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Chemical Structure| 13794-72-4
Chemical Structure| 13794-72-4
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Product Details of [ 13794-72-4 ]

CAS No. :13794-72-4 MDL No. :MFCD01570147
Formula : C10H10N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :DMSRMHGCZUXCMJ-UHFFFAOYSA-N
M.W : 206.20 Pubchem ID :135495016
Synonyms :

Calculated chemistry of [ 13794-72-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.2
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 55.35
TPSA : 64.21 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.05 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.41
Log Po/w (XLOGP3) : 0.71
Log Po/w (WLOGP) : 0.94
Log Po/w (MLOGP) : 0.6
Log Po/w (SILICOS-IT) : 2.03
Consensus Log Po/w : 1.14

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.93
Solubility : 2.44 mg/ml ; 0.0118 mol/l
Class : Very soluble
Log S (Ali) : -1.64
Solubility : 4.76 mg/ml ; 0.0231 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.5
Solubility : 0.0657 mg/ml ; 0.000318 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.88

Safety of [ 13794-72-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13794-72-4 ]

* 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 [ 13794-72-4 ]
  • Downstream synthetic route of [ 13794-72-4 ]

[ 13794-72-4 ] Synthesis Path-Upstream   1~55

  • 1
  • [ 13794-72-4 ]
  • [ 16064-15-6 ]
YieldReaction ConditionsOperation in experiment
98.62%
Stage #1: With hydrogen bromide In water at 110℃; Reflux
Stage #2: With ammonia In water
(i) Preparation of 6,7-dihydroxy-4 (3H)-quinazolinone of formula (9)Into a 2.0 Lt four necked round bottomed flask equipped with a mechanical stirrer, reflux condenser and thermometer socket are charged 48percent (w/w) hydrobromic acid (1000 g) and 6,7-dimethoxy-4 (3H)-quinazolinone (100 g). Slowly heated the reaction mass to reach 110° C. and maintained for 1 hour at the same temperature. Then raised mass temperature to reach reflux condition and refluxed for 12 hours. Monitored the completion of the reaction by TLC. Then cooled the reaction mass to 25-35° C. and filtered the mass. Transferred the wet cake into another 2.0 Lt round bottomed flask containing 1000 ml of DM water. Stirred for 10-15 minutes and adjusted the pH to 7.0-7.5, by adding aqueous ammonia solution. Filtered the resulting product and washed the cake with DM water and dried to get 85.2 g (98.62percent by theory) of 6,7-dihydroxy-4 (3H)-quinazolinone as off-white crystalline solid.Purity: 99.25percent (by HPLC)Melting point: >250° C.IR (KBr): 3208.7, 1679.0, 1614.5, 1514.7, 1427.7, 1374.3, 1316.2, 1293.9, 1261.0, 1214.5, 1195.5, 866.0, 845.3, 780.7, 523.8, and 449.2 cm-1.1H NMR (300 MHz, DMSO-D6): 6.93 (s, 1H); 7.35 (s, 1H); 7.84 (s, 1H); 9.75 (s, 1H); 10.13 (s, 1H); 11.2-12.4 (s, 1H).Mass: 179 (M+1), 177 (M-1).
97% at 120℃; 6,7-dimethoxy-3H-quinazolin-4-one (25 g, 124 mmol) was stirred in HBr, 48percent (150 mL) at 120 °O overnight. The mixture was cooled to room temperature and filtered. The filter cake was stirred in water and treated with ammonium hydroxide to pH = 8 and the mixture was filtered. The filter cake was stirred in acetone and the resulting mixture was filtered. The filter cake was washed with diethyl ether and dried giving the desired product as a fine, pale powder (21 g, 97 percent). 1H NMR (d6-DMSO) O 11.82 (brs, 1H), 10.13 (5, 1 H), 9.75 (5, 1 H), 7.84 (5, 1 H), 7.34 (5, 1 H), 6.92 (5, 1 H).
84% With hydrogen bromide In water at 120℃; for 12 h; Heating / reflux To 6,7-dimethoxy- 4(3H)-quinazolinone, 10 (3.0 g, 14.5 mmol) was added 48percent HBr (36 mL) and the solution was heated to reflux at 100 0C for 12 h. The reaction mixture was cooled to room temperature and the solids were filtered. The solid obtained was neutralized with aq. NH3 (pH = 8) and the solution was filtered and washed with water and dried to give 6,7-dihydroxy-4(3H)-quinazolinone, 11 as a off-white crystalline solid (2.20 g, 84percent).
84%
Stage #1: at 100℃; for 12 h;
Stage #2: With ammonia In water
Step 1. 6,7-Dihvdroxy-4(3H)-quinazorinone (11). A solution of 6,7- dimethoxy-4(3H)-quinazolinone 10 (3.0 g, 14.5 mmol) and 48percent HBr (36 mL) was heated to reflux at 100 0C for 12 hours. The reaction mixture was cooled to room temperature and the solids were removed by filtration then neutralized with aqueous NH3 (pH = 8). The resulting solution was filtered and the solids were washed with water and dried to give 6,7-dihydroxy-4(3H)-quinazolinone 11 as an off-white crystalline solid (2.20 g, 84percent).
80.5% With boron tribromide In dichloromethane at -78 - 25℃; Inert atmosphere (1)Compound a (10 g, 1.0 eq) and dichloromethane (100 ml) were added to a three-necked flask under nitrogen.The temperature was lowered to -78 ° C, and a solution of boron tribromide (10 eq) in dichloromethane (1 g / 3 ml) was added.After the addition, the reaction was kept for 1 h, and the temperature was raised to 25 ° C for 4-6 h.After the reaction is over,Wash with 10 ml of water and dry over anhydrous sodium sulfate.Concentrate the organic phase to dryness,Over the fast column,Yielding 6.97 g of compound b,Yield: 80.5percent.
75% at 110 - 140℃; for 31 h; 10 g of the resulting product synthesized in step 1 was added in 85 ml of 40percent H13r solution, and then the mixture was slowly added with 30 ml of acetic anhydride in a water bath. The water bath is removed, and the system was heated to 110° C. in an oil bath, reacted for 1 hr, then heated to 140° C. and reacted for 30 hrs. A large amount of white solids was precipitated in the flask. The reaction solution was filtered after cooled. The filter cake was dissolved in 75 ml of water, and the mixture was added with aqua ammonia until the pH value was adjusted to 9 and then filtered. The filter cake was washed with 75 ml of 1M NaHCO3 solution and dried to obtain 6.5 g of the resulting product (75percent). ‘H NMR (400 MHz, DMSO) ö 7.78 (s, 1H), 7.29 (s, 1H), 6.84 (s, 1H)

Reference: [1] Patent: US2009/306377, 2009, A1, . Location in patent: Page/Page column 5-6
[2] Patent: WO2016/123706, 2016, A1, . Location in patent: Paragraph 00170
[3] Patent: WO2008/76949, 2008, A2, . Location in patent: Page/Page column 11; 29
[4] Patent: WO2009/121042, 2009, A1, . Location in patent: Page/Page column 39
[5] Patent: CN108727400, 2018, A, . Location in patent: Paragraph 0055; 0057; 0059
[6] Patent: US2016/175453, 2016, A1, . Location in patent: Paragraph 0088; 0089
[7] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 10, p. 1086 - 1090
  • 2
  • [ 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
  • 3
  • [ 4101-33-1 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
83% With peracetic acid; sulfuric acid In ethanol at 60℃; for 4 h; General procedure: To a solution of 6,7-dimethoxyquinazoline 1a (200.0 mg, 1.05 mmol) in ethanol (20 mL) were added 40percent peracetic acid (1.0mL, 5.26 mmol) and 0.01 mL sulfuric acid (1.8 mmol). After the reaction was stirred at 60°C for 4–12 h (see Table 2) and then cooled to room temperature, excess sodium bisulfite (541.8 mg, 5.26 mmol) was added to get rid of the peroxide. The solid was filtered off after stirring for 20 min, and the filtrate was concentrated under reduced pressure to give the crude product, which was washed by ethanol and petroleum ether to give 2a as a light yellow solid (179.7 mg, 83percent), mp>300°C. 1H NMR (DMSO-d6, 400 MHz) δ : 12.19 (brs, 1H, -NH), 7.96 (s, 1H, 2-H), 7.41 (s, 1H, 8-H), 7.11 (s, 1H, 5-H), 3.88 (s, 3H,OCH3), 3.84 (s, 3H, OCH3). ESI-MS: m/z (percent)207 (100) [MH+]. ESI-HRMS:m/z calcd. For C10H11N2O3 [MH+]: 207.07642; found: 207.07613.
Reference: [1] Tetrahedron, 2010, vol. 66, # 4, p. 962 - 968
[2] Synthetic Communications, 2014, vol. 44, # 3, p. 346 - 351
[3] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 416 - 425
  • 4
  • [ 6313-33-3 ]
  • [ 5653-40-7 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: at 210℃; for 0.25 h; Heating / reflux
Stage #2: With sodium hydroxide In water at 80℃;
A solution of 9.85 g of compound 10 (5 mmol) and 6.8 g of formamidine hydrochloride (85 mmol) was heated under reflux for 15 min at 210° C. After cooling to 80° C., the solution was basified with saturated sodium hydroxide and washed with n-hexane and water to give 6.59 g of compound 11 (yield, 64percent). 1H-NMR (300 MHz, d6-DMSO): δ 7.98 (s, 1H), 7.42 (s, 1H), 7.11 (s, 1H), 3.89 (d, 6H).
64%
Stage #1: at 210℃; for 0.5 h;
Stage #2: With sodium hydroxide In water
Example 1: Preparation of l-((3S)-3-(4-(3-chloro-2,4-difluorophenylamino)- 7-methoxyquinazolin-6-yloxy)pyrrolidin-l-yl)pro-2-pen-l-one; (1-1) 6,7-dimethoxyquinazolin-4(3H)-one; 36.9 g of 4,5-dimethoxyanthranilic acid was mixed with 25.0 g of formamidine hydrochloride, and the mixture was stirred at 210 °C for 30 minutes. After completion of the reaction, the solid thus obtained was cooled to room temperature, stirred with 200 mi (0.33 M) of aqueous sodium hydroxide and filtered under a reduced pressure. The solid thus obtained was washed with water and air-dried to obtain the title compound (24.6 g, 64percent). 1H-NMR (300MHz, DMSO-d6) δ 7.99 (s, IH), 7.44 (s, IH), 7.13 (s, IH),3.90 (5, 3H), 3.87 (5, 3H).
Reference: [1] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 267 - 276
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7445 - 7456
[3] Patent: US2005/187231, 2005, A1, . Location in patent: Page/Page column 17
[4] Patent: WO2008/150118, 2008, A2, . Location in patent: Page/Page column 20
  • 5
  • [ 77287-34-4 ]
  • [ 5653-40-7 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
89% at 150℃; General procedure: A mixture of 2-aminobenzoic acid (anthranilic acid)or 2-amino-4,5-dimethoxybenzoic acid (20 mmol) and formamide(20 mmol) was heated at 150 C for 10–18 h. To the resulting mixture50 ml water was added, which resulted in precipitation of a lotof solid. The reaction mixture was stirred for another 30–45 minand the resulting precipitate was filtered and washed with water.The product was recrystallized from ethanol to yield white to paleyellow crystals.
86% for 4 h; Reflux 6,7-dimethoxyquinazolin-4(3H)-one (6a) was prepared accordingto a similar procedure of Luth and Lowe [62], with formamidein replace of formamidine acetate. Briefly, a solution of 5a(5 g, 25.4 mmol) in formamide (30 mL) was heated to reflux for 4 h,cooled to rt and poured onto ice-water, extracted with ethyl acetate,washed with brine and dried over Na2SO4, After removal of thesolvent, the residue was purified by silica gel column to give 6,7-dimethoxyquinazolin-4(3H)-one (6a) as a white solid (4.5 g, yield86percent). mp 310-312 °C (reference mp 300 °C [64]).
86% at 130℃; for 4 h; The intermediate 2 (5 g, 25.37 mmol) was dissolved in 30 ml of formamide and heated at 130 ° C for 4 hours. The reaction was completed by TLC. After the reaction was completed, the reaction solution was poured into a large amount of ice water and extracted with ethyl acetate three times with saturated chlorine. The aqueous sodium chloride solution was washed three times, dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure to give a white solid.4.5g yield 86percent,
84.7% at 190 - 200℃; for 2 h; A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190-200 0C for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8g, 84.7percent): LCMS: m/z 207[M+l]+; 1UNMR(DMSO) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, IH), 7.43 (s, IH), 7.97 (s, IH),12.08 (bs, IH).
84.7% at 190 - 200℃; for 2 h; A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190-200 0C for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8g, 84.7percent): LCMS: m/z 207[M+l]+; 1U <n="39"/>NMR(DMSO) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, IH), 7.43 (s, IH), 7.97 (s, IH),12.08 (bs, IH).
73% at 140℃; General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
48% at 150℃; General procedure: Method A: To an amount of 1 eq. anthranilic acid or 2-amino-4,5-dimethoxybenzoic acid was added 4 eq. formamide and the reaction mixture was heated for 8-10 h at 150 °C. Then, the mixture was cooled to room temperature and diluted with 50 ml water which resulted in the precipitation of solid. The precipitate was filtered and washed with water. 5.2.2
6,7-Dimethoxyquinazolin-4(3H)-one (2)
Synthesized from 2-amino-4,5-dimethoxybenzoic acid (5 mmol, 1 g) and formamide (20 mmol, 0.92 g).
The product was recrystallized from ethanol to yield brown solid (48percent).
1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.96 (s, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
13C NMR (126 MHz, DMSO-d6) δ 160.13, 154.58, 148.68, 144.99, 143.92, 115.73, 108.15, 105.08, 56.03, 55.81.
40% at 145℃; for 4 h; Preparation 24 6, 7-Dimethoxyquinazolin-4 (3H) -one A mixture of 2-amino-4, 5-dimethoxybenzoic acid (29.6g, 0.15 mol) and formamide (0.6 mol, 24 mL) was stirred vigorously under nitrogen atmosphere. The mixture was then heated to 145 °C for 4 h. After completion the reaction mixture was cooled and water (120 mL) was added. The solid was filtered, washed with cold water (2 x 20 mL) followed by hexane (2 x 20 mL) to give 12. 5g of the desired product in 40percent yield.
18% at 20 - 190℃; for 8 h; a)
A mixture of 4,5-dimethoxyanthranilic acid (19.7g, 100 mmol) and formamide (10ml) was heated at 190 °C for 5 hours.
The mixture was allowed to cool to approximately 80 °C and water (50ml) was added.
The mixture was then allowed to stand at ambient temperature for 3 hours.
Collection of the solid by suction filtration, followed by washing with water (2 x 50 ml) and drying in vacuo, yielded 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65g, 18 percent yield) as a white solid.
1H-NMR (DMSO d6): 12.10 (s, 1H), 7.95 (s, 1H), 7.42 (s, 1H), 7.11 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H):
MS (-ve ESI): 205 (M-H)-.
18% at 190℃; for 5 h; a)
A mixture of 4,5-dimethoxyanthranilic acid (19.7 g, 100 mmol) and formamide (10 ml) was heated at 190° C. for 5 hours.
The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added.
The mixture was then allowed to stand at ambient temperature for 3 hours.
Collection of the solid by suction filtration, followed by washing with water (2*50 ml) and drying in vacuo, yielded 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g, 18percent yield) as a white solid.
1H-NMR (DMSO d6): 12.10 (s, 1H), 7.95 (s, 1H), 7.42 (s, 1H), 7.11 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H):
MS (-ve ESI): 205 (M-H)-.

Reference: [1] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 420 - 425
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7858 - 7873
[3] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[4] Patent: CN108484574, 2018, A, . Location in patent: Paragraph 0127; 0128; 0129
[5] Patent: WO2008/33747, 2008, A2, . Location in patent: Page/Page column 107
[6] Patent: WO2008/33748, 2008, A2, . Location in patent: Page/Page column 37-38
[7] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[8] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3911 - 3913
[9] Tetrahedron, 2003, vol. 59, # 9, p. 1413 - 1419
[10] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 212 - 229
[11] Patent: WO2005/40163, 2005, A1, . Location in patent: Page/Page column 70-71
[12] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[13] Synthesis, 2004, # 3, p. 429 - 435
[14] Patent: EP1218357, 2005, B1, . Location in patent: Page/Page column 14
[15] Patent: US7081461, 2006, B1, . Location in patent: Page/Page column 31
[16] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6373 - 6377
[17] Patent: EP1154774, 2005, B1, . Location in patent: Page/Page column 51
[18] Patent: EP1119567, 2005, B1, . Location in patent: Page/Page column 25
[19] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 2, p. 215 - 222
[20] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
[21] Chemistry and Biodiversity, 2018, vol. 15, # 6,
[22] Letters in Drug Design and Discovery, 2018, vol. 15, # 7, p. 757 - 765
  • 6
  • [ 16712-16-6 ]
  • [ 5653-40-7 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
93% With trimethyl orthoformate In methanol at 70℃; for 4 h; Reflux Step 1 ) 6,7-dimethoxyquinazolin-4(3H)-oneA suspension of 2-amino-4,5-dimethoxybenzoic acid (23.40 g), trimethoxymethane (52 mL), ammonium formate (30.00 g) and methanol (400 mL) was heated to 70 °C and refluxed for 4 h. After the reaction mixture was cooled to room temperature, 160 mL of water was added to the reaction. The mixture was filtered to afford the title compound as a yellow solid (22.70 g, 93.00 percent). The compound was characterized by the following spectroscopic data: ? NMR (400 MHz, d6-DMSO) ?: 3.87 (s, 3H), 3.91 (s, 3H), 7.13 (s, 1 H), 7.45 (s, 1 H), 7.98 (s, 1H).
93% With trimethyl orthoformate In methanol at 70℃; for 4 h; A suspension of 2-amino-4,5-dimethoxybenzoic acid (23.40 g), trimethoxymethane (52 mL), ammonium formate (30.00 g) and methanol (400 mL) was heated to 70° C. and refluxed for 4 h. After the reaction mixture was cooled to room temperature, 160 mL of water was added to the reaction. The mixture was filtered to afford the title compound as a yellow solid (22.70 g, 93.00percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, d6-DMSO) δ: 3.87 (s, 3H), 3.91 (s, 3H), 7.13 (s, 1H), 7.45 (s, 1H), 7.98 (s, 1H).
Reference: [1] Patent: WO2013/71697, 2013, A1, . Location in patent: Paragraph 00191
[2] Patent: US2014/228361, 2014, A1, . Location in patent: Paragraph 0265-0266
  • 7
  • [ 13790-39-1 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
91% With potassium hydroxide In tetrahydrofuran; water at 75℃; for 24 h; To a solution of 4-chloro-6,7-dimethoxyquinazoline (8.00 g, 35.6 mmol) in 72 mL of H2O and 40 mL of THF was added a solution of KOH (7.0 g, 0.12 mol) in 14 mL of H2O. The mixture was stirred 24 h at 75 °C. Acetic acid (6.4 mL) was added and the precipitate was filtrated and rinsed with H2O and Et2O. A yellow solid (6.64 g) was obtained in 91percent yield. Mp: 300-302 °C; IR (ATR, ZnSe): ν (cm-1) 2822, 1649, 1488, 1272, 1218, 1079, 900, 874, 786, 727; 1H NMR (500 MHz, DMSO-d6): δ (ppm) 12.08 (s, 1H), 7.98 (s, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H).
13C NMR (126 MHz, DMSO-d6): δ (ppm) 160.1, 154.4, 148.5, 144.9, 143.9, 115.6, 108.0, 104.9, 55.9, 55.7. HRMS-ESI calcd for C10H10N2O3 [M+H]+ 207.0764 found 207.0765.
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149
  • 8
  • [ 20323-74-4 ]
  • [ 77287-34-4 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
89% at 168 - 170℃; Inert atmosphere A solution of compound 1b (8.0 g, 35.5 mmol) in formamide (80 mL) was heated to 168–170 °C under N2 atmosphere overnight. The reaction mixture was cooled and the resultant precipitate was filtered, washed with water, ether to afford 2 (6.48 g, 89percent) as a beige solid.
73.2% at 165 - 170℃; for 6 h; Inert atmosphere A solution of 5 (2.5 g, 0.011 mol) in formamide (50 mL) was heated to 165–170 °C under N2 for 6 h. When TLC indicated the absence of starting material, the reaction mixture was cooled and the amber sticky precipitate was filtered using a sintered glass frit and dried on the air (1.90 g, yield 73.2percent), m.p.: 295–296 °C. IR (cm−1): ν 3159, 3015, 2843, 2768, 1658,1610, 1504, 1439, 1357, 1271, 1078, 877, 642; 1H-NMR (DMSO-d6) δ (ppm): 12.03 (1H, s, -NH),7.99 (1H, s, 2-H), 7.42 (1H, s, 5-H), 7.11 (1H, s, 8-H), 3.88(3H, s, -OCH3), 3.85 (3H, s, -OCH3); 13C-NMR (DMSO-d6) δ (ppm): 159.99 (4-C), 154.43 (7-C), 148.53 (6-C), 144.84 (2-C) 143.77 (9-C),115.58 (10-C), 108.00 (5-C), 104.93 (8-C), 55.88 (-OCH3), 55.66 (-OCH3).
65% at 160℃; for 10 h; Inert atmosphere The 4,5-dimethoxy-2-aminobenzoic acid ethyl ester (8g, 0.035mol) and formamide 30 ml is added to the 100 ml in the reaction bottle, under protection of nitrogen gas, heating to 160 °C, stirring react about 10h, cooling to 0 °C the following, precipitated solid, filtered, washing the filter cake of methanol, infrared drying, forms offwhite solid, yield 65percent.
65% at 160℃; for 10 h; Inert atmosphere The compound 4,5-dimethoxy-2-amino-benzoic acid ethyl ester (8g, 0. 035mol) and formamide was added to 30mL lj1OOmL reaction flask through the nitrogen and heated to 160 ° C, stirring The reaction about 1Oh, cooled to 0 ° C or less, to precipitate a solid, filtration, the filter cake washed with methanol, infrared drying to give an off-white solid, yield 65percent.

Reference: [1] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[3] Molecules, 2014, vol. 19, # 5, p. 5508 - 5521
[4] Patent: CN103254139, 2016, B, . Location in patent: Paragraph 0092-0094
[5] Patent: CN103254140, 2016, B, . Location in patent: Paragraph 0080-0082
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[7] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
  • 9
  • [ 5653-40-7 ]
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YieldReaction ConditionsOperation in experiment
18% With formamide In water a)
A mixture of 4,5-dimethoxyanthranilic acid (19.7 g, 100 mmol) and formamide (10 ml) was heated at 190° C. for 5 hours.
The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added.
The mixture was then allowed to stand at ambient temperature for 3 hours.
Collection of the solid by suction filtration, followed by washing with water (2*50 ml) and drying in vacuo, yielded 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g, 18percent yield) as a white solid:
1H-NMR (DMSO-d6): 12.10 (s, 1H), 7.95 (s, 1H), 7.42 (s, 1H), 7.11 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H):
MS (-ve ESI): 205 (M-H)-.
Reference: [1] Patent: US7235559, 2007, B1,
[2] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 817 - 821
[3] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 817 - 821
[4] Patent: US6414148, 2002, B1,
[5] Patent: US6593333, 2003, B1,
[6] Patent: US6184225, 2001, B2,
[7] Patent: US6265411, 2001, B1,
[8] Patent: US6291455, 2001, B1,
  • 10
  • [ 67-56-1 ]
  • [ 5004-88-6 ]
  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
86% at 130℃; for 2 h; Inert atmosphere; Microwave irradiation 2-amino-4,5-dimethoxybenzamide(98 mg, 0.5 mmol), [Cp * Ir (2,2'-bpyO) (H2O)](5.4 mg, 0.005 mmol, 1 molpercent),Cesium carbonate (49 mg, 0.15 mmol, 0.3 equiv.) And methanol (0.5 ml) were sequentially added to a dried 5 mL microwave reaction tube.The tube was nitrogen protected and placed in a single mode pressure microwave synthesizer (Discover CEM, USA). After the reaction mixture was reacted at 130 ° C for 2 hours, it was cooled to room temperature. Rotary evaporation to remove the solvent,Pure target compound was then obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), yield: 86percent
Reference: [1] Organic Letters, 2016, vol. 18, # 11, p. 2580 - 2583
[2] Patent: CN107337646, 2017, A, . Location in patent: Paragraph 0050; 0051; 0052; 0053
  • 11
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  • [ 16712-16-6 ]
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YieldReaction ConditionsOperation in experiment
84.7% at 190 - 200℃; for 2 h; Example 1Preparation of 2-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyacetamide (Compound 1)Step 1a. 6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102); A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190200° C. for 2 hours. Then the mixture was cooled to room temperature. The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7percent): LCMS: m/z 207[M+1]+; 1HNMR (DMSO) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
Reference: [1] Patent: US2009/111772, 2009, A1, . Location in patent: Page/Page column 54; 64
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 10, p. 1086 - 1090
  • 12
  • [ 128823-83-6 ]
  • [ 77287-34-4 ]
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YieldReaction ConditionsOperation in experiment
86% at 170℃; for 12 h; To the reactor was added ethyl 2-amino-3,4-dimethoxybenzoate (5.3 g, 25 mmol)Add 30mL formamide dissolved, adding ammonium formate, heating to 170 ° C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature,And then cooled with ice water to solid precipitation, filtration,The resulting solid was recrystallized from methanol to give 4.43 g of 6,7-dimethoxy-4 (3H) -quinazolinone,Yield 86.0percent.
Reference: [1] Patent: CN106083740, 2016, A, . Location in patent: Paragraph 0022; 0023; 0024
  • 13
  • [ 201230-82-2 ]
  • [ 16791-41-6 ]
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YieldReaction ConditionsOperation in experiment
27 g With palladium diacetate In toluene at 50℃; for 4 h; Autoclave; Inert atmosphere In an autoclave, 23 g (0.1 mol) of 2-bromo-4,5-dimethoxyaniline, 2.3 g of palladium acetate and 10 g of formamide20mL was added toluene 100mL, with nitrogen after replacing the gas in the autoclave, the carbon monoxide was passed under vacuumThe pressure in the reactor reached 0.2MPa, slowly warmed to 50 , TLC 4h after the reaction monitoring reaction was complete, the reaction was filteredLiquid, the solvent was evaporated under vacuum, the residue was added to methylene chloride, and then washed three times with pure water, the organic phase was dried over anhydrousAfter drying with sodium sulfate, the solvent is distilled off6,7-dimethoxyquinazolin-4-one 27g
Reference: [1] Patent: CN106946857, 2017, A, . Location in patent: Paragraph 0035; 0036; 0037
  • 14
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  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
93% at 150℃; for 2 h; Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1.
92.1% at 150℃; for 2 h; Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
88.8% at 150℃; for 2 h; Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
87.5% at 150℃; for 2 h; Example 1: (Production of 6,7-dimethoxyquinazolin-4-one); Using acetic acid and an inorganic base, ammonia, as a catalyst, 6,7-dimethoxyquinazolin-4-one was produced in the manner mentioned below. 0.84 g (4 mmol) of methyl 4,5-dimethoxyanthranilate, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.05 g (2.8 mmol) of ammonia from a pressure cylinder were put into an autoclave of SUS316 having a capacity of 25 mL and equipped with a stirrer, a thermometer and a pressure gauge in a nitrogen atmosphere, and reacted at 150°C for 2 hours. After the reaction, the reaction liquid was cooled to room temperature, and the precipitated crystal was collected by filtration, washed with methanol and then dried in vacuum at 70°C for 2 hours to obtain 0.77 g of a crystal. The obtained crystal was analyzed for the purity by high-performance liquid chromatography, and its purity was 99.5 percent; and 6,7-dimethoxyquinazolin-4-one was obtained at a yield of 93.0 percent. The result is shown in Table 1. Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
87% at 140℃; for 24 h; 30 g of methyl 2-amino-4,5-dimethoxybenzoate was suspended in 240 ml of formamide, and the system was heated to 140° C. and reacted for 24 hrs. A large amount of solids was precipitated in the flask. The reaction solution was filtered after cooled. The filter cake was washed with a small amount of water and then dried to obtain 29.3 g of the resulting product (87percent).10087] ‘H NMR (400 MHz, DMSO) ö 12.01 (br., 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H)
84.7% at 190 - 200℃; for 2 h; Step 1e.
6,7-Dimethoxyquinazolin-4(3H)-one (Compound 107)
A mixture of compound 106 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 mL) was stirred and heated to 190~200° C. for 2 hours.
The mixture was cooled to room temperature and the resulting precipitate was isolated, washed with water and dried to provide the title compound 107 as a brown solid (1.8 g, 84.7percent): LCMS: 207 [M+1]+; 1H NMR (DMSO-d6); δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
84.7% at 190 - 200℃; for 2 h; Step 1a.
6,7-Dimethoxyquinazolin-4(3H)-one (Compound 0102)
A mixture of methyl 2-amino-4,5-dimethoxybenzoic acid 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred and heated to 190~200° C. for 2 hours.
Then the mixture was cooled to room temperature.
The precipitate was isolated, washed with water and dried to provide the title compound 0102 as a brown solid (1.8 g, 84.7percent): LCMS: m/z 207 [M+1]+; 1H-NMR (DMSO.) δ 3.87 (s, 3H), 3.89 (s, 3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.97 (s, 1H), 12.08 (bs, 1H).
78.7% With trichlorophosphate In toluene for 5 h; Reflux In a 100 mL three-necked flask were added 1.5 g (6.2 mmol) of methyl 6-amino-3,4_-dimethoxybenzoate, 3 mL (75.5 mmol) of formamide, 3 mL (32.77 mmol) Oxygen Phosphorus and 25 mL of toluene were mixed and heated to reflux. TLC was carried out for 5 h and the reaction was completed. The mixture was taken out to obtain a brown solid. After adding water, the pH value was neutralized with ammonia water. A precipitate of yellowish brown color was precipitated. : ΕΑ = 5: 1, V / V) to obtain a white flocculent solid 1.2 g, yield 78.7percent, mp: 184-1860C.
67.5% at 150℃; for 2 h; Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.
54% at 168 - 170℃; Inert atmosphere A solution of compound 1a (5.0 g, 23.7 mmol) in formamide (50 mL) was heated to 168–170 °C under N2 atmosphere overnight. The reaction mixture was cooled and the resultant precipitate was filtered, washed with water, ether to afford 2 (2.63 g, 54percent) as a beige solid, mp 300–302 °C. 1H NMR (DMSO-d6): d 12.07 (s, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
36.4% at 150℃; for 2 h; Examples 2 to 4, and Comparative Examples 1 and 2: (Production of 6,7-dimethoxyquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 1, for which, however, the catalyst was changed as in Table 2. In Example 4, ammonium acetate was used as the catalyst; and in Comparative Examples 1 and 2, formic acid or potassium carbonate, respectively, was used alone as the catalyst like in JP-A 2002-338550 (Patent Reference 4). From the results in Table 1, it is known that the reaction system with acetic acid and a base coexisting therein of the present invention gives 6,7-dimethoxyquinazolin-4-one at a higher yield than the conventional reaction system with formic acid or potassium carbonate alone therein.

Reference: [1] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[3] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[4] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[5] Patent: US2016/175453, 2016, A1, . Location in patent: Paragraph 0085; 0086; 0087
[6] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 25-26
[7] Patent: US2009/76022, 2009, A1, . Location in patent: Page/Page column 66
[8] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 8089 - 8103
[9] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1189 - 1204
[10] Patent: CN105037279, 2017, B, . Location in patent: Paragraph 0049; 0050
[11] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[12] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[13] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[14] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[15] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 6-7
[16] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 21, p. 2723 - 2728
[17] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1359 - 1366
[18] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 45
[19] MedChemComm, 2014, vol. 5, # 9, p. 1290 - 1296
[20] Bioorganic Chemistry, 2018, vol. 80, p. 433 - 443
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Reference: [1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 46, p. 8113 - 8126
  • 16
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  • [ 77287-34-4 ]
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YieldReaction ConditionsOperation in experiment
84.22% at 160℃; for 10 h; To a 250 mL round bottom flask, 2-amino-4,5-dimethoxybenzoic acid methyl ester (20 g, 94.7 mmol), formamide (160 mL), formic acid (4 mL) were added sequentially, and refluxed at 160 ° C for 10 h. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1: 1). The resulting mixture was poured rapidly into ice-water, stirring, standing for a while, solid precipitation, filtration, followed by washing with distilled water (3 X 15mL), washed with ethyl acetate (3 X 15 mL), dried, recrystallized from ethyl acetate and dried to give off-white granular crystals, (16.44 g, 84.22percent).
Reference: [1] Patent: CN104292170, 2016, B, . Location in patent: Paragraph 0189; 0190
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Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2186 - 2192
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Reference: [1] Heterocycles, 2007, vol. 71, # 1, p. 39 - 48
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Reference: [1] Arzneimittel-Forschung/Drug Research, 2003, vol. 53, # 6, p. 428 - 439
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 581 - 583
[3] Journal of Cardiovascular Pharmacology, 2000, vol. 35, # 2, p. 179 - 188
[4] Patent: CN106632271, 2017, A,
[5] Molecules, 2018, vol. 23, # 1,
[6] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[7] Patent: CN108484574, 2018, A,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[2] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[3] Molecules, 2014, vol. 19, # 5, p. 5508 - 5521
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
[5] Patent: CN103254139, 2016, B,
[6] Patent: CN103254140, 2016, B,
[7] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[2] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[3] Molecules, 2014, vol. 19, # 5, p. 5508 - 5521
[4] Patent: CN103254139, 2016, B,
[5] Patent: CN103254140, 2016, B,
[6] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
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  • [ 4959-60-8 ]
  • [ 5004-88-6 ]
  • [ 13794-72-4 ]
Reference: [1] Patent: US6172071, 2001, B2,
  • 23
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  • [ 13794-72-4 ]
YieldReaction ConditionsOperation in experiment
20 g Microwave irradiation The compound of 20g GG1, methyl acetate 17g (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, filtered to obtain compound 20g GG2.
Reference: [1] Patent: CN103570738, 2016, B, . Location in patent: Paragraph 0319-0321
  • 24
  • [ 93-07-2 ]
  • [ 13794-72-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[2] Patent: CN103254139, 2016, B,
[3] Patent: CN103254140, 2016, B,
[4] Patent: CN105037279, 2017, B,
[5] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[6] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 227 - 237
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
[8] Patent: CN108484574, 2018, A,
  • 25
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YieldReaction ConditionsOperation in experiment
17 g for 10 h; Inert atmosphere; Reflux In a 500 mL reaction flask equipped with a stirrer,20 g of 2-amino-4,5-dimethoxybenzoic acid and 9 g of formamide were added(Ethanol and benzene in a volume ratio of 1: 3), then add 10 g of ammonium formate, under nitrogen protection, heated to reflux reaction, reaction 10h, TLC monitoring of raw materials reaction is complete, steam After removing the solvent, 150 mL of saturated brine was added, and the reaction solution was extracted three times with 100 mL of chloroform. The organic phase was combined and the solvent was evaporated to give 6,7-dimethoxyquinazolin-4-one17g.
Reference: [1] Patent: CN106632271, 2017, A, . Location in patent: Paragraph 0038; 0039; 0040
  • 26
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Reference: [1] Arzneimittel-Forschung/Drug Research, 2003, vol. 53, # 6, p. 428 - 439
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 581 - 583
[3] Journal of Cardiovascular Pharmacology, 2000, vol. 35, # 2, p. 179 - 188
  • 27
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Reference: [1] Synthetic Communications, 2014, vol. 44, # 3, p. 346 - 351
[2] Molecules, 2018, vol. 23, # 1,
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Reference: [1] Synthetic Communications, 2014, vol. 44, # 3, p. 346 - 351
[2] Molecules, 2018, vol. 23, # 1,
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YieldReaction ConditionsOperation in experiment
87%
Stage #1: at 120℃; for 24 h;
Stage #2: at 100℃; for 22 h;
To a solution of 8 (1.80 g, 8.73 mmol) in 11 mL of methanesulfonic acid, d,l-methionine was added (2.15 g, 14.4 mmol) and the mixture was stirred 24 h at 120 °C. The solution was cooled to room temperature and a solution of NaOH 2 M was added until precipitation. The solid was filtered, dissolved in 6.2 mL of acetic anhydride and pyridine (1.41 mL, 17.5 mmol) was added. The mixture was stirred 22 h at 100 °C. H2O was added (60 mL) and after filtration 9 was obtained as a brown solid (1.79 g) in 87percent yield. Mp: 290 °C (dec.); IR (ATR, ZnSe): ν (cm-1) 2635, 1755, 1682, 1618, 1289, 1217, 918, 833, 674; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.21 (br s, 1NH), 8.08 (s, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 3.91 (s, 3H), 2.30 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ (ppm) 168.7, 159.9, 156.1, 148.9, 145.9, 138.9, 119.1, 115.6, 109.2, 56.5, 20.4; HRMS-ESI calcd for C11H10N2O4 [M+H]+ 235.0713 found 235.0714.
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YieldReaction ConditionsOperation in experiment
94% at 100℃; for 22 h; ( 1 -2) 6-hydroxy-7-methoxyquinazolin-4(3H)-one; 3.06 g of the compound obtained in (1-1) was diluted with 20 mi of methanesulfonic acid. 2.66 g of /--methionine was added to the resulting solution and stirred at 100 °C for 22 hours. Ice was added to the reaction mixture and neutralized with 40percent aqueous sodium hydroxide to induce the crystallization of the product. The solid was filtered under a reduced pressure, washed with water, and air-dried to obtain the title compound (2.67 g, 94percent).1H-NMR (300MHz, DMSO-d6) δ 11.94 (s, IH), 9.81 (s, IH), 7.92 (_?, IH), 7.39 (s, IH), 7.11 (s, IH), 3.91 (s, 3H).
93% at 130℃; for 5 h; The procedure for the synthesis of the title compound is depicted in Figure 1. 1-2: 6-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one was obtained according to W096/33980 in 93percent yield. 1H NMR (DMSO-d6, ppm) : No. 7.92 (s, 1H), 7.39 (s, 1 H), 7.09 (s, 1H), 3.89 (s, 3H). 13C NMR (DMSO-d6, ppm) : No. 160.0, 153.8, 152.3, 146.4,143.7, 115.9, 108.6, 108.1, 55.9.
90% at 120℃; for 6 h; The 6,7-dimethoxy -3H quinazolin-4-one (5g, 0.024mol), methanesulfonic acid (30 ml) and L-methionine (5g, 0.033mol) adding 50 ml reaction flask, slow heating to 120 °C, reaction 6h, proper amount of ice added in the reaction solution, then using 40percent NaOH to pH=7, generating a large amount of white precipitation, filtration, ice water washing, get white solid, yield 90percent
90% at 90 - 95℃; for 6 h; Into a reaction flask, concentrated sulfuric acid (607.2g; 25.5 m.eq), 6,7-dimethoxy- quinazoline-4(3H)-one of formula-XI (50g; 1.0 m.eq) and DL-Methionine (41.5g; 1.15 m.eq) were sequentially added under stirring. The reaction mass was heated to 90-95°C and maintained for about 6h. The progress of the reaction was monitored by TLC. After completion of the reaction, cooled the reaction mass to 25-35°C and quenched by adding ice-flakes (~1300g) at 25-35°C and stirred for lh. The resulting product was filtered and suspended the wet product in DM water (800 mL). The pH of the reaction mixture was adjusted to about 7.5 with lye solution. The product was filtered, washed with DM water and dried at 70-75°C to afford 6-hydroxy-7- methoxy-quinazoline-4(3H)-one of formula-XIV (41. Og; 90.0percent by theory).
60% at 120℃; for 18 h; A mixture of compound 2 (9.11 g, 44.3 mmol), L-methionine (7.25 g, 48.6 mmol) and methanesulfonic acid (65 mL) was heated to 120 °C for 18 h. The reaction mixture was cooled and poured into ice-water, then neutralized with 40percent NaOH to pH 7. The resultant precipitate was filtered, washed with water and dried under vacuum.The crude product was recrystallized from MeOH to afford 3 (5.06 g, 60percent) as a pale yellow solid, mp 306 °C (dec.). 1H NMR (DMSO-d6): d 11.9 (s, 1H), 9.82 (s,1H), 7.92 (s, 1H), 7.39 (s, 1H), 7.10 (s, 1H), 3.91 (s, 3H).
7.1 g at 130℃; for 3 h; A suspension of 6,7-dimethoxyquinazolin-4(3H)-one (6.18 g), methionine (4.70 g) and methanesulfonic acid (40 mL) was stirred at 130° C. for 3 h, then poured into ice-water. The reaction mixture was adjusted to pH 7 with 40percent sodium hydroxide. The mixture was filtered to give the title compound (7.10 g).

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