated in vacuo to provide a white solid residue which was dissolved in ice cold water (100 mL), then acidified to pH 1 to 2 using 2N HCl. The resulting precipitate was filtered and the solid collected was washed with water and dried under vacuum to provide compound 1 IB as an off-white solid (8.1 g, 90%).
(4,6-dihydroxy-pyrimidin-5-yl)-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99.99%
Preparation 153 Methyl 2-(4,6-dihydroxypyrimidin-5-yl)acetate Add triethyl ethane-1,1,2-tricarboxylate (74.75 g; 1.00 equiv; 303.54 mmol; 69.41 mL) to a solution of sodium methoxide (139.6 mL of 25% wt in MeOH, 4.35M) (131.2 g; 2.00 equiv; 607 mmol) in methanol (224.8 mL), then add <strong>[6313-33-3]formamidine hydrochloride</strong> (25.19 g, 1.01 equiv; 306.58 mmol) at RT. Stir the mixture overnight. Acidify with 37% HCl at 0 C.; filter the solids and dry in vacuo overnight to give the title compound (55.89 g; 99.99% yield) as a white solid. 1H NMR (300 MHz, DMSO): 8.03 (s, 1H), 3.55 (s, 3H), 3.24-3.15 (m, 2H).
Multi-step reaction with 2 steps
1.1: potassium etoxide / ethanol / 0.67 h / 0 °C
1.2: 20 °C
2.1: water monomer; lithium chloride / dimethyl sulfoxide / 160 °C
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