* 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.
With ammonium acetate In acetonitrile at 120℃; for 3 h;
The procedures of Example I-2 were repeated except that methanol was replaced with acetonitrile. There was obtained 0.98 g (reaction yield: 94percent) of 6-iodoquinazolin-4-one.
93%
With ammonium acetate In methanol at 120℃; for 3 h;
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.0 g (3.8 mmol) of 5-iodoanthranilic acid, 0.81 g (7.6 mmol) of methyl orthoformate, 0.59 g (7.6 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.97 g (isolated yield: 93percent) of 6-iodoquinazolin-4-one as a pale gray crystalline product. 6-Iodoquinazolin-4-one had the following characteristics. m.p.: 259°C (decomp.) 1H-NMR (DMSO-d6, δ (ppm)): 7.46 (1H, d, J=8.4Hz), 8.08-8.15 (2H, m), 8.39 (1H, d, J=1.8Hz), 12.5 (1H, brs) CI-MS (m/e): 273 (M+1); [Example I-2] Preparation of 6-iodoquinazolin-4-one The procedures of Example I-1 were repeated except that the amounts of methyl orthoformate and ammonium acetate were changed to 1.61 g (15.2 mmol) and 1.17 g (15.2 mmol), respectively. There was obtained 0.98 g (reaction yield: 94percent) of 6-iodoquinazolin-4-one.
91%
at 120℃; for 3 h;
The procedures of Example I-2 were repeated except that the amount of methyl orthoformate was changed to 3.60 g (34 mmol) and that no methanol was used. There was obtained 0.94 g (reaction yield: 91percent) of 6-iodoquinazolin-4-one.
90%
With ammonium 2,4-dichlorobenzoate In methanol at 120℃; for 3 h;
The procedures of Example I-2 were repeated except that ammonium acetate was replaced with 3.20 g (15.2 mmol) of ammonium 2,4-dichlorobenzoate. There was obtained 0.97 g (reaction yield: 90percent) of 6-iodoquinazolin-4-one.
85%
With ammonium formate In methanol at 120℃;
The procedures of Example I-2 were repeated except that ammonium acetate was replaced with 0.95 g (15.2 mmol) of ammonium formate. After the reaction was complete, the reaction mixture was treated in the manner of Example I-1. There was obtained 0.88 g (isolated yield: 85percent) of 6-iodoquinazolin-4-one as a pale gray crystalline product
2-Amino-5-iodobenzoic acid (II) (6.8 g, 0.05 mol),Mixed with 20ml of formamide and heated to 180°C,Stir the reaction for 12h, cool, pour into ice water, filter,After washing with water, 12.6 g of needle-like crystals of 6-iodoquinazolin-4-one (III) were obtained with a yield of 92.6percent and HPLC purity of 99.83percent.
1.8 g (6.90 mmol) of the compound obtained in the preceding step was suspended in 30 ml [OF TRIETHYL ORTHOFORMATE.] A catalytic amount of para-toluene sulfonic acid was added, and the suspension was refluxed for 3 hours. All volatiles were removed in vacuo, and the residue was washed with 1 : [1] dichloromethane: hexane to yield 1.5 g [(80percent)] of an off white powder as the desired product. N. M. R (DMSO-d6) 1H δ (ppm): 7.42 (d, [J= 8. 5HZ, 1H),] 8.09 (dd, J1 = 8. [5HZ,] [J2] = 2. 2Hz, 1H), 8.09 (s, 1H), 8.34 (d, [J=] 2.2Hz, 1H), 12. 38 (broad s, 1H) ; MS (APCI), M/z 270.9 [(M-1) ;]
Example 5: (Production of 6-iodoquinazolin-4-one); With acetic acid and a base coexisting as a catalyst in the reaction system, 6-iodoquinazolin-4-one was produced in the manner mentioned below. 1.05 g (4 mmol) of 5-iodoanthranilic acid, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.17 g (2.8 mmol) of diethylamine 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 acetic acid and then dried in vacuum at 70°C for 2 hours to obtain 1.01 g of a crystal. The above mother liquid was 3.98 g. The obtained crystal and the mother liquid were analyzed for the purity by high-performance liquid chromatography using 5-iodo-2-methylbenzoic acid as an internal standard substance; and the purity of the crystal was 99.5 percent, 6-iodoquinazolin-4-one in the mother liquid was a trace, and the yield of 6-iodoquinazolin-4-one was 92.3 percent. The result is shown in Table 2 and Table 3. Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
93%
at 150℃; for 2 h;
Example 5: (Production of 6-iodoquinazolin-4-one); With acetic acid and a base coexisting as a catalyst in the reaction system, 6-iodoquinazolin-4-one was produced in the manner mentioned below. 1.05 g (4 mmol) of 5-iodoanthranilic acid, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.17 g (2.8 mmol) of diethylamine 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 acetic acid and then dried in vacuum at 70°C for 2 hours to obtain 1.01 g of a crystal. The above mother liquid was 3.98 g. The obtained crystal and the mother liquid were analyzed for the purity by high-performance liquid chromatography using 5-iodo-2-methylbenzoic acid as an internal standard substance; and the purity of the crystal was 99.5 percent, 6-iodoquinazolin-4-one in the mother liquid was a trace, and the yield of 6-iodoquinazolin-4-one was 92.3 percent. The result is shown in Table 2 and Table 3. Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
93%
at 120℃; for 4 h;
2-amino-5-iodobenzoic acid (1g, 3.8mmol), formamide (5ml) was heated to 120 °C stirred for 4h. Cooled to room temperature, diluted with 50percent ethanol (10ml). The filter cake were washed with 50percent ethanol (5ml), EtOH/PE (1: 1,10ml), PE (5ml) and dried under vacuum to give a brown solid soil (0.9g, 93percent).
90.1%
at 150℃; for 2 h;
Example 5: (Production of 6-iodoquinazolin-4-one); With acetic acid and a base coexisting as a catalyst in the reaction system, 6-iodoquinazolin-4-one was produced in the manner mentioned below. 1.05 g (4 mmol) of 5-iodoanthranilic acid, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.17 g (2.8 mmol) of diethylamine 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 acetic acid and then dried in vacuum at 70°C for 2 hours to obtain 1.01 g of a crystal. The above mother liquid was 3.98 g. The obtained crystal and the mother liquid were analyzed for the purity by high-performance liquid chromatography using 5-iodo-2-methylbenzoic acid as an internal standard substance; and the purity of the crystal was 99.5 percent, 6-iodoquinazolin-4-one in the mother liquid was a trace, and the yield of 6-iodoquinazolin-4-one was 92.3 percent. The result is shown in Table 2 and Table 3. Examples 10 to 12, and Comparative Examples 6 and 7: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the amount of acetic acid or the amount of diethylamine (DEA) relative to 5-iodoanthranilic acid (IAAc) was changed. Comparative Examples demonstrate a case with acetic acid (2.8 mmol) alone and a case with diethylamine (2.8 mmol) alone. The results are shown in Table 3 including Example 5.
90.2%
at 150℃; for 2 h;
Example 5: (Production of 6-iodoquinazolin-4-one); With acetic acid and a base coexisting as a catalyst in the reaction system, 6-iodoquinazolin-4-one was produced in the manner mentioned below. 1.05 g (4 mmol) of 5-iodoanthranilic acid, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.17 g (2.8 mmol) of diethylamine 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 acetic acid and then dried in vacuum at 70°C for 2 hours to obtain 1.01 g of a crystal. The above mother liquid was 3.98 g. The obtained crystal and the mother liquid were analyzed for the purity by high-performance liquid chromatography using 5-iodo-2-methylbenzoic acid as an internal standard substance; and the purity of the crystal was 99.5 percent, 6-iodoquinazolin-4-one in the mother liquid was a trace, and the yield of 6-iodoquinazolin-4-one was 92.3 percent. The result is shown in Table 2 and Table 3. Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
89.9%
at 150℃; for 2 h;
Example 5: (Production of 6-iodoquinazolin-4-one); With acetic acid and a base coexisting as a catalyst in the reaction system, 6-iodoquinazolin-4-one was produced in the manner mentioned below. 1.05 g (4 mmol) of 5-iodoanthranilic acid, 3.60 g (80 mmol) of formamide, 0.17 g (2.8 mmol) of acetic acid and 0.17 g (2.8 mmol) of diethylamine 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 acetic acid and then dried in vacuum at 70°C for 2 hours to obtain 1.01 g of a crystal. The above mother liquid was 3.98 g. The obtained crystal and the mother liquid were analyzed for the purity by high-performance liquid chromatography using 5-iodo-2-methylbenzoic acid as an internal standard substance; and the purity of the crystal was 99.5 percent, 6-iodoquinazolin-4-one in the mother liquid was a trace, and the yield of 6-iodoquinazolin-4-one was 92.3 percent. The result is shown in Table 2 and Table 3. Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
89%
at 120℃; for 18 h; Heating / reflux
Reflux 2-amino-5-iodo-benzoic acid (Aldrich ; 10 g, 38 mmol) in formamide (30 mL) at 120 °C for 18 h. Upon cooling to room temperature, the product is crystallized from the solvent. The product is collected via filtration and the resulting crystals are washed with ether providing the desired 9.2 g (89percent) of the titled compound as a pale solid. MS ES+ m/e 273.0 (M+1).
86.1%
at 150℃; for 2 h;
Examples 10 to 12, and Comparative Examples 6 and 7: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the amount of acetic acid or the amount of diethylamine (DEA) relative to 5-iodoanthranilic acid (IAAc) was changed. Comparative Examples demonstrate a case with acetic acid (2.8 mmol) alone and a case with diethylamine (2.8 mmol) alone. The results are shown in Table 3 including Example 5.
85.1%
at 150℃; for 2 h;
Examples 10 to 12, and Comparative Examples 6 and 7: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the amount of acetic acid or the amount of diethylamine (DEA) relative to 5-iodoanthranilic acid (IAAc) was changed. Comparative Examples demonstrate a case with acetic acid (2.8 mmol) alone and a case with diethylamine (2.8 mmol) alone. The results are shown in Table 3 including Example 5.
82%
at 150℃; for 2 h;
Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
81%
at 150℃; for 2 h;
Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
81%
for 10 h; Reflux
Step C: 6-Iodo-4-quinazolinone (compound 1.3) [0104] A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamide (100 mL) was refluxed for 10 hours. After cooling to room temperature, water (100 mL) was added. The solid product was collected by filtration, washed with water. Further drying in a vacuum provided 6-Iodo-4-quinazolinone (11 g, 81percent) as a gray solid.
75%
at 150℃; for 2 h;
Examples 6 to 9, and Comparative Examples 3 to 5: (Production of 6-iodoquinazolin-4-one); The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the catalyst was changed. Comparative Examples demonstrate a case with no catalyst, a case with an acid catalyst alone, and a case of a base catalyst alone. The results are shown in Table 2.
75%
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.
Reference：
[1] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[3] Patent: CN103772371, 2016, B, . Location in patent: Paragraph 0052; 0053
[4] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7; 8
[5] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[6] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[7] Patent: WO2005/92894, 2005, A1, . Location in patent: Page/Page column 18
[8] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 8
[9] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 8
[10] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[11] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[12] Patent: WO2011/2523, 2011, A1, . Location in patent: Page/Page column 42-43
[13] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 7
[14] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[15] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[16] J. Madras Univ., 1954, vol. 24, p. 183,184
5
[ 77287-34-4 ]
[ 77317-55-6 ]
[ 16064-08-7 ]
Yield
Reaction Conditions
Operation in experiment
87.1%
at 150℃; for 2 h;
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
56.1%
at 190℃; for 2 h;
Methyl 2-amino-5-iodobenzoate (17.8 g, 64 mmmol) was heated in 300 mL of formamide at 19O0C for 2 hours. The mixture was cooled to room temperature and the solid product was filtrated and dried in vacuum. The formed product 1403-174 was used without further purifcation.(10 g, 56.1percent): LC-MS: 273 [M+l]+, 1H NMR (DMSO-J6): δ 7.46 (d, J= 9.0 Hz, 1 H), 8.10 (m, 2H), 8.36 (d, J= 2.1 Hz, 1 H), 12.40 (s, 1 H).
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.
1.8 g (6.90 mmol) of compound obtained in the preceding Step 1 is suspended in 30 ml of triethyl orthoformate. A catalytic amount of para-toluene sulfonic acid is added, and the suspension is refluxed for 3 hours. All volatiles are removed in vacuo, and the residue is washed with 1:1 dichloromethane:Hexane to yield 1.5 g (80percent) of an off white powder as the desired product. [00374] MS(APCI), M/z 270.9 (M-1) [00375] N.M.R (DMSO-d6) 1H δ(ppm): 7.42 (d, J=8.5 Hz, 1H), 8.09 (dd, J1=8.5 Hz, J2=2.2 Hz, 1H), 8.09 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 12.38 (broad s, 1H).
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 5, p. 616 - 620
9
[ 68-12-2 ]
[ 5326-47-6 ]
[ 16064-08-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3820 - 3832
10
[ 16064-08-7 ]
[ 98556-31-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With Vilsmeier reagent In 1,2-dichloro-ethane for 4.5 h; Heating / reflux
Step B: 4-chloro-6-iodoquinazoline. To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2*50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99percent) of desired product as a tan solid.
99%
for 4.5 h; Reflux
Step D: 4-chloro-6-iodoquinazoline (compound 1.4).[0105] To a solution of 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) in thionyl chloride (10 mL) was added slowly DMF (0.5 mL) and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture was then evaporated under reduced pressure to dryness. The residue was then redesolved ' in DCM (20 mL), and to it was added toluene (50 mL), and the mixture was then evaporated under reduced pressure to dryness. The procedure was repeated one more time to rid the product of thionyl chloride to yield 5.2 g (99percent) of desired product as a tan solid.
99%
With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 3 h;
Compound 1 (784 mg, 2.88 mmol) was dissolved in 10 ml of tetrahydrofuran (THF), and oxalyl chloride (731 mg, 5.76 mmol) was added. Two droplets of DMF were immediately added as a reaction catalyst. And the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was completely concentrated to obtain Compound 2 (828 mg, 2.85 mmol, 99percent).
92.4%
With thionyl chloride In N,N-dimethyl-formamide for 4 h; Reflux
Compound 102 (14.4 g) was dissolved in thionyl chloride (50 ml)Adding 1 mL of the catalytic amount of anhydrous DMF,The reaction was refluxed for 4 hours.After completion of the reaction, excess thionyl chloride was distilled off under reduced pressure to give Compound 103. Yield 92.4percent.
88%
With triethylamine; trichlorophosphate In toluene at 2 - 80℃; for 3.5 h; Inert atmosphere
Solution of 6-iodo-quinazolin-4-one (0.54g, 2mmol) was added phosphorus oxychloride (0.37g, 2.4mmol), under nitrogen in dry toluene (2ml), triethylamine (0.24 g, 2.4mmol), leopard after the dropping was raised to 80 stirred 2.5h. The reaction solution was cooled to 2 stirred for 1h, and filtered. The filter cake was washed with acetone, washed with 1mol / L aqueous sodium hydroxide solution (in 3 ml of), washed with water and then with acetone. Vacuum dried to give a beige powder (0.5g, 88percent)
84%
Stage #1: With Chloro-oxo-acetic acid In 1,2-dichloro-ethane at 20 - 75℃; Heating / reflux Stage #2: With sodium carbonate In water; 1,2-dichloro-ethane at 20℃;
Oxalyl chloride (11.8 g, 8.1 mL, 92.6 mmol, 2.0 equiv) was added to a suspension of 6-iodoquinazolin-4-ol (12.6 g, 46.2 mmol, 1.0 equiv), DMF (0.5 ml) and 1,2-dichloroethane (300 mL) resulting in the reaction temperature increasing from 21 to 25° C. The mixture was heated at about 75° C. overnight. TLC (50percent EtOAc/heptane) of an aliquot quenched with NaHCO3 showed the reaction to be incomplete. The mixture was cooled to room temperature, oxalyl chloride (2.0 mL, 0.5 equiv) added and the mixture refluxed for 7 hr. The clear dark brown solution was cooled to room temperature and poured very slowly into 10percent aqueous Na2CO3 solution (500 mL). The aqueous mixture was extracted with EtOAc (500 mL). Most of the aqueous phase was separated and the remaining mixture filtered to remove some insolubles at the interface. The phases of filtrate were separated, the organic phase washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was triturated with cold heptane (about 200 mL), filtered and dried to give 11.2 g (84percent) of 14 as a light brown solid that was used without further purification.
77%
With thionyl chloride In N,N-dimethyl-formamide for 6 h; Reflux
4-chloro-6-iodoquinazoline 6-iodo-4(1H)-quinazolinone (10 g, 37 mmol) was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5 mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux. Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77percent) of the title compound.
71%
at 0 - 90℃;
Step B: Preparation of 4-chloro-6-iodoquinazoline: To a cooled (0 °C) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90 °C for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71percent) as white solid.
Reference：
[1] Patent: US2005/101617, 2005, A1, . Location in patent: Page/Page column 6
[2] Patent: WO2011/2523, 2011, A1, . Location in patent: Page/Page column 43
[3] Patent: KR2017/15848, 2017, A, . Location in patent: Paragraph 0067; 0071; 0072
[4] Patent: CN106317026, 2017, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078
[5] Patent: CN103772411, 2016, B, . Location in patent: Paragraph 0017; 0027; 0028
[6] Patent: US2008/51422, 2008, A1, . Location in patent: Page/Page column 13-14
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5531 - 5538
[8] Patent: EP2744501, 2016, B1, . Location in patent: Paragraph 0156; 0157
[9] Patent: EP2090575, 2009, A1, . Location in patent: Page/Page column 61
[10] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[11] Patent: US2006/281772, 2006, A1, . Location in patent: Page/Page column 58-59
[12] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[13] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 1, p. 27 - 37
[14] Chinese Chemical Letters, 2017, vol. 28, # 6, p. 1220 - 1227
[15] Patent: CN106986895, 2017, A, . Location in patent: Paragraph 0012; 0113
11
[ 16064-08-7 ]
[ 98556-31-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 4.5 h; Heating / reflux
To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2- dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-IODO-QUINAZOLIN-4-OL (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2X50 ml). The combined organic extracts are dried (NA2SO4) and concentrated under reduced pressure to yield 5.2 g (99percent) of desired product as a tan solid.
92.7%
With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 1 h; Inert atmosphere; Reflux
3.2 ml of dry anhydrous DMF was added to 10 ml of dry DCE.At the same time, the reaction system was placed in a low-temperature cooling bath and stirred at 0°.Then 5.3 ml (60 mmol) of oxalyl chloride was added to 25 ml of dry anhydrous DCE to prepare a solution.The solution was slowly dropped into the appeal reaction system dropwise, kept stirring, and protected with nitrogen throughout.During the addition, a white solid precipitated in the reaction system and the reaction was removed after the dripping.Stir at room temperature for 5 minutes. Then compound 1 (5.0 g 18 mmol) was added to the reaction system.After the addition was complete, the reaction was transferred to an oil bath and the reaction was heated to reflux for 1 hour. Nitrogen protection was maintained throughout the reaction.After 1 hour, the reaction was removed from the oil bath and kept stirring to cool to room temperature.About 100 ml of ice water was added and the mixture was extracted with DCM (100 mL×3). The aqueous layer was separated and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.36 g of a light gray solid (yield: 92.7). percent).
88%
With triethylamine; trichlorophosphate In toluene at 80℃; for 2.5 h; Inert atmosphere
To 6-iodo-quinazolin-4-one (0.54g, 2mmol) in dry toluene (2ml), was added a solution of phosphorus oxychloride (0.37g, 2.4mmol) under nitrogen, triethylamine (0.24 g, 2.4mmol) was added dropwise and the mixture was raised to 80 °C stirred for 2.5h. The reaction solution was cooled to 2 °C stirred for 1h and filtered. The filter cake was washed with acetone, washed with 1mol/L aqueous sodium hydroxide solution (in 3 ml) then washed with water and acetone and dried in vacuo to give a beige powder (0.5g, 88percent).
77%
With thionyl chloride In N,N-dimethyl-formamideReflux
6-iodo-4(1H)-quinazolinone (10 g, 37 mmol)was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux.Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77percent) of the title compound.
Reference：
[1] Patent: WO2004/46101, 2004, A2, . Location in patent: Page 19-20
[2] Patent: CN105085496, 2018, B, . Location in patent: Paragraph 0038; 0039
[3] Patent: CN103772371, 2016, B, . Location in patent: Paragraph 0054; 0055
[4] Patent: WO2013/25958, 2013, A1, . Location in patent: Page/Page column 55; 56
[5] Patent: WO2008/33747, 2008, A2, . Location in patent: Page/Page column 169
[6] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[7] Patent: WO2008/67144, 2008, A2, . Location in patent: Page/Page column 23
[8] Patent: WO2006/26313, 2006, A2, . Location in patent: Page/Page column 23
[9] Patent: WO2006/113649, 2006, A1, . Location in patent: Page/Page column 46
[10] Patent: US2011/281896, 2011, A1, . Location in patent: Page/Page column 7
[11] Patent: WO2013/116786, 2013, A1, . Location in patent: Page/Page column 18
[12] Patent: WO2014/134169, 2014, A1, . Location in patent: Page/Page column 5
[13] Patent: WO2005/120512, 2005, A2, . Location in patent: Page/Page column 23
[14] Patent: WO2005/120504, 2005, A2, . Location in patent: Page/Page column 30
[15] Patent: WO2004/43940, 2004, A1, . Location in patent: Page 82
12
[ 16064-08-7 ]
[ 98556-31-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2 h; Stage #2: at 20℃; for 0.25 h;
In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus oxychloride, and 10 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to room temperature, and 100 mL of methanol was added. The mixturewas stirred for 15 minutes at the same temperature, to give 6-iodo-4-methoxyquinazoline. Analysis of the reactionmixture by high performance liquid chromatography indicated that 2.11 g (reaction yield: 99percent) of 6-iodo-4-chloroquinazolinewas produced.
91%
Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-9 were repeated except for replacing acetone with methyl isopropyl ketone. There was produced 48.6 g (isolated yield: 91percent) of 6-iodo-4-chloroquinazoline.
90%
Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2 h; Stage #2: at 0℃; for 1 h;
In a 100 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed20.0 g (73.5 mmol) of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus oxychloride, and 60 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to 0C and stirred for one hour. Thus precipitated pale yellow crystallineproduct of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in100 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature.The crystalline product was collected by filtration, washed with 120 mL of water, and dried under reduced pressure,to give 19.3 g (isolated yield: 90percent, purity 99.3percent in terms of area percentage determined by high performanceliquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.The analysis of 6-halogeno-4-chloroquinazoline in the reaction mixture was performed by the following procedures: After the reaction was complete, 6-halogeno-4-chloroquinazoline was reacted with methanol to give 6-halogeno-4-methoxyquinazoline quantitatively, which was then analyzed by high performance liquid chromatography. 6-Iodo-4-chloroquinazoline had the following physical properties.1H-NMR (CDCl3, d (ppm)): 7.80 (1H, d, J=7.8Hz), 8.20 (1H, dd, J=2.1, 9.0Hz), 8.65 (1H, d, J=2.1Hz), 9.06 (1H, s)CI-MS (m/e): 291 (M+1)
90%
Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-9 were repeated except for replacing acetone with chloroform. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline.
90%
Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-9 were repeated except for replacing acetone with acetonitrile. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline.
90%
Stage #1: With triethylamine; trichlorophosphate In chlorobenzene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-1 were repeated except for replacing toluene with chlorobenzene. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline.
89%
Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
In a 500 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed50.0 g (184 mmol) of 6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus oxychloride, and 300 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 22.3 g (221 mmol) of triethylamine wasslowly added. The resulting mixture was heated at 60C for 30 minutes and then heated at 75C for 2 hours, for carryingout reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL ofacetone was added. The mixture was then cooled to 0C and stirred for 30 minutes. Thus precipitated pale yellowcrystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product wasplaced in 200 mL of water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added. The aqueous mixture (pH 10- 11) was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed successivelywith 100 mL of acetone, 200 mL of water and 100 mL of acetone, and dried at 60C under reduced pressure,to give 47.4 g (isolated yield: 89percent, purity 99percent in terms of area percentage determined by high performance liquidchromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.
89%
Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-9 were repeated except for replacing acetone with tetrahydrofuran. There was produced 47.6 g (isolated yield: 89percent) of 6-iodo-4-chloroquinazoline.
84%
Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h;
The procedures of Example IV-9 were repeated except for replacing acetone with methyl ethyl ketone. There was produced 44.9 g (isolated yield: 84percent) of 6-iodo-4-chloroquinazoline
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 406 - 413
[2] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[3] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[4] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[5] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[6] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
[7] Organic Process Research and Development, 2005, vol. 9, # 4, p. 440 - 450
With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 4.5h;Heating / reflux;
To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2- dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-IODO-QUINAZOLIN-4-OL (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2X50 ml). The combined organic extracts are dried (NA2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
92.7%
With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 1h;Inert atmosphere; Reflux;
3.2 ml of dry anhydrous DMF was added to 10 ml of dry DCE.At the same time, the reaction system was placed in a low-temperature cooling bath and stirred at 0.Then 5.3 ml (60 mmol) of oxalyl chloride was added to 25 ml of dry anhydrous DCE to prepare a solution.The solution was slowly dropped into the appeal reaction system dropwise, kept stirring, and protected with nitrogen throughout.During the addition, a white solid precipitated in the reaction system and the reaction was removed after the dripping.Stir at room temperature for 5 minutes. Then compound 1 (5.0 g 18 mmol) was added to the reaction system.After the addition was complete, the reaction was transferred to an oil bath and the reaction was heated to reflux for 1 hour. Nitrogen protection was maintained throughout the reaction.After 1 hour, the reaction was removed from the oil bath and kept stirring to cool to room temperature.About 100 ml of ice water was added and the mixture was extracted with DCM (100 mL×3). The aqueous layer was separated and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.36 g of a light gray solid (yield: 92.7). %).
88%
With triethylamine; trichlorophosphate; In toluene; at 80℃; for 2.5h;Inert atmosphere;
To 6-iodo-quinazolin-4-one (0.54g, 2mmol) in dry toluene (2ml), was added a solution of phosphorus oxychloride (0.37g, 2.4mmol) under nitrogen, triethylamine (0.24 g, 2.4mmol) was added dropwise and the mixture was raised to 80 C stirred for 2.5h. The reaction solution was cooled to 2 C stirred for 1h and filtered. The filter cake was washed with acetone, washed with 1mol/L aqueous sodium hydroxide solution (in 3 ml) then washed with water and acetone and dried in vacuo to give a beige powder (0.5g, 88%).
77%
With thionyl chloride; In N,N-dimethyl-formamide;Reflux;
<strong>[16064-08-7]6-iodo-4(1H)-quinazolinone</strong> (10 g, 37 mmol)was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux.Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77%) of the title compound.
53%
With trichlorophosphate;
6-Iodoquinazolin-4(3H)-one (1Og, 37 mmol) was refluxed in POCI3 (100 mL) overnight. Then POCI3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL ). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC- MS: 291 [M+l]+, 1H NMR (CDCl3): delta 7.81 (d, J= 9.0 Hz, 1 H), 8.21 (dd, Ji = 9.0 Hz, J2 = 1.8 Hz, I H), 8.65 (d, J= 1.8 Hz, 1 H), 9.06 (s, 1 H).
With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux;
Example 1; Preparation of GW572016F; STAGE 1; A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. <n="25"/>Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux;
A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 7O0C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
With tributyl-amine; trichlorophosphate; In toluene; at 70 - 80℃; for 2h;Heating / reflux;
A stirred suspension of 3W-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)rnethyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo. EPO <DP n="48"/>
With thionyl chloride; In N,N-dimethyl-formamide;Reflux;
Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506
With thionyl chloride; for 2h;Reflux;
Example 1 Synthesis of CD 8/CD 19 inhibitors SNX-2-1-165 was synthesized according to the scheme shown in Figure 2. All other compounds were synthesized using similar procedures.
With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux;
A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid, the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals.
With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux;
A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux.
With P,P-dichlorophenylphosphine oxide; at 150℃; for 1h;
A mixture of 6-iodoquinazolin-4 (3H)-one (Intermediate 11,100 mg, 0.37 mmol) and phenylphosphonic dichloride (1.5 ML) was heated at 150 C for one h. After cooling the reaction mixture in an ice bath, isopropyl ether was added. The resultant crystalline precipitate was collected by filtration, and was then stirred with saturated aqueous sodium bicarbonate solution. The solution was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product. Purification by preparative thin layer chromatography (silica gel, 5% and 10% ethyl acetate/hexanes) afforded the desired product. LC/MS 291 (M+1).
With acetic acid; diethylamine; at 150℃; for 2h;Product distribution / selectivity;
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
56.1%
at 190℃; for 2h;
Methyl 2-amino-5-iodobenzoate (17.8 g, 64 mmmol) was heated in 300 mL of formamide at 19O0C for 2 hours. The mixture was cooled to room temperature and the solid product was filtrated and dried in vacuum. The formed product 1403-174 was used without further purifcation.(10 g, 56.1%): LC-MS: 273 [M+l]+, 1H NMR (DMSO-J6): delta 7.46 (d, J= 9.0 Hz, 1 H), 8.10 (m, 2H), 8.36 (d, J= 2.1 Hz, 1 H), 12.40 (s, 1 H).
Reflux;
Example 1 Synthesis of CD 8/CD 19 inhibitors SNX-2-1-165 was synthesized according to the scheme shown in Figure 2. All other compounds were synthesized using similar procedures.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
0.9 g (3.31 mmol) of the compound obtained in the preceding step was dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of t-butyl 4-bromomethyl-benzoate were then added. The reaction mixture was stirred at room temperature for 24 hours. 200 ml of EtOAc were then added, and the organic layer was washed with 3 x 100 ml of water, dried over [MGS04] and concentrated. The residue was purified on a silica gel column using 4: 1 dichloromethane : hexane increasing gradually to a 1: 1 ratio, to yield 0.97 g (62%) of white powder as the desired product. N. M. R [(CDCL3) 1H A] (ppm) 5.21 (s, 2H), 7.36 (d, [J=] 8. 5Hz, 2H), 7.43 (d, [J=] 8.5 Hz, [1H),] 7.96 (dd, Jl = 6. 6Hz, [J2] = 3. 1Hz, 2H), 8.01 (dd, Jl = 6. [5HZ,] [J2] = 2. 1Hz, [1H),] 8.07 (s, 1H), 8.64 (d, [J=] [1.] 8Hz, [1EI)] ; MS (APCI), M/z 270.9 [(M-1).]
62%
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
0.9 g (3.31 mmol) of compound obtained in the preceding Step 2 is dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of ter-butyl 4-bromomethyl-benzoate is added. The reaction is stirred at room temperature for 24 hours. 200 ml of EtOAc is then added, and then washed with 3×100 ml of water. The organic layer is dried over MgSO4 and concentrated. The residue is purified on a silica gel column using 4:1 dichloromethane:hexane increasing gradually to a 1:1 ratio, to yield 0.97 g (62%) of white powder as the desired product. [00378] MS(APCI), M/z 270.9 (M-1) [00379] N.M.R (CDCl3) 1H delta(ppm) 5.21 (s, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.96 (dd, J1=6.6 Hz, J2=3.1 Hz, 2H), 8.01 (dd, J1=6.5 Hz, J2=2.1 Hz, 1H), 8.07 (s, 1H), 8.64 (d, J=1.8 Hz, 1H)
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 0C the solid product was collected by filtration. Further drying in a vacuum provided 6-IODO-4-QUINAZOLINONE (11 G, 81%) as a gray solid.
In ethanol; for 2h;Heating / reflux;
A mixture of 2-amino-5-iodobenzoic acid (2.0 g, 7.6 mmol) and formamidine acetate (0.99 g, 9.5 mmol) in absolute ethanol (80 mL) was heated at reflux for 2 h. The reaction was then cooled in an ice bath, and water (10 mL) was added with stirring. The resultant precipitate was collected by filtration to afford the desired product as pale crystals. LC/MS 272.7 (M+1).
With toluene-4-sulfonic acid; for 3h;Heating / reflux;
1.8 g (6.90 mmol) of compound obtained in the preceding Step 1 is suspended in 30 ml of triethyl orthoformate. A catalytic amount of para-toluene sulfonic acid is added, and the suspension is refluxed for 3 hours. All volatiles are removed in vacuo, and the residue is washed with 1:1 dichloromethane:Hexane to yield 1.5 g (80%) of an off white powder as the desired product. [00374] MS(APCI), M/z 270.9 (M-1) [00375] N.M.R (DMSO-d6) 1H delta(ppm): 7.42 (d, J=8.5 Hz, 1H), 8.09 (dd, J1=8.5 Hz, J2=2.2 Hz, 1H), 8.09 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 12.38 (broad s, 1H).
With ammonium acetate; In acetonitrile; at 120℃; for 3h;
The procedures of Example I-2 were repeated except that methanol was replaced with acetonitrile. There was obtained 0.98 g (reaction yield: 94%) of 6-iodoquinazolin-4-one.
93 - 94%
With ammonium acetate; In methanol; at 120℃; for 3h;
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.0 g (3.8 mmol) of 5-iodoanthranilic acid, 0.81 g (7.6 mmol) of methyl orthoformate, 0.59 g (7.6 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.97 g (isolated yield: 93%) of 6-iodoquinazolin-4-one as a pale gray crystalline product. 6-Iodoquinazolin-4-one had the following characteristics. m.p.: 259C (decomp.) 1H-NMR (DMSO-d6, delta (ppm)): 7.46 (1H, d, J=8.4Hz), 8.08-8.15 (2H, m), 8.39 (1H, d, J=1.8Hz), 12.5 (1H, brs) CI-MS (m/e): 273 (M+1); [Example I-2] Preparation of 6-iodoquinazolin-4-one The procedures of Example I-1 were repeated except that the amounts of methyl orthoformate and ammonium acetate were changed to 1.61 g (15.2 mmol) and 1.17 g (15.2 mmol), respectively. There was obtained 0.98 g (reaction yield: 94%) of 6-iodoquinazolin-4-one.
91%
With ammonium acetate; at 120℃; for 3h;
The procedures of Example I-2 were repeated except that the amount of methyl orthoformate was changed to 3.60 g (34 mmol) and that no methanol was used. There was obtained 0.94 g (reaction yield: 91%) of 6-iodoquinazolin-4-one.
90%
With ammonium 2,4-dichlorobenzoate; In methanol; at 120℃; for 3h;
The procedures of Example I-2 were repeated except that ammonium acetate was replaced with 3.20 g (15.2 mmol) of ammonium 2,4-dichlorobenzoate. There was obtained 0.97 g (reaction yield: 90%) of 6-iodoquinazolin-4-one.
85%
With ammonium formate; In methanol; at 120℃;
The procedures of Example I-2 were repeated except that ammonium acetate was replaced with 0.95 g (15.2 mmol) of ammonium formate. After the reaction was complete, the reaction mixture was treated in the manner of Example I-1. There was obtained 0.88 g (isolated yield: 85%) of 6-iodoquinazolin-4-one as a pale gray crystalline product
toluene-4-sulfonic acid; In orthoformic acid triethyl ester; for 3h;Heating / reflux;
1.8 g (6.90 mmol) of the compound obtained in the preceding step was suspended in 30 ml [OF TRIETHYL ORTHOFORMATE.] A catalytic amount of para-toluene sulfonic acid was added, and the suspension was refluxed for 3 hours. All volatiles were removed in vacuo, and the residue was washed with 1 : [1] dichloromethane: hexane to yield 1.5 g [(80%)] of an off white powder as the desired product. N. M. R (DMSO-d6) 1H delta (ppm): 7.42 (d, [J= 8. 5HZ, 1H),] 8.09 (dd, J1 = 8. [5HZ,] [J2] = 2. 2Hz, 1H), 8.09 (s, 1H), 8.34 (d, [J=] 2.2Hz, 1H), 12. 38 (broad s, 1H) ; MS (APCI), M/z 270.9 [(M-1) ;]
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 2.33333h;
Suspend sodium hydride (1.13 g, 47 mmol) in a solution of 6-iodo-3H-quinazolin- 4-one (2.5 g, 9.2 mmol) in DMF. Stir at room temperature for 20 min, add iodomethane (6.6 g, 46 mmol) into the mixture and stir for 2 h. Dilute the mixture with 3: 1 chloroform/isopropyl alcohol and wash with saturated sodium chloride solution. Dry the organic phase (sodium sulfate) and concentrate in vacuo. Purify the residue with flash chromatography (dichloromethane to dichloromethane/methanol) to give 2.5 g (95%) of the titled compound as a white solid. MS ES+ m/e 287 (M+1).
With pyridine; In methanol; methylene chloride (CH2Cl2);
EXAMPLE 1 (1H-Indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine 6-Iodo-3H-quinazolin-4-one (50 gm, 18.3 mmol) was slurried in 60 mL methylene chloride (CH2Cl2) with several drops of DMF. Oxalyl chloride (6.99 g, 4.83 mL, 55.1 mmol) was added dropwise to the slurry at 0 C. The reaction was refluxed for 48 hours and then concentrated in vacuo. Pyridine (2.9 gm, 2.97 mL, 36.7 mmol) and tert-butyl alcohol (10 mL) was added to dissolve the 4-chloro-6-iodo quinazoline. 5-Aminoindole (2.9 gm, 22.0 mmol) was added and the reaction was heated to 60 C. overnight. Diluted the reaction mixture with chloroform (CHCl3) and washed with brine, saturated aqueous NaCHO3 and dried over NaSO4. The organic layer was concentrated in vacuo to a black oil. The crude product was chromatographed on silica gel (2 parts methanol to 1 part methylene chloride (2 MeOH/CH2Cl2)) to provide 2.99 gm of white crystalline product. M.P. 261 C.; LC-MS; 387 (M+); RP18-HPLC RT: 4.12 min.
bis-benzonitrile (palladium (II) chloride[ No CAS ]
[ 497-19-8 ]
[ 98-80-6 ]
[ 206190-28-5 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; hexane; ethyl acetate; toluene;
EXAMPLE 44 6-Phenyl-3H-quinazolin-4-one The catalyst was prepared by adding bis-benzonitrile (palladium (II) chloride (140 mg, 0.37 mmol) to a solution of bis-(diphenylphosphine butane) (157 mg, 0.37 mmol) in 18 mL of toluene. The mixture stirred at room temperature for 20 min. <strong>[16064-08-7]6-iodo-3H-quinazolin-4-one</strong> (1.0 gm, 3.67 mmol), phenyl boronic acid (896 mg, 7.35 mmol), 1M aqueous Na2CO3 (3.67 mL, 7.35 mmol) and 9 mL of ethanol were added to the catalyst solution. The reaction mixture was refluxed for 24 hours. Reaction mixture was cooled to room temperature, filtered through celite, washed with saturated aqueous NaHCO3 and dried over Na3SO4. The organic layer was concentrated to a yellow solid and chromatographed on silica gel using 20% hexane/ethyl acetate. Five hundred ten milligrams (63%) of the title compound were isolated. PB-MS:223 (MH+); RP18-HPLC RT: 3.47 min.
At ambient temperature,The 5: 2 v / v mixture solvent (1400 mL) of dimethylsulfoxide (DMSO) was mixed with H2O for 30 minutes using nitrogen.Under nitrogen protection,5-formylfuran-2-ylboronic acid ((VIa);26.8 g, 193 mmol) to a mixed solvent,Dissolve.Add [HP (t-Bu) 3] BF4 (840 mg, 2.94 mmol)And palladium acetate Pd (OAc) 2 (680 mg, 2.94 mmol)And at ambient temperature,After stirring the mixture for 20 minutes,Potassium acetate (AcOK, 18.8 g, 192 mmol) was added to the reactor,Stirring was continued for 20 minutes,6-iodoquinazolin-4 (3H) -one ((Va))40 g, 147 mmol).The reaction mixture was heated to 80 ± 5 C (internal temperature).After the HPLC monitoring reaction was complete,The reaction mixture was filtered while hot,The hot water (400 mL, 80 + 5 [deg.] C) was then added to the filtrate.It was slowly cooled to 0-15 C (solid began to precipitate at an internal temperature of 70 C)Then filtered,The filter cake was washed successively with H2O (80 mL), MeCN (60 mL).The filter cake was vacuum dried at 60 ± 5 C for 6 hours,5- (4-oxo-3,4-dihydroquinazolin-6-yl) -furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol)HPLC analysis purity of 99.7%The yield was 97.6%.
97.6%Chromat.
With tri tert-butylphosphoniumtetrafluoroborate;palladium diacetate; In water; dimethyl sulfoxide; at 20 - 80℃;Inert atmosphere;Product distribution / selectivity;
Example 1: Synthesis of 5-(4-oxo-3,4-dihydroquinazolin-6-yl)furan-2-carbaldehyde (IMl)IM1A 5:2 v/v mixture of DMSO and H20 (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. 5-Formylfuran-2-ylboronic acid (SM2a; 26.8 g, 193 mmol) was added dissolved in this mixture. [HP(i-Bu)3] BF4" (840 mg, 2.94 mmol) and Pd(OAc)2 (680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 20 min. AcOK (18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min at ambient temperature. 6-Iodoquinazolin-4(3 /)-one (SMla; 40 g, 147 mmol) was added and heated to 80+/-5C (internal temperature) in an oil bath under nitrogen, Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80+/-5C) was added into the filtrate. This was slowly cooled to 0-15C (solid started to precipitate at 70C (internal temperature) and was then filtered. The filter cake was washed with H20 (80 mL), then with MeCN (60 mL), and dried in vacuo at 60+5C for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2- carbaldehyde (IMl; 34.6 g, 144 mmol) with 99.7 % HPLC purity in 97.6% HPLC yield. XH NMR (300 MHz, de-DMSO): delta 7.47 (d, / = 3.8 Hz, 1H), 7.69 (d, / = 3.8 Hz, 1H), 7.77 (d, / = 8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, / = 8.6, 2.1 Hz, 1H), 8.52 (d, = 2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDC13): delta 110.5, 122, 6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178,8; ESI-MS, Pos: [M+H]+ mJz 241; IR (cm 1): 1713, 1671, 1604,1462; m.p.: 267C. See Figure 2 for the DSC/TGA of IMl; See Figure 3 for the X-ray powder diffraction pattern of IMl; Residual concentration of palladium: 230 ppm.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 30.0h;
6-(4-(Morpholinosulfonyl)phenyl)quinazolin-4(3H)-one (18). A mixture of 6-iodoquinazolin-4(3H)-one (4.5 g, 16.54 mmol), (4- (morpholinosulfonyl)phenyl)boronic acid (4.93 g, 18.20 mmol), sodium carbonate (10.52 g, 99 mmol), and tetrakis-(triphenylphosphine)palladium(0) (1.338 g, 1.158 mmol) were combined in a flask, and 400 mL of 1,2-dimethoxyethane was added with ethanol (26.7 mL) and water (33.3 mL). The reaction mixture was heated with stirring at 80 C. for 30 h. The reaction progress was monitored by LC-MS. Upon completion of the reaction, the mixture was cooled to room temperature and the product precipitated. Solids were collected by filtration, washed with cold water, and air-dried, affording 18 (5.35 g, 14.40 mmol, 87% yield). 1H NMR (500 MHz, DMSO-d6) delta: 12.40 (br s, 1H), 8.44 (d, J=2.44 Hz, 1H), 8.22 (dd, J=2.20, 8.55 Hz, 1H), 8.16 (d, J=3.42 Hz, 1H), 8.07 (d, J=8.30 Hz, 2H), 7.84 (d, J=8.30 Hz, 2H), 7.80 (d, J=8.79 Hz, 1H), 3.64 (t, J=4.65 Hz, 4H), 2.91 (t, J=4.65 Hz, 4H). MS: m/z=372.2 (M+H)+.
2-Amino-5-iodobenzoic acid (II) (6.8 g, 0.05 mol),Mixed with 20ml of formamide and heated to 180C,Stir the reaction for 12h, cool, pour into ice water, filter,After washing with water, 12.6 g of needle-like crystals of 6-iodoquinazolin-4-one (III) were obtained with a yield of 92.6% and HPLC purity of 99.83%.
5-Iodoanthranilic acid methyl ester (1 g, 3.61 mmol) and formamide (2 ml) were used as a reactant and solvent, then the reaction was carried out in a microwave reactor for 1 hour at 200 C in a microwave reactor vial. After the completion of the reaction, the resulting solid compound was washed with water and then the water was removed from the oven at 100 C for about 1 hour to obtain Compound 1 (784 mg, 2.88 mmol, 80%).
6-(3-morpholinophenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 85℃; for 6h;
6-iodoquinazolin-4(3H)-one (0.672g, 2.469mmol), <strong>[852227-95-3]4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine</strong> (1.785g, 6.17mmol), a 2M aqueous solution of sodium carbonate (7.41mL, 14.81mmol), [1,1?-bis(diphenylphoshpino)ferrocene] dipalladium(II) dichloromethane adduct (0.141g, 0.173mmol), dimethoxyethane (5mL), and ethanol (3.3mL) were added together and heated at 85C for 6h. The reaction mixture was concentrated under reduced pressure, filtered through celite, and the product was collected by silica column chromatography (dichloromethane/methanol). The collected fractions were concentrated under reduced pressure. A mixture of 70% hexanes/30% toluene was added and the precipitated product was collected by vacuum filtration to obtain a 66% yield as a tan solid. 1H NMR (500MHz, DMSO-d6) delta ppm 3.21 (m, 4H), 3.76 (m, 4H), 7.00 (dd, J=8.3, 2.4Hz, 1H), 7.17 (d, J=7.8Hz, 1H), 7.25 (m, 1H), 7.36 (t, J=7.8Hz, 1H), 7.74 (d, J=8.3Hz, 1H), 8.12 (m, 2H), 8.31 (d, J=2.0Hz, 1H), 12.31 (br. s, 1H). LCMS found 308.1, [M+H]+.
With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130℃; for 2h;Microwave irradiation; Inert atmosphere;
[0357] To a solution of Example 18a (1.00 g, 3.67 mmol) in DMF (10 mL) were added Cul (351 mg, 1.83 mmol), Cs2C03 (2.38 g, 7.30mmol), Example 18b(476 mg, 4.41 mmol), andN1,N2-dimethyl- cyclohexane-l,2-diamine (105 mg, 0.74 mmol). The resulting mixture was degassed with N2 and stirred at 130°C under microwave for 2 h. The mixture was diluted with MeOH and filtered. The filtrate was concentrated under vacuum and the residue was purified byPrep-HPLC (by Ultimate XB-C18, 50 x 250 mm, 10 mum, speed: 80 mL/min, eluent: H20/CH3CN = from 80/20 to 20/80 over 50 min)to give the desired product Example 18c (110 mg, yield 12percent) as a yellow solid. LC-MS: [M+H]+ = 253.0
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