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Chen, Jing ; Ji, Peng ; Gnawali, Giri , et al. DOI: PubMed ID:

Abstract: The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as "overexpressed" biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local activation of prodrug, which ultimately leads to effective and safe cancer therapy.

Keywords: Artificial receptor ; Click and release ; Local activation ; Protein degradation

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Product Details of [ 78-39-7 ]

CAS No. :78-39-7 MDL No. :MFCD00009223
Formula : C8H18O3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 162.23 Pubchem ID :-
Synonyms :

Safety of [ 78-39-7 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P403+P235 UN#:3272
Hazard Statements:H225 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 78-39-7 ]

* 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 [ 78-39-7 ]
  • Downstream synthetic route of [ 78-39-7 ]

[ 78-39-7 ] Synthesis Path-Upstream   1~42

  • 1
  • [ 452-58-4 ]
  • [ 78-39-7 ]
  • [ 68175-07-5 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 6, p. 1719 - 1722
[2] Tetrahedron Letters, 2009, vol. 50, # 16, p. 1828 - 1833
[3] Journal of Chemical Research - Part S, 2000, # 12, p. 584 - 585
  • 2
  • [ 78-39-7 ]
  • [ 1575-37-7 ]
  • [ 1964-77-8 ]
YieldReaction ConditionsOperation in experiment
87% With zirconium(IV) chloride In methanol at 20℃; for 3 h; General procedure: A mixture of o-phenylenediamine (1.0 mmol), triethyl orthoformate (1.2 mmol) and ZrCl4 (0.1 mmol) in 10 mL MeOH was stirred at room temperature for 3 h. After completion of the reaction, as indicated by TLC, the solvent was concentrated and the resulting product was directly purified by silica gel column chromatography (4:1 / 1:1, v/v, petroleum ether/EtOAc) to afford compound 11a-h.
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 241 - 250
  • 3
  • [ 610-81-1 ]
  • [ 78-39-7 ]
  • [ 41292-66-4 ]
Reference: [1] Heterocycles, 2008, vol. 75, # 8, p. 1907 - 1911
  • 4
  • [ 40851-95-4 ]
  • [ 78-39-7 ]
  • [ 40851-92-1 ]
Reference: [1] Patent: US6348474, 2002, B1, . Location in patent: Page column 44
  • 5
  • [ 1575-36-6 ]
  • [ 78-39-7 ]
  • [ 20223-87-4 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3794 - 3797
  • 6
  • [ 1068-57-1 ]
  • [ 78-39-7 ]
  • [ 13148-65-7 ]
Reference: [1] Journal of Organic Chemistry, 1966, vol. 31, p. 3442 - 3444
  • 7
  • [ 16867-03-1 ]
  • [ 78-39-7 ]
  • [ 86467-39-2 ]
YieldReaction ConditionsOperation in experiment
65.8%
Stage #1: at 120℃; for 4 h;
Stage #2: Cooling
80 mL of ethyl orthoacetate was added to 15 g (136 mmol) of 2-amino-3-hydroxypyridine, followed by addition of p-toluenesulfonic acid in a catalytic amount, and the mixture was reacted at 120° C. for 4 hours. After the reaction solution was cooled, triethylamine was added to the solution, to neutralize p-toluenesulfonic acid. Then, the solution was subjected to distillation under reduced pressure by using an evaporator, and then purified by silica gel column chromatography.Amount of the product: 12.0 g, Yield: 65.8percent.
Reference: [1] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
[2] Heterocycles, 1995, vol. 41, # 3, p. 477 - 486
[3] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[4] Patent: US2009/247736, 2009, A1, . Location in patent: Page/Page column 13
[5] Tetrahedron Letters, 1990, vol. 31, # 8, p. 1155 - 1156
[6] Synthetic Communications, 1992, vol. 22, # 20, p. 2891 - 2901
  • 8
  • [ 78-39-7 ]
  • [ 95-85-2 ]
  • [ 19219-99-9 ]
YieldReaction ConditionsOperation in experiment
97% With tungstate sulfuric acid In neat (no solvent) at 80 - 90℃; for 0.116667 h; General procedure: To a mixture of orthoester (1.1 mmol) and o-aminophenol or o-aminothiophenol (1 mmol) was added TSA (1 molpercent). The mixture was stirred at 80–90 °C for the appropriate time according to Table 4. After the completion of the reaction (as indicated by TLC), the mixture was diluted with chloroform (10 mL) and the catalyst was separated by filtration. Further purification was achieved by column chromatography
Reference: [1] Comptes Rendus Chimie, 2013, vol. 16, # 11, p. 1029 - 1034
  • 9
  • [ 78-39-7 ]
  • [ 95-85-2 ]
  • [ 19219-99-9 ]
Reference: [1] Combinatorial Chemistry and High Throughput Screening, 2013, vol. 16, # 8, p. 618 - 627
[2] Monatshefte fur Chemie, 2007, vol. 138, # 7, p. 663 - 667
[3] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 6, p. 1719 - 1722
[4] Organic Preparations and Procedures International, 2013, vol. 45, # 1, p. 57 - 65
[5] Monatshefte fur Chemie, 2011, vol. 142, # 1, p. 87 - 91
  • 10
  • [ 5348-42-5 ]
  • [ 78-39-7 ]
  • [ 6478-79-1 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 32, p. 10380 - 10381
[2] Patent: US8716491, 2014, B2, . Location in patent: Page/Page column 12
  • 11
  • [ 78-39-7 ]
  • [ 5202-85-7 ]
  • [ 7142-09-8 ]
YieldReaction ConditionsOperation in experiment
92% With acetic acid In ethanol at 110℃; for 24 h; Inert atmosphere; Sealed tube General procedure: The 2-aminobenzamide (1 equiv), the orthoester (2–3 equiv) and absolute ethanol (2–3 mL) wereplaced in a 15-mL Chemglass screw-cap pressure tube (No. CG-1880-01, Chemglass, Vineland, NJ,USA). Glacial acetic acid (3 equiv) was added, N2 was introduced to the vessel and the cap wastightened. The vessel was heated at 110 °C for 12–72 h, then cooled and concentrated to give thequinazolinone, which was purified by crystallization from absolute ethanol or trituration from 5percentether in pentane. The following compounds were prepared:
Reference: [1] Molecules, 2018, vol. 23, # 11,
  • 12
  • [ 78-39-7 ]
  • [ 5794-88-7 ]
  • [ 5426-59-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7261 - 7272
  • 13
  • [ 78-39-7 ]
  • [ 121-88-0 ]
  • [ 5683-43-2 ]
Reference: [1] Arkivoc, 2012, vol. 2012, # 9, p. 262 - 279
  • 14
  • [ 78-39-7 ]
  • [ 2678-54-8 ]
Reference: [1] Journal of the American Chemical Society, 1951, vol. 73, p. 1400
  • 15
  • [ 98-97-5 ]
  • [ 78-39-7 ]
  • [ 6924-68-1 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 6, p. 1309 - 1317
  • 16
  • [ 78-39-7 ]
  • [ 105-53-3 ]
  • [ 3044-06-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6351 - 6363
[2] Journal of the American Chemical Society, 1931, vol. 53, p. 1837
[3] Anales de la Real Sociedad Espanola de Fisica y Quimica, 1944, vol. 40, p. 946,947,948
[4] Patent: US5041619, 1991, A,
[5] Patent: EP2143724, 2010, A1, . Location in patent: Page/Page column 45
  • 17
  • [ 570-08-1 ]
  • [ 78-39-7 ]
  • [ 3044-06-2 ]
YieldReaction ConditionsOperation in experiment
56% at 95℃; for 4 h; Inert atmosphere a) diethyl 2-(1-ethoxyethylidene)malonate. A mixture of diethyl 2-acetylmalonate (10 g, 0.049 mol), 1 , 1 ,1 -triethoxyethane (24 g, 0.15 mol) and ZnCI2 (70 mg, 0.0049 mol) was stirred at 95 °C for 4 h under an inert atmosphere. The mixture was concentrated and the residue was purified by silica gel chromatography (10percent pet. ether in ethyl acetate) to give the desired product as an oil (6.4 g, 56percent). LC/MS: MS (ES+) m/e 231 (MH+); 1H NMR (300 MHz, CDCI3) δ ppm 1.22-1.33 (m, 9 H), 2.43 (s, 3H), 4.06 (q, J = 6.9 Hz, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.26 (q, J = 7.2 Hz, 2 H).
Reference: [1] Patent: WO2013/96153, 2013, A1, . Location in patent: Page/Page column 162
  • 18
  • [ 141-52-6 ]
  • [ 2678-54-8 ]
  • [ 105-53-3 ]
  • [ 854838-42-9 ]
  • [ 78-39-7 ]
  • [ 3044-06-2 ]
Reference: [1] Journal of the American Chemical Society, 1942, vol. 64, p. 1833
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 1285
[3] Patent: US2394195, 1942, ,
  • 19
  • [ 108-24-7 ]
  • [ 78-39-7 ]
  • [ 105-53-3 ]
  • [ 3044-06-2 ]
Reference: [1] Journal of the American Chemical Society, 1931, vol. 53, p. 1837
[2] Anales de la Real Sociedad Espanola de Fisica y Quimica, 1944, vol. 40, p. 946,947,948
[3] Journal of the American Chemical Society, 1931, vol. 53, p. 1837
  • 20
  • [ 420-04-2 ]
  • [ 78-39-7 ]
  • [ 1558-82-3 ]
YieldReaction ConditionsOperation in experiment
78% for 6 h; Reflux General procedure: These compounds were prepared by methods taken from the literature. We recall here the general procedure that we used. A mixture of orthoester (0.12 mol), cyanamide (0.1 mol), and few drops of acetic acid was refluxed for 6 h and distilled under vacuum (14 mmHg).
30% at 100 - 140℃; Step E: Preparation of ethyl M-cvanoacctiinidate: A mixture of cyanamidc (1.00 g,23.8 mmol) and 1,1.1-triethoxycthane (4.34 mL, 23.8 mmol) in acetic anhydride (4.49 niL, 47.6 mmol) was heated to 1000C in a distillation apparatus. After the volume of distillate diminished, the mixture was heated to 140°C, distilling most of the acetic acid. The residue was distilled under vacuum to afford the product (0.80 g, 30percent) as colorless liquid (b.p. 9O0C at 20 mm).
30% at 100 - 140℃; Step E: Preparation of ethyl M-cvanoacctiinidate: A mixture of cyanamidc (1.00 g,23.8 mmol) and 1,1.1-triethoxycthane (4.34 mL, 23.8 mmol) in acetic anhydride (4.49 niL, 47.6 mmol) was heated to 1000C in a distillation apparatus. After the volume of distillate diminished, the mixture was heated to 140°C, distilling most of the acetic acid. The residue was distilled under vacuum to afford the product (0.80 g, 30percent) as colorless liquid (b.p. 9O0C at 20 mm).
Reference: [1] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 5, p. 759 - 764
[2] Patent: US5750545, 1998, A,
[3] Patent: WO2008/42928, 2008, A2, . Location in patent: Page/Page column 33
[4] Patent: WO2008/42928, 2008, A2, . Location in patent: Page/Page column 33
[5] Journal of Organic Chemistry, 1963, vol. 28, p. 1816 - 1821
[6] Patent: US2012/316161, 2012, A1, . Location in patent: Page/Page column 42
  • 21
  • [ 75-75-2 ]
  • [ 78-39-7 ]
  • [ 62-50-0 ]
Reference: [1] Tetrahedron Letters, 1993, vol. 34, # 46, p. 7355 - 7358
  • 22
  • [ 6829-40-9 ]
  • [ 78-39-7 ]
  • [ 1068-90-2 ]
YieldReaction ConditionsOperation in experiment
87% for 2 h; Reflux In a 250 mL round bottom flask, to 4 g (18.90 mmol) of diethylaminomalonate hydrochloride 5 were added 9.43 mL (0.885 g mL−1) of triethylorthoacetate, and the reaction mixture was refluxed for 2 h (oil bath). In the meantime, the colourless solution became yellow-brown. At the end, the solution was concentrated in a rotary evaporator giving a light yellow oily product.
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 62, p. 486 - 497
  • 23
  • [ 78-39-7 ]
  • [ 109-77-3 ]
  • [ 5417-82-3 ]
YieldReaction ConditionsOperation in experiment
99% at 95℃; for 1.5 h; Neat (no solvent) A mixture of malononitrile (17 g, 257.5 λ7 mmol) and triethylorthoacetate (45.95 g, 283.25 mmol) was heated at 95 0C for 1.5 h. The mixture was then evaporated in vacuo to give a solid that was filtered off yielding compound Dl (34 g, 99percent) as a yellow solid. This compound was used in the next reaction step without further purification.Compound Dl is also commercially available CAS: 5417-82-3.
99% at 95℃; for 1.5 h; Description 1; 2-(l-Ethoxy-ethylidene)-malononitrile (Dl); A mixture of malononitrile (17 g, 257.57 - mΛmol) and triethylorthoacetate (45.95 g,283.25 mmol) was heated at 95 0C for 1.5 h. The mixture was then evaporated in vacuo to yield compound Dl (34 g, 99percent) as a yellow solid. This compound was used in the next reaction step without further purification. Compound Dl is also commercially available CAS: 5417-82-3.
91% at 85 - 140℃; for 0.666667 h; Heating / reflux Triethyl orthoacetate (97 g, 0.6 mol), malononitrile (33 g, 0.5 mol) and glacial acetic acid (1.5 g) were placed in a 1 L flask equipped with a stirrer, thermometer and a VIGREUX column (20 x 1 in. ) on top of which a distillation condenser was placed. The reaction mixture was heated and ethyl alcohol began to distill when the temperature of the reaction mixture was about 85-90 C. After about 40 min. , the temperature of the reaction mixture reached 140 C. Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was crystallized from absolute alcohol to yield the pure product (62.2 g, 91percent) as a light yellow solid [MP 91. 6 C (lit. 90-92 C, MCCALL. M. A. J. ORG CHE7N. 1962,27, 2433-2439.)].
91% at 85 - 140℃; for 0.666667 - 3 h; Triethyl orthoacetate (97 g, 0.6 mol), malononitrile (33 g, 0.5 mol) and glacial acetic acid (1.5 g) were placed in a 1 L flask equipped with a stirrer, thermometer and a Vigreux column (20.x.1 in.) on top of which a distillation condenser was placed. The reaction mixture was heated and ethyl alcohol began to distill when the temperature of the reaction mixture was about 85-90° C. After about 40 min., the temperature of the reaction mixture reached 140° C. Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was crystallized from absolute alcohol to yield the pure product (62.2 g, 91percent) as a light yellow solid mp 91.6° C. ; Method 1 Triethyl orthoacetate (1.6 L, 9 mol), malononitrile (500 g, 7.57 mol) and glacial acetic acid (25 ml) were placed in a 5 l RB flask equipped with a stirrer, thermometer and a Vigreux column (20*1 in.) on top of which a distillation condenser was placed.
The reaction mixture was heated and ethyl alcohol began to distil when the temperature of the reaction mixture was about 85-90° C.
After about 3 h., the temperature of the reaction mixture reached 140° C.
Then the reaction was concentrated in a rotary evaporator to remove the low-boiling materials and the residue was stirred with isopropyl alcohol (1 l) and cooled in an ice bath.
The crystallized product was filtered off washed with isopropyl alcohol (200 ml), hexanes (600 ml) and dried at 50° C. in a vacuum oven overnight to yield 2-(1-ethoxy-ethylidene)-malononitrile (974 g, 94percent) as a golden yellow solid [mp 92° C. (lit. 90-92° C., MCCall. M. A. J. Org. Chem. 1962, 27, 2433-2439.)].
86% at 80℃; for 0.75 h; Step 1: 2-(1-ethoxy-ethylidene)-malononitrile A mixture of malononitrile (5.0 g, 76 mmol), (EtO)3CCH3 (14.8 g, 91 mmol) and CH3COOH (1 mL) was stirred at 80° C. for 45 min. Then the mixture was cooled to room temperature and filtred to give 2-(1-ethoxy-ethylidene)-malononitrile (8.9 g, yield 86percent) as a yellow solid.
80% for 15 h; Reflux To a stirred solution of malononitrile (2.64 g, 40.0 mmol) in acetic anhydride (9 mL) was added 1 , 1 , 1 -triethoxyethane (6.48 g, 40.0 mmol). The solution was stirred for 15 h at reflux, cooled, and poured into water. The mixture was extracted with ether, and the organic extract was washed with aqueous NaHC03 and then brine. The solution was dried (MgSC^) and concentrated under reduced pressure to afford a solid identified as 2-(l-ethoxyethylidene) malononitrile (4.35 g, 80percent). The procedure was adapted from /. Med. Chem. 2004, 47, 5894-5911
80% for 15 h; Reflux Step (a): To a stirred solution of malononitrile (2.64 g, 40.0 mmol) in acetic anhydride (9 mL) was added 1,1,1-triethoxyethane (6.48 g, 40.0 mmol). The solution was stirred for 15 h at reflux, cooled, and poured into water. The mixture was extracted with ether, and the organic extract was washed with aqueous NaHCO3 and then brine. The solution was dried (MgSO4) and concentrated under reduced pressure to afford a solid identified as 2-(1-ethoxyethylidene)malononitrile (4.35 g, 80percent). The procedure was adapted from J. Med. Chem. 2004, 47, 5894-5911.
79% at 80℃; for 1 h; (75 a) (1-ethoxyethylidene)malononitrile; An acetic acid (1 mL) solution of malononitrile (4.41 g, 66.8 mmol) and orthotriethyl acetate (14.7 mL, 80.2 mmol) was stirred at 80°C for one hour. The reaction liquid was cooled to room temperature and generated powder was separated by filtration and the title compound (7.14 g, yield 79percent) was obtained. White powder 1H NMR(DMSO-d6, 400 MHz) δ 1.32 (3H, t, J = 7.0 Hz), 2.45 (3H, s), 4.42 (2H, q, J = 7.0 Hz).

Reference: [1] Tetrahedron, 2006, vol. 62, # 26, p. 6222 - 6227
[2] Patent: WO2009/62676, 2009, A2, . Location in patent: Page/Page column 46-47
[3] Patent: WO2010/60589, 2010, A1, . Location in patent: Page/Page column 28
[4] Patent: WO2004/78758, 2004, A1, . Location in patent: Page 32; 63; 65; 70; 74; 79
[5] Patent: US2006/41128, 2006, A1, . Location in patent: Page/Page column 13; 20
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6734 - 6750
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 3, p. 591 - 599
[8] Patent: US2012/202785, 2012, A1, . Location in patent: Page/Page column 258-259
[9] Patent: WO2011/42475, 2011, A1, . Location in patent: Page/Page column 31-32
[10] Patent: US2012/202853, 2012, A1, . Location in patent: Paragraph 0140; 0141
[11] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2966 - 2979
[12] Patent: EP1764367, 2007, A1, . Location in patent: Page/Page column 113
[13] Chemische Berichte, 1938, vol. 71, p. 87,99
[14] Bulletin of the Chemical Society of Japan, 1936, vol. 11, p. 566
[15] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[16] Patent: WO2005/40110, 2005, A1, . Location in patent: Page/Page column 80
[17] Patent: US6187084, 2001, B1,
[18] Patent: US2011/263559, 2011, A1, . Location in patent: Page/Page column 45
[19] Patent: WO2012/97683, 2012, A1, . Location in patent: Page/Page column 83
[20] Tetrahedron Letters, 2013, vol. 54, # 10, p. 1274 - 1278
[21] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[22] Patent: US2014/171429, 2014, A1, . Location in patent: Paragraph 0347
[23] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 14, p. 3201 - 3204
[24] Patent: US2824121, 1954, ,
  • 24
  • [ 399-97-3 ]
  • [ 78-39-7 ]
  • [ 701-16-6 ]
YieldReaction ConditionsOperation in experiment
87% at 20℃; for 0.5 h; 2. 5-Fluoro-2-methylbenzoxazole; 2-Amino-4-fluorophenol (1.01g, 7.95mmol, 1.0eq), triethyl orthoacetate (1.60ml, 8.7mmol, 1.1eq) and bismuth (III) trifluoromethanesulfonate (50mg) were mixed and stirred at ambient temperature for 30mins. The resulting solution was then diluted with dichloromethane and purified by silica flash chromatography (dichloromethane) to give the title compound as a clear liquid, 1.045g (87percent). The liquid transformed to a crystalline solid at temperatures below 5°C. MS (MALDI-TOF): MH+ = 152. UV/VIS (MeOH): ABS λmax = 282, 276 230nm. δH/ppm (400MHz&1 CDCI3): 2.60 (s, 3H), 7.02 (1 H, td), 7.33 (1 H, dd) and 7.39 (1 H, dd).
1.65 g With ytterbium(III) triflate In ethanol for 2 h; Reflux (a) 5-Fluoro-2-methylbenzo[d]oxazole (2665) To a solution of 2-amino-4-fluorophenol (2.72 g) and triethyl orthoacetate (7.89 ml) in ethanol (100 ml) was added ytterbium(lll) trifluoromethanesulfonate (310 mg, 0.500 mmol). The reaction was heated at reflux for 2 hours whereupon LCMS indicated complete conversion. The resulting dark solution was cooled, concentrated to a dark residue, then purified directly on a pre-packed silica column (SF40-150g), using a gradient of 0-100percent ethyl acetate in hexanes to afford the titled compound(1 .65 g) as an orange oil, which was used without further purification. LCMS m/z 151 .9 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3H), 7.19 (td, J=9.35, 2.53 Hz, 1 H), 7.52 (dd, J=8.84, 2.53 Hz, 1 H), 7.68 (dd, J=8.84, 4.29 Hz, 1 H).
Reference: [1] Patent: WO2008/40994, 2008, A2, . Location in patent: Page/Page column 25
[2] Patent: WO2017/98421, 2017, A1, . Location in patent: Page/Page column 223
  • 25
  • [ 78-39-7 ]
  • [ 149-73-5 ]
  • [ 1445-45-0 ]
  • [ 57999-64-1 ]
  • [ 53170-28-8 ]
  • [ 25595-98-6 ]
  • [ 122-51-0 ]
Reference: [1] Chemical Science, 2015, vol. 6, # 2, p. 1399 - 1403
  • 26
  • [ 38191-34-3 ]
  • [ 78-39-7 ]
  • [ 151230-42-1 ]
YieldReaction ConditionsOperation in experiment
88.5% at 25℃; for 0.166667 h; 2-Amino-5-bromophenol (561 mg, 3.00 mmol)Was added to triethyl orthoacetate (656 μL, 3.6 mmol),1,3-Dibromo-5,5-dimethylhydantoin (17.2 mg, 6.00 × 10 -2 mmol) was added,And the mixture was stirred at room temperature for 10 minutes.And extracted with ethyl acetate (50 mL × 2).The organic layer was washed with saturated brine,After dehydration with anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure,The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4 (volume ratio)) as an elution solvent,Compound 16 was obtained in a yield of 560 mg (88.5percent).
65% for 0.5 h; Reflux To 2-amino-5- bromophenol ( l .OOg, 5.32 mmol) , acetic acid ((0.006 ml) and triethylorthoacetate ( 1.75 ml, 9.58 mmol) were added and refluxed for 3o min. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was column chromatographed with ethyl acetate : petroleum ether to afford the title compound as a orange solid ((0.756 g, 65percent). -NMR (δ ppm, CDC13, 400 MHz): δ 7.64 (d, 7 = 1.7 Hz, 1 H), 7.51 (d, 7 = 8.4 Hz, 1 H), 7.43 (dd, 7 = 8.4, 1.7 Hz, 1 H), 2.67 (s, 3H).
65% for 0.5 h; Reflux Intermediate 126
6-bromo-2-methylbenzo[d]oxazole:
To 2-amino-5-bromophenol (1.00 g, 5.32 mmol), acetic acid ((0.006 ml) and triethylorthoacetate (1.75 ml, 9.58 mmol) were added and refluxed for 30 min.
The reaction mixture was quenched with water, extracted with ethyl acetate, dried over sodium sulphate and concentrated.
The crude product was column chromatographed with ethyl acetate:
petroleum ether to afford the title compound as a orange solid ((0.756 g, 65percent).
1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.64 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 1.7 Hz, 1H), 2.67 (s, 3H).
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7241 - 7257
[2] Patent: JP2016/79108, 2016, A, . Location in patent: Paragraph 0063
[3] Patent: WO2012/151525, 2012, A1, . Location in patent: Page/Page column 128
[4] Patent: US2012/289496, 2012, A1, . Location in patent: Page/Page column 113
  • 27
  • [ 78-39-7 ]
  • [ 63286-28-2 ]
  • [ 68774-78-7 ]
YieldReaction ConditionsOperation in experiment
2 g Reflux Step 2: 8-chloro-3-methyl-[l,2,4]triazolo[4,3-a]pyrazine [0197] To a stirred solution of 2-chloro-3-hydrazinylpyrazine (2.0 g, 14 mmol) in xylene (20 mL) was added triethyl orthoformate (5.8 mL, 32 mmol). The mixture was heated under reflux overnight and then cooled to room temperature. The resulting precipitate was collected by filtration to afford the title compound as a brown powder (2.0 g, 87percent). MS (ESI) calcd forC6H5CIN4: 168.0 ; found: 169.2 [M+H]. *H NM (400 MHz, CDCI3) δ 7.80 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 2.83 (s, 3H).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4606 - 4613
[2] Patent: WO2016/100349, 2016, A2, . Location in patent: Paragraph 0197
  • 28
  • [ 2033-24-1 ]
  • [ 78-39-7 ]
  • [ 85920-63-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 2, p. 365 - 369
  • 29
  • [ 78-39-7 ]
  • [ 1079-66-9 ]
  • [ 719-80-2 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1968, vol. 712, p. 21 - 27
  • 30
  • [ 121-34-6 ]
  • [ 78-39-7 ]
  • [ 617-05-0 ]
Reference: [1] Synthetic Communications, 2002, vol. 32, # 14, p. 2209 - 2213
  • 31
  • [ 623-05-2 ]
  • [ 78-39-7 ]
  • [ 57726-26-8 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1988, # 5, p. 901 - 904
  • 32
  • [ 156-38-7 ]
  • [ 78-39-7 ]
  • [ 17138-28-2 ]
Reference: [1] Synthetic Communications, 2002, vol. 32, # 14, p. 2209 - 2213
  • 33
  • [ 23761-23-1 ]
  • [ 78-39-7 ]
  • [ 87121-89-9 ]
YieldReaction ConditionsOperation in experiment
93.5% for 5 h; Reflux triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with iN HC1. Organic layer was separated off and the aq.phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCO3 solution followed by water (50 mL) and dried over Na2SO4. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. ‘HNMR (400 MHz, CDC13): ö 4.20 (q, J= 7.1 Hz, 2H), 3.44-3.37 (m, 2H), 3.31 -3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5% for 5 h; Reflux Step 1 : ethyl 3-oxocyclobutane-l-carboxylate: triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S0 . Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H)
93.5% at 110℃; for 5 h; triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J = 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5% at 110℃; for 5 h; triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCC solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
85% for 6 h; Reflux triethyl orthoacetate (21.31 g,0.13 1 mol) was added to a solution of 3-oxocyclobutane-1-carboxylic acid (5.0 g, 0.043 mol) intoluene (100 mL) and the reaction mixture was refluxed for 6 h. The reaction mixture wasquenched with a IN HCI solution and the layers were separated off. The organic layer waswashed with saturated NaHCO3 solution (2 x 50 mL), brine (2 x 50 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to get the product (5.3 g, 85percent) as a yellow liquid. ‘H NMR (400 MHz, CDC13): ö 4.23-4.17 (q, J 7.0 Hz, 2H), 3.44-3.37 (m, 2H), 3.32-3.16 (m, 3H), 1.30-1.26 (t, J 7.0 Hz, 3H).
80% at 110℃; for 5 h; 1A. 3-Oxo-cyclobutanecarboxylic acid ethyl ester A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80percent yield) as an oil. 1H NMR (400 MHz, DMSO-d4) 1.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
69% at 110℃; for 5 h; A solution of 3-oxo-cyclobutanecarboxylic acid (0.5 g, 4.38 mmol), triethylorthoacetate (2.4 mL, 13.1 mmol) and toluene (10 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI. The organic phase was separated, washed with a saturated NaHC034percent and brine, dried, filtered and concentrated in vacuo to provide the title compound (0.43 g, 69percent yield) as an oil.H NMR (400 MHz, cdcl3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.49 - 3.36 (m, 2H), 3.35 - 3.17 (m, 3H), 1.30 (t. J = 7.1 Hz, 3H).

Reference: [1] Patent: WO2015/196071, , A1, . Location in patent: Paragraph 0274[1] Patent: , 2015, , . Location in patent: Paragraph 0274
[3] Patent: WO2016/105468, 2016, A1, . Location in patent: Paragraph 0171
[4] Patent: WO2016/115090, 2016, A1, . Location in patent: Paragraph 0268
[5] Patent: WO2017/40606, 2017, A1, . Location in patent: Paragraph 0227
[6] Patent: WO2016/105477, 2016, A1, . Location in patent: Page/Page column 0139
[7] Patent: US2007/270438, 2007, A1, . Location in patent: Page/Page column 32
[8] Patent: WO2011/35900, 2011, A1, . Location in patent: Page/Page column 105
[9] Patent: WO2016/24185, 2016, A1, . Location in patent: Page/Page column 126; 127
  • 34
  • [ 1122-28-7 ]
  • [ 78-39-7 ]
  • [ 133123-67-8 ]
Reference: [1] Synthesis, 1991, # 1, p. 75 - 78
  • 35
  • [ 5326-23-8 ]
  • [ 78-39-7 ]
  • [ 49608-01-7 ]
Reference: [1] Patent: US5659042, 1997, A,
  • 36
  • [ 78-39-7 ]
  • [ 118292-41-4 ]
  • [ 118292-40-3 ]
Reference: [1] Patent: US2007/238881, 2007, A1, . Location in patent: Page/Page column 7
  • 37
  • [ 952294-18-7 ]
  • [ 78-39-7 ]
  • [ 118292-40-3 ]
Reference: [1] Patent: US2007/238881, 2007, A1, . Location in patent: Page/Page column 7
  • 38
  • [ 129012-04-0 ]
  • [ 78-39-7 ]
  • [ 219762-28-4 ]
Reference: [1] Patent: US6573274, 2003, B1,
  • 39
  • [ 129012-04-0 ]
  • [ 78-39-7 ]
  • [ 219762-28-4 ]
Reference: [1] Patent: US6348474, 2002, B1, . Location in patent: Page column 45
  • 40
  • [ 78-39-7 ]
  • [ 187834-88-4 ]
  • [ 280110-69-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4430 - 4448
  • 41
  • [ 934758-27-7 ]
  • [ 78-39-7 ]
  • [ 494747-09-0 ]
Reference: [1] Patent: WO2007/45622, 2007, A1, . Location in patent: Page/Page column 32
  • 42
  • [ 78-39-7 ]
  • [ 105-56-6 ]
  • [ 1188-33-6 ]
  • [ 1174046-84-4 ]
YieldReaction ConditionsOperation in experiment
26%
Stage #1: at 120℃; for 12 h;
Stage #2: at 70℃; for 2 h;
Ethyl cyanoacetate 70.5 mL (0.66 mol) of triethyl ortho-acetate in 249.6 mL (1.32 mmol), acetic acid 19.6 mL (0.33 mol) into a 120 after 12 hours stirring. Concentrating the solvent of the reaction mixture, it was added DEA-DMF (N, N- dimethylformamide diethyl acetal) 141 mL (0.55 mol). At 70 was stirred for at least 2 hours. To the reaction mixture Place 500 mL of distilled water and 60 mL of acetic acid was refluxed for 12 hours or more. The reaction mixture was cooled to ambient temperature, it was added a saturated aqueous solution of sodium hydrogen carbonate and water. Of dichloromethane and methanol, 9: 1 and extracted with a mixed solvent. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Add 100 mL ethyl acetate and concentrated. At this time, the generated gas by filtration to give the compound methyl 4-methoxy-2-oxo-1,2-dihydropyridine-3-carboxylate 37 g (26percent).
26%
Stage #1: at 120℃; for 12 h;
Stage #2: at 70℃; for 2 h;
Stage #3: With acetic acid In water for 12 h; Reflux
Ethyl cyanoacetate (70.5 mL, 0.66 mol) was added with triethyl orthoacetate (249.6 mL, 1.32 mmol) and acetic acid (19.6 mL, 0.33 mol) and stirred at 120°C for at least 12 hours. The solvent of the reaction mixture was concentrated and added with N,N-dimethylformamide diethylacetal (DMF-DEA) (141 mL, 0.55 mol) and stirred at 70°C for at least 2 hours. The reaction mixture was added with acetic acid (500 mL) and distilled water (60 mL) and refluxed for at least 12 hours. The reaction mixture was cooled to room temperature and added with a saturated aqueous solution of sodium hydrogen carbonate and water. The resultant was extracted using a mixed solvent (dichloromethane : methanol = 9 : 1). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resultant was added with ethyl acetate (100 mL) and concentrated. The thus-obtained solid was filtered to obtain 37 g (26percent) of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridin-3-carboxylate.
26%
Stage #1: at 120℃; for 12 h;
Stage #2: at 70℃; for 2 h;
Stage #3: With acetic acid In water for 12 h; Reflux
Ethyl cyanoacetate (70.5 mL, 0.66 mol) was added with triethyl orthoacetate (249.6 mL, 1.32 mmol) and acetic acid (19.6 mL, 0.33 mol) and stirred at 120° C. for at least 12 hours.
The solvent of the reaction mixture was concentrated and added with N,N-dimethylformamide diethylacetal (DMF-DEA) (141 mL, 0.55 mol) and stirred at 70° C. for at least 2 hours.
The reaction mixture was added with acetic acid (500 mL) and distilled water (60 mL) and refluxed for at least 12 hours.
The reaction mixture was cooled to room temperature and added with a saturated aqueous solution of sodium hydrogen carbonate and water.
The resultant was extracted using a mixed solvent (dichloromethane:methanol=9:1).
The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
The resultant was added with ethyl acetate (100 mL) and concentrated.
The thus-obtained solid was filtered to obtain 37 g (26percent) of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridin-3-carboxylate.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (bs, 1H), 7.46 (d, J=7.6 Hz, 1H), 6.21 (d, J=7.6 Hz, 1H), 4.++14 (m, 4H), 1.22 (m, 6H)
MS: 212 [M+H]+
Reference: [1] Patent: KR2016/8142, 2016, A, . Location in patent: Paragraph 0148-0152
[2] Patent: KR101598664, 2016, B1, . Location in patent: Paragraph 0148-0150
[3] Patent: US2016/207931, 2016, A1, . Location in patent: Paragraph 0217; 0218; 0219; 0220
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