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Chemical Structure| 3473-63-0
Chemical Structure| 3473-63-0
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Product Details of [ 3473-63-0 ]

CAS No. :3473-63-0 MDL No. :MFCD00012866
Formula : C3H8N2O2 Boiling Point : -
Linear Structure Formula :NH2CHNH·CH3COOH InChI Key :XPOLVIIHTDKJRY-UHFFFAOYSA-N
M.W : 104.11 Pubchem ID :160693
Synonyms :
Chemical Name :Formamidine acetate

Calculated chemistry of [ 3473-63-0 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.33
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 3.0
Molar Refractivity : 26.72
TPSA : 87.17 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.62 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.82
Log Po/w (XLOGP3) : -0.97
Log Po/w (WLOGP) : -0.36
Log Po/w (MLOGP) : -0.99
Log Po/w (SILICOS-IT) : -0.48
Consensus Log Po/w : -0.4

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : 0.13
Solubility : 139.0 mg/ml ; 1.34 mol/l
Class : Highly soluble
Log S (Ali) : -0.38
Solubility : 43.9 mg/ml ; 0.422 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 0.53
Solubility : 356.0 mg/ml ; 3.42 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 3473-63-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280 UN#:N/A
Hazard Statements:H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3473-63-0 ]

* 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 [ 3473-63-0 ]
  • Downstream synthetic route of [ 3473-63-0 ]

[ 3473-63-0 ] Synthesis Path-Upstream   1~87

  • 1
  • [ 3473-63-0 ]
  • [ 7579-20-6 ]
  • [ 19178-25-7 ]
YieldReaction ConditionsOperation in experiment
35% at 160℃; for 0.5 h; Microwave irradiation A Biotage microwave vial was charged with 3-aminoisonicotinic acid (691 mg, 5.0 mmol), formamidine acetate (573 mg, 5.5 mmol), and ethanol (10 mL). The reaction mixture was heated in the microwave at 160 °C for 30 min, diluted with H20 (20 mL), and cooled to 0 °C. The suspension was filtered and the solids were washed with cold H20 (10 mL) to provide quinazoline A2 (259 mg, 35percent) as a white solid: LC-MS (>98percent) m/z = 148.0[M+H], Rt= 0.604.
Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1370 - 1387
[2] Patent: WO2014/179237, 2014, A1, . Location in patent: Paragraph 00491
  • 2
  • [ 4651-81-4 ]
  • [ 3473-63-0 ]
  • [ 14080-50-3 ]
YieldReaction ConditionsOperation in experiment
77.7% at 80℃; for 24 h; 250 mL of a three-necked flask,A solution of methyl 2-aminothiophene-3-carboxylate (20 g, 0.127 mol) and formamidine acetate (30 g, 0.29) was dissolved in ethanol at 80 °C for 24 hours and the reaction was complete until the reaction was complete. After the reaction solution was cooled, the mixture was stirred in water,The precipitated solid was filtered and the cake was dried to obtain 15 g of soil yellow powder in a yield of 77.7percent.
Reference: [1] Patent: CN107253964, 2017, A, . Location in patent: Paragraph 0101; 0102; 0103; 0104
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 245 - 256
  • 3
  • [ 3473-63-0 ]
  • [ 150464-08-7 ]
  • [ 21190-16-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2310 - 2315
  • 4
  • [ 3473-63-0 ]
  • [ 61241-07-4 ]
  • [ 13877-56-0 ]
Reference: [1] Nucleosides and Nucleotides, 1995, vol. 14, # 1-2, p. 105 - 116
  • 5
  • [ 3473-63-0 ]
  • [ 16617-46-2 ]
  • [ 2380-63-4 ]
YieldReaction ConditionsOperation in experiment
84.1% at 120℃; for 45 h; Inert atmosphere 1L the reaction bottle 54.05g (0.5mol) 3-amino-4-cyano pyrazole, 540 ml in glycol monomethyl ether, under the protection of nitrogen at room temperature by adding 67.68g (0.65mol) carboximidamide acetate, system protection of nitrogen, 120 °C reaction 45h. After the reaction is complete cooling to room temperature, the system there is a large amount of solid precipitated, filtering, ponders the cake to use 100 ml methyl alcohol minute 2 run washes, and get crude intermediate 62.2g, crude product by 250 ml of toluene and 250 ml acetic acid re-crystallization, filtration, ≥ 99percent purity by white solid 56.82g, yield: 84.1percent, HPLC: 99.91percent.
Reference: [1] Patent: CN105859728, 2016, A, . Location in patent: Paragraph 0070; 0071; 0072
[2] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1132 - 1135
  • 6
  • [ 3473-63-0 ]
  • [ 333-20-0 ]
  • [ 7552-07-0 ]
Reference: [1] Patent: US2009/124655, 2009, A1, . Location in patent: Page/Page column 14
[2] Patent: US2009/131440, 2009, A1, . Location in patent: Page/Page column 19
  • 7
  • [ 3473-63-0 ]
  • [ 3435-28-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4448 - 4458
  • 8
  • [ 3473-63-0 ]
  • [ 141-97-9 ]
  • [ 3524-87-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1601 - 1606
  • 9
  • [ 3473-63-0 ]
  • [ 4949-44-4 ]
  • [ 124703-78-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 16, p. 2031 - 2036
[2] Patent: CN108395408, 2018, A, . Location in patent: Paragraph 0073; 0100-0102
  • 10
  • [ 30414-53-0 ]
  • [ 3473-63-0 ]
  • [ 124703-78-2 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 5, p. 1369 - 1370
[2] Patent: US5278175, 1994, A,
  • 11
  • [ 107-31-3 ]
  • [ 6290-49-9 ]
  • [ 3473-63-0 ]
  • [ 695-87-4 ]
Reference: [1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 10, p. 4179 - 4191
  • 12
  • [ 3473-63-0 ]
  • [ 1885-29-6 ]
  • [ 15018-66-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 421 - 425
  • 13
  • [ 3473-63-0 ]
  • [ 109-77-3 ]
  • [ 16357-69-0 ]
  • [ 26979-05-5 ]
Reference: [1] Organic Preparations and Procedures International, 2002, vol. 34, # 3, p. 321 - 325
  • 14
  • [ 28112-11-0 ]
  • [ 3473-63-0 ]
  • [ 16357-69-0 ]
Reference: [1] Liebigs Annalen der Chemie, 1980, # 3, p. 372 - 388
  • 15
  • [ 3473-63-0 ]
  • [ 109-77-3 ]
  • [ 16357-69-0 ]
Reference: [1] Patent: EP1462452, 2004, A1, . Location in patent: Page 23
  • 16
  • [ 5345-47-1 ]
  • [ 3473-63-0 ]
  • [ 24410-19-3 ]
Reference: [1] ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527
  • 17
  • [ 4389-45-1 ]
  • [ 3473-63-0 ]
  • [ 77287-34-4 ]
  • [ 19181-54-5 ]
YieldReaction ConditionsOperation in experiment
94% at 180℃; for 3 h; 2-Amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol) and formamide (32.5 mL, 0.8200 mol) wereminxed in a 2L R.B fitted with Mechanical stirrer. The reactionminxture was heated at 180 °C for 3h. The reaction completion was monitored by LCMS. After completion, the reactionminxture was cooled to RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reactionminxture neutralized with 1 .5N HC1 solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94percent) as an off white solid. 1H NMR (400 MHz, DMSO-d6, ppm) 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC/MS(ESI)161 (M+H).
Reference: [1] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00223
  • 18
  • [ 3473-63-0 ]
  • [ 5202-85-7 ]
  • [ 16064-14-5 ]
YieldReaction ConditionsOperation in experiment
88.6% for 16 h; Reflux General procedure: To a refluxing solution of corresponding anthranilamide (1 mmol) in ethanol (30 mL) was added formamidine acetate (2 mmol). The solution was refluxed for about 6 h (monitored by TLC & LCMS for completion), and solvent evaporated under reduced pressure. The residue was further diluted with water (30 mL) and ethyl acetate (50 mL) and the layers separated. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexane: ethyl acetate as eluent to give the corresponding quinazolin-4(3H)-one (4a-b) in good yield.
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 613 - 627
  • 19
  • [ 3473-63-0 ]
  • [ 89-77-0 ]
  • [ 31374-18-2 ]
YieldReaction ConditionsOperation in experiment
95% Microwave irradiation 10g of compound BB1, formamidine acetate 8g (1.3eq) into 100ml eggplant-shaped flask, uniformly mixed, the microwave reaction 4πη (60percent power). After cooling, 30ml of water was added, the solid was washed and filtered to give the BB2 compound 10g, yield 95percent.
88.1% at 120℃; for 16 h; 4-Chloro-2-aminobenzoic acid(10.26, 60.0mmol) and formamidine acetate (12.5g, 120.0mmol]Into the 250mL ethylene glycol monomethyl ether, heated to 120 ° C, insulation reaction 16h,Cooled to room temperature, concentrated to dryness under reduced pressure,Washed with 0.0lmol / L ammonia to neutral, filtered and dried to give an off-white solid of 7-chloro-3H-quinazolin-4-one in a yield of 88.1percent
Reference: [1] Patent: CN103570738, 2016, B, . Location in patent: Paragraph 0303; 0304; 0306
[2] Patent: CN103382182, 2016, B, . Location in patent: Paragraph 0272-0275
[3] Patent: WO2012/88712, 2012, A1, . Location in patent: Page/Page column 16
[4] MedChemComm, 2015, vol. 6, # 1, p. 222 - 229
  • 20
  • [ 3473-63-0 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
YieldReaction ConditionsOperation in experiment
94% at 100℃; for 8 h; In a 100 mL round bottom flask, 2.16 g (10 mmol) of 2-amino-5-bromobenzoic acid was added.Formamidine acetate 1.04g (10mmol), isopropanol 30ml,Stir at 100 ° C for 8 hours, cool,Precipitated white solid was filtered off with suction, and dried to give 6-bromo -4 (3H) - quinazolinone 2.1g, 94percent yield.
Reference: [1] Patent: CN108239067, 2018, A, . Location in patent: Paragraph 0066-0068
[2] Patent: WO2008/89307, 2008, A2, . Location in patent: Page/Page column 44-45
[3] Patent: WO2008/89310, 2008, A2, . Location in patent: Page/Page column 47
  • 21
  • [ 4692-98-2 ]
  • [ 3473-63-0 ]
  • [ 32084-59-6 ]
Reference: [1] Patent: WO2008/8539, 2008, A2, . Location in patent: Page/Page column 121
  • 22
  • [ 20776-50-5 ]
  • [ 3473-63-0 ]
  • [ 194851-16-6 ]
YieldReaction ConditionsOperation in experiment
98% for 13 h; Heating / reflux 3) Formamidine acetate (1.96 g, 18.9 mmol) and 2-ethoxyethanol (25 mL) were added to 4-bromoanthranyl acid (1.63 g, 7.55 mmol) and the mixture was heated under reflux for 7 hrs. Formamidine acetate (1.45 g) was added and the mixture was further refluxed for 6 hrs. Dilute aqueous ammonia solution (30 mL) was added, and after stirring for a while, the product was collected by filtration and dried to give the objective 7-bromo-3H-quinazolin-4-one (1.67 g, 98percent). [CHEMMOL-00362] [0144] 1H NMR (DMSO-d6) δ ppm: 7.69 (dd, J=1.9, 8.4 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.14 (br s, 1H).
Reference: [1] Patent: US2004/116422, 2004, A1, . Location in patent: Page/Page column 31
  • 23
  • [ 3473-63-0 ]
  • [ 5326-47-6 ]
  • [ 16064-08-7 ]
YieldReaction ConditionsOperation in experiment
81% for 20 h; Heating / reflux A solution of 2-AMINO-5-IODOBENZOIC acid (14.2 g, 50 mmol) and formamidine acetate (6.75 g, 65 mmol) in ethanol (200 ML) was refluxed for 20 hours. After cooling to 0°C the solid product was collected by filtration. Further drying in a vacuum provided 6-IODO-4-QUINAZOLINONE (11 G, 81percent) as a gray solid.
Reference: [1] Patent: WO2004/46101, 2004, A2, . Location in patent: Page 19
[2] Patent: WO2004/43940, 2004, A1, . Location in patent: Page 80
  • 24
  • [ 3473-63-0 ]
  • [ 6705-03-9 ]
  • [ 19181-64-7 ]
Reference: [1] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0502
  • 25
  • [ 3473-63-0 ]
  • [ 4294-95-5 ]
  • [ 16064-24-7 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: for 12 h; Heating / reflux
Stage #2: With ammonia In 2-methoxy-ethanol at 25℃; for 0.5 h;
Method 31; 7-Methoxy-3H-quinazolin-4-one; A mixture of 2-amino-4-methoxy benzoic acid (Method 30; 4.85 g, 88.9 mmol) and formamidine acetate (18.49 g, 177.8 mmol) in 2-methoxyethanol (100 ml) was stirred at reflux for 12 h. The reaction mixture was cooled to 25 °C and diluted with 0.01 M ammonia (100 ml). The mixture was then stirred at 25 0C for 30 min and the resulting solid was collected by filtration. The solid was washed with 0.01M ammonia and water. The product was dried by high vacuum to obtain a light brown solid 11.5 g (73percent). NMR: 12.10 (s, br, IH), 8.05 (m, 2H), 7.10 (m, 2H), 3.90 (s, 3H); m/z 167.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 4963 - 4966
[2] Patent: WO2007/71963, 2007, A2, . Location in patent: Page/Page column 52
[3] Patent: CN104447769, 2016, B, . Location in patent: Paragraph 0056-0057
  • 26
  • [ 3473-63-0 ]
  • [ 616-79-5 ]
  • [ 6943-17-5 ]
YieldReaction ConditionsOperation in experiment
92% at 124℃; for 1 h; Microwave irradiation A mixture of 2-amino-5-nitrobenzoic acid (36.9 g, 0.203 mol) and formamidine acetate (42.5 g, 0.360 mol) in ethylene glycol monomethyl ether (150mL) was heated under reflux for 30 h, or the reaction vessel was open and heated under microwave irradiation for 1 h at 124 °C. After completion of the reaction, the excess ethyleneglycol monomethyl ether was removed by vacuo. The residue was washed by 0.01 M ammonia water to give compound (2) [78 percent thermal, 92 percent microwave], m.p.: 283 °C [Lit. m.p.: 283-285 °C]
78.5% Reflux To a 100 mL three-necked flask was added 2-amino-5-nitrobenzoic acid (3.64 g, 20 mmol)Acetamidine acetate (4.16 g, 40 mmol)50 mL of ethylene glycol monomethyl ether,Reflux reaction.TLC monitoring, after the reaction, the reaction solution into the beaker,Set at -20 freezer overnight, filtered yellow solid 3.0g,Yield 78.5percent
Reference: [1] Asian Journal of Chemistry, 2016, vol. 28, # 1, p. 95 - 98
[2] Patent: CN106083836, 2016, A, . Location in patent: Paragraph 0178; 0179; 0180
[3] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 393 - 405
  • 27
  • [ 3473-63-0 ]
  • [ 619-17-0 ]
  • [ 20872-93-9 ]
YieldReaction ConditionsOperation in experiment
84% at 130℃; for 18 h; A mixture of 2-amino-4-nitrobenzoic acid (10.0 g, 54.93 mmol) was refluxed at 130° C. for 18 h in methoxyethanol (50 mL) and formamidine acetate (11.43 g, 109.81 mmol).
The clear reaction mixture was cooled to room-temperature to form a yellowish precipitant.
The solvent was removed under vacuum, and the precipitant was washed several times with aqueous ammonia (0.01 M).
The solid was dried in vacuo to yield 8.9 g (84percent) of a light yellow powder. 1H NMR Data: dmso-d6-ppm (δ); 12.68 (1H), 8.37 (d, 1H), 8.33 (d, 1H), 8.26 (1H) and 8.23 (dd, 1H).
Reference: [1] Patent: US2016/376298, 2016, A1, . Location in patent: Paragraph 0220
[2] Spectroscopy Letters, 2012, vol. 45, # 7, p. 530 - 540,11
[3] Patent: CN103360382, 2016, B, . Location in patent: Paragraph 0228; 0244; 0245
  • 28
  • [ 28697-53-2 ]
  • [ 3473-63-0 ]
  • [ 76-83-5 ]
  • [ 15469-97-3 ]
  • [ 142822-28-4 ]
  • [ 33769-07-2 ]
Reference: [1] Tetrahedron, 1992, vol. 48, # 21, p. 4327 - 4346
  • 29
  • [ 3473-63-0 ]
  • [ 252932-48-2 ]
  • [ 5655-01-6 ]
YieldReaction ConditionsOperation in experiment
75% at 100 - 105℃; for 16 h; Step C; The title compound from Step B above (23 g) was dissolved in EtOH (210 ml) and formamidine acetate (23.3 g) added. The mixture was heated at 100-105 0C oil-bath temperature for 16 h. The mixture was cooled to room temperature and the precipitate collected by filtration. The precipitate was then washed with EtOH until the washing solution was colorless. The precipitate was then dried in HV to afford the product as a grey solid (15.3 g; 75 percent; MH+ = 136).
61% for 16 h; Reflux Step 3: 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one Into a 250-mL round-bottom flask was placed a solution of ethyl 3-amino-1H-pyrrole-2-carboxylate (10 g, 58.38 mmol, 1.00 equiv, 90percent) in ethanol (150 mL) and formamidine acetate (10 g, 94.13 mmol, 1.61 equiv, 98percent). The resulting solution was stirred at reflux for 16 h. The precipitates were collected by filtration, washed with ethanol and dried under reduced pressure to afford 5 g (61percent) of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one as a gray solid
Reference: [1] Patent: WO2008/63669, 2008, A1, . Location in patent: Page/Page column 67
[2] Patent: US2012/202785, 2012, A1, . Location in patent: Page/Page column 129
[3] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8411 - 8412
[4] Patent: US6693193, 2004, B1, . Location in patent: Page column 15-17
[5] Patent: WO2016/187183, 2016, A1, . Location in patent: Paragraph 0062
  • 30
  • [ 3473-63-0 ]
  • [ 5655-01-6 ]
YieldReaction ConditionsOperation in experiment
80% at 110℃; for 18 h; Example 46: l-(5-AUyl-4-chloro-5H-pyrrolo[3,2-rf]pyrimidin-7-yl)-2,2,2-trifluoro-l-[l-(4- fluorophenyl)-lH-indazol-5-yl]ethanol; To a solution of 3-amino-lH-pyrrole-2-carboxylic acid ethyl ester hydrochloride (3.4 g, 17.7 mmol, 1 equiv.) in 40 mL of EtOH was added formamidine acetic acid salt (2.8 g, 26.6 mmol) and the mixture warmed at 1100C. After 18 hours, the reaction was cool to room temperature and the solids were filtered, rinsed with EtOH, and dried to provide 1.92 g (80percent) of 3,5- dihydropyrrolo[3,2-?]pyrimidin-4-one as a beige solid.
80% at 83℃; for 18 h; Ethyl 3-amino-lH-pyrrole-2-carboxylate hydrochloride (3.00 g, 15.7 mmol) was dissolved in EtOH (40 mL). Formamidine acetic acid salt (2.44 g, 23.5 mmol) was added and the reaction mixture was heated under reflux at 83 °C for 18 h. The reaction mixture was cooled to r.t. and the precipitate was collected by filtration, washed with EtOH and dried in vacuo to give the title compound as a beige solid (1.70 g, 80percent). LCMS (ES+): 135.9 (M+H)+.
Reference: [1] Patent: WO2008/70507, 2008, A2, . Location in patent: Page/Page column 150
[2] Patent: WO2011/113798, 2011, A2, . Location in patent: Page/Page column 59
  • 31
  • [ 446-32-2 ]
  • [ 3473-63-0 ]
  • [ 16499-57-3 ]
YieldReaction ConditionsOperation in experiment
99% for 24 h; 7-fluoroquinazoline-4(3H)-one
2-amino-4-fluorobenzoic acid (13.5 g, 87 mmol) was dissolved in ethanol (15 mL), added to formamidine acetate (18.1 g, 174 mmol) and refluxed for 1 d.
Water (250 mL) was then added, the precipitated product was filtered out and washed with 70percent ethanol. (Yield: 14.2 g, 99percent).
[Alternatively, the conversion was conducted in several cases (e.g. in the production of exemplary compound 881) without solvent, with formamide at 175° C.]
96.4% for 24 h; Reflux A mixture of 2-amino-4-fluorobenzoic acid (50.0 g, 0.323 mol), formamidine acetate (67.0 g, 0.644 mol) and ethanol (300 mL) was heated and refluxed for 24 h and the reaction was monitored by thin-layer chromatography (TLC).
The reaction mixture was poured into ice-water, then filtered and the filter cake was washed with 50 percent ethanol, dried to obtained 1 as white solid
14
(51.0 g, 96.4percent) and was used for next step without further purification.
Mp 260.1-261.0 °C. ESI-MS m/z: [M-H]-163.1. 1H NMR (400 MHz, CDCl3) δ 12.35 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 9.8 Hz, 1H), 7.37 (t, J = 8.8 Hz, 1H).
96.4% at 80℃; for 24 h; To sequentially with 300 ml of anhydrous ethanol is added in three-necked bottle 50.0g of 4-fluoro-2-aminobenzoic acid and 67.0g carboximidamide acetate, mixture heating reflux reaction 24h. After the reaction, most of the solvent to dryness under reduced pressure, the reaction solution is poured into the 1000 ml in sodium chloride aqueous solution stirring 30 min, filtered, with 60percent aqueous solution of ethanol of the washing, drying, be 51.0g white solid, i.e., 7- [...] -4-one (II), yield: 96.4percent.
96.4% for 24 h; Reflux To a three-necked flask equipped with 300 mL of absolute ethanol was added 50.0 g of 4-fluoro-2-aminobenzoic acid and67.0 g of formamidine acetate, the mixture was heated to reflux for 24 h. After completion of the reaction, most of the solvent was evaporated under reduced pressure,The reaction solution was poured into 1000 mL of sodium chloride aqueous solution for 30 min,The filter cake was washed with 60percent aqueous ethanol and dried to give 51.0 g of a white solid,Namely, 7-fluoroquinazolin-4-one (II) in a yield of 96.4percent.
96.4% for 24 h; Reflux To a three-necked flask equipped with 300 mL of absolute ethanol was added 50.0 g4-fluoro-2-aminobenzoic acid and67.0gAcetic acid formamidine,Acetamidine AcetateThe mixture was heated to reflux for 24 h.After completion of the reaction, most of the solvent was evaporated under reduced pressure, and the reaction solution was poured into 1000 mL of sodium chloride aqueous solution for 30 min,The filter cake was washed with 60percent aqueous ethanol, dried,To give 51.0 g of a white solid, i.e., 7-fluoroquinazolin-4-one (II), in a yield of 96.4percent.
96.4% for 24 h; Reflux Followed by a three-necked flask equipped with 300 mL of absolute ethanol50.0 g of 4-fluoro-2-aminobenzoic acid and67.0 g formamidine acetate,The mixture was heated to reflux for 24 h.The reaction was completed, most of the solvent was evaporated to dryness under reduced pressure,The reaction solution was poured into 1000mL of sodium chloride solution and stirred for 30min,Suction filtered, the filter cake was washed with 60percent aqueous ethanol, dried,51.0 g of a white solid was obtained,7-fluoroquinazolin-4-one (II), yield: 96.4percent.
95.1% for 24 h; Reflux Add 50.0 g (322.6 mmol) of 4-fluoro-2-aminobenzoic acid to a three-necked flask containing 300 mL of absolute ethanol in sequence.67.0 g (650.5 mmol) of formamidine acetate, and the mixture was heated under reflux for 24 h.After the reaction was completed, most of the solvent was evaporated under reduced pressure, and the mixture was poured into 1000.0 mL of sodium chloride aqueous solution, stirred for 30 min, and filtered.The filter cake was washed with a 60percent aqueous solution of ethanol.Drying, 50.0 g of white solid, yield 95.1percent.
91%
Stage #1: at 165℃; for 2 h;
Stage #2: With sodium hydrogencarbonate In water for 1 h;
Step 1
A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 h.
The reaction mixture was suspended in H2O and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 h.
The brown solid was collected by filtration, washed with H2O and air dried to afford 8.42 g (91percent) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
Step 1A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 hours. The reaction mixture was suspended in water and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 hour. The brown solid was collected by filtration, washed with water and air dried to afford 8.42 g (91percent) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
91%
Stage #1: at 130℃; for 24 h;
Stage #2: With ammonia In 2-methoxy-ethanol; water
7-fluoroquinazolin-4(3H)-one: A mixture of 2-amino-4-fluorobenzoic acid (1.5 g, 9.4 mmol) and formamidine acetate (2.Og, 18.8 mmol) in ethyleneglycol monomethyl ether (15 mL) was heated at 13O0C for 24 h. After cooling to room temperature, ca. half of the solvent was evaporated and a white solid precipitated. Aqueous ammmonia (2 mL of 30percent ammonium hydroxide in 20 mL water) was added and the solid was filtered, was washed with water, was washed with hexanes, and was dried in vacuo to give 1.4 g (91percent yield) of the title compound. MS (AP/CI): 165.2 (M+H)+.
90% for 16 h; Heating / reflux 7-fluoro-3H-quinazolin-4-one
A solution of 2-amino-4-fluorobenzoic acid (8.8 g, 56.7 mmol) and formamidine acetate (23.63 g, 227 mmol, 4 equivalents) in ethoxyethanol (400 ml) was refluxed for 16 hours.
The solvent was removed in vacuo and the residue crystallized from methanol-water to provide the titled compound as a light brown solid (8.35 g, 90percent yield, M+1=165).
Elemental Analysis for: C8H5FN2O Calculated: C, 58.54; H, 3.07; N, 17.07 Found: C, 58.60; H, 3.19; N, 17.27
90% for 16 h; Heating / reflux EXAMPLE 1023 7-fluoro-3H-quinazolin-4-one <n="83"/>A solution of 2-amino-4-fluorobenzoic acid (8.8 g, 56.7 mmol) and formamidine acetate (23.63 g, 227 mmol, 4 equivalents) in ethoxyethanol (400 ml) was refluxed for 16 hours. The solvent was removed in vacuo and the residue crystallized from methanol-water to provide the titled compound as a light brown solid (8.35 g , 90percent yield, M+1 = 165). Elemental Analysis for: C8HsFN2O Calculated: C, 58.54; H, 3.07; N, 17.07 Found: C, 58.60; H, 3.19; N, 17.27
89% for 16 h; Heating / reflux Example 33 Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine; Formamidine acetate (31.2 g, 300 mmol) and 2-amino-4-fluorobenzoic acid (23.3 g, 150 mmol) are heated at reflux in ethoxyethanol for 16 h. The crude product is poured into saturate sodium bicarbonate solution. The solid is collected, washed, and dried, affording the titled 7-Fluoro-3H-quinazolin-4-one (21.8 g, 89percent).
88% for 18 h; Reflux A mixture of 2-amino-4-fluorobenzoic acid (126 g, 0.82 mol) and formamidineacetate (170 g, 1.64 mol) in 2-methoxyethanol (800 mL) washeated under reflux for 18 h, and the solution was concentrated.The residue was diluted with water, and the suspension was filtered,washed with water, and dried to give pure product (yield88percent). Mp 235–237 C. 1H NMR (500 MHz, DMSO) d 12.37 (s, 1H),8.19 (dd, J = 8.5, 6.5 Hz, 1H), 8.15 (s, 1H), 7.46 (dd, J = 10.0,2.5 Hz, 1H), 7.40 (td, J = 9.0, 2.5 Hz, 1H). HRMS (ESI): m/z calcdfor (C8H5FN2O+H)+: 165.0464; found: 165.0459.
83% at 140℃; for 18 h; Compound 1 (6.3 g, 41.0 mmol) and Compound 2 (8.5 g, 82.0 mmol) were added to ethyl acetate monomethyl ether (40 mL) and stirred at 140 ° C for 18 hr. After the completion of the reaction, the mixture was concentrated to dryness, diluted with EtOAc (methanol), and then evaporated, and evaporated, evaporated, and dried to give Compound 3 (5.6 g, 83percent).
82% for 16 h; Reflux 25.0 g (0.156 mol) of   2-amino-4-fluorobenzoic acid and 33.0 g (0.317 mol) of   formamidine acetate were suspended in 250 ml of   ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 21.1 g (Y=82percent) of   7-fluoro-3H-quinazolin-4-one.1H NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 8.19 (dd, J=8.8, 6.4, 1H), 8.14 (s, 1H), 7.45 (dd, J=10.1, 2.5, 1H), 7.39 (td, J=8.7, 2.6, 1H).
81% at 130℃; for 18 h; A mixture of 2-amino-4-fluorobenzoic acid (14.6 g, 94 mmol) and formamidine acetate (19.6 g, 18.8 mmol) in 2-methoxyethanol (110 mL) was heated at 130°C for 18 h. After cooling, the mixture was half evaporated and an off-white solid formed. The mixture was diluted with ammonia (25percent, 10 mL in 90 mL water) and the solid filtered off and washed with water. The solid was then washed with hexane and dried under high vacuum to afford the title compound (12.5 g, 81percent) as an off-white solid. MS: m/e = 165.2 (M+H+).
80% at 120℃; for 22 h; 2-Amino-4-fluorobenzoic acid lc (10 g, 0.065 mol)Was dissolved in 150 mL of 2-methoxyethanol,Formamidine acetate was added(16.79 g, 0.16 mol),Heated to 120 ° C,The reaction was stirred for 22 hours.The reaction solution was concentrated under reduced pressure,The residue was beaten with 50 mL of water, filtered, the filter cake rinsed with a small amount of ethanol,To give the title product 7-fluoroquinazolin-4 (3H) -one ld (8.42 g, gray powdery solid)Yield: 80percent.
69% for 10 h; Reflux A solution of 2-amino-4-fluorobenzoic acid 1 (31.5 g, 0.20 mol) and formamidine acetate (42.5 g, 0.36 mol) in 2-methoxyethanol (150 mL) was heated and refluxed for 10 h. The solvent was then removed under reduced pressure and the residue washed with ammonia water (0.01 M), and then dried to afford 2 (23.1 g, 69percent) as beige solid, mp: 237–239 C (lit.40 mp: 234 C).
65%
Stage #1: for 18 h; Heating / reflux
Stage #2: With ammonia In water for 1 h;
a) 2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol) was added and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4 (3H) -one as an off- white solid (10. 35 g, 65 percent yield): 1H-NMR (DMSO d6): 12.32 (br s, 1H), 8.19 (dd, 1H), 8.14 (s, 1H), 7.45 (dd, 1H), 7.39 (M, 1H) : MS (-ve ESI) : 163 (M-H)-, MS (+ve ESI): 165 (M+H) +.
65% for 18 h; Heating / reflux 2-AMINO-4-FLUOROBENZOIC acid (15 g, 96.7 mmol) was dissolved in 2-methoxyethanol (97 ml) and formamidine acetate (20.13 g, 193.4 mmol) was added before the mixture was heated at reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in 0.01 N aqueous ammonium hydroxide solution (250 ml) for 1 hour. The suspension was filtered, washed with water and dried over PHOSPHORUS PENTOXIDE to yield 7-fluoroquinazolin- 4 (3H)-one as an off-white solid (10. 35 g, 65 percent yield): 'H-NMR (DMSO d6): 12.32 (br s, 1H), 8.19 (dd, 1H), 8.14 (s, 1H), 7.45 (dd, 1H), 7.39 (M, 1H): MS (+VE ESI) : 165 (M+H) + MS (-ve ESI) : 163 (M-H)-
65% for 18 h; Heating / reflux 2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in 2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol) was added and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4 (3H) -one as an off- white solid (10. 35 g, 65 percent yield): 1H-NMR (DMSO D6) : 12.32 (br s, 1H), 8.19 (dd, 1H), 8.14 (s, 1H), 7.45 (dd, 1H), 7.39 (m, 1H) : MS (-ve ESI) : 163 (M-H)-, MS (+ve ESI) : 165 (M+H) +.

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  • [ 4815-24-1 ]
  • [ 18593-44-7 ]
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  • [ 69267-75-0 ]
  • [ 3473-63-0 ]
  • [ 89830-98-8 ]
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[2] Patent: US2011/9410, 2011, A1, . Location in patent: Page/Page column 30
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  • [ 52133-67-2 ]
  • [ 3473-63-0 ]
  • [ 7400-06-8 ]
Reference: [1] Archiv der Pharmazie, 2018, vol. 351, # 8,
  • 35
  • [ 3473-63-0 ]
  • [ 40876-98-0 ]
  • [ 6299-87-2 ]
YieldReaction ConditionsOperation in experiment
25%
Stage #1: With sodium hydroxide In water at 20℃; for 16 h;
Stage #2: With hydrogenchloride In water at 0℃; for 1 h;
In a 1 L round bottom flask, 55 g of sodium ethyloxalacetate (1.05 eq, 0.26 mol) and 26 g of formamidine acetate (1 eq, 0.25 mol) were added to a solution of sodium hydroxide (10 g) in 500 mL of water. The reaction mixture was stirred at room temperature for 16 hours.[00262] Concentrated HCl was added carefully to the mixture until pH = 1, a fine solid precipitated and the reaction mixture was stirred at 0°C for 1 hour. The solid was filtered then washed with water and ether. The white solid was then left in a vacuum oven heated at4O0C for 20 hours. Trituration in methanol gave the title compound in 25percent yield. 1H NMR(dβ-DMSO): 12.88 (IH, OH), 8.24 (s, IH), 6.83 (s, IH).
15% With sodium hydroxide In water at 20℃; for 12 h; To a solution of formamidine acetate (10 g, 96 mmol) in 200 mL of water was added diethyl oxalacetate sodium salt (21 g, 100 mmol) and sodium hydroxide (3.8 g, 96 mmol). The reaction mixture was stirred overnight at room temperature, before 6 N HCl was added carefully to adjust PH = 1. The mixture was allowed to stand overnight at 0 °C, and the resultant precipitate was filtered and dried in vacuum to give the desired product (2 g, 15percent) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.25 (s, 1H), 6.83 (s, 1H).
Reference: [1] Patent: WO2010/20432, 2010, A2, . Location in patent: Page/Page column 91
[2] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 30 - 44
[3] Patent: US2011/21500, 2011, A1, . Location in patent: Page/Page column 39
[4] Patent: US2011/59954, 2011, A1, . Location in patent: Page/Page column 71
[5] Patent: US2011/172218, 2011, A1, . Location in patent: Page/Page column 28
[6] Patent: US2011/195954, 2011, A1, . Location in patent: Page/Page column 79
  • 36
  • [ 3473-63-0 ]
  • [ 88330-76-1 ]
  • [ 6299-87-2 ]
YieldReaction ConditionsOperation in experiment
16.3% With sodium hydroxide In water at 25℃; for 16 h; (c) 6-hydroxypyrimidine-4-carboxylic acid _:To a solution of sodium (Z)-l,4-diethoxy-l,4-dioxobut-2-en-2-olate (55.0 g, 262 mmol) in water (500 mL) was added formamidine acetate (27.3 g, 262 mmol) and sodium hydroxide (10.5 g). After addition, the resulting mixture was stirred at 25 °C for 16 hours then concentrated and then acidified by added aqueous hydrochloric acid (IN) until pH = 1. The resulting solid was collected by filtration, washed with water and ether to give 6- hydroxypyrimidine-4-carboxylic acid (6.0 g, yield: 16.3percent). 1H NMR (400 MHz, DMSO- de) δ 12.89 (s, 1H), 8.24 (s, 1H), 6.83 (s, 1H).
Reference: [1] Patent: WO2015/198229, 2015, A1, . Location in patent: Page/Page column 22
  • 37
  • [ 3473-63-0 ]
  • [ 200116-47-8 ]
  • [ 6299-87-2 ]
Reference: [1] Patent: WO2005/4863, 2005, A1, . Location in patent: Page/Page column 132
  • 38
  • [ 383-63-1 ]
  • [ 3473-63-0 ]
  • [ 60406-75-9 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With hydrazine hydrate In methanol; ethanol at 0 - 20℃;
Stage #2: at 80℃; for 2.5 h;
Hydrazine monohydrate (4.8 g, 96 mmol) was dissolved in industrial methylated spirits (160 ml_) and cooled to 0 0C before ethyl trifluoroacetate (14 g, 100 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wl) was added dropwise. The resulting reaction mixture was then warmed to ambient temperature and stirred for 1 hour. After this time, the solvent was removed under vacuum and the residue re-dissolved in industrial methylated spirits (100 ml_). Formamidine acetate (9.9 g, 95 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wl) was then added and the reaction mixture heated to 80 0C for 2.5 hours. The reaction was then cooled to ambient temperature and the solvent removed under vacuum. To the residue was then added NaHCO3 (aq.) (100 ml_), and the product was extracted with ethyl acetate (2 x 100 ml_), dried over MgSO4, filtered and the solvent removed under vacuum. The crude product was then purified by flash chromatography (1 :3 hexane/ethyl acetate), giving -10 g of a pale peach oil, which crystallised on standing overnight. The crystals were then filtered, washed with hexane and dried overnight in an oven to afford (1-15a) as colorless crystals (8.73 g, 66 percent yield): 1H NMR (400 MHz, DMSO-d6): δ 8.81 (1 H).
20%
Stage #1: With hydrazine hydrate In ethanol at 0℃; for 2 h; Inert atmosphere
Stage #2: at 0℃; for 4 h; Inert atmosphere
To a stirred solution of hydrazine hydrate (3.52 g, 70.42 mmol) in EtOH (15 mL) under argon atmosphere efliyi 2. 2, 2-trifluoroacetate ( A; 5 g, 35.21 mniol) in EtOH (10 mL) dro wise for 15 min at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The volariies were concentrated under reduced pressure. Then the residue was dissolved in EtOH (25 mL.) under argon atmosphere was added forrnirnidamide acetate (3.66 g, 35.21 rnmol) at 0 "C. The reaction mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The volatiles were concentrated under reduced pressure. The residue was diluted with water (50 mL), basified with saturated sodium bicarbonate solution (50 mL) and extracted with EiOAc (2 x 50 mL). The combmed organic exiracis were dried over anhydrous Na?S0 and concentrated under rediiced ressiiie. The cmde material was purified by silica gel column chromatography (eluenfc 30percent EtOAc Hexane) to afford compound NB (1 g, 7.29 mmol, 20percent) as an off-white solid. 1H NMR (400 MHz, CDC1;): δ 12.60 (br s, 1H), 8.45 (s. Η).
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  • [ 1538-08-5 ]
  • [ 3473-63-0 ]
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Reference: [1] Patent: EP1710234, 2006, A1, . Location in patent: Page/Page column 62
  • 40
  • [ 67751-23-9 ]
  • [ 3473-63-0 ]
  • [ 25746-87-6 ]
YieldReaction ConditionsOperation in experiment
64% at 110 - 120℃; for 4 h; 4-(Dimethoxymethyl)pyrimidine (C11)
A mixture of (3E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (C10) (147 g, 0.85 mol) and formamidine acetate (131 g, 1.26 mol) was heated at 110-120° C. for 4 hours.
After cooling to room temperature, the reaction was poured into water (250 mL) and extracted with chloroform (5*100 mL).
The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
Distillation of the residue under vacuum afforded the product as an oil. Yield: 84 g, 0.54 mol, 64percent.
Boiling point: 45-50° C./0.2 torr. NMR data was obtained using the product of a reaction run under similar conditions. 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 6H), 5.21 (s, 1H), 7.46 (dd, J=5.1, 1.4 Hz, 1H), 8.68 (d, J=5.1 Hz, 1H), 9.12 (d, J=1.4 Hz, 1H).
Reference: [1] Patent: US2009/143385, 2009, A1,
[2] Patent: US2011/98272, 2011, A1, . Location in patent: Page/Page column 22
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  • [ 5922-60-1 ]
  • [ 3473-63-0 ]
  • [ 19808-35-6 ]
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  • 42
  • [ 3473-63-0 ]
  • [ 609-15-4 ]
  • [ 7752-72-9 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
The preparation of 4-hydroxyl-5-chloro-6-methylpyrimidine ;8.80g (0.16mol) of CH3ONa in methanol was added slowly to a solution of 11.30g (0.11mol of formimidamide in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 hrs after addition at room temperature. ;Followed by addition of 11.17g ( 0.068mol ) of ethyl 2-chloro-3-oxobutanoate, the mixture was continued stirring for another 5-7 hrs at room temperature. ;After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HCl, and then filtered to afford orange-yellow soilid, the water phase was extracted with ethyl acetate (3x50mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. ;The residue was dissolved to 50ml of ethyl acetate, stand overnight to obtain 6.48g as orange-yellow soilid with yield of 66percent. m.p. 181~184°C.
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
1) Preparation of 4-hydroxy-5-chloro-6-methylpyrimidine
Stirring at room temperature to a solution of methanol 50ml 11.30g (0.11mol) of formamidine acetate was added slowly dropwise 8.80g (0.16mol) of sodium methoxide methanol solution was dropwise completed stirring was continued at room temperature 2h. To the above solution was then added dropwise 11.17g (0.068mol) of 2-chloroacetyl ethyl acetate, the reaction was stirred for 5-7 hours at room temperature continued, monitored by TLC after completion of the reaction, the solvent was distilled off under reduced pressure, adjusted to pH = 5 with hydrochloric acid 1-6, orange solid was suction filtered, the aqueous phase with (3 × 50ml) and extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and desolvation. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66percent, m.p. 181 ~ 184 .
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
With stirring at room temperature, to 11.30g (0.11mol) of formamidine acetate in 50ml of methanol was slowly added dropwise 8.80g (0.16mol) of methanol solution of sodium methoxide, after dropwise addition, at room temperature and stirring was continued for 2h. To the above solution was then added dropwise 11.17g (0.068mol) of intermediate ethyl 2-chloroacetoacetate, continued stirring for 5-7 hours at room temperature. After completion of the reaction monitored by TLC, the solvent was distilled off under reduced pressure, adjusted with hydrochloric acid pH = 5 ~ 6, orange solid was suction filtered, the aqueous phase was extracted with ethyl acetate (3 × 50ml), dried over anhydrous magnesium sulfate, filtered, removing solvent. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66percent, m.p. 181 ~ 184 deg. C.
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
Stirring at room temperature to a solution of methanol 50ml 11.30g (0.11mol) of formamidine acetate was added slowly dropwise 8.80g (0.16mol) of sodium methoxide in methanol, stirring was continued at room temperature completion of dropwise 2h. Then added dropwise 11.17g (0.068mol) ethyl 2-chloroacetoacetate intermediate to the above solution, the reaction was stirred for 5-7 hours at room temperature continued. After completion of the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, adjusted to pH = 5 with hydrochloric acid to 6, orange solid was suction filtered, the aqueous phase with (3 × 50ml) and extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered off solution. The residue was dissolved in 50ml of ethyl acetate and allowed to stand overnight, and filtered to give an orange solid 6.48g. Yield 66percent
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
To a solution of 11.30 g (0.11 mol) methylhydrazine acetate in 50 ml of methanol was slowly added dropwise 8.80 g with stirring at room temperature.(0.16 mol) of sodium methoxide in methanol, and the mixture was stirred at room temperature for 2 h. Then 11.17 g (0.068 mol) was added dropwise to the above solution.Ethyl 2-chloro-acetoacetate was stirred at room temperature for 5-7 hours. After TLC monitoring was completed, the solvent was distilled off under reduced pressure and salt was used.The pH was adjusted to 5-6, and the orange solid was filtered by suction. The aqueous phase was extracted with ethyl acetate (3×50 ml), dried over anhydrous magnesium sulfate, and dissolved.The combined product was dissolved in 50 ml of ethyl acetate, allowed to stand overnight and filtered to give 6.48 g of an orange-yellow solid. Yield 66.0percent
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
A solution of 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise to a solution of 11.30 g (0.11 mol) of methylacetoacetate in 50 ml of methanol at room temperature with stirring, and the mixturewas stirred at room temperature for 2 hours. Then, 11.17 g (0.068 mol) of the intermediate 2-chloroacetoacetic acid ethylacetate was added dropwise to theabove solution, and the reaction was continued for 5-7 hours while stirring at room temperature. After the TLCmonitoring reaction was completed, the solvent was evaporated under reduced pressure, and the pH wasadjusted to 5-6 with hydrochloric acid. The orange solid was collected by suction filtration, and the aqueousphase was extracted with ethyl acetate (3×50 ml), dried over anhydrous magnesium sulfate, filtered and shaken.Dissolved. The residue was dissolved in 50 ml of ethyl acetate, allowed to stand overnight and filtered to give 6.48g of an orange-yellow solid. The yield of 66percent.
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
10343] A solution of 8.80 g (0.16 mol) of CH3ONa in methanol was added slowly to a solution of 11.30 g (0.11 mol) of formimidamideacetate in 50 mL of methanol at room temperature under stirring, the mixture was stirred for another 2 h after addition at room temperature. Followed by addition of 11.17 g (0.068 mol) of ethyl 2-chloro-3-oxobu- tanoate, the mixture was continued stirring for another 5-7 h at room temperature. Afier the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure and pH was adjusted to 5-6 with HC1, and then filtered to afford orangeyellow solid, the water phase was extracted with ethyl acetate (3x50 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was dissolved to 50 ml of ethyl acetate, stand overnight to obtain 6.48 g as orange-yellow solid with yield of 66percent. m.p. 181-184° C.
66%
Stage #1: With sodium methylate In methanol at 20℃; for 2 h;
Stage #2: at 20℃;
To a solution of 11.30 g (0.11 mol) of formamidine acetate in 50 ml of methanol, a solution of 8.80 g (0.16 mol) of sodium methoxide in methanol was slowly added dropwise with stirring at room temperature.Stirring was continued for 2 h at room temperature.Then, 11.17 g (0.068 mol) of an intermediate ethyl 2-chloroacetoacetate was added dropwise to the above solution, and the reaction was further stirred at room temperature for 5-7 hours.After the TLC monitoring reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was adjusted to pH 5 to 6 with hydrochloric acid, and filtered to give an orange-yellow solid.The aqueous phase was extracted with (3 × 50ml) of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, desolventized.The residue was dissolved in 50ml of ethyl acetate, allowed to stand overnight, and filtered to give an orange-yellow solid 6.48g. Yield 66percent,

Reference: [1] Patent: EP2913325, 2015, A1, . Location in patent: Paragraph 0451; 0452
[2] Patent: CN105348298, 2016, A, . Location in patent: Paragraph 0418; 0419; 0420
[3] Patent: CN105732585, 2016, A, . Location in patent: Paragraph 0368; 0369; 0370
[4] Patent: CN105777717, 2016, A, . Location in patent: Paragraph 0356; 0357; 0358; 0359
[5] Patent: CN104292169, 2018, B, . Location in patent: Paragraph 0457; 0458; 0459
[6] Patent: CN108059629, 2018, A, . Location in patent: Paragraph 0267-0270
[7] Patent: US2018/141961, 2018, A1, . Location in patent: Paragraph 0342; 0343
[8] Patent: CN107778298, 2018, A, . Location in patent: Paragraph 0400; 0401; 0402; 0403
[9] Journal of Fluorine Chemistry, 2017, vol. 201, p. 49 - 54
  • 43
  • [ 100130-05-0 ]
  • [ 7518-70-9 ]
  • [ 3473-63-0 ]
  • [ 98550-19-7 ]
Reference: [1] Patent: US5977102, 1999, A,
  • 44
  • [ 110-80-5 ]
  • [ 100130-05-0 ]
  • [ 3473-63-0 ]
  • [ 98550-19-7 ]
Reference: [1] Patent: US5821240, 1998, A,
  • 45
  • [ 3473-63-0 ]
  • [ 5472-38-8 ]
  • [ 6214-46-6 ]
YieldReaction ConditionsOperation in experiment
55%
Stage #1: With sodium ethanolate In ethanol at 0℃; for 0.0833333 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 48 h; Inert atmosphere
Stage #3: With hydrogenchloride In ethanol; water at 20℃; for 0.5 h; Inert atmosphere
General procedure: A solution of sodium ethoxide in ethanol was cooled to0 C under argon atmosphere. Diethyl 2-formylsuccinatewas added under stirring. After 5 min, the correspondingamidine was added at 0 C and stirring was continued at rtfor 3 days. Aqueous hydrogen chloride solution (5 percent) wasadded and it was stirred for 30 min. After addition of waterthe ethanol was removed in vacuo at 30 C. The precipitatewas filtered off to give compound 1 (X = H, Me, Ph, SMe;Y = H, R1 = Et)
Reference: [1] Monatshefte fur Chemie, 2016, vol. 147, # 4, p. 767 - 773
  • 46
  • [ 3473-63-0 ]
  • [ 5653-40-7 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
95.7% at 140 - 170℃; Compound 4 (5.0 g, 25.38 mmol) and formamidine acetate (4.0 g, 38.83 mmol) were dissolved in5 mL of DMSO and heated to 140–170 C under stirring. The initial black color went brown and somesolid was formed. The reaction mixture was constantly stirred for 4h and then cooled to 25 C. 50 mLH2O was added to the mixture and the product was obtained by filtration as a light yellow solid 5.0 gwith a yield of 95.7percent, m.p. 295.5–297.0 °C.
89%
Stage #1: Reflux
Stage #2: With ammonium hydroxide In water
A solution of 2-amino-4,5-dimethoxybenzoic acid 1 (2.02 g, 10 mmol) and formamidine acetate (2.10 g, 20 mmol) in 2-methoxyethanol (50 mL) was refluxed overnight. After evaporation of the solvent, the residue was stirred after adding 10percent NH4OH (18 mL). The resulting residue was filtered, washed with water, and dried to give compound 2 as a dark brown solid (1.83 g, 89percent). 1H NMR (300 MHz, DMSO-d6) δ: 12.11 (1H, s, NH), 8.0 (1H, s, -NCH), 7.44 (1H, s, aromatic-H), 7.14 (1H, s, aromatic-H), 3.90 (3H, s, -OCH3), 3.87 (3H, s, -OCH3).
Reference: [1] Molecules, 2018, vol. 23, # 1,
[2] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
[3] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 968 - 977
[4] Synthesis, 2004, # 3, p. 429 - 435
[5] Patent: CN104447769, 2016, B, . Location in patent: Paragraph 0048-0049
  • 47
  • [ 62009-47-6 ]
  • [ 3473-63-0 ]
  • [ 56973-26-3 ]
Reference: [1] Patent: EP2196460, 2010, A1, . Location in patent: Page/Page column 6
  • 48
  • [ 4815-36-5 ]
  • [ 3473-63-0 ]
  • [ 35978-39-3 ]
Reference: [1] Patent: WO2004/111057, 2004, A1, . Location in patent: Page 30
  • 49
  • [ 923283-63-0 ]
  • [ 3473-63-0 ]
  • [ 13877-55-9 ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 1 h; Compound 27: Formamidine acetate (40.3 mmol, 4.2 g) was added to a solution containing 26 (8.85 g, 36.7 mmol) in Hunig's base (40 mL) and n-BuOH (40 mL). The stirred solution was heated at 110° C. for 1 hour. After cooling to ambient temperature the resulting solid was collected, washed with dichloromethane, and dried under reduced pressure to afford 27 (4.46 g, 89percent), ES (+) MS m/e=137.
Reference: [1] Patent: US2007/27166, 2007, A1, . Location in patent: Page/Page column 84-85
  • 50
  • [ 2049-80-1 ]
  • [ 3473-63-0 ]
  • [ 16019-30-0 ]
YieldReaction ConditionsOperation in experiment
4 g
Stage #1: at 0 - 20℃; for 24 h; Inert atmosphere
Stage #2: With acetic acid In ethanol
Step 2:Sodium metal (4.5 g) was added slowly into ethanol (100 mL) in a 500 mlL round bottom flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature until all the sodium metal dissolved, before being cooled to 0°C. Diethyl 2- allylmalonate (12 g) was added into the reaction mixture, followed by formamidine acetate (6.24 g) under nitrogen atmosphere at 0°C. The reaction was stirred at room temperature for 24 hours under nitrogen atmosphere, before being quenched by acetic acid (20 mL), followed by water (100 mL). The white precipitate was filtered, washed with water (4 x 50 mL), methanol (2 x 50 mL) and dried under vacuum to afford 5- allylpyrimidine-4,6-diol (4 g) as white solid. NMR (DMSO-d6): δ 2.96 (d, 2H), 4.85 (dd, 1H), 4.91 (dd, 1H), 5.76 (dd, 1H), 7.89 (s, 1H), 11.64 (bs, 2H).
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3639 - 3648
[2] Patent: US2010/144758, 2010, A1, . Location in patent: Page/Page column 65-66
[3] Patent: WO2013/138436, 2013, A1, . Location in patent: Page/Page column 61
  • 51
  • [ 108-31-6 ]
  • [ 3473-63-0 ]
  • [ 557-24-4 ]
  • [ 32040-41-8 ]
Reference: [1] Journal of Chemical Research, 2008, # 3, p. 170 - 172
  • 52
  • [ 108-73-6 ]
  • [ 3473-63-0 ]
  • [ 34374-88-4 ]
Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 3, p. 581 - 583
  • 53
  • [ 96-26-4 ]
  • [ 3473-63-0 ]
  • [ 32673-41-9 ]
Reference: [1] Synthesis, 1983, # 7, p. 576
  • 54
  • [ 64-19-7 ]
  • [ 122-51-0 ]
  • [ 3473-63-0 ]
Reference: [1] Patent: JP5722560, 2015, B2, . Location in patent: Sheet 0056; 0057
  • 55
  • [ 122-51-0 ]
  • [ 3473-63-0 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 3, p. 673 - 683
  • 56
  • [ 33884-41-2 ]
  • [ 3473-63-0 ]
  • [ 87379-42-8 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1987, # 2, p. 318 - 324
  • 57
  • [ 18856-72-9 ]
  • [ 3473-63-0 ]
  • [ 87379-55-3 ]
  • [ 87379-42-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 3, p. 649 - 654
  • 58
  • [ 1421259-21-3 ]
  • [ 3473-63-0 ]
  • [ 86347-15-1 ]
YieldReaction ConditionsOperation in experiment
43%
Stage #1: With ammonia In ethanol; water at 120℃; for 2 h; Autoclave; Large scale
Stage #2: With hydrogenchloride In water; acetoneLarge scale
To a SS pressure reactor is added intermediate 2, 1154g, 4.53 mol, formamidine acetate, 939g, 9.02 mol, ethanol, 5280g and finally 25percent aqueous ammonia, 3050g, 44.9 mol. The mixture is heated at 120°C for 2h. Ethanol and ammonia is stripped at atmospheric pressure and the residue dissolved in 1200ml water and 700ml ethyl acetate. pH is adjusted to 9-10 with sodium carbonate and the water phase separated. The product is extracted to water by three successive washes with diluted hydrochloric acid. The pH of the acidic aqueous phase is adjusted to 9- 10 with sodium carbonate and the product extracted to 500ml ethyl acetate. The water phase is separated and the ethyl acetate removed at reduced pressure. The residual oil is dissolved in acetone, 4L, and the product precipitated as the HCl salt by addition of 37 percent hydrochloric acid to pH 6. Filtration and washing with acetone gives 366g of Medetomidine x HCl. A second crop of product, 96g, was isolated by distilling the solvent from the mother liquor followed by the addition of water free acetone. In total, 462g, 1.95 mol, 43percent, of pure Medetomidine x HCl was isolated.
Reference: [1] Patent: WO2013/14428, 2013, A1, . Location in patent: Page/Page column 36
  • 59
  • [ 134653-70-6 ]
  • [ 3473-63-0 ]
  • [ 110960-73-1 ]
Reference: [1] Patent: WO2011/42797, 2011, A1, . Location in patent: Page/Page column 69
  • 60
  • [ 3473-63-0 ]
  • [ 3788-94-1 ]
  • [ 110960-73-1 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1987, # 2, p. 318 - 324
  • 61
  • [ 937046-97-4 ]
  • [ 3473-63-0 ]
  • [ 159326-68-8 ]
YieldReaction ConditionsOperation in experiment
81% With potassium phosphate In ethanol at 78℃; for 18 h; To a stirred suspension of i-Amino-I H-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 ml.) was added formamidine acetate (181.3 g, 1.74 mol) .bul. and potassium phosphate- (370 g, 1.74 mol). The suspension was heated for 18 hours (at)5 78 0C (under N2), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved (on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow10 filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1percent yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23percent). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14percent) of clean product, bringing the total recovery to15 37.6g (81percent). 1H-NMR (CD3OD): δ 7.72 (s, 1H), 7.52 (dd, 1H, J =2.5, 1.6 Hz), 6.85 (dd, 1H1 J= 4.5, 1.6 Hz), 6.64 (dd, 1 H, J= 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].
81% With potassium phosphate In ethanol at 78℃; for 18 h; To a stirred suspension of 1 -Amino- lH-pyrrole-2-carbonitrile hydrochloride (50 g, 0.35 mol) in absolute ethanol (800 mL) was added formamidine acetate (181.3 g, 1.74 mol) and potassium phosphate (370 g, 1.74 mol). The suspension was heated for 18 hours at 78 0C (under N2), then cooled, filtered and concentrated to dryness in vacuo. The residue was mixed with ice water (2L) and the dark grayish-brown solids were collected by suction filtration. The filter cake was washed with water, sucked dry and the solids were dissolved(on the funnel) with hot ethyl acetate and filtered into a collection vessel. The dark solution was filtered through a long plug of 30/40 Magnesol and the pale yellow filtrate was concentrated to dryness in vacuo to afford a yellow-tinged solid (20.6 g, 44.1percent yield). The plug was washed with ethyl acetate/ethanol and the washings were concentrated in vacuo to afford additional material, 10.7 g (23percent). Extraction of the aqueous work-up filtrate with ethyl acetate followed by drying, Magnesol filtration and concentration gave another 6.3 g (14percent) of clean product, bringing the total recovery to 37.6g (81percent). 1H-NMR (CD3OD): δ 7.72 (s, IH), 7.52 (dd, IH, J =2.5, 1.6 Hz), 6.85 (dd, IH, J = 4.5, 1.6 Hz), 6.64 (dd, IH, / = 4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].
Reference: [1] Patent: WO2007/56170, 2007, A2, . Location in patent: Page/Page column 73-74
[2] Patent: WO2007/64931, 2007, A2, . Location in patent: Page/Page column 163
  • 62
  • [ 3473-63-0 ]
  • [ 159326-66-6 ]
  • [ 159326-68-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 781 - 786
  • 63
  • [ 3473-63-0 ]
  • [ 58483-95-7 ]
  • [ 171178-47-5 ]
YieldReaction ConditionsOperation in experiment
92% for 18 h; Heating / reflux Step (e) 6-Chloro-3H-pyrido [3,4-d] pyrimidin-4-one A 1 L round bottomed flask was charged with 5-amino-2-chloro- isonicotinic acid (69.5 g, 0.40 moles), formamidine acetate (84 g, 0.81 moles, 2 mole equivalents), and 600 mL of methoxyethanol. The resulting solution was heated at reflux for 18 hours. After cooling to 5°C, a precipitate was collected by filtration, washed twice with methoxyethanol, and dried overnight in the vacuum oven at 45°C. The reaction yielded 67 g (92percent total yield) of 6-chloro-3H- pyrido [3, 4-D] PYRIMIDIN-4-ONE as a tan solid that was sufficiently pure by NMR to use in the next reaction. 8H (DMSO) 12.70 (1 H, s), 8.86 (1 H, d), 8. 19 (1 H, s), 7.93 (1 H, d) MS [M+H3+ 182
Reference: [1] Patent: WO2005/16926, 2005, A1, . Location in patent: Page/Page column 123-124
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
  • 64
  • [ 909912-09-0 ]
  • [ 3473-63-0 ]
  • [ 286371-64-0 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: at 130℃; for 24 h;
Stage #2: With ammonia In 2-methoxy-ethanol; water at 20℃;
6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one: Preparation 9 (5 g,18.3 mmol) was mixed with amidine acetate (3.8 g, 36.6 mmol) in ethylene glycol monomethyl ether (25 mL) and the mixture was heated at 13O0C for 24 h. After cooling to room temperature, part of the solvent was removed in vacuo and ammonium hydroxide (5 mL, 30percent in water) and water (50 mL) were added. The solid was filtered, was washed with water and hexanes, and was then dried under vacuum to afford 4.87 g (94percent yield) of the title compound; MS (AP/CI): 283.1 (M+H)+ .
Reference: [1] Patent: WO2008/20302, 2008, A2, . Location in patent: Page/Page column 29
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4536 - 4547
  • 65
  • [ 855793-63-4 ]
  • [ 3473-63-0 ]
  • [ 286371-64-0 ]
YieldReaction ConditionsOperation in experiment
38.4 g for 12 h; Reflux A mixture of iron powder (29 g, 0.527 mol) and acetic acid 270 mL was stirred and heated to 50-60°C till a grey white suspension was formed. The suspension was diluted with 150 mL methanol. Methyl 4-methoxy-3-benzyloxy-6-nitrobenzoate 7 (50g, 0.1575 mol) was added portion wise at regular intervals. The reaction was maintained at the same temperature for 5-6 hr. The mixture was filtered hot and the filtrate was evaporated to a residue mass under reduced pressure. The residue was extracted with ethyl acetate 2 × 300 mL. The combined organic layers were washed with water* and formamidine acetate 28.6 g (0.2747 mol) was added to the organic layer and refluxed for 12 hr. Reaction mass was cooled to 25-30°C and stirred for 1 hr and precipitated solid was collected by filtration. Isolated solid was slurry washed with 250 mL methanol and dried to get the off white powder 9, 38.4 g (yield 91percent, purity 98percent); m.p. 258-60°C; 1HNMR (DMSO-d6, 300 MHz): 12.076 (s, 1H), 7.986 (s, 1H), 7.342-7.545 (m, 6H), 7.152 (s, 1H), 5.206 (s, 2H), 3.913 (s, 3H); MS (EI): m/z 283 (M + 1).
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53B, # 10, p. 1269 - 1274
  • 66
  • [ 3473-63-0 ]
  • [ 179688-27-8 ]
  • [ 179688-29-0 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 80℃; for 5 h; Inert atmosphere
Stage #2: for 1 h; Reflux
Compound (v) (171.1g), formamidine acetate (79.8 g) was dissolved in n-butanol (1027mL), and nitrogen at elevatedTemperature to 80 ° C for 5 hours, the reaction was complete by HPLC. Spin dry n-butanol, was added 1711g of isopropyl acetate heated to reflux for 1Hours, cooled to _5 ° C for 4 hours. Filtered, 50 ° C and dried under blast (vi) (164.0g), yield 98percent, purity>95percent. NMR data identified compound (vi) as follows
98.5% at 55℃; for 3 h; Green chemistry 2375 ml of absolute ethanol and 255 g of compound III prepared by the method of Example 9 were added to the reaction vessel,After stirring to dissolve, add formamidine acetate 95g, heated to 55°C , temperature control reaction for 3 hours, cooled to 15 crystal out. Filtration, the filtrate evaporated condensate recovery of ethanol applied to the next batch of ring reactor, non-condensable gas into the exhaust absorption device. The filter cake was collected and dried at 40-50 ° C,The structure was confirmed to give the finished product 6,7-bis (methoxyethoxy) quinazolin-4-one 235.7g, the yield was 98.5percent, by HPLC purity of 99.9percent.
Reference: [1] Patent: CN103709110, 2016, B, . Location in patent: Paragraph 0067; 0068
[2] Patent: CN107382880, 2017, A, . Location in patent: Paragraph 0029-0041
[3] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
  • 67
  • [ 3473-63-0 ]
  • [ 476168-17-9 ]
  • [ 179688-29-0 ]
Reference: [1] Patent: WO2006/84882, 2006, A2, . Location in patent: Page/Page column 12
[2] Medicinal Chemistry, 2011, vol. 7, # 4, p. 295 - 300
  • 68
  • [ 379228-57-6 ]
  • [ 3473-63-0 ]
  • [ 379228-58-7 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1078 - 1087
  • 69
  • [ 379228-57-6 ]
  • [ 3473-63-0 ]
  • [ 379228-58-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 22, p. 6465 - 6488
  • 70
  • [ 3473-63-0 ]
  • [ 149506-35-4 ]
  • [ 706811-25-8 ]
YieldReaction ConditionsOperation in experiment
80 g
Stage #1: at 0 - 5℃; for 1.25 h; Inert atmosphere
Stage #2: at 0 - 30℃; for 6 h;
Stage #3: With hydrogenchloride In methanol; water at 25 - 30℃; for 1.5 h;
A solution of 2-(4-bromophenyl) malonic acid dimethyl ester (Formula III) (100 g) in methanol (1500 ml) was added to pre-cooled 25percent sodium methoxide solution in methanol (240 mL) at 0-5 °C over a period of 60 mins under nitrogen atmosphere and stirred for 15 mins.Formamidine acetate (47.1 g) was added at 0-5°C. Then reaction mass temperature was raised to 25-30°C and stirred for 6 hrs Aqueous hydrochloric acid (2N, 1000 mL) was added to the reaction mass at 25-30°C for 90 mins, cooled to 0-5°C and stirred for 30 mins. The pH of the reaction mass was adjusted to 4 using aqueous sodium hydroxide at 0-5 °C and stirred for 15 mins. The solid obtained was filtered, washed with water followed by acetone and suck dried. Acetone (300 mL) was added to the wet compound and stirred for 1 hr at 25-35°C. The reaction mass was filtered, washed with acetone and dried at 60-65°C for 12 hrs to get the title compound.Yield: 80 g; Purity by HPLC: 99.5percent
Reference: [1] Patent: WO2017/93903, 2017, A1, . Location in patent: Page/Page column 20
  • 71
  • [ 93139-85-6 ]
  • [ 3473-63-0 ]
  • [ 706811-25-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 72
  • [ 3473-63-0 ]
  • [ 52763-21-0 ]
  • [ 62458-96-2 ]
YieldReaction ConditionsOperation in experiment
79% With sodium methylate In methanol at 25℃; for 20 h; Inert atmosphere To a solution of sodium methoxide (25 wt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 °C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 °C for 20 h. The mixture was cooled to 0 °C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 °C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) δ12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H).
79%
Stage #1: With sodium methylate In methanol at 25℃; for 20 h;
Stage #2: With acetic acid In methanol; water at 0 - 25℃;
Preparation of 1 -(4-methoxy-7-(3 -methyl- IH-1 ,2,4-triazol- 1 -yl)- 1 H-pyrrolo[2,3 - c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)- yl)ethane-l,2-dione, compound 18; [00126] Part A: To a solution of sodium methoxide (25 wgt-percent in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 0C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 0C for 20 h. The mixture was cooled to 0 0C. Water (90 mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 0C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and then dried under vacuum to afford 7-benzyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 percent) as an off-white solid; Mass Spec: m/e: 242.06 (M+H)+ [calc'd: 242.12]; 1H NMR (500 MHz, CDCl3) I'12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H), 3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H).
70%
Stage #1: With sodium methylate In methanol at 20℃; for 20 h;
Stage #2: With acetic acid In methanol; water at 0 - 20℃; for 1 h;
To a solution of sodium methoxide (1.67 g, 30.9 mmol) in anhydrous MeOH (10 mL) at room temperature was added formamidine acetate (1.15 g, 11 mmol) in one portion as solid followed by ethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2.63 g, 8.83 mmol) in one portion. The reaction mixture was stirred at rt for 20 h. The reaction was cooled at 0° C., and water (6 mL) was added followed by acetic acid (0.63 mL, 11 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to remove the methanol and then stirred at rt overnight. The resulting solid was collected by filtration and washed with water (5 mL.x.3) and dried on filter to afford the title compound a (1.50 g, 70percent) as an orange solid. LCMS [M+H]+ 242.16.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 160 - 167
[2] Patent: WO2009/158396, 2009, A1, . Location in patent: Page/Page column 67
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 18, p. 5019 - 5024
[4] Patent: US2008/275052, 2008, A1, . Location in patent: Page/Page column 45
  • 73
  • [ 39514-19-7 ]
  • [ 3473-63-0 ]
  • [ 62458-96-2 ]
YieldReaction ConditionsOperation in experiment
61.8%
Stage #1: With sodium methylate In methanol at 20℃; for 20 h;
Stage #2: With acetic acid In methanol at 10℃; for 1 h;
To a slurry of sodium methoxide (10.0 g, 185 mmol) in anhydrous MeOH (60 mL) at room temperature was added formamidine acetate (6.60 g, 63.4 mmole) followed by ethyl-l-benzyl-3-oxo-4-piperidine-carboxylate (15.8 g, 52.9 mmol) in one portion. After stirring at rt for 20h, the mixture was cooled to 10°C whereupon 36 mL of water was added followed by 3.8 mL of acetic acid, and the mixture was stirred for an additional hour. The resulting mixture was concentrated and 150 mL of water was added. The solid was collected by filtration and washed with water and air dried. The crude product (9.60 g) was purified by recrystallization from MeOH (~100 mL) to provide 69A as near white needles (7.86 g, 61. 8percent yield). HPLC Ret. Time: 0.46 min. MH+ (m/z) 253. 1H NMR (400 MHz, CDC13, ppm) : 8 2.65 (t, 3H), 2.75 (t, 3H), 3.50 (s, 2H), 3.70 (s, 2H), 7.35 (m, 5H), 7.98 (s, 1H).
2.5 g
Stage #1: With sodium methylate In methanol at 5℃; for 0.5 h;
Stage #2: at 40℃;
The Preparation of Compound 12E:
Sodium methoxide (MeONa, 11 g, 161.65 mmol) was dissolved in methanol (280 mL), cooled to 5° C., and then formamidine acetate (3.0 g, 29.15 mmol) was added. The reaction mixture was stirred for 0.5 hour, and then compound 12D (17 g, 65.1 mmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction was monitored via TLC (DCM/Methanol=10:1). After the reaction was completed, the reaction mixture was cooled to room temperature, evaporated to remove most of the solvent. The residue was extracted with EA. The organic phase was washed with brine, dried with Na2SO4 and concentrated, to obtain a crude product. The crude product was purified by silica gel chromatography to obtain a purified compound 12E (2.5 g, yield: 16percent) as a light yellow solid.
2.5 g
Stage #1: With sodium methylate In methanol at 5℃; for 0.5 h;
Stage #2: at 40℃;
Sodium methoxide (MeONa, 11 g, 161.65 mmol) was dissolved in methanol (280 mL), cooled to 5° C., and then formamidine acetate (3.0 g, 29.15 mmol) was added. The reaction mixture was stirred for 0.5 hour, and then compound 12D (17 g, 65.1 mmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction was monitored via TLC (DCM/Methanol=10:1). After the reaction was completed, the reaction mixture was cooled to room temperature, evaporated to remove most of the solvent. The residue was extracted with EA. The organic phase was washed with brine, dried with Na2SO4 and concentrated, to obtain a crude product. The crude product was purified by silica gel chromatography to obtain a purified compound 12E (2.5 g, yield: 16percent) as a light yellow solid.
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9273 - 9285
[2] Patent: WO2005/42537, 2005, A1, . Location in patent: Page/Page column 85
[3] Patent: WO2007/28022, 2007, A2, . Location in patent: Page/Page column 41-42
[4] Patent: US2016/75708, 2016, A1, . Location in patent: Paragraph 0086; 0089
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 16, p. 3905 - 3912
[6] Patent: KR2015/139962, 2015, A, . Location in patent: Paragraph 0118-0119; 0127-0128
  • 74
  • [ 3473-63-0 ]
  • [ 1454-53-1 ]
  • [ 62458-96-2 ]
YieldReaction ConditionsOperation in experiment
90% With sodium methylate In methanol for 2 h; Heating / reflux Example 1 7- (3-Chloropyridin-2-yl)-N- (4- (trifluoromethyl) phenyl)-5, 6,7, 8-tetrahydropyrido [3,4- d] pyrimidin-4-amine A. 7-Benzyl-5,6, 7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one [00227] 1-Benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89g, 43.3mmol) was suspended in a sodium methoxide solution in methanol (25percent wt/wt, 50mL, 216. 2mmol) and formamidine acetate (5.4g, 51.9 mmol) was added to the mixture. The reaction mixture was refluxed until all of the starting material was consumed (2 h). The methanol was removed under vacuum, and the resulting white solid was dissolved in a 3: 1 mixture of chloroform: isopropanol. The mixture was washed with water and brine, dried over Na2SO4, filtered and evaporated to give the desired product as a white solid (9.4g, 90percent).
Reference: [1] Patent: WO2005/66171, 2005, A1, . Location in patent: Page/Page column 58-59
  • 75
  • [ 685-88-1 ]
  • [ 3473-63-0 ]
  • [ 106615-61-6 ]
Reference: [1] Green Chemistry, 2015, vol. 17, # 5, p. 3000 - 3009
[2] Patent: US9145373, 2015, B2, . Location in patent: Page/Page column 37
  • 76
  • [ 3473-63-0 ]
  • [ 1454-53-1 ]
  • [ 109229-22-3 ]
YieldReaction ConditionsOperation in experiment
61.4%
Stage #1: With sodium methylate In methanol at 85℃; for 16 h; in sealed vessel
Stage #2: With sodium hydroxide In water at 0℃;
Stage #3: With acetic acid In water
6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one
A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL, 5 mol) was heated to 85° C. for 16 hour in a 350 ml sealed reaction vessel.
The mixture was allowed to cool and reduced in vacuo.
The residue was dissolved in 1N NaOH (150 ml) and poured over ice.
Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out.
the solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid. (26.2 g, 61.4percent).
MS: M+H=242.2.
1H NMR (DMSO-d6): δ 2.29 (t, 5.8 Hz, 2H); 2.61 (t, 5.8 Hz, 2H); 3.26 (s, 2H); 3.64 (s, 2H); 7.21-7.36 (m, 6H); 7.96 (s, 1H).
61.4%
Stage #1: With sodium methylate In methanol at 85℃; for 16 h;
Stage #2: With sodium hydroxide In water
Stage #3: With acetic acid In water at 0℃;
Intermediate 16-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85° C. for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in 1N NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4percent).LC-MS: 242.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 2.29 (t, 2H, J=5.8 Hz), 2.61 (t, 2H, J=5.8 Hz), 3.26 (s, 2H), 3.64 (s, 2H), 7.21-7.36 (m, 6H), 7.96 (s, 1H).
61.4%
Stage #1: With sodium methylate In methanol at 85℃; for 16 h;
Stage #2: With sodium hydroxide In waterCooling with ice
Stage #3: With acetic acid In water
INTERMEDIATE 1 6-Benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4(3H)-one[00273] A mixture of ethyl l-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g,0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL) was heated at 85 0C for 16 hour in a 350 mL sealed reaction vessel. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in IN NaOH (150 mL) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out. The solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid (26.2 g, 61.4 percent).MS: 242.2 [M+l]+; 1H NMR (400 MHz, DMSO-d6): 2.29 (t, 2H, J = 5.8 Hz), 2.61 (t, 2H, J = 5.8 Hz), 3.26 (s, 2H), 3.64 (s, 2H), 7.21-7.36 (m, 6H), 7.96 (s, IH).
Reference: [1] Patent: US2006/258689, 2006, A1, . Location in patent: Page/Page column 22; 23; 27; 28
[2] Patent: US2008/275037, 2008, A1, . Location in patent: Page/Page column 22
[3] Patent: WO2008/123963, 2008, A1, . Location in patent: Page/Page column 44
[4] Patent: WO2011/103715, 2011, A1, . Location in patent: Page/Page column 38
[5] Patent: WO2011/106276, 2011, A1, . Location in patent: Page/Page column 38
  • 77
  • [ 41276-30-6 ]
  • [ 3473-63-0 ]
  • [ 109229-22-3 ]
YieldReaction ConditionsOperation in experiment
55% Reflux Preparation 16-Benz i-5,6,7,8-tetrah dropyrido[4,3-rf]pyrimidin-4 3H)-Sodium methylate (43 g, 0.8 mol) was added to a mixture of imidoformamide acetate (39.85 g, 0.383 mol) and ethyl l-benzyl-4-oxopiperidine-3-carboxylate (110 g, 0.37 mol) in absolute ethanol (250 mL). The reaction mixture was refluxed for 3-4 h, during which time the course of the reaction was monitored by TLC (Merck UV-254; chloroform/methanol 4:1 ). The mixture was then filtered, and the filtrate was evaporated. Water (-400 mL) was added to the residue, and the obtained aqueous solution was acidified to pH 7-8. The product was then extracted with chloroform, and the extract was dried over MgS04 and evaporated to give the title compound in 55percent (50.7 g) yield. The product was then recrystallized from ethylacetate.
Reference: [1] Patent: WO2013/54185, 2013, A1, . Location in patent: Page/Page column 44
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9273 - 9285
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 16, p. 3905 - 3912
  • 78
  • [ 853058-40-9 ]
  • [ 3473-63-0 ]
  • [ 853058-41-0 ]
YieldReaction ConditionsOperation in experiment
72% at 105℃; for 20 h; A mixture of amino pyrrole 3. (10.0 g, 44.2 mmol) and formamidine acetate (13.8 g, 133 mmol) in ethanol (100 ml) was heated at 105° C. for 20 h. The reaction mixture was filtered while still hot to collect solids that were rinsed with EtOH. The filtrate was allowed to cool to r.t., filtered to collect solids that were washed with EtOH. The combined solids were slurried with Et2O, filtered and dried under vacuum to yield 4,6-diazaindole 4 (6.60 g 31.9 mmol, 72percent) as a pale yellow solid which was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.89 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.17 (s, 2H), 1.27 (t, J=7.2 Hz, 3H); LC/MS: (ES+) m/z (M+H)+=208; HPLC Rt=0.55 min., column N.
Reference: [1] Patent: US2005/124623, 2005, A1, . Location in patent: Page/Page column 43
  • 79
  • [ 759-67-1 ]
  • [ 3473-63-0 ]
  • [ 137234-87-8 ]
Reference: [1] Patent: CN103896855, 2016, B, . Location in patent: Paragraph 0023; 0033; 0036; 0037
  • 80
  • [ 3473-63-0 ]
  • [ 192869-49-1 ]
YieldReaction ConditionsOperation in experiment
78% With sodium ethanolate In ethanol at 20℃; for 0.5 h; Inert atmosphere Methyl hydrazine acetate (403 mg, 3.87 mmol) was suspended in 15 mL of absolute ethanol solution and sodium ethoxide (395 mg, 5.81 mmol) was added. The reaction solution was stirred under nitrogen for 30 minutes at room temperature.Compound 37B (984 mg, 3.87 mmol) was dissolved in 10 mLIn the absolute ethanol, the solution was added dropwise to the stirred reaction system. After the addition is completed, the temperature is raised to the reflux temperature, under nitrogen protection.The reaction was stirred overnight. The reaction solution was quenched with water and the ethanol was spun off.The aqueous phase was extracted three times with ethyl acetate and dried.Purification with petroleum ether / ethyl acetate = 2:1 to give compound 37B as a yellow oil.(715 mg, 78percent yield).
Reference: [1] Patent: CN108250128, 2018, A, . Location in patent: Paragraph 0648; 0650; 0653; 0654
  • 81
  • [ 923283-54-9 ]
  • [ 3473-63-0 ]
  • [ 314021-93-7 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 1 h; Compound 8: To a solution of 7 (0.92 g, 5.9 mmol) in 5 mL of Hunig's base and 5 mL of n-butanol was added formamidine acetate (0.68 g, 6.5 mmol). The reaction mixture was heated and stirred at 110° C. for 1 hour. After cooling to room temperature, the white precipitate was collected by filtration and washed with diethyl ether. The resulting white precipitate was dried under reduced pressure to afford 8 (0.83 g, 94percent). 1H NMR (d6-DMSO) δ 4.33 (s, 3H) 8.50 (s, 1H) 8.80 (s, 1H); ES (+) MS m/e=151 (M+1).
Reference: [1] Patent: US2007/27166, 2007, A1, . Location in patent: Page/Page column 80
  • 82
  • [ 3473-63-0 ]
  • [ 5794-88-7 ]
  • [ 155690-79-2 ]
YieldReaction ConditionsOperation in experiment
91% for 16 h; Heating / reflux To a 1.2 M solution of 5-bromoanthranilic acid (1 equiv) in N,N-dimethylformamide was added formamidine acetate (1 equiv). The mixture was heated to reflux and stirred at this temperature for 16 hours. After this time, the reaction was cooled and NaHCO3 solution (5 percent in H2O) (3 volumes) were carefully added and the mixture stirred vigorously. The resulting <n="113"/>precipitate was collected by filtration and then washed with water (2 X 1 volume) and then t- butyl methylether (2 X 1 volume) before being dried in a vacuum oven to give the desired product which required no further purification.6-Bromo-3H-pyrido[2,3-d]pyriniidin-4-one: (91 percent yield, insert) m/z (LC-MS,ESP):225 [M- H]- R/T = 2.31 minutes)
Reference: [1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 111-112
  • 83
  • [ 3473-63-0 ]
  • [ 52833-94-0 ]
  • [ 155690-79-2 ]
YieldReaction ConditionsOperation in experiment
1.7 g at 120℃; for 36 h; Inert atmosphere 2-Amino-S -bromonictoinic acid (2 g) and formamidine acetate (3.0 g) were heated at 120 °C in2-methoxyethanol (15 ml) for 36 h under argon. The heterogeneous reaction mixture was diluted with water and filtered. The solid was suction dried to obtain 1.7 g of 6-bromopyrido[2,3- d]pyrimidin-4(3H)-one. ‘H NMR (300 MHz, DMSO-d6) ö 12.70 (s, 1H), 9.01 (d, J= 2.6 Hz, 1H), 8.59 (d, J= 2.6 Hz, 1H), 8.33 (s, 1H).
Reference: [1] Patent: WO2015/157093, 2015, A1, . Location in patent: Paragraph 1314; 1315
  • 84
  • [ 67-56-1 ]
  • [ 488-11-9 ]
  • [ 3473-63-0 ]
  • [ 1009826-93-0 ]
Reference: [1] Synlett, 2012, # 3, p. 443 - 447
  • 85
  • [ 13091-43-5 ]
  • [ 3473-63-0 ]
  • [ 215115-09-6 ]
Reference: [1] Patent: US2009/18163, 2009, A1, . Location in patent: Page/Page column 46
  • 86
  • [ 1612774-50-1 ]
  • [ 3473-63-0 ]
  • [ 1022150-11-3 ]
Reference: [1] Patent: WO2014/139970, 2014, A1, . Location in patent: Page/Page column 19; 25
  • 87
  • [ 3473-63-0 ]
  • [ 1219130-47-8 ]
YieldReaction ConditionsOperation in experiment
82.3% Reflux To a refluxing solution of 2-amino-6-bromo-3-methoxybenzaldehyde (695 mg, 3.02 mmol, 1.0 eq) in ethanol (30.0 mL) was added formamidine acetate (628 mg, 6.04 mmol, 2.0 eq). The mixture was stirred under reflux overnight, then cooled and concentrated. The residue was purified on gel chromatography to provide 5-bromo-8-methoxyquinazoline as a white solid (595 mg, 82.3percent).
Reference: [1] Patent: WO2018/35061, 2018, A1, . Location in patent: Paragraph 0427
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