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Product Citations

Dube, Phelelisiwe S. ; Angula, Klaudia T. ; Legoabe, Lesetja J. , et al. DOI: PubMed ID:

Abstract: Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-pos. and -neg. bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

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Product Details of [ 87-13-8 ]

CAS No. :87-13-8 MDL No. :MFCD00009148
Formula : C10H16O5 Boiling Point : -
Linear Structure Formula :C2H5O2CC(CHOC2H5)CO2C2H5 InChI Key :LTMHNWPUDSTBKD-UHFFFAOYSA-N
M.W : 216.23 Pubchem ID :6871
Synonyms :

Calculated chemistry of [ 87-13-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.6
Num. rotatable bonds : 8
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 53.36
TPSA : 61.83 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.81
Log Po/w (XLOGP3) : 1.49
Log Po/w (WLOGP) : 1.03
Log Po/w (MLOGP) : 0.63
Log Po/w (SILICOS-IT) : 1.28
Consensus Log Po/w : 1.45

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.59
Solubility : 5.54 mg/ml ; 0.0256 mol/l
Class : Very soluble
Log S (Ali) : -2.4
Solubility : 0.869 mg/ml ; 0.00402 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.47
Solubility : 7.28 mg/ml ; 0.0337 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 5.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 2.69

Safety of [ 87-13-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 87-13-8 ]

* 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.

  • Upstream synthesis route of [ 87-13-8 ]
  • Downstream synthetic route of [ 87-13-8 ]

[ 87-13-8 ] Synthesis Path-Upstream   1~90

  • 1
  • [ 87-13-8 ]
  • [ 57-13-6 ]
  • [ 28485-17-8 ]
YieldReaction ConditionsOperation in experiment
23% With sodium ethanolate In ethanol at 20 - 90℃; for 48 h; Step 1. Urea (12 g, 200 mmol) was added to EtOH (300 mL) containing NaOC2H5 previously prepared from sodium (5.52 g, 240 mmol, 1.2 eq). Diethyl 2-(ethoxymethylene)malonate (43.2 g, 200 mmol, 1.0 eq) was added and the solution was stirred at 2O0C for 24h, and then stirred at 90 0C for 24h. The alcohol was removed by reduced pressure distillation. Ice- water (100 mL) was added to dissolve the residue. The product was precipitated by adding cold dilute hydrochloric acid. The solid was filtered off to afford ethyl 2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (8.5 g, 23percent), which was used in next step without further purification.
Reference: [1] Patent: WO2011/19405, 2011, A1, . Location in patent: Page/Page column 119
  • 2
  • [ 87-13-8 ]
  • [ 28485-17-8 ]
Reference: [1] Journal of the American Chemical Society, 1942, vol. 64, p. 794,797
[2] Journal of the American Chemical Society, 1952, vol. 74, p. 4267,4269
  • 3
  • [ 17284-97-8 ]
  • [ 87-13-8 ]
  • [ 28593-24-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 6, p. 1527 - 1529
[2] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 4, p. 1341 - 1350
[3] Arkivoc, 2011, vol. 2011, # 10, p. 298 - 311
  • 4
  • [ 87-13-8 ]
  • [ 371-40-4 ]
  • [ 391-78-6 ]
Reference: [1] Patent: US2009/99220, 2009, A1, . Location in patent: Page/Page column 8-9
[2] Patent: US4560692, 1985, A,
  • 5
  • [ 87-13-8 ]
  • [ 7251-53-8 ]
YieldReaction ConditionsOperation in experiment
80% With sodium ethanolate; hydrazine hydrate In ethanol at 80℃; Cooling with ice 3-Oxo-2,3-dihydro-lH-pyrazole-4-carboxylic acid ethyl ester:[00358] To a solution of sodium ethoxide (20.8 g, 0.31 mol) and diethyl ethoxymethylenemalonate (20 mL, 0.10 mol) in ethanol (400 mL), was added hydrazine monohydrate (10.0 mL, 0.20 mol) with cooling in an ice-cold water bath. The mixture was then heated at 80 0C for 3h. The resulting mixture was diluted with water (200 mL) and neutralized with 1OM HCl solution until pη 6. The mixture was extracted several times with chloroform. The aqueous layer was acidified to pη 2 and extracted again with chloroform. The combined organic layers were dried (Na2SO4) and concentrated to a solid which was washed with methanol and ether and dried to give the product (13.2 g, 80percent) as a solid. 1H NMR (400MHz, DMSO-c/6) δ 7.89 (s, IH), 4.15 (q, 2H, J= 7.12 Hz), 1.23 (t, 3H, J= 7.11 Hz).
76%
Stage #1: With hydrazine In ethanol for 0.333333 h;
Stage #2: With sodium hydroxide In ethanol; water at 20℃; for 1.5 h; Cooling with ice
XX. Ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate A solution of diethyl 2-(ethoxymethylene)malonate (40 g, 185 mmol) in absolute ethanol (400 mL) was treated with hydrazine hydrate (8.99 mi, 185 mmol) dropwise. After approximately 20 min, 2N NaOH (25 mL) was added slowly (reaction in an ice-bath), then water (25 mL). The ice-bath was removed and the mixture stirred at rt for 1.5 hrs. The ethanol was removed in vacuo and the aqueous layer diluted with water (25 mL) and partitioned over EtOAc (100 mL). The aqueous layer was collected and cooled in an ice- bath. The pH was adjusted to 5 with 1M HCI, forming a precipitate. The precipitate was filtered, washing with water and dried in vacuo in the presence of CaCI2 to afford ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4- carboxylate (22.31 g, 76percent yield). [MH]* = 157.1
35%
Stage #1: With sodium ethanolate In ethanol at 20℃; for 0.166667 h;
Stage #2: With hydrazine hydrate In ethanol at 80℃; for 18 h; Heating
Stage #3: With hydrogenchloride In ethanol; water; ethyl acetate at 0 - 20℃; for 1 h;
This compound was synthesized according to the method described in .To a 500-mL recovery flask, a 20percent solution of sodium ethoxide in ethanol (60 mL) and ethyl 2-(ethoxymethylene)malonate (10.5 mL, 524 mmol) were added, and the resulting mixture was stirred at room temperature for 10 minutes. To the obtained mixture, hydrazine monohydrate (5.1 mL, 104 mmol) was added, the resulting mixture was stirred at 80°C for 18 hours with heating, and then the obtained yellow suspension was cooled to 0°C. To the reaction solution vigorously stirred, 1 N hydrochloric acid (180 mL) was slowly added to the mixture at the same temperature to obtain a yellow solution. To the obtained solution, ethyl acetate (150 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The organic layer was separated, and then the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was crystallized by using ethyl acetate and hexane to obtain the title compound (2.82 g, 35percent) as yellow crystals (mixture of tautomers). MS ES M-H = 155
Reference: [1] Patent: WO2009/89057, 2009, A1, . Location in patent: Page/Page column 56
[2] Patent: WO2016/83816, 2016, A1, . Location in patent: Page/Page column 48
[3] Patent: EP3272750, 2018, A1, . Location in patent: Paragraph 0219; 0220
[4] Yakugaku Zasshi, 1957, vol. 77, p. 800[5] Chem.Abstr., 1957, p. 17893
  • 6
  • [ 87-13-8 ]
  • [ 7251-53-8 ]
  • [ 332066-58-7 ]
YieldReaction ConditionsOperation in experiment
41% With hydrazine hydrochloride In ethanol for 16 h; Reflux Diethylethoxymethylenemalonate (7) (37.4 g, 0.172 mol) and hydrazine hydrochloride (12.2 g, 0.178 mol) were refluxed in ethanol (500 mL) for 16 hours.
The solvent was removed under reduced pressure, the residue was dispersed in water (500 ml) and slowly made basic by the addition of solid sodium hydrogencarbonate.
The aqueous phase was extracted with dichloromethane; this organic phase was washed with a 1N solution of sodium hydrogencarbonate three times, dried over sodium sulfate and concentrated to dryness to yield compound 8 as an oil that solidified very slowly (13.22 g, 41 percent).
The aqueous phase was cautiously made acid with concentrated hydrochloric acid, saturated with sodium chloride and the resulting precipitate was filtered, washed with water and dried under vacuum while heating at 60 °C to yield compound 9 (10 g, 37 percent) as a white powder.
Reference: [1] Patent: EP2151434, 2010, A1, . Location in patent: Page/Page column 7; 12
[2] Chemistry - A European Journal, 2010, vol. 16, # 15, p. 4669 - 4677
  • 7
  • [ 87-13-8 ]
  • [ 5472-46-8 ]
Reference: [1] Journal of the Chemical Society, 1937, p. 367[2] Journal of the Chemical Society, 1938, p. 28
  • 8
  • [ 87-13-8 ]
  • [ 2134-36-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1645 - 1648
[2] Journal of the Chemical Society, 1937, p. 367[3] Journal of the Chemical Society, 1938, p. 28
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6756 - 6761
[5] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5771 - 5780
  • 9
  • [ 87-13-8 ]
  • [ 51940-64-8 ]
Reference: [1] Patent: WO2011/19405, 2011, A1,
[2] Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 133 - 136
  • 10
  • [ 124-42-5 ]
  • [ 87-13-8 ]
  • [ 53135-24-3 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: at 0℃; for 0.333333 h;
Stage #2: at 0℃; for 0.5 h;
Stage #3: With triethylamine In ethanol for 2 h; Reflux
(0294) To a solution of sodium (2.90 g, 126 mmol) in ethanol (150 mL) was added acetoamidine hydrochloride (11.9 g, 126 mmol) at 0° C. The mixture was stirred at 0° C. for 20 minutes, diethyl (ethoxymethylene)malonate (28.6 g, 132 mmol) was added dropwise thereto, the mixture was stirred at 0° C. for 30 minutes, and triethylamine (20 mL, 145 mmol) was added thereto. The mixture was heated under reflux for 2 hours, the reaction mixture was concentrated, water (400 mL) was added thereto, citric acid was added to adjust pH to 4 to 5, and the mixture was extracted with dichloromethane (200 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtrated, and concentrated. To the resulting concentrated residue was added tert-butyl methyl ether (200 mL), and the precipitate was collected on a filter to give the title compound (14.0 g, 61percent) (0295) 1H-NMR (400 MHz, CDCl3) δ: 1.40 (3H, t, J=7.2 Hz), 2.61 (3H, s), 4.39 (2H, q, J=7.2 Hz), 8.73 (1H, s).
27% With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate EXAMPLE 30
Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR55
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes.
Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours.
The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL).
The solution was filtered, washing the solid cake with dichloromethane.
The filtrate was concentrated at reduced pressure.
The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL).
The pH of the aqueous layer was 1.
The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was dissolved in hot dichloromethane (50 mL).
Ethyl acetate was added (50 mL).
The product precipitated.
The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL).
The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane).
The title compound also was prepared by the route described in Example 102.
27% With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate Example 30
Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR57
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes.
Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours.
The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL).
The solution was filtered, washing the solid cake with dichloromethane.
The filtrate was concentrated at reduced pressure.
The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL).
The pH of the aqueous layer was 1.
The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was dissolved in hot dichloromethane (50 mL).
Ethyl acetate was added (50 mL).
The product precipitated.
The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL).
The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane).
The title compound also was prepared by the route described in Example 102.
27% With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate Example 30
Ethyl 2-methyl-pyrimidin-6(1H)-one-5-carboxylate STR52
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes.
Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours.
The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL).
The solution was filtered, washing the solid cake with dichloromethane.
The filtrate was concentrated at reduced pressure.
The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL).
The pH of the aqueous layer was 1.
The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was dissolved in hot dichloromethane (50 mL).
Ethyl acetate was added (50 mL).
The product precipitated.
The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL).
The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane).
The title compound also was prepared by the route described in Example 102.
27% With hydrogenchloride In ethanol; dichloromethane; sodium ethanolate; ethyl acetate Example 30
Ethyl 2-Methyl-pyrimidin-6(1H)-one-5-carboxylate STR50
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21percent solution, 0.20 mole) for 5 minutes.
Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours.
The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL).
The solution was filtered, washing the solid cake with dichloromethane.
The filtrate was concentrated at reduced pressure.
The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL).
The pH of the aqueous layer was 1.
The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was dissolved in hot dichloromethane (50 mL).
Ethyl acetate was added (50 mL).
The product precipitated.
The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL).
The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf =0.27 (silica gel, 10percent isopropanol in dichloromethane).
The title compound also was prepared by the route described in Example 102.
27% With sodium ethanolate In ethanol for 5 h; Heating / reflux
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 ML of a 21percent solution, 0.20 mole) for 5 minutes..
diethyl ethoxymethylenemalonate (31.5 ML, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours..
The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 ML)..
The solution was filtered, washing the solid cake with dichloromethane..
The filtrate was concentrated at reduced pressure..
The residue was dissolved in dichloromethane (150 ML) and 2.0N HCl (30 ML)..
The PH of the aqueous layer was 1..
The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure..
The residue was dissolved in hot dichloromethane (50 ML)..
ethyl acetate was added (50 ML)..
The product precipitated..
The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 ML)..
The resulting crystals were filtered, then washed with ethyl acetate (20 ML) followed by hexanes (50 ML) to yield the title compound (7.22 g, 27percent) as off-white crystals. Rf=0.27 (silica gel, 10percent isopropanol in dichloromethane)..
The title compound also was prepared by the route described in Example 102.

Reference: [1] Patent: US2016/122319, 2016, A1, . Location in patent: Paragraph 0293-0295
[2] Patent: US6008351, 1999, A,
[3] Patent: US6011158, 2000, A,
[4] Patent: US5656645, 1997, A,
[5] Patent: US5658930, 1997, A,
[6] Patent: US6342504, 2002, B1, . Location in patent: Page column 58
[7] Journal of Organic Chemistry, 1946, vol. 11, p. 741,749
[8] Journal of the Chemical Society, 1937, p. 367[9] Journal of the Chemical Society, 1938, p. 28
  • 11
  • [ 87-13-8 ]
  • [ 53135-24-3 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With sodium In ethanol at 0℃; for 0.333333 h;
Stage #2: With triethylamine In ethanol at 0℃; for 2.5 h; Reflux
Sodium (2.90g, 126mmol) and acetamidine hydrochloride (11.9g, 126mmol) in ethanol solution (150mL), it was added at 0°C. After stirring for 20 minutes at 0°C, Ethoxymethylene diethyl malonate (28.6g, 132mmol) It was added dropwise triethylamine (20mL, 145mmol) and stirred for 30 minutes at 0°C. After heated to reflux for 2 hours, The reaction mixture was concentrated, after addition of water (400 mL), citric acid is added to adjust to pH4 ~ 5, and extracted 3 times with dichloromethane (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting concentrated residue tert- butyl methyl ether (200 mL) was added, the precipitate By collected by filtration to give the title compound (14.0g, 61percent).
49.5% With sodium ethanolate In ethanol at 20 - 60℃; for 6.0833 h; Inert atmosphere ethyl 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate
diethyl 2-(ethoxymethylene)malonate (9.35 mL, 46.25 mmol) was added dropwise to acetimidamide hydrochloride (4.37 g, 46.25 mmol), and sodium ethoxide (17.27 mL, 46.25 mmol) in ethanol (50 mL) at room temperature over a period of 5 minutes under nitrogen.
The resulting solution was stirred at 60° C. for 6 hours.
The reaction mixture was evaporated to dryness and redissolved in EtOAc (50 mL).The precipitate was collected by filtration, washed with EtOH (10 mL) and dried under vacuum to afford ethyl 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (4.17 g, 49.5percent) as a cream solid, which was used without further purification.
1H NMR (400.13 MHz, DMSO-d6) δ 1.15-1.23 (3H, t), 2.21 (3H, s), 4.09-4.17 (2H, q), 8.31 (1H, s)
m/z (ESI+) (M+H)+=183; HPLC tR=0.78 min.
Reference: [1] Patent: JP2016/108326, 2016, A, . Location in patent: Paragraph 0224; 0225
[2] Patent: US2009/264401, 2009, A1, . Location in patent: Page/Page column 117
  • 12
  • [ 36896-17-0 ]
  • [ 87-13-8 ]
  • [ 53135-24-3 ]
YieldReaction ConditionsOperation in experiment
46% for 26.25 h; Heating / reflux
Acetamidine acetate (37.21 g, 0.31 mole) and diethyl ethoxymethylenemalonate (63 ML, 0.31 mole) were refluxed for 4 h in ethanol (60 ML)..
The reaction mixture was allowed to cool for 15 minutes, then acetamidine acetate (37.21 g, 0.31 mole) was added..
The reaction mixture was refluxed for 22 hours, allowed to cool to room temperature, and diluted with water (200 ML) and dichloromethane (200 ML)..
The aqueous layer was extracted with 10percent isopropanol/dichloromethane (2*200 ML)..
The combined organic extracts were washed with water (50 ML), brine (50 ML), dried over magnesium sulfate, filtered and the solvent was removed..
The residue was recrystallized from chloroform/hexanes in two crops to afford the title compound (24.92 g) in 46percent yield as yellowish crystals. Rf=0.27 (silica gel, 10percent isopropanol in dichloromethane); m.p. 187 to 188° C.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 12, p. 1543 - 1548
[2] Patent: US6008351, 1999, A,
[3] Patent: US6011158, 2000, A,
[4] Patent: US5656645, 1997, A,
[5] Patent: US5658930, 1997, A,
[6] Patent: US6342504, 2002, B1, . Location in patent: Page column 92
  • 13
  • [ 143-37-3 ]
  • [ 87-13-8 ]
  • [ 53135-24-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 3, p. 403 - 406
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6756 - 6761
  • 14
  • [ 87-13-8 ]
  • [ 626-43-7 ]
  • [ 171850-29-6 ]
Reference: [1] Journal of the American Chemical Society, 2001, vol. 123, # 28, p. 6801 - 6808
  • 15
  • [ 87-13-8 ]
  • [ 626-43-7 ]
  • [ 171850-29-6 ]
  • [ 158591-48-1 ]
Reference: [1] Patent: US6362340, 2002, B1, . Location in patent: Page column 8
  • 16
  • [ 108-73-6 ]
  • [ 87-13-8 ]
  • [ 2732-18-5 ]
Reference: [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 246, p. 1701
  • 17
  • [ 87-13-8 ]
  • [ 5909-24-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1645 - 1648
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 350,352
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 14, p. 6210 - 6225
[4] Patent: WO2015/1567, 2015, A1,
[5] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 673 - 690
[6] Journal of the Chinese Chemical Society, 2018, vol. 65, # 4, p. 445 - 451
[7] Patent: CN108707141, 2018, A,
  • 18
  • [ 109-06-8 ]
  • [ 87-13-8 ]
  • [ 88612-71-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4773 - 4780
[2] Chemische Berichte, 1955, vol. 88, p. 1831,1837
[3] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 6, p. 263 - 267
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1710 - 1715
  • 19
  • [ 87-13-8 ]
  • [ 53554-29-3 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: at 0℃; Inert atmosphere
Stage #2: at 0 - 20℃; Inert atmosphere
To a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol (15 mL) was added S-methylisothiourea sulfate (5.57 g, 40.0 mmol) at 0 °C. After a few minutes, diethyl ethoxymethylenemalonate (4.00 mL, 19.8 mmol) was added. After stirring at 0 °C for 3 h, a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol (15 mL) was added. The resulted solution was stirred at room temperature overnight. Ethanol was removed under reduced pressure and the pale yellow residue was dissolved in water. After filtration, the aqueous filtrate was washed with ether and acidified with acetic acid (10 mL). The organic materials were extracted with CHCl3. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Recrystallization of the residue with CHCl3 gave compound 10 (3.44 g, 81percent) as colorless needles. Mp 129-130 °C (CHCl3), lit.16 132-133 °C (benzene/petroleum ether). IR (KBr) 3435, 2902, 2805, 1739, 1701, 1529, 1170 cm-1. δH (400 MHz, CDCl3) 1.42 (3H, t, J 6.8 Hz, CH2CH3), 2.60 (3H, s, SCH3), 4.43 (2H, q, J 6.8 Hz, CH2CH3), 8.75 (1H, s, C4-H). δC (150 MHz, DMSO;d6) 13.0, 14.1, 60.2, 111.7, 157.8, 158.9, 163.6, 168.0. LRMS (EI) m/z 214 (M+). HRMS (EI): M+, found 214.0458. C8H10N2O3S requires 214.0412.
Reference: [1] Tetrahedron, 2011, vol. 67, # 14, p. 2661 - 2669
[2] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 673 - 690
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Reference: [1] American Chemical Journal, 1907, vol. 37, p. 396
  • 22
  • [ 62-53-3 ]
  • [ 87-13-8 ]
  • [ 26892-90-0 ]
YieldReaction ConditionsOperation in experiment
76% at 100 - 200℃; for 3 h; Aniline (1.02 mL, 0.011 mol) and diethyl ethoxymethylenemalonate (0.5-2 eq) were weighed into ethanol and heated at 100-200 ° C for three hours.Cool to room temperature, add phenyl ether, heat at 100-200 ° C for 30 min, cool to room temperature,After the reaction was completed, ice water was added, and ethyl acetate (100 mL × 2) was added, and the organic phase was combined, and the organic phase was washed with saturated brine.Dry over anhydrous sodium sulfate, filter,The organic phase was concentrated and the residue was purified by silica gel column chromatography1.6 g (76percent yield);
76% at 100 - 200℃; for 3 h; Aniline (1.02 mL, 0.011 mol) and diethyl ethoxymethylenemalonate (0.5-2 eq) were weighed into ethanol and heated at 100-200 ° C for three hours.Cool to room temperature, add phenyl ether, heat at 100-200 ° C for 30 min,Cool to room temperature,After the reaction was completed, ice water was added, and ethyl acetate was extracted (100 mL × 2).The organic phase was combined and the organic phase was washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the organic phase.The residue was subjected to silica gel column chromatography to give the productWhite solid 1.6g (76percent yield);
69%
Stage #1: for 3 h; Reflux
Stage #2: for 1 h; Reflux
Weigh aniline (1.0 mL) and diethyl ethoxymethylenemalonate (2.2 mL) into an appropriate amount of ethanol, and heat to reflux threeAfter cooling to room temperature, add 40 mL of phenylethyl ether, reflux under heating for 1 hour, and cool to room temperature. After completion of the reaction, add ice water, extract with ethyl acetate (100 mL×2), combine the organic phase, and saturate the organic phase. The mixture was washed with brine, dried over anhydrous sodium sulfate.
66% at 90 - 100℃; for 3.5 h; Weighed aniline (0.011 mol) and diethyl ethoxymethylenemalonate (0.012 mol) were added to 20 mL of ethanol and heated at 90 ° C for three hours. Cool to room temperature, add 40 mL of phenyl ether, heat at 100 ° C for 30 min, cool to room temperature.After the reaction was completed, ice water was added, and ethyl acetate was extracted (100 mL×2).The organic phase was combined and the organic phase was washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the organic phase.The residue was subjected to silica gel column chromatography to ethyl 4-hydroxy-2-hydro-quinoline-3-carboxylate (66percent yield)
66% at 90℃; for 3 h; Weigh aniline (0.011 mol) and diethyl ethoxymethylenemalonate (0.012 mol) into 20 mL of ethanol.Heated at 90 oC for three hours,Cool to room temperature, add 40 mL of phenyl ether and heat at 100 °C for 30 min.After cooling to room temperature, after completion of the reaction, ice water was added, and ethyl acetate was extracted (100 mL×2), the organic phase was combined, and the organic phase was saturated.Washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated.The residue was subjected to silica gel column chromatography toield ethyl 4-hydroxy-2-hydro-quinoline-3-carboxylate (66percent yield)
32%
Stage #1: at 20 - 110℃; for 17 h;
Stage #2: at 255℃; for 0.333333 h;
Synthesis of Lipophilic Group Modified Peptide Sequence Based on Nisvastatin; Scheme A; Scheme A; Ethyl 4-hydroxyquinoline-3-carboxylate (Al); [0183] Aniline (2.15g, 23mmol) and diethyl ethoxymethylene malonate (5g, 23mmol) were mixed neat and heated at 110°C for 2h then cooled and allowed to stand at room temperature for 15h. During this time the reaction mixture crystallized. [0184] Dowtherm A (70 mL) was heated to 255°C and the melted crystals were added and the mixture heated at 255°C for 20 min. The mixture was then poured into a stainless steel container cooled to 0°C with an ice bath. Hexanes were added to the cold solution to precipitate the product which was collected by filtration and rinsed with another portion of hexanes. The product was recrystallized from EtOH to give the product as a white solid. (1.6g, 7.3mmol, 32percent, M.P. 309C) that was used without further purification in the next step.

Reference: [1] Patent: CN108623581, 2018, A, . Location in patent: Page/Page column 6
[2] Patent: CN108623561, 2018, A, . Location in patent: Paragraph 0014
[3] Patent: CN108690024, 2018, A, . Location in patent: Paragraph 0144
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[6] Patent: WO2005/123686, 2005, A1, . Location in patent: Page/Page column 75-76
[7] Journal of Medicinal Chemistry, 1993, vol. 36, # 11, p. 1669 - 1673
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[9] European Journal of Medicinal Chemistry, 2010, vol. 45, # 5, p. 1821 - 1827
[10] Patent: US2012/309758, 2012, A1,
[11] Patent: WO2018/107100, 2018, A1,
[12] Patent: US2018/280349, 2018, A1,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 23, p. 2661 - 2664
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 11, p. 1669 - 1673
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1448 - 1452
[4] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 1 - 16
[5] Patent: CN108623562, 2018, A,
[6] Patent: CN108690024, 2018, A,
[7] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 12, p. 1205 - 1210
[8] Patent: CN108623560, 2018, A,
[9] Patent: CN108623561, 2018, A,
[10] Patent: CN108623581, 2018, A,
[11] Patent: CN108623588, 2018, A,
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  • [ 104-94-9 ]
  • [ 87-13-8 ]
  • [ 77156-78-6 ]
YieldReaction ConditionsOperation in experiment
78% With dowtherm A In ethanol for 0.5 h; Heating / reflux A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).
78% for 0.5 h; Heating / reflux Preparation 10; Preparation of 4-ethenyl-3-fluoro-6-(methyloxy)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).
78% for 0.5 h; Heating / reflux Preparation 8; Preparation of 4-ethenvl-3-fluoro-6-(methvloxv)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (40g, 0.32 mole) and diethylethoxymethylenemalonate (65 ml, 0.32 mole) in Dowtherm A (500 ml_) was heated atreflux in a flask fitted with side-arm and condenser, and heating was continued until all theethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added togive a sticky precipitate. The solvents were decanted off and the residue was treated withmore pentane and allowed to stand overnight. The solid was filtered off and washed wellwith pentane to give the title compound (62.4 g; 78percent, contains traces of Dowtherm A).
17%
Stage #1: at 120℃; for 4 h; Inert atmosphere
Stage #2: at 260℃; for 8 h; Inert atmosphere
A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120 °C under nitrogen for 4 hrs. The solution was cooled to room temperature and Ph20 (100 mL) was added. The reaction mixture was refluxed at 260 °C under nitrogen for 8 hrs. The solution was cooled to room temperature and diluted with hexanes. The resultant precipitate was collected by filtration, washed with 25percent ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale- yellow solid (4.21 g, 17percent). 1H NMR (400 MHz, DMSO-i¾ δ 1.26 (t, J = 7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J = 7.0 Hz, 2H), 7.32 (dd, J = 3.2, 9.6 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).
17%
Stage #1: at 120℃; for 4 h; Inert atmosphere
Stage #2: at 260℃; for 8 h; Inert atmosphere
Example 1c
ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate
A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120° C. under nitrogen for 4 hrs.
The solution was cooled to room temperature and Ph2O (100 mL) was added.
The reaction mixture was refluxed at 260° C. under nitrogen for 8 hrs.
The solution was cooled to room temperature and diluted with hexanes.
The resultant precipitate was collected by filtration, washed with 25percent ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale-yellow solid (4.21 g, 17percent).
1H NMR (400 MHz, DMSO-d6) δ 1.26 (t, J=7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.32 (dd, J=3.2, 9.6 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.56 (d, J=9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).

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YieldReaction ConditionsOperation in experiment
3.5 g at 100℃; for 5 h; Inert atmosphere A solution of 2-bromoaniline (2.5 g, 14.62 mmol) and ethyl ethoxymethylenemalonate (3.16 g, 14.62 mmol) was heated at 100° C. for 3 h.
Then the volatiles were removed by passing a stream of nitrogen and the molten mass was added slowly onto boiling diphenyl ether (10 mL) and the mixture was heated at reflux for 2 h.
Then petroleum ether was added to the reaction mixture at rt and the precipitated solid was collected by filtration and dried to afford 3.5 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 11.65 (br s, 1H), 8.45 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.39-7.34 (t, J=7.8 Hz, 1H), 4.26-4.19 (q, J=7.2, 14.1 Hz, 2H), 1.30-1.26 (t, J=6.9 Hz, 3H).
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YieldReaction ConditionsOperation in experiment
95% With potassium hydroxide In water at 20 - 35℃; Large scale In a 20 L flask 1.070 Kg of KOH was dissolved with 10 L of distilled water, stirred to get clear solution and 5 g of silica functionalized magnetic nanoparticles (Fe3O4(at)SiO2) was added. To the above mixture 2 Kg of guanidine carbonate was added and stirring is continued fordissolution. Temperature of the reaction mixture was main-tained around 20 °C. Diethylethoxy methyl melonate (2.4 kg) was added dropwise over 3 h, the temperature of reaction mixture was raised from 20 to 35 °C. A yellow solid was precipitated and reaction was cooled. Then with the help of external magnet Fe3O4SiO2 particles was removed, particles were washed with acetone and dried. The reaction mixture was cooled to 0-5 °C and pale yellow colour thick mixture was filtered and washed with ice cold water and padded well. The product was recrystallized from ethanol/water and dried in oven at 40 °C. The dried product is divided into two parts and recrystallizedin 15 L of 60 percent H2O/40 percent EtOH. The recrystallization was hazy at first but goes clearer in appearance after 1 h of steam heating. This compound is to crystallize and first sign is observedat 39 °C and continued with slow cooling. The process was done for both the parts and dried under vacuum oven. Yield: 95 percent
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YieldReaction ConditionsOperation in experiment
100% at 120 - 130℃; for 16.5 h; Aniline (2.733 mL, 29.99 mMol) was stirred in diethyl ethoxymethylenemalonate (6.063 mL, 30.00 mMol) at 120-130°C for 16.5 hours. T.l.c. analysis (ethyl acetate cyclohexane, 1 : 1) showed the presence of one UV-active product (Rf 0.84) and complete consumption of both starting materials. Upon cooling down of the reactionsolution to room temperature, intermediate diethyl 2-((phenylamino)methylene)malonate 35 solidified (as dark yellow crystalline solid,7.899 g, quant.). M.p. 36-37°C; HRMS (EIj: found 263.11531 [M] C14H17N04requires 263.11521; Vmax (thin film): 3265, 3184 (w, NH), 3050 (w, ArC-H), 2981,2936, 2904, 2871 (m, alkyl C-H), 1717 (s, 2 x intramolecularly hydrogen-bondedC=O conjugated with C=C), 1691 (s, C=C-NH), 1655 (s, C=N-), 1623 (s, aryl conjugated C=C), 1255 (s, C-N stretch) cm’; 6H (CD3CN, 500 MHz): 1.31 (3H, t, JCH3,CH2 7.1 Hz, CH3), 1.32 (3H, t, JCH3,CH2 7.2 Hz, CH3), 4.19 (2H, q, JCH2,CH3 7.2 Hz, CH2), 4.25 (2H, q, JCH2,CH3 7.1 Hz, CH2), 7.16 (1H, tt, JparaArH,metaArHs 7.4 Hz, JparaArH,orthoArHs 1.1 Hz, para-ArH), 7.20 (2H, dt, Jortho&-Hs,metaArHs 7.6 Hz,JorthoArHsparaArH 1.0 Hz, 2 x orthoArHs), 7.38 (2H, m, J 7.4 Hz, 2 x metaArHs), 8.48(1H, d, JCH,NH 13.8 Hz, CH-NH), 10.81 (1H, d, JNH,CH 13.6 Hz, CH-NI]); 6c(CD3CN, 125 MHz): 14.1, 14.2 (2 x CH3), 60.3, 60.6(2 x CH2), 93.9 (O=C-C-C=O),117.6(2 x orthoArCs), 125.1 (paraArC), 130.1 (2 x metaArCs), 139.8 (ArCquat-NH),151.9 (NH-CH), 165.6 (C=O), 168.8 (hydrogen bonded C=O).
90% Reflux General procedure: To a stirred solution of substituted aniline 8 (50 mmol), diethyl 2-(ethoxymethylene)malonate (55 mmol) in ethanol (EtOH) (250 mL) was refluxed for 3 h. TLC analysis indicated that the reaction was complete. After cooling the reaction mixture solid was separated. The separated solid was filtered and washed with 3percent ethyl acetate:hexane for further purification to afford desired compound as an off-white solid in good yield (89-92percent). 4.1.4.1. Diethyl 2-((phenylamino)methylene)malonate (9a). The compound was prepared according to the general procedure C using compound 8a (4.65 g, 50 mmol), diethyl 2-(ethoxymethylene)malonate (11.87 g, 55 mmol) as an off-white solid (11.83 g, 90percent); m.p: 94-96 C; ESI-MS was found at m/z 264.23 [M+H]+. 1H NMR (300 MHz, CDCl3, TMS):d 8.46 (s, 1H), 7.32e6.84(m, 5H), 6.62 (s, 1H), 4.35 (q,J 7.0 Hz, 4H), 1.32 (t,J 6.8 Hz, 6H).
82% for 3 h; Reflux General procedure: A solution of the appropriate aniline (100 mmol), and diethyl ethoxymethylenemalonate (20.4 mL,100 mmol) was heated under reflux for 3 h. The mixture was allowed to cool and then was poured into ice-cold water (100 g). The precipitate was collected by filtration and recrystallized from hexane to give derivatives 8a–c [20,26,27].
62% at 120℃; for 1 h; General procedure: A mixture of aryl amines (6 mmol) and EMME (6 mmol)was heated at 120 °C for 1–2 h. The mixture was thenevaporated to dryness to give a residue that was trituratedwith cyclohexane to give a solid that was filtered and driedto afford compound 2e–k. Diethyl 2-((phenylamino)methylene)malonate (2e) Starting from aniline (3 ml); Yield (white powder): 5 g(62 percent); m.p. 44–45 °C; IR (KBr) νmax 1400–1600(aromatic), 1660, 1690 (carbonyl) cm−1; LC-MS (ESI) m/z286.1 (M+Na+).
25 g at 20 - 55℃; for 3 h; In a clean round bottom flask charge aniline (10 gm), and di-ethyl (ethoxymethylene) malonate (2.40 gm). The reaction mass was heated to 50 55 C for 3.0 hr and cooled to 25-30 C. To this 80.0 ml of water was added. Again cool to 15-20 C and stir for 2.0 hr . Filter the product and wash with water to 25.0 gm title compound.Purity by HPLC - 98.78 percent.

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YieldReaction ConditionsOperation in experiment
70% With ethyl phosphate In diethyl ether Example 6
Ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate
A mixture of 2.66 g of (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, as such produced in example 4, and 3.11 g of diethyl ethoxymethylenemalonate was stirred under a nitrogen atmosphere and heated at 140-145°C for 2 hours.
After cooling 20 g of ethyl polyphosphate were added and the mixture was again heated at 140-145°C for 1 hour.
After cooling the reaction mixture was poured into ice water and extracted three times with chloroform.
The collected organic layers were washed with 5percent sodium carbonate solution and water.
The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
Diethyl ether was added to the residue and the crystalline material was filtered, washed and dried to afford 3.1g of title product (70percent). M.p. 254-255°C.[α] [22/D ] = -64.8° (c=0.25, acetic acid).
1H NMR (CF3COOD, ppm) delta = 1.19 (tr, 3H), 1.44 (d, 3H), 4.38 (m, 4H), 4.84 (m, 1H), 7.75 (dd, 1H), 8.97 (s, 1H).
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YieldReaction ConditionsOperation in experiment
50% With NaOEt In ethanol Example 15
ETHYL 2-TRIFLUOROMETHYL-4-HYDROXYPYRIMIDINE-5-CARBOXYLATE
A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetaridine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h.
The reaction mixture was concentrated and H2 O (48 naL) was added.
The resulting solid was filtered, washed with Et2 O (300 mL) and H2 O (200 mL), and dried to give the title compound (21 g, 50percent yield); m.p.>220° C. (dec.); 1 H NMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H).
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YieldReaction ConditionsOperation in experiment
50% With NaOEt In ethanol Example 33
ETHYL 2-TRIFLUOROMETHYL-4-HYDROXYPYRIMIDINE-5-CARBOXYLATE
A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h.
The reaction mixture was concentrated and H2 O (48 mL) was added.
The resulting solid was filtered, washed with Et2 O (300 mL) and H2 O (200 mL), and dried to give the title compound (21 g, 50percent yield); m.p. >220° C. (dec.); 1 H-NMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H).
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