There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 78-39-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] 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 ]
Yield
Reaction Conditions
Operation 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
Reference：
[1] Journal of Organic Chemistry, 1966, vol. 31, p. 3442 - 3444
7
[ 16867-03-1 ]
[ 78-39-7 ]
[ 86467-39-2 ]
Yield
Reaction Conditions
Operation 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.
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] 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 ]
Yield
Reaction Conditions
Operation 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
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 ]
Yield
Reaction Conditions
Operation 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] 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 ]
Yield
Reaction Conditions
Operation 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
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 ]
Yield
Reaction Conditions
Operation 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 ]
Yield
Reaction Conditions
Operation 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] Chemical Science, 2015, vol. 6, # 2, p. 1399 - 1403
26
[ 38191-34-3 ]
[ 78-39-7 ]
[ 151230-42-1 ]
Yield
Reaction Conditions
Operation 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 ]
Yield
Reaction Conditions
Operation 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
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).
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
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).
58%
With acetic anhydride;
(1) Ethyl N-cyanoacetoimidate A solution of cyanamide (3.52 g), acetic anhydride (15.7 ml) and triethyl orthoacetate (15.0 ml) was stirred at 140 C. for 2.5 hours. After the reaction, the mixture was distilled under reduced pressure to give 5.29 g of a colorless transparent liquid (yield 58%). Boiling point: 50-60 C./2.5 mmHg IR (KBr): 2990, 2940, 2210, 1700, 1668, 1604 cm-1 1 H-NMR (CDCl3) delta: 1.35 (3H, t, J=7.1 Hz), 2.40 (3H, s), 4.29 (2H, q, J=7.1 Hz)
30%
With acetic anhydride; 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 140C, distilling most of the acetic acid. The residue was distilled under vacuum to afford the product (0.80 g, 30%) as colorless liquid (b.p. 9O0C at 20 mm).
In acetonitrile; at 20℃; for 39.0h;Reflux;
Intermediate 32Preparation of Ethyl N-cyanoacetimidateTo a solution of 1,1,1-triethoxyethane (3.66 mL; 20 mmol) in acetonitrile (40 mL) was add cyanamide (0.882 g; 21 mmol) and the reaction mixture was stirred at room temperature for 21 h. No reaction so the mixture was heated to reflux for 18 h. The volatiles were removed under reduced pressure and the 2.24 g (100%) of the crude white solid were dried and used without further purification. ESI/APCI(+): 113 (M+H). NMR (1H): DMSO-d6 4.24 (q, 2H, CH2), 2.37 (s, 3H, CH3), 1.27 (t, 3H, CH3).
Preparation Example 9-3 5-Bromo-2-methyl-1H-imidazo[4,5-b]pyridine <strong>[129012-04-0]2,3-Diamino-6-bromopyridine</strong> (8.16 g) and triethyl orthoacetate (12.0 ml) were mixed in acetic acid (41 ml), and the mixture was refluxed under heating for 29 hr.. The mixture was allowed to cool and the solvent was evaporated to give a crude product (10 g).. This was dissolved in a sufficient amount of dichloromethane.. Anhydrous potassium carbonate and active carbon were added and the mixture was stirred at room temperature.. The insoluble matter was filtered off and the solvent was evaporated to give the objective compound (7.59 g) as a pale-yellow powder. 1H-NMR(DMSO-d6): 2.51(3H, s), 7.31(1H, d, J=8 Hz), 7.82(1H, d, J=8 Hz) Mass(ESI): m/e 212, 214 (M+H)+
With potassium carbonate; In dichloromethane; acetic acid;
PREPARATION EXAMPLE 16-2 <strong>[129012-04-0]2,3-Diamino-6-bromopyridine</strong> (8.16 g) and triethyl orthoacetate (12.0 ml) were mixed in acetic acid (41 ml), and the mixture was refluxed under heating for 29 hr. After allowing to cool, the solvent was evaporated under reduced pressure to give a crude product (10 g). This was dissolved in a sufficient amount of dichloromethane and anhydrous potassium carbonate and active charcoal were added. The mixture was stirred at room temperature. The insoluble matter was removed by filtration and the solvent was evaporated to give 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (7.59 g) as a pale-yellow powder. 1H-NMR (DMSO-d6): 2.51 (3H, s), 7.31 (1H, d, J=8 Hz), 7.82 (1H, d, J=8 Hz). MASS (ESI): m/e 212,214 (M+H)+.
(A) In the same manner as described in the step (B) of Reference Example 11, 730 mg of N-(4-ethyl-1H-pyrazol-3-yl)acetamidoxime was obtained from 3.0 g of <strong>[64781-79-9]3-amino-4-methyl-1H-pyrazole</strong> and 4.4 g of triethyl orthoacetate.
b) 2,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one; According to Scheme 5 Step 2 and 3: A solution of 2-amino-5-methylthiophene-3- carboxamide (2.0Og, 12.8mmol) and triethylorthoacetate (7ml, 38.4mmol) in toluene (10ml) was heated 170C under micro wave for lhour, three times. The solvent was removed in vacuo and the residue was taken up in dichloromethane, filtered and dried, yielding title compound (1.56g, 67%) as a brown solid.
Example V Preparation of the compound No. 26 of Table I 5,6-[(1-Ethoxyethylidene)dioxy]indole In a round-bottom flask equipped with a distillation system, 14.6 ml (0.08 mole) of triethyl orthoacetate and 3 g (0.02 mole) of <strong>[3131-52-0]5,6-dihydroxyindol</strong>e are heated on an oil bath brought to 120 C., in such a way that the ethanol formed distills continuously (reaction time: 4 hours). The excess triethyl orthoacetate is distilled off and the fraction of boiling point 160 C. at 1.06*102 Pa isolated. The colorless oil obtained crystallizes to give the compound 26 (2.71 g; yield: 62%). Analysis: C12 H13 NO3 Calculated: C 65.74; H 5.98; N 6.39. Found: C 65.34; H 6.01; N 6.29.
With hydrazine; In pyridine; hexane; dichloromethane;
A mixture of 1.3 g of <strong>[53344-73-3]2-chloro-4,4'-bipyridine</strong> and 6.5 ml of anhydrous hydrazine in 40 ml of dry pyridine was refluxed for 24 hours under argon and then concentrated. The residue was dissolved in methylene chloride, treated with activated carbon and the solvent was removed giving an oil which was crystallized from ether-hexane-methylene chloride. A 1.3 g portion of these crystals of 2-hydrazino-4,4'-bipyridine was combined with 50 ml of triethyl orthoacetate and heated on a steam bath for 1 hour. After standing overnight, hexane was added and after further standing, crystals separated. These crystals were collected and recrystallized from acetonehexane, giving the desired product as off-white crystals, mp 223-226 C.
2-(3,4-Difluorobenzoyl)-3-hydroxycrotononitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; water;
EXAMPLE 55 2-(3,4-Difluorobenzoyl)-3-hydroxycrotononitrile A solution of 10.2 g. of <strong>[71682-97-8]3,4-difluorobenzoylacetonitrile</strong>, 9.2 g. of triethyl orthoacetate and 20 ml. of acetic anhyride is heated on a steam bath for 0.5 hour and then poured into 200 ml. of water which is then heated on the steam bath for 2 hours. On cooling, the solid is filtered and then dissolved in methylene chloride. This solution is extracted with two portions of aqueous sodium bicarbonate and the aqueous extracts are combined and acidified with concentrated hydrochloric acid. The precipitate is extracted into methylene chloride, passed through a pad of Magnesol.(R)., heated and diluted with hexane. Upon cooling, colorless crystals result, yielding the title compound, m.p. 51°-54° C. Similarly prepared are 2-(2,5-difluorobenzoyl)-3-hydroxycrotononitrile, 2-(3,4,5-trimethoxybenzoyl)-3-hydroxycrotononitrile, 2-(2,4,6-trimethylbenzoyl)-3-hydroxycrotononitrile, and 2-(2,5-dichlorobenzoyl)-3-hydroxycrotononitrile.
step 1 : A mixture of <strong>[4635-08-9]5-bromopyridine-3,4-diamine</strong> (20 g, 107 mmol) and (EtO^CMe (100 mL) in HO Ac (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS(ESI) m/z: 212 [M+l] +.
step 1 : A mixture of <strong>[4635-08-9]5-bromopyridine-3,4-diamine</strong> (20 g, 107 mmol) and (EtO^CMe (100 mL) in HO Ac (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-1H-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS(ESI) m/z: 212 [M+l] +. step 2: To a solution of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate (10 g, 37 mmol) in anhydrous THF (200 mL) was added sodium hydride (4.5 g, 120 mmol) portionwise at 0 C. After stirring at 0C for 0.5 h, SEMCl (9.1g, 55.5 mmol) was added. The reaction mixture was stirred at RT for 5 h and then poured into water. The mixture was extracted with EtOAc. The organic layers were dried (Na2SO i), filtered, and concentrated in vacuo. The crude product was purified by S1O2 chromatography to afford 8.0 g (63%) of a 1 :1 mixture of 7-bromo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-c]pyridine and 7-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- c]pyridine as an oil: MS(ESI) m/z: 342 / 344 [M+l] +.
step 1 : A mixture of <strong>[4635-08-9]5-bromopyridine-3,4-diamine</strong> (20 g, 107 mmol) and (EtO^CMe (100 mL) in HO Ac (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS(ESI) m/z: 212 [M+l] +. step 2: To a solution of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate (10 g, 37 mmol) in anhydrous THF (200 mL) was added sodium hydride (4.5 g, 120 mmol) portionwise at 0 C. After stirring at 0C for 0.5 h, SEMCl (9.1g, 55.5 mmol) was added. The reaction mixture was stirred at RT for 5 h and then poured into water. The mixture was extracted with EtOAc. The organic layers were dried (Na2SO i), filtered, and concentrated in vacuo. The crude product was purified by S1O2 chromatography to afford 8.0 g (63%) of a 1 :1 mixture of 7-bromo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-c]pyridine and 7-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- c]pyridine as an oil: MS(ESI) m/z: 342 / 344 [M+l] +. step 2: To a solution of 7-bromo-lH-imidazo[4,5-c]pyridine (3 g, 15. 6 mmol) in DMF (10 mL) was added Pd(PPh3)4 (1.0 g) and Zn(CN)2 (1.2 g, 10 mmol). The reaction mixture was irradiated in a microwave at 100 C for 2 h under Ar. The reaction mixture was poured into aqueous NuEta4OmicronEta and extracted with DCM. The organic extracta were dried (Na2S04), filtered and concentrated in vacuo. The crude product was purified by S1O2 chromatography to afford 1.5 g (67%) of 3H-imidazo[4,5-c]pyridine- 7-carbonitrile as a white solid; MS(ESI) m/z: 145.0 [M+l] +.
step 1 : A mixture of <strong>[4635-08-9]5-bromopyridine-3,4-diamine</strong> (20 g, 107 mmol) and (EtO^CMe (100 mL) in HO Ac (40 mL) was stirred and heated at reflux for 2 h then the EtOH was removed by distillation to afford a solid. The solid was filtered to give 15 g (52%) of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate as a light yellow solid: MS(ESI) m/z: 212 [M+l] +. step 2: To a solution of 7-bromo-2-methyl-lH-imidazo-[4,5-c]pyridine acetate (10 g, 37 mmol) in anhydrous THF (200 mL) was added sodium hydride (4.5 g, 120 mmol) portionwise at 0 C. After stirring at 0C for 0.5 h, SEMCl (9.1g, 55.5 mmol) was added. The reaction mixture was stirred at RT for 5 h and then poured into water. The mixture was extracted with EtOAc. The organic layers were dried (Na2SO i), filtered, and concentrated in vacuo. The crude product was purified by S1O2 chromatography to afford 8.0 g (63%) of a 1 :1 mixture of 7-bromo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-c]pyridine and 7-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- c]pyridine as an oil: MS(ESI) m/z: 342 / 344 [M+l] +. step 2: To a solution of 7-bromo-lH-imidazo[4,5-c]pyridine (3 g, 15. 6 mmol) in DMF (10 mL) was added Pd(PPh3)4 (1.0 g) and Zn(CN)2 (1.2 g, 10 mmol). The reaction mixture was irradiated in a microwave at 100 C for 2 h under Ar. The reaction mixture was poured into aqueous NuEta4OmicronEta and extracted with DCM. The organic extracta were dried (Na2S04), filtered and concentrated in vacuo. The crude product was purified by S1O2 chromatography to afford 1.5 g (67%) of 3H-imidazo[4,5-c]pyridine- 7-carbonitrile as a white solid; MS(ESI) m/z: 145.0 [M+l] +. step 4: To a stirred solution of l-(tetrahydro-2H-pyran-2-yl)-lH-imidazo[4,5-c]- pyridine-7-carbonitrile and 3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-c]pyridine-7- carbonitrile (1.4 g, 6 mmol, 1 :1 mixture) in NH3/MeOH (7M, 10 mL) was added Raney-Ni (200 mg). The reaction mixture was stirred under an atmospheric pressure of H2 overnight. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 1.1 g (75%) of a 1 :1 mixture of the title compounds as an oil: MS(ESI) m/z: 233.1 [M+l] +.
(S)-tert-butyl (1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-phenylethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In toluene; at 80℃; for 2.0h;Inert atmosphere;
To (5)-tert-butyl (l-hydrazinyl-l-oxo-3-phenylpropan-2-yl)carbamate (120 mg, 0.43 mmol) in PhMe (4.3 mL) was added triethyl orthoacetate (396 mu^, 2.15 mmol) and AcOH (443 mu,, 7.73 mmol). The resulting solution was stirred at 80 C for 2 h, then concentrated in vacuo and used in the subsequent step without purification. MS(ESI+) m/z 304.3 (M+H)+
methyl 5-chloro-2-methylbenzo[d]oxazole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid; at 100℃; for 18h;
c) Methyl 5-chloro-2-methylbenzo[d]oxazole-7-carboxylate A solution of <strong>[5043-81-2]methyl 3-amino-5-chloro-2-hydroxybenzoate</strong> (1.32 g, 6.53 mmol), triethylorthoacetate (4 mL, 21.2 mmol), and p-toluenesulfonic acid (40 mg, 0.21 mmol) was heated at 100 C. for 18 hours. The resulting mixture was concentrated in vacuo and the resulting residue purified by flash column chromatography on silica gel with 30% EtOAc/heptane to yield methyl 5-chloro-2-methylbenzo[d]oxazole-7-carboxylate.
6-(6-methyl-1,2,4,5-tetrazin-3-yl)nicotinic Acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfur; hydrazine hydrate; at 100℃; for 2h;Inert atmosphere;
6-Cyanonicotinic acid (593 mg, 4.00 mmol, 1 equiv), sulfur (90 mg,2.80 mmol, 0.7 equiv), and triethyl orthoacetate (18.3 mL, 100 mmol,25 equiv) were placed in a round-bottomed flask and flushed with N2. Hydrazine monohydrate (15 mL, 300 mmol, 75 equiv) was added andthe reaction mixture was stirred vigorously at 100 C for 2 h. After cooling to r.t., the solution was diluted with EtOAc (200 mL) and washed with 10% (m/m) citric acid solution (2 × 75 mL), sat. aq NaHCO3 (2 × 50 mL) and brine (30 mL), and dried (MgSO4). The solution was filtered and the solvent was evaporated. The crude dihydrotetrazine was suspended in CH2Cl2 (150 mL) and oxidized with in situ generated nitrous gases (NOx) until TLC (eluent: CH2Cl2-MeOH, 10:1v/v) indicated the consumption of all dihydrotetrazine and the solution turned deep red. After evaporation of the solvent, the crude product was purified by column chromatography (SiO2, CH2Cl2-MeOH, 9:1 v/v) to yield 218 mg (25%) of 6 as a purple-red solid.
With hydrogenchloride; In ethanol; water; at 100℃; for 16h;
To a solution of intermediate 13 (16.00 g, 89.88 mmol) in EtOH (60 mL) was added triethyl orthoacetate (50 mL) and conc. HCl (4 mL) and the mixture was stirred at 100 C for 16 hours. The mixture was concentrated and diluted with water and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (mobile phase gradient: from 100% petrol, 0% EtOAc to 0% petrol, 100% EtOAc). The product containing fractions were collected and the solvent was evaporated to give 11 g of intermediate 14 (57% yield, yellow solid).
With acetic acid; In ethanol; at 110℃; for 24h;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:2,7-Dimethylquinazolin-4(3H)-one (8a). This compound was prepared from<strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (100 mg, 0.67 mmol), triethyl orthoacetate (217 mg, 245 L, 1.34 mmol)and acetic acid (121 mg, 115 L, 2.01 mmol) in absolute ethanol (2 mL) at 110 °C for 24 h to give105 mg (90percent) as a white solid, m.p. 260?262 °C (lit [49] m.p. 263?264 °C); IR (CHCl3): 3169, 1677 cm-1;1H-NMR (400 MHz, CDCl3): delta 11.6 (br s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.47 (br s, 1H), 7.29 (dd, J =8.1, 1.0 Hz, 1H), 2.57 (s, 3H), 2.51 (s, 3H); 13C-NMR (101 MHz, CDCl3): delta 163.9, 153.2, 149.5, 146.0,128.0, 126.8, 126.1, 117.9, 22.1, 22.0; HRMS (ESI): m/z for C10H10N2O [M + 1]+: calcd.: 175.0871; found:175.0867.
With acetic acid; In ethanol; at 110℃; for 24h;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:
With acetic acid; In ethanol; at 110℃; for 24h;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:
With acetic acid; In ethanol; at 110℃; for 12h;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 5%ether in pentane. The following compounds were prepared:
A mixture of compound B112 (1.00 g, 5.32 mmol) in 1,1,1 -triethoxy ethane (4.40 g, 27.1 mmol) was stirred at 120C under N2 for 2 hours to form a black red solution. LCMS showed 91.7% of desired MS. Most of MeC(OEt)3 was removed under reduced pressure to give compound B113 (950 mg) as a red powder.
General procedure: N -(2-aminobenzoyl)benzotriazoles (0.25 mmol) 1 previously synthesized by our group were reacted with orthoester (0.50 mmol) 2 and ammonium acetate (1.0 mmol) in dioxane for 6-10 h. After completion of the reaction, the solvent was evaporated under reduced pressure. The reaction mixture was purified by column chromatography over silica gel with a EtOAc/n-hexane mixture (from 1:2 or 1:1) to obtain white crystals (62%-95%).
With toluene-4-sulfonic acid; In toluene; at 130℃; for 1.0h;
Triethyl orthoacetate (CAS: 78-39-7; 4.82 mL, 26.48 mmol) was added to a stirred mixture of <strong>[934758-27-7]2-amino-6-bromopyridin-3-ol</strong> (CAS: 934758-27-7; 4.17 g, 22.06 mmol) and /;-tolucncsulfonic acid monohydrate (CAS: 104-15-4; 0.21 g, 1.10 mmol) in toluene (24.2 mL). The mixture was stirred at 130 C for 1 h and then the solvent evaporated in vacuo. The residue was purified by flash column chromatography (Si02; EtOAc in heptane, gradient from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate l7a as a yellow solid (0.27 g, 65%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
HazMat Fee +
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
