There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 1575-37-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide
Step 87a: 73/4rt-butyl 5-bromo-lH-benzo[d]imidazole-l-carboxylate (Compound 0601-187)To a solution of 4-bromobenzene-l,2-diamine (3 g, 16 mmol) in DMF (22 mL) were added trimethyl orthoformate (44 mL) and cone. HC1 (1.5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (200 mL) and adjusted to pH7 with saturated aqueous NaHC03, extract with ethyl acetate (200 mL). The organic layer was dried over Na2S04, concentrated to give 5-bromo-lH-benzo[d]imidazole (3.25 g, 100percent) as an off-white solid. LCMS: 197 [M+l]+. 1H NMR (400 MHz, DMSO-<3/4) δ 7.33 (t, J= 8.8 Hz, 1H), 7.55 (dd, J; = 7.6 Hz, J= 40 Hz, 1H), 7.79 (d, J= 47.2 Hz, 1H), 8.26 (s, 1H), 12.61 (d, J= 25.6 Hz, 1H).
100%
With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 1 h;
Step 87a: Tert-butyl 5-bromo-1H-benzo[d]imidazole-1-carboxylate (Compound 0601-187)[0581]To a solution of 4-bromobenzene-1,2-diamine (3 g, 16 mmol) in DMF (22 mL) were added trimethyl orthoformate (44 mL) and conc. HCl (1.5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (200 mL) and adjusted to pH7 with saturated aqueous NaHCO3, extract with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, concentrated to give 5-bromo-1H-benzo[d]imidazole (3.25 g, 100percent) as an off-white solid. LCMS: 197 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (t, J=8.8 Hz, 1H), 7.55 (dd, J1=7.6 Hz, J=40 Hz, 1H), 7.79 (d, J=47.2 Hz, 1H), 8.26 (s, 1H), 12.61 (d, J=25.6 Hz, 1H).
100%
With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃; for 1 h;
4-bromobenzene -l, 2-diamine (3 g, 16 mmol) in solution in DMF (22 mL) of trimethyl orthoformate (44 mL) and concentrated HCl (1.5 mL) was added, 1 hour and the mixture is stirred at room temperature did. The mixture was diluted with water (200 mL), adjusted to pH7 with saturated aqueous NaHCO3, issued extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, and concentrated to give 5-bromo -1H- benzo [d] imidazole as an off-white solid (3.25g, 100percent).
Reference：
[1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 228
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0580; 0581
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0493
[4] Patent: US2009/326029, 2009, A1, . Location in patent: Page/Page column 33
2
[ 122-51-0 ]
[ 1575-37-7 ]
[ 4887-88-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
With zirconium(IV) chloride In methanol at 20℃; for 3 h;
General procedure: A mixture of o-phenylenediamine (1.0 mmol), triethyl orthoformate (1.2 mmol) and ZrCl4 (0.1 mmol) in 10 mL MeOH was stirred at room temperature for 3 h. After completion of the reaction, as indicated by TLC, the solvent was concentrated and the resulting product was directly purified by silica gel column chromatography (4:1 / 1:1, v/v, petroleum ether/EtOAc) to afford compound 11a-h.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 241 - 250
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 827 - 832
[3] Patent: US2008/300247, 2008, A1, . Location in patent: Page/Page column 38
3
[ 64-18-6 ]
[ 1575-37-7 ]
[ 4887-88-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 100℃;
Example 8 (5)- N2 -(l-(lH-benzo[d]imidazol-5-yl)ethyl)- N4 -(5-cyclopropyl-lH-pyrazol-3-yl)- N2 - methylpyrimidine-2,4-diamine (1-9) and (R)- N2 -(l-(lH-benzo[d]imidazol-5-yl)ethyl)- N4 -(5- cyclopropyl- 1 H-pyrazol-3 -yl)-N2-methylpyrimidine-2,4-diamine (1-55) step 1 : A mixture of 4-bromobenzene-l,2-diamine (4.0 g, 21.5 mmol) and formic acid (95 percent>, 100 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to RT and concentrated in vacuo to afford a dark oil. The crude oil was partitioned between EtOAc (500 mL) and NH3/H20 (50 mL). The EtOAc layer was separated and concentrated in vacuo to afford 4.5 g (100percent) of 5-bromo-lH- benzo[d] imidazole (78) as brown solid: MS (ESI) m/z = 197.0 (M+l).
85%
for 2 h; Reflux
[0990] A solution of XXXV-1 (10 g, 53.4 mmol) in HCOOH (50 mL) was heated at reflux for 2 hours, after cooled to rt, aq.NaOH (10percent) was added slowly until the mixture was basic.Then extracted with EtOAc (100 mLx3), the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give XXXV-2 (9 g, 85percent yield).
Reference：
[1] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 131
[2] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[3] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0990
[4] Journal of the Chemical Society, 1931, p. 1143,1153
[5] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 42
4
[ 124-38-9 ]
[ 1575-37-7 ]
[ 4887-88-1 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 1, p. 95 - 99
5
[ 144-62-7 ]
[ 1575-37-7 ]
[ 4887-88-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1337 - 1342
Reference：
[1] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8282 - 8287
8
[ 78-39-7 ]
[ 1575-37-7 ]
[ 1964-77-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
With zirconium(IV) chloride In methanol at 20℃; for 3 h;
General procedure: A mixture of o-phenylenediamine (1.0 mmol), triethyl orthoformate (1.2 mmol) and ZrCl4 (0.1 mmol) in 10 mL MeOH was stirred at room temperature for 3 h. After completion of the reaction, as indicated by TLC, the solvent was concentrated and the resulting product was directly purified by silica gel column chromatography (4:1 / 1:1, v/v, petroleum ether/EtOAc) to afford compound 11a-h.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 241 - 250
9
[ 78191-00-1 ]
[ 1575-37-7 ]
[ 1964-77-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With boron trifluoride diethyl etherate In 1,4-dioxane at 20 - 100℃; for 1 h; Inert atmosphere
General procedure: To a solution of o-diaminobenzene (5.0 mmol, 0.5405 g) and Weinreb amide (N-methoxy-Nmethylbenzamide, 5.0 mmol, 0.82595 g) in dioxane (10 mL), boron trifluoride diethyl etherate (5.0 mmol) was added at room temperature. The reaction mixture was stirred for the specified time (Table 3) at 100 °C. TLC revealed the complete consumption of starting material. Subsequently hydrolysis was achieved by the addition of saturated NH4Cl solution (50 mL). The aqueous layer was extracted with ethyl acetate (3 X 25 mL), washed with water (2 X 25 mL), brine solution (2 X 25 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to get crude product. This was purified by column chromatography over silica gel using hexane/ethyl acetate mixture in 1:1 ratios as eluent.
Reference：
[1] European Journal of Inorganic Chemistry, 2013, # 26, p. 4654 - 4661
[2] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[3] Patent: WO2007/80382, 2007, A1, . Location in patent: Page/Page column 132-133
11
[ 141-82-2 ]
[ 1575-37-7 ]
[ 1964-77-8 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1337 - 1342
12
[ 105919-36-6 ]
[ 64-19-7 ]
[ 1575-37-7 ]
[ 1964-77-8 ]
Reference：
[1] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1774 - 1783
13
[ 108-24-7 ]
[ 1575-37-7 ]
[ 1964-77-8 ]
Reference：
[1] Journal of the Chemical Society, 1931, p. 1143,1153
14
[ 1575-37-7 ]
[ 32046-62-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
With acetic acid; sodium nitrite In water at 0 - 85℃; for 2 h;
To a solution of 4-bromobenzene-1,2-diamine (10 g, 53.5 mmol) in a mixture of acetic acid (20 ml, 349 mmol) and water (100 ml) at 0-5° C. was added a solution of sodium nitrite (4.06 g, 58.8 mmol) in water (10 ml) dropwise. Stirred in the ice bath for 1 h, more acetic acid (20 ml, 349 mmol) was added, heated to 80-85° C. with stirring during 1 h, the solution was filtered hot to remove insoluble black material, cooled to 0-5° C., aged for 30 min, precipitate collected, washed with water, dried in vacuum at 45° C. Yield 9.48 g (90percent).
67%
With acetic acid; sodium nitrite In water at 4 - 20℃; for 16 h; Reflux; Inert atmosphere
A 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, nitrogen inlet and bubble counterEach o-diaminobenzene (0.031 mol) (Formula 1a) was added dropwise to glacial acetic acid (50 mL) under a nitrogen atmosphere.The resulting slurry was cooled to 4 [deg.] C in an ice-bath. Sodium nitrite in water (6 mL) (2.24 g,0.032 mol) in THF Was added dropwise over 40 minutes while maintaining the temperature of the reaction mixture below & lt; RTI ID = 0.0 & gt; 10 C. & lt; / RTI & gt; GeneratedThe slurry was allowed to warm to room temperature and analyzed using a KI / amylose test paper until analysis for free HNO2 was negative and starting material was not visible in thin layer chromatography (16 h)Under stirring. The resulting slurry was filtered; the solid residue washed with water (100 mL) and the resulting solid was further purified by recrystallization from ethanol (20 mL). The product was dried for 24 h at 50° C. and 5 mbar and obtained as off-white solid. Yield: 67percent.
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 37, p. 6902 - 6907
[2] Patent: US2012/65191, 2012, A1, . Location in patent: Page/Page column 26; 27
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 827 - 832
[4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 20, p. 6832 - 6846
[5] Patent: KR2016/30566, 2016, A, . Location in patent: Paragraph 0267-0270
[6] Journal of the Chemical Society, 1931, p. 1143,1153
[7] Patent: US2003/187026, 2003, A1,
[8] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 74
15
[ 1575-37-7 ]
[ 1753-75-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
for 1 h; Heating / reflux
Example 2 Synthesis of 5-bromo-2,1,3-benzothiadiazole A mixture was prepared by mixing 4.0 g (21 mmol) of 4-bromo-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resulting precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.5 g of 5-bromo-2,1,3-benzothiadiazole as a crude product (melting point, 48 to 50° C.; yield, 96.5percent).
Reference：
[1] RSC Advances, 2016, vol. 6, # 71, p. 66978 - 66989
[2] Patent: US2009/149676, 2009, A1, . Location in patent: Page/Page column 5
[3] ChemMedChem, 2018, vol. 13, # 21, p. 2332 - 2348
[4] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1967, vol. 3, p. 662 - 666[5] Khimiya Geterotsiklicheskikh Soedinenii, 1967, vol. 3, # 5, p. 839 - 844
[6] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1979, vol. 17, p. 13 - 16
[7] Journal of Heterocyclic Chemistry, 1970, vol. 7, p. 629 - 633
[8] Patent: US2004/152738, 2004, A1,
[9] Chemistry - A European Journal, 2010, vol. 16, # 3, p. 899 - 906
[10] Chemistry--A European Journal, 2012, vol. 18, # 37, p. 11685 - 11694,10
16
[ 530-62-1 ]
[ 1575-37-7 ]
[ 39513-26-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 80℃; for 5 h;
2.1a. 5-bromo-1,3-dihydrobenzimidazol-2-one 4.29 g (26.46 mmol) of carbonyldiimidazole (CDI) is added to a solution of 4.5 g (24.05 mmol) of 4-bromobenzene-1,2-diamine in 95 mL of DMF and the reaction mixture is stirred for 5 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60° C. Yield: 4.6 g (90percent of theoretical); C7H5BrN2O (M=213.03); calc.: molpeak (M+H)+: 213/215; found: molpeak(M+H)+: 213/215; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
70%
at 40℃; for 1 h;
Step 89a: 5-Bromo-lH-benzo[d]imidazol-2(3H)-one (Compound 0601-186)A mixture of 4-bromobenzene-l,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1 ,4-dioxane(20 mL) was stirred for 1 hr at 40°C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70percent>) as a white solid. LCMS: 213 [M+l]+, 1H NMR (400 MHz, DMSO-^ δ 6.86 (d, J= 8.0 Hz, 1H), 7.06(m, 1 H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
at 40℃; for 1 h;
Step 89a: 5-Bromo-1H-benzo[d]imidazol-2(3H)-one (Compound 0601-186)[0593]A mixture of 4-bromobenzene-1,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1,4-dioxane (20 mL) was stirred for 1 hr at 40° C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70percent) as a white solid. LCMS: 213 [M+1]+, 1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J=8.0 Hz, 1H), 7.06 (m, 1H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
at 40℃; for 1 h;
1,4-dioxane (20mL) solution of 4-bromo-1,2-diamine (3.74g, 20mmol), CDI (3.9g, 24mmol) and the mixture was stirred for 1 hour at 40 of. The mixture was washed and filtered with petroleum ether and dichloromethane to give the compound 0601-186 as a white solid (3.0g, 70percent).
4 g
at 80℃; for 4 h;
To a solution of 4-bromobenzene-1 ,2-diamine (3 g,16 mmol) in DMF (60 mL) was added CDI (3.1 g, 19.3mmol). The reaction was stirred at 80° C. for 4 h. After themixture was cooled toRT, water (100 mL) was added. Theprecipitate was collected by filtration and dried to give 4 gof 5-bromo-1,3-dihydro-28-benzo[d]imidazol-2-one as adark red solid. GC-MS: 212/214 (M).
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[2] Patent: US2005/267115, 2005, A1, . Location in patent: Page/Page column 35
[3] Patent: WO2005/103029, 2005, A1, . Location in patent: Page/Page column 75
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[5] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 231
[6] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0592; 0593
[7] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0503
[8] Patent: US2010/249124, 2010, A1, . Location in patent: Page/Page column 51
[9] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[10] Patent: WO2014/100695, 2014, A1, . Location in patent: Paragraph 00357
[11] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000862
[12] Patent: US2018/258065, 2018, A1, . Location in patent: Paragraph 0267
Stage #1: With sodium hydrogencarbonate In methanol; water at 20℃; for 3.5 h; Stage #2: With sodium hydroxide In methanol; water at 20℃;
Add phenyl CHLOROFORMATE (922mg, 5. 89MMOL) to a suspension of 4-bromo-benzene-1, 2- diamine (L. OOG, 5. 35MMOL) AND NAHC03 (483mg, 5. 89MMOL) in methanol (20ML) and H20 (lOmL). Stir at room temperature for 3. 5h and add 1. OON aqueous NAOH (6mL, 6. 00MMOL). Stir overnight at room temperature and filter. Wash the filter cake with HA0 and dry in-vacuo overnight to obtain 386mg (34percent) of the title compound as a brown powder. MS (ES) 213,215 (M+H), 211,213 (M-H) ; HPLC shows 95percent purity.
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 1662
[2] Patent: WO2007/80382, 2007, A1, . Location in patent: Page/Page column 134
20
[ 57-13-6 ]
[ 1575-37-7 ]
[ 39513-26-3 ]
Yield
Reaction Conditions
Operation in experiment
27%
at 130℃;
A mixture of 4-bromobenzene-1 ,2-diamine (1.00 g, 5.3 mmol) and urea (0.97 g, 15.0 mmol)was stirred at 130 oc for overnight. The residue was purified by column chromatography onsilica gel (ethyl acetate/petroleum ether= 1/10 ~ 3/1) to give CAP-004-21-1 (0.31 g, 27 percent) as a pale yellow solid
Reference：
[1] ACS Chemical Neuroscience, 2017, vol. 8, # 11, p. 2477 - 2495
22
[ 1575-37-7 ]
[ 108229-82-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1809 - 1814
23
[ 1575-37-7 ]
[ 72023-79-1 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1979, vol. 17, p. 13 - 16
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1967, vol. 3, p. 662 - 666[3] Khimiya Geterotsiklicheskikh Soedinenii, 1967, vol. 3, # 5, p. 839 - 844
24
[ 875-51-4 ]
[ 1575-37-7 ]
Yield
Reaction Conditions
Operation in experiment
94%
With stannous chloride In ethanol
a. 4-Bromo-o-phenylenediamine. 4-Bromo-2-nitroaniline 600 mg (2.76 mmol) was dissolved in 25 ml absolute ethanol and 2.72 g (14 mmol) SnCl2 was added. The mixture was refluxed overnight. Ethanol was removed in vacuo and the mixture basified with 2N NaOH to pH 11. Ether extraction, drying the ether layer over anhydrous Na2 SO4 and concentration in vacuo afforded 486 mg (2.6 mmol, 94percent yield) of the crude 4-bromo-o-phenylenediamine which was used for the next step without characterization.
94%
With stannous chloride In ethanol
(D) 4-Bromophenylenediamine (JSK IV-35) To 2-nitro-4-bromoaniline (340 mg, 1.57 mmol) in absolute ethanol (20 mL) was added SnCl2 (1.50g, 7.91 mmol) and refluxed overnight. The reaction mixture was then basified to pH 11 with 2N NaOH and extracted with ether to give 275 mg (94percent) of product. This product was used without further purification for the synthesis of JSK IV-37.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 827 - 832
[2] Australian Journal of Chemistry, 1983, vol. 36, # 11, p. 2317 - 2325
[3] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 11, p. 2591 - 2600
[4] Patent: US6063801, 2000, A,
[5] Journal of Organic Chemistry, 2007, vol. 72, # 9, p. 3186 - 3193
[6] Angewandte Chemie - International Edition, 2011, vol. 50, # 16, p. 3803 - 3806
[7] RSC Advances, 2015, vol. 5, # 113, p. 93194 - 93208
[8] Heterocycles, 1987, vol. 26, # 9, p. 2433 - 2442
[9] Organic Preparations and Procedures International, 2000, vol. 32, # 5, p. 485 - 488
[10] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 2, p. 281 - 291
[11] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 11, p. 2172 - 2181
[12] Justus Liebigs Annalen der Chemie, 1881, vol. 209, p. 358
[13] Journal of the Chemical Society, 1949, p. 1271,1275
[14] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 2, p. 163 - 172
[15] Russian Journal of General Chemistry, 1998, vol. 68, # 4, p. 620 - 629
[16] Archiv der Pharmazie, 2000, vol. 333, # 5, p. 123 - 129
[17] Patent: US2004/92521, 2004, A1, . Location in patent: Page/Page column 45
[18] Patent: US2003/28018, 2003, A1,
[19] Patent: US2002/107392, 2002, A1,
[20] Patent: US5770617, 1998, A,
[21] Patent: US2004/224953, 2004, A1,
[22] Patent: US2005/256157, 2005, A1,
[23] Patent: US2005/261307, 2005, A1,
[24] Patent: US2008/300247, 2008, A1, . Location in patent: Page/Page column 38
[25] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 279
[26] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 74
[27] Patent: US2004/224952, 2004, A1, . Location in patent: Page 41
[28] Patent: US2004/248899, 2004, A1, . Location in patent: Page 33
[29] Patent: US2009/326029, 2009, A1, . Location in patent: Page/Page column 33
[30] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4790 - 4793
[31] Journal of the Serbian Chemical Society, 2014, vol. 79, # 3, p. 277 - 282
[32] Science China Chemistry, 2015, vol. 58, # 7, p. 1152 - 1158
[33] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6289 - 6304
[34] Patent: WO2007/143456, 2007, A2, . Location in patent: Page/Page column 88
Reference：
[1] Australian Journal of Chemistry, 1983, vol. 36, # 11, p. 2317 - 2325
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 11, p. 2172 - 2181
[3] Science China Chemistry, 2015, vol. 58, # 7, p. 1152 - 1158
32
[ 881-50-5 ]
[ 1575-37-7 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1271,1275
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 2, p. 281 - 291
33
[ 54558-18-8 ]
[ 1575-37-7 ]
[ 49764-63-8 ]
Reference：
[1] Journal of Biological Chemistry, 1952, vol. 194, p. 729,734
34
[ 103-88-8 ]
[ 1575-37-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1881, vol. 209, p. 358
35
[ 106-40-1 ]
[ 1575-37-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1881, vol. 209, p. 358
36
[ 51686-78-3 ]
[ 1575-37-7 ]
Reference：
[1] Chemische Berichte, 1873, vol. 6, p. 1544
Reference：
[1] Green Chemistry, 2017, vol. 19, # 23, p. 5591 - 5598
41
[ 75-15-0 ]
[ 1575-37-7 ]
[ 68468-39-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1306 - 1309
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6289 - 6304
42
[ 144-62-7 ]
[ 1575-37-7 ]
[ 1910-90-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1809 - 1814
43
[ 924-44-7 ]
[ 1575-37-7 ]
[ 55687-34-8 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 19, p. 10077 - 10091
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 15, p. 2697 - 2704
44
[ 54558-18-8 ]
[ 1575-37-7 ]
[ 49764-63-8 ]
Reference：
[1] Journal of Biological Chemistry, 1952, vol. 194, p. 729,734
45
[ 1575-37-7 ]
[ 147021-89-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
46
[ 1575-37-7 ]
[ 113269-07-1 ]
Reference：
[1] Heterocycles, 1987, vol. 26, # 9, p. 2433 - 2442
[2] Patent: CN108341791, 2018, A,
47
[ 506-68-3 ]
[ 1575-37-7 ]
[ 791595-74-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 50℃; for 1 h;
O. 5-Bromo-2-aminobenzimidazole (11) 5-Bromo-2-aminobenzimidazole (11) was synthesized according to a modified version of a reported procedure. [31] In brief, 4-bromo-1,2-diaminobenzene (1.0 g, 5.35 mmol, 1.0 eq.) was dissolved in a 1:1 mixture of MeOH (40 mL) and water (40 mL) in a 250 mL round bottom flask. The reaction mixture was treated with CNBr (1.7 g, 16.04 mmol, 3.0 eq.) and heated at 50° C. for 1 h. After cooling to room temperature, the MeOH was removed in vacuo, and the remaining mixture was basified with 1.0 M aq. NaOH (to pH=8.0) and extracted with EtOAc (3*30 mL).
86%
for 0.0833333 h;
Step A5-bromo-N-(tert-butyl)- e-3-sulfonamide[00400] A deep brown solution of 4-bromo-1 ,2-benzenediamine (4 g, 21.39 mmol) in MeOH (20 mL) was treated with cyanic bromide (2.492 g, 23.52 mmol). The reaction was exothermic, and the methanol began to boil after a few seconds. After 5 minutes the reaction mixture was diluted with EtOAc (100 mL), washed with a sat. NaHC03 solution (100 mL) and a sat. NaCI solution (100 mL). The organic layer was concentrated to a few mL, loaded onto silica cartridge and purified by column chromatography (0-20percent MeOH/EtQAc) to obtain 5-bromo-1 H- benzimidazol-2-amine (3.9 g, 18.39 mmol, 86 percent yield) as a black solid: 1H NMR (400 MHz, DMSO-cfe) δ ppm 6.47 (br. s., 2 H) 6.94 - 7.00 (m, 1 H) 7.01 - 7.06 (m, 1 H) 7.23 (d, J=1.85 Hz, 1 H) 8.70 - 1 1.33 (m, 1 H); ES LC-MS m/z =212.2 (Br79, M+H)+, ES LC-MS m/z =214.2 (Br81, M+H).
53%
at 0 - 20℃; for 14 h;
EXAMPLE 157; Scheme for the synthesis of N4-(5-brorao-lH-benzimidazol-2-yl)-N5-(5-bromo-2- methylphenyl)-lH-imidazole-4,5-dicarboxamide; Synthesis of 5-bromo-lH-benzo[d]imidazol-2-amine; [00421] Cyanogen bromide was added to a solution of 4-bromo-l,2-phenyldiamine (1.87 g, 10 mmole, commercially available from Aldrich) in acetonitrile (10 mL) and water (2 ml) at 0 0C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 ml) and shaken. The resulting solid was filtered off, washed with water and dried at reduced pressure to give 1.13 g of 5-bromo-lH- benzo[d]imidazol-2-amine (yield, 53percent) as a yellow solid. MS (EI): 213 (MH+).
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 21, p. 5226 - 5229
[2] Patent: US2013/136782, 2013, A1, . Location in patent: Paragraph 0216; 0217
[3] Patent: WO2012/174312, 2012, A2, . Location in patent: Page/Page column 283-284
[4] Patent: WO2008/42282, 2008, A2, . Location in patent: Page/Page column 219-220
[5] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1943 - 1948
48
[ 55305-43-6 ]
[ 1575-37-7 ]
[ 791595-74-9 ]
Yield
Reaction Conditions
Operation in experiment
60%
With lithium hexamethyldisilazane In tetrahydrofuran; hexane at 5 - 20℃; for 1 h; Green chemistry
General procedure: To a solution of o-aminophenol (400 mg, 3.67 mmol) and NCTS (998 mg, 3.67 mmol) in THF (6 mL), 1 M LiHMDS in hexane (3.67 mL, 3.67 mmol) was added and stirred at 5 °C to r.t. for 1h. Then the reaction mixture was poured in ice water and stirred for 15 min. Then extracted with EtOAc, the organic layer was separated. The organic layer was washed with brine solution.Then organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtained pure 2-aminobenzaxozole in 90percent yield (471 mg).
Stage #1: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 10 - 20℃; for 20 h; Cooling with ice Stage #2: With acetic acid In tert-butyl methyl ether at 55℃; for 18 h;
C. Synthesis of Intermediate 28 [0255] To a reactor was charged the 26/27 mixture (50.0 g, 0.106 mol). MTBE (200 mL, 4V) was charged and to the suspension was added glacial acetic acid (30.4 mL, 0.532 mol, 5 equiv.). The mixture was heated to 55° C. resulting in a brown, homogeneous solution, and was stirred at this temperature for 18 h. Upon reaction completion as determined by HPLC, the solution was cooled to ca. 10° C. and was then quenched with aqueous KOH (35 g in 200 mL H2O) keeping the internal temperature below 20° C. The biphasic mixture was stirred vigorously for 15 min. Agitation was stopped and the layers were allowed to separate. The aqueous layer was drained and back-extracted again with MTBE (50 mL). The organic extracts were combined, H2O (300 mL) was charged, and the biphasic mixture was stirred vigorously for 15 min. Agitation was stopped and the layers were allowed to separate. The aqueous layer was drained, and the tan organic layer was polish filtered. The solvent was distilled to a volume of ca. 50 mL. Diisopropyl ether (IPE, 150 mL) was added while keeping the internal temperature above 48° C. and the solution was distilled to a total volume of ca. 80 mL. IPE (150 mL) was again added and the solution was distilled to ca. 120 mL. This process was continued until the solvent was mainly diisopropyl ether as indicated by an internal temperature during distillation of about 69° C. or as determined by 1H NMR. The total volume was then adjusted to ca. 120 mL, and the solution was allowed to cool slowly (10° C./h) overnight to 0° C. resulting in slurry formation. The slurry was then filtered and rinsed with cold IPE (100 mL). The solids were collected and dried in a vacuum oven to give 28 (39.23 g, 94percent yield, >99.5percent AN). 1H NMR (400 MHz, CDCl3, δ): 10.70 (s, 1H), 7.86 (s, 0.5H), 7.58 (d, J=8.6 Hz, 0.5H), 7.54 (s, 0.5H), 7.30 (d, 8.3 Hz, 1H), 7.25 (d, J=8.0 Hz, 0.5H), 4.52 (d, J=3.6 Hz, 1H), 4.15 (s, 1H), 3.43 (d, J=3.2 Hz, 1H), 2.03-1.94 (m, 1H), 1.93-1.81 (m, 1H), 1.80-1.55 (m, 4H), 1.52 (s, 9H). MS-ESI+: [M+H]+ calcd for C18H23BrO2N3, 392.1, 394.1. found, 392.1, 393.9
1.59 g
Stage #1: With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 115℃; for 48 h;
Compound 8 (768 mg) was added,Compound 9 (890 mg),Add 15mL N, N-dimethylformamide at room temperature stirring dissolved,N-methylmorpholine (830 mg) and 2- (7-azobenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU, 1.71 g) ,Room temperature reaction.After 1 hour, 150 mL of water was added to the reaction solution, extracted with ethyl acetate (25 mL x 3)Salt washed organic phase,Anhydrous magnesium sulfate - dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a mixture of 10 and 11 as a reddish brown oil.Above the oil and add 20mL of anhydrous ethanol dissolved,115 oil bath pot sealed heating reaction 48 hours.Steamed ethanol,Column chromatography (petroleum ether-ethyl acetate, 2: 1) to give compound 12 as a tan oil or foamy solid (1.59 g).
Reference：
[1] Patent: US2013/324496, 2013, A1, . Location in patent: Paragraph 0254-0255
[2] Patent: CN106117187, 2016, A, . Location in patent: Paragraph 0069; 0070
With acetic acid; sodium nitrite; In water; at 0 - 85℃; for 2h;
To a solution of 4-bromobenzene-1,2-diamine (10 g, 53.5 mmol) in a mixture of acetic acid (20 ml, 349 mmol) and water (100 ml) at 0-5 C. was added a solution of sodium nitrite (4.06 g, 58.8 mmol) in water (10 ml) dropwise. Stirred in the ice bath for 1 h, more acetic acid (20 ml, 349 mmol) was added, heated to 80-85 C. with stirring during 1 h, the solution was filtered hot to remove insoluble black material, cooled to 0-5 C., aged for 30 min, precipitate collected, washed with water, dried in vacuum at 45 C. Yield 9.48 g (90%).
67%
With acetic acid; sodium nitrite; In water; at 4 - 20℃; for 16h;Reflux; Inert atmosphere;
A 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, nitrogen inlet and bubble counterEach o-diaminobenzene (0.031 mol) (Formula 1a) was added dropwise to glacial acetic acid (50 mL) under a nitrogen atmosphere.The resulting slurry was cooled to 4 [deg.] C in an ice-bath. Sodium nitrite in water (6 mL) (2.24 g,0.032 mol) in THF Was added dropwise over 40 minutes while maintaining the temperature of the reaction mixture below & lt; RTI ID = 0.0 & gt; 10 C. & lt; / RTI & gt; GeneratedThe slurry was allowed to warm to room temperature and analyzed using a KI / amylose test paper until analysis for free HNO2 was negative and starting material was not visible in thin layer chromatography (16 h)Under stirring. The resulting slurry was filtered; the solid residue washed with water (100 mL) and the resulting solid was further purified by recrystallization from ethanol (20 mL). The product was dried for 24 h at 50 C. and 5 mbar and obtained as off-white solid. Yield: 67%.
With sodium nitrite; In sulfuric acid; water;
Example 248B 5-Bromo-1H-benzotriazole A mixture of Example 248A (262 mg; 1.4 mmol) in 10% H2SO4 (4 mL) was treated with NaNO2 (120 mg; 1.7 mmol) in water (1 mL), stirred for 30 min., diluted with water, and extracted with EtOAc. The extracts were rinsed with brine, dried (Na2SO4), concentrated and purified by flash chromatography (5% MeOH/CH2Cl2) to provide the desired product.
With sulfuric acid; sodium nitrite; In water; for 0.5h;
Example 248B 5-Bromo-1H-benzotriazole A mixture of Example 248A (262 mg; 1.4 mmol) in 10% H2SO4 (4 mL) was treated with NaNO2 (120 mg; 1.7 mmol) in water (1 mL), stirred for 30 min., diluted with water, and extracted with EtOAc. The extracts were rinsed with brine, dried (Na2SO4), concentrated and purified by flash chromatography (5% MeOH/CH2Cl2) to provide the desired product.
With acetic acid; sodium nitrite; In water; at 0 - 20℃; for 2h;
General procedure: A solution of 10 mmol of the appropriate benzene-1,2-diamine in3.5 mL of acetic acid (AcOH) and 1 mL of water was cooled to 0-5 C,followed by the addition of 15 mmol of sodium nitrite in 2 mL ofwater. The mixture was stirred for 2 h at room temperature. Afterthe completion of the reaction, a solventwas evaporated and the residuewasco-evaporatedwith toluene (3 × 20mL). The crude productwas partitioned between water (20 mL) and ethyl acetate (20 mL),the organic phase was washed with the saturated solution of sodiumhydrogen carbonate and dried overmagnesiumsulfate (MgSO4). Theproducts were purified by crystallization from nitromethane and/orby column chromatography on silica gel using a chloroform - methanol97:3-95:5 v/v mixture as eluent. Reaction products were analyzedby use of mass-spectrometry (Waters Q-TOF Premier MassSpectrometer) and NMR spectroscopy (Varian INOVA 500 Spectrometer,see Supp. Fig. 1). Purity of the products was assessed using internalstandard quantitative NMR method (qNMR) [49]. It shouldbe noted that the formal qNMR-derived purity determined for 4-BrBt, 4-ClBt, 5,6-Cl2Bt and 5,6-Br2Bt increased significantly upon additiona small amount of water to the DMSO solution, which increasedproton exchange rates. This observation indicates that thenuclear relaxation process accompanying protomeric equilibrium(generally N1-H and N3-H forms predominates) significantly contributeto the obtained NMR spectra, the best proof of which is thestrong broadening of the H-7 resonance line in 4-BrBt and 4-ClBt(Supp. Fig. 1A,B).
With thionyl chloride; sulfuric acid; for 1h;Heating / reflux;
Example 2 Synthesis of 5-bromo-2,1,3-benzothiadiazole A mixture was prepared by mixing 4.0 g (21 mmol) of 4-bromo-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resulting precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.5 g of 5-bromo-2,1,3-benzothiadiazole as a crude product (melting point, 48 to 50 C.; yield, 96.5%).
With thionyl chloride; In N,N-dimethyl-formamide;
Preparation 1 5-Bromo-benzo[1,2,5]thiadiazole To 4-bromo-benzene-1,2-diamine (17 g, 91 mmol) was added thionyl chloride (200 ml). One drop of DMF was added to the reaction mixture. The reaction mixture was heated at reflux under argon at 80 C. overnight. The reaction mixture was cooled to room temperature and added portionwise to ice in a large beaker and neutralised with solid sodium bicarbonate. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was collected and dried (MgSO4). The solvent was removed under reduced pressure. The title compound was isolated by column chromatography on silica gel eluding with 90% ethyl acetate/10% methanol. (12 g, 62%); 1H NMR (250 MHz, CDCl3) delta: 7.61 (1H, dd, J=9, 2 Hz), 7.82 (1H, d, J=9 Hz), 8.16 (1H, s).
2.1a. 5-bromo-1,3-dihydrobenzimidazol-2-one 4.29 g (26.46 mmol) of carbonyldiimidazole (CDI) is added to a solution of 4.5 g (24.05 mmol) of 4-bromobenzene-1,2-diamine in 95 mL of DMF and the reaction mixture is stirred for 5 hours at 80 C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60 C. Yield: 4.6 g (90% of theoretical); C7H5BrN2O (M=213.03); calc.: molpeak (M+H)+: 213/215; found: molpeak(M+H)+: 213/215; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
70%
In 1,4-dioxane; at 40℃; for 1h;
Step 89a: 5-Bromo-lH-benzo[d]imidazol-2(3H)-one (Compound 0601-186)A mixture of 4-bromobenzene-l,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1 ,4-dioxane(20 mL) was stirred for 1 hr at 40C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70%>) as a white solid. LCMS: 213 [M+l]+, 1H NMR (400 MHz, DMSO-^ delta 6.86 (d, J= 8.0 Hz, 1H), 7.06(m, 1 H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
In 1,4-dioxane; at 40℃; for 1h;
Step 89a: 5-Bromo-1H-benzo[d]imidazol-2(3H)-one (Compound 0601-186)[0593]A mixture of 4-bromobenzene-1,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1,4-dioxane (20 mL) was stirred for 1 hr at 40 C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70%) as a white solid. LCMS: 213 [M+1]+, 1H NMR (400 MHz, DMSO-d6) delta 6.86 (d, J=8.0 Hz, 1H), 7.06 (m, 1H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
In 1,4-dioxane; at 40℃; for 1h;
1,4-dioxane (20mL) solution of 4-bromo-1,2-diamine (3.74g, 20mmol), CDI (3.9g, 24mmol) and the mixture was stirred for 1 hour at 40 of. The mixture was washed and filtered with petroleum ether and dichloromethane to give the compound 0601-186 as a white solid (3.0g, 70%).
47%
In N,N-dimethyl-formamide; at 20℃;
4-bromo-1,2-phenylenediamine (0.94 g, 5 mmol) was placed in a 50 mL round bottom flask as in the above reaction equation, and 5 mL of N,N-dimethylformamide was added, followed by N,N' -carbonyldiimidazole (0.81 g, 5 mmol), and allowed to react overnight at room temperature. After completion of the reaction, 5 mL of water was added, and the precipitated solid was filtered, and the solid was washed with water and ethyl acetate, and dried to give a pure product (0.5 g, 47%).
In 1-methyl-pyrrolidin-2-one; at 100℃; for 2h;
1,1'-Carbonyldiimidazole (2.1 g) in NMP (5 ml) was added to a solution of 4-bromo-o-phenylenediamine (CAS Reg. No. 1575-37-7, 2 g) in NMP (5 ml). The mixture was heated to 100 C. for 2 h and then allowed to cool to 60 C. MeOH (3 ml) was added, and the mixture was allowed to cool to room temperature. Water (50 ml) was added. The mixture was filtered. The residue was washed with isopropanol and then dried in vacuo to give the title compound (1.65 g) as a dark brown solid. MS (m/e, ISP neg. ion)=213.1 [M-H+].
In tetrahydrofuran; dichloromethane; at 20℃; for 6.5h;
General procedure: To a solution of 4-methyl-1,2-phenylenediamine (25 g, 0.205 mol) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1'-carbonyldiimidazole (36.5 g, 0.225 mol) in dichloromethane (375 mL). After stirring for 6.5 h at ambient temperature, to the reaction mixture was added diisopropyl ether (375 mL). After stirring at ambient temperature, the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether and dried in vacuo to give 5-methyl-1,3-dihydrobenzimidazol-2-one (24.6 g, 70.1%).
In 1,4-dioxane; at 50℃; for 16h;
The mixture of 4-bromobenzene-l,2-diamine (200 mg, 1.1 mmol), CDI (174 mg, 1.1 mmol) in dioxane was reacted at 50 C for 16 hours. The mixture was concentrated and the residue was dissolved in DCM and extracted with water with the combined organic phases dried by Na2S04 and concentrated to give 300 mg of crude product which was used without further purification. LCMS (m/z): 213.1/214.1 [M+H]+/ [M+2H]+
In tetrahydrofuran; at 20℃;Inert atmosphere;
[000862j To a stirred solution of compound i (1 g, 1 eq) in dry THF (10 mE), CDI (0.953 g, 1.1 eq) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography on silica gel 100-200 mesh using 40% EtOAc-hexane to afford the title compounds 2. LCMS (mlz): 214.05 (M + 1).
4 g
In N,N-dimethyl-formamide; at 80℃; for 4h;
To a solution of 4-bromobenzene-1 ,2-diamine (3 g,16 mmol) in DMF (60 mL) was added CDI (3.1 g, 19.3mmol). The reaction was stirred at 80 C. for 4 h. After themixture was cooled toRT, water (100 mL) was added. Theprecipitate was collected by filtration and dried to give 4 gof 5-bromo-1,3-dihydro-28-benzo[d]imidazol-2-one as adark red solid. GC-MS: 212/214 (M).
5-bromo-2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of Compound 6a (1.04 g, 5.04 mmol), in 25 mL of POCl3 was added 4-bromo-benzene-1,2-diamine (0.946 g, 5.06 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for 2.5 h then concentrated in vacuo. The residue was treated with 25 mL benzene and evaporated in vacuo. The residue was partitioned between 50 mL EtOAc and 50 mL saturated NaHCO3. The organic fractions were washed with 50 mL of saturated NaHCO3 and with 50 mL brine. The organic fraction was dried with Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, EtOAc:Heptane, 2:8-4:6)) to yield the title Compound 6b (0.726 g, 2.03 mmol) as a tan powder. 1H-NMR (d6-DMSO) delta (ppm): 12.48-12.32 (m, 1H), 7.74-7.58 (m, 1H), 7.51-7.38 (m, 1H), 7.33-7.22 (m, 3H), 7.17 (d, 2H), 3.10 (m, 4H), 1.27 (s, 9H). MS (ESI pos. ion) m/z: 357.1/359.1 (M+H+).
O. 5-Bromo-2-aminobenzimidazole (11) 5-Bromo-2-aminobenzimidazole (11) was synthesized according to a modified version of a reported procedure. [31] In brief, 4-bromo-1,2-diaminobenzene (1.0 g, 5.35 mmol, 1.0 eq.) was dissolved in a 1:1 mixture of MeOH (40 mL) and water (40 mL) in a 250 mL round bottom flask. The reaction mixture was treated with CNBr (1.7 g, 16.04 mmol, 3.0 eq.) and heated at 50 C. for 1 h. After cooling to room temperature, the MeOH was removed in vacuo, and the remaining mixture was basified with 1.0 M aq. NaOH (to pH=8.0) and extracted with EtOAc (3*30 mL).
86%
In methanol; for 0.08333330000000001h;
Step A5-bromo-N-(tert-butyl)- e-3-sulfonamide[00400] A deep brown solution of 4-bromo-1 ,2-benzenediamine (4 g, 21.39 mmol) in MeOH (20 mL) was treated with cyanic bromide (2.492 g, 23.52 mmol). The reaction was exothermic, and the methanol began to boil after a few seconds. After 5 minutes the reaction mixture was diluted with EtOAc (100 mL), washed with a sat. NaHC03 solution (100 mL) and a sat. NaCI solution (100 mL). The organic layer was concentrated to a few mL, loaded onto silica cartridge and purified by column chromatography (0-20% MeOH/EtQAc) to obtain 5-bromo-1 H- benzimidazol-2-amine (3.9 g, 18.39 mmol, 86 % yield) as a black solid: 1H NMR (400 MHz, DMSO-cfe) delta ppm 6.47 (br. s., 2 H) 6.94 - 7.00 (m, 1 H) 7.01 - 7.06 (m, 1 H) 7.23 (d, J=1.85 Hz, 1 H) 8.70 - 1 1.33 (m, 1 H); ES LC-MS m/z =212.2 (Br79, M+H)+, ES LC-MS m/z =214.2 (Br81, M+H).
53%
In water; acetonitrile; at 0 - 20℃; for 14.0h;
EXAMPLE 157; Scheme for the synthesis of N4-(5-brorao-lH-benzimidazol-2-yl)-N5-(5-bromo-2- methylphenyl)-lH-imidazole-4,5-dicarboxamide; Synthesis of 5-bromo-lH-benzo[d]imidazol-2-amine; [00421] Cyanogen bromide was added to a solution of 4-bromo-l,2-phenyldiamine (1.87 g, 10 mmole, commercially available from Aldrich) in acetonitrile (10 mL) and water (2 ml) at 0 0C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 ml) and shaken. The resulting solid was filtered off, washed with water and dried at reduced pressure to give 1.13 g of 5-bromo-lH- benzo[d]imidazol-2-amine (yield, 53%) as a yellow solid. MS (EI): 213 (MH+).
Add phenyl CHLOROFORMATE (922mg, 5. 89MMOL) to a suspension of 4-bromo-benzene-1, 2- diamine (L. OOG, 5. 35MMOL) AND NAHC03 (483mg, 5. 89MMOL) in methanol (20ML) and H20 (lOmL). Stir at room temperature for 3. 5h and add 1. OON aqueous NAOH (6mL, 6. 00MMOL). Stir overnight at room temperature and filter. Wash the filter cake with HA0 and dry in-vacuo overnight to obtain 386mg (34%) of the title compound as a brown powder. MS (ES) 213,215 (M+H), 211,213 (M-H) ; HPLC shows 95% purity.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃; for 23.0833h;
2.50 g (6.24 mmol) of the dicyclohexylammonium salt of N-Boc-(S)-O-methyl-serine are dissolved in 20 ml 5percent citric acid, the aqueous phase is extracted 2.x. with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50percent solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. Yield: 2.38 g (98percent) mixture of the two regioisomers C15H22BrN3O4 (388.26) Mass spectrum: (M+H)+=388/390 (bromine isotope) Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1)
6-Bromo-quinoxaline: In a round bottom flask under nitrogen was combined 4-bromo-benzene-1,2-diamine (2.01 g, 10.7 mmol), methanol (50 mL), and glyoxal (40% by wt. 3.1 mL, 26.9 mmol) and the resulting solution stirred overnight. The reaction was then concentrated in vacuo and purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane as eluant to yield 1.14 g (50% yield) of 6-Bromo-quinoxaline as a yellow-orange solid. 1H NMR (DMSO-d6): 9.00 (d,2H,J=2.8 Hz), 8.36 (d,1H,J=2.2 Hz), 8.07 (d,1H,J=9.0 Hz), 8.02 (dd,1H,J=8.8,2.1 Hz). CHN for C8H5BrN2: calc. C 45.97, H 2.41, N 13.4; found C 45.99, H 2.09, N 13.09. LC/MS (Method A): r.t.=1.10 min., purity=99%, calculated mass=208, [M+H]+=209/211. HPLC (Method B): r.t.=7.4 min., purity=98.52% at 210-370 and 98.8% at 322 nm.
In ethanol; water; for 10h;Heating / reflux;
To a solution of 4-bromobenzene-1, 2-diataunine (4.0 g, 21 mtnol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) soultion in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mLof EtOAc. The organic soultion was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos . ion) m/z: 208.9 (M+l) .
Example 7; Synthesis of Compounds According to Formula (4); [00528] 5-bromo-2-(trichloromethyl)-lH-benzimidazole 2; To a solution of 4- bromo-o-phenylenediamine 1 (2.52Og, 13.5 mmol) in acetic acid (35mL) cooled to 0 0C was added methyl trichloroacetimidate (2.64Og, 15 mmol) under N2 atmosphere and resulting reaction mixture was stirred at room temperature for 3h. Diluted with water (200 mL) and resulting precipitate was filtered , washed with water (100 mL), dried in vacuum oven at 40 0C to give 5-bromo-2-(trichloromethyl)-lH-benzimidazole (4.1g, 97%). 1H NMR (300 MHz, DMSOd6) : 57.48 (d, J= 6.0 Hz, 1 H), 7.63 (d, J= 6.0 Hz, 1 H), 7.88 (s, 1 H); LCMS mlz 315 (M + H+), ELSD 100%. Reference: Louvet, P.; Lallement, G.; Pernot-Marino, L; Luu- Duc, C; Blanchet, G. Eur. J.Med.Chem. 1993, 28, 71-75.
95%
With acetic acid; at 0 - 20℃; for 0.5h;
This intermediate was prepared using the procedure described in Anikin, A. V. et al. WO 2007056155 page 264.Methyl 2,2,2-trichloroacetimidate (8.55 g, 48.5 mmol) was added to a 0 C solution of 4-bromo- benzene-1,2-diamine (5 g, 26.7 mmol) in AcOH (60 mL). The mixture was allowed to warm to room temperature and ice-water was added. The mixture was stirred for 30 mm. The solid was filtered off and air-dried to give 5-bromo-2-trichloromethyl-1H-benzoimidazole (7.95 g, 95%) asa brown powder. ?H NMR (300 MHz, DMSO-d6) oe ppm 13.32 (br. s., 1 H) 7.87 (br. s., 1 H) 7.63 (d, J=8.7 Hz, 1 H) 7.48 (dd, J=8.7, 1.7 Hz, 1 H). MS calcd. for C8H5BrC13N2 [(M+H)?i 313, obsd.312.8.
With acetic acid; at 0 - 20℃; for 3h;
To a solution of 4-bromobenzene-1,2-diamine (4.78 g, 25.5 mmol)in AcOH (50 mL) at 0C was added 5-bromo-2-(trichloromethyl)-1H-benzo[djimidazole (5.0 g, 28.3 mmol), then the mixture was stirred at room temperature for 3 hrs. Water was added and the precipitate was collected by filtration. The solid was washed with water, then dried under vacuum to afford the cmde product that was used directly in the next step without further purification. LC-MS (ESI): 312 (M + 1).
A. 5-bromo-2-(chloro-difluoro-methyl)-1H-benzoimidazole A mixture of 4-bromo-phenylene-diamine (1.00 g, 5.35 mmol), chlorodifluoroacetic acid (3.0 mL, 35.4 mmol), and a drop of water was heated to 80 C. for 14 hours. The crude product was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a colorless oil (0.63 g, 42%).
Commercial 4-bromo-l,2-phenylenediamine (561 mg) and 3-(4-chlorophenyl)- glutaric anhydride (674 mg) were dissolved in THF (1 ml) with heating. The dark solution was stirred at rt for 1 h. Then the solution was decolourised with activated carbon and filtered. The filtrate was concentrated and the solid residue dried in vacuo. The solid was dissolved in a mixture of acetic acid (4 ml) and cone. HCI (2 ml) and stirred under reflux for 3 h. All volatiles were removed at the water aspirator and the residue was recrystallised from ethanol/EtOAc 1 : 3 to give a crude (0.47 g). The impure crude was again refluxed with acetic acid/cone. HCI 2: 1 for 1 h to leave after concentration and acetone trituration 4-(5-bromo-2- benzimidazolyl)-3-(4-chlorophenyl)butanoic acid HCI (0.3 g) as light greyish solid.1H-NMR (500 MHz, DMSOd6): delta (ppm) = 2.72 (dd, J = 16.2, 8.6 Hz, IH), 2.83 (dd, J = 16.3, 8.2 Hz, IH), 3.43 (dd, J = 14.9, 9.2 Hz, IH), 3.55 (dd, J = 14.9, 6.9 Hz, IH), 3.85 (m, IH), 7.30 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, IH), 7.60 (dd, J = 8.7, 1.7 Hz, IH), 7.67 (d, J = 8.7 Hz, IH), 7.94 (d, J = 1.7 Hz, IH). 13C-NMR and DEPT (125 MHz, DMSOd6) : delta (ppm) = 32.66 (CH2), 39.19 (CH),39.60 (CH2), 115.57 (CH), 116.42 (CH), 117.34 (C), 128.14 (CH), 128.34 (2 CH), 129.14 (2 CH), 130.26 (C), 131.44 (C), 132.32 (C), 140.69 (C), 153.07 (C), 172.12 (CO). MS ( + ESI) : m/z = 393 (M + H).
To a solution of diamino benzene Int-4a (6.1 g, 32.7 mrnol), <strong>[68-95-1]N-acetyl-L-proline</strong> (5.4g, 34.35 mmol) and HATU (13.7 g, 34.35 mmol) in anhydrous DMF (100 niL) was added DIPEA (Hunigs base) (16.91 niL, 96.9 mmol) dropwise over 15 minutes at ice temperature. The reaction was warmed to room temperature and allowed to stir for 3 h. The reaction was then diluted with EtOAc (500 mL) and the organic layer washed with water (200 mLx 2). The aqueous layer was back-extracted with EtOAc (100 mLx 2). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified using flash chromatography using a 1% -2 % MeOHZCH2Cl2 as eluent to provide the intermediate amide (4.1 g). The amide was dissolved in glacial acetic acid and was heated at 60 - 70 0C for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and cooled in ice bath. Saturated Na2CO3 solution was added slowly until the pH = 8. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mLx 2). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to provide the intermediate Int-4b (3.75g, 38 %). LCMS: M+ = 308
38%
To a solution of diamino benzene Int-14a (6.1 g, 32.7 mmol), <strong>[68-95-1]N-acetyl-L-proline</strong>(5.4g, 34.35 mmol) and HATU (13.7 g, 34.35 mmol) in anhydrous DMF (100 mL) was added DIPEA (16.91 niL, 96.9 mmol) dropwise over 15 minutes at ice temperature. The reaction was warmed to room temperature and allowed to stir for 3 hours. The reaction was then diluted with EtOAc (500 mL) and the organic layer washed with water (200 niLx 2). The aqueous layer was back-extracted with EtOAc (100 mLx 2). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified using flash chromatography using 1% -2 % MeOHZCHiCl2 as eluent to provide the intermediate amide (4.1 g). The amide was dissolved in glacial acetic acid and was heated at 60 - 70 0C for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and cooled in ice bath. Saturated Na2CO3 solution was added slowly until the solution was at pH 8.0. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mLx 2). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide Compound Int-14b (3.75g, 38 %). LCMS: M+ = 308
38%
EXAMPLE 6Preparation of Intermediate Compound Int-6c Step A - Synthesis of Compound Int-6bInt-6a Int-6bTo a solution of compound Int-6a (6.1 g, 32.7 mmol), <strong>[68-95-1]N-acetyl-L-proline</strong> (5.4 g, 34.35 mmol) and HATU (13.7 g, 34.35 mmol) in anhydrous DMF (100 mL) was added DlPEA (Hunigs base) ( 16.91 mL, 96.9 mmol) dropwise over 15 minutes at ice temperature. The reaction was warmed to room temperature and stirred for 3 hours. The reaction was then diluted with EtOAc (500 mL) and the organic layer washed with water (200 mLx 2). The aqueous layer was back-extracted with EtOAc ( 100 mLx 2). The combined organic layers were washed with brine, dried over MgStheta4, filtered and concentrated. The crude product was purified using flash chromatography using a 1% - 2% MeOH/C^Cb as eluent to provide the intermediate amide (4.1 g). The amide was dissolved in glacial acetic acid and was heated at 60 - 700C for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and cooled in an ice bath. Saturated Na^CO^ solution was added slowly until the pH = 8. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mLx 2). The combined organic layers were washed with water and brine, dried over MgStheta4, filtered and concentrated in vacuo to provide compound Int-6b (3.75g, 38 %). MS: MH+ = 308.
38%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
To a 0 C solution of Compound Int-2a (6.1 g, 32.7 mmol), <strong>[68-95-1]N-acetyl-L-proline</strong> (5.4g, 34.35 mmol) and HATU (13.7 g, 34.35 mmol) in anhydrous DMF (100 mL) was added diisopropylemylamine (16.91 mL, 96.9 mmol) dropwise over 15 minutes. The reaction was allowed to warm to room temperature with stirrmg for 3 hours. The reaction was then diluted with EtOAc (500 mL) and the organic layer washed with water (200 mLx 2). The aqueous layer was back-extracted with EtOAc (100 mL x 2) and the combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (1% -2 % MeOH/CH2Cl2) to provide an intermediate amide (4.1 g) which was dissolved in glacial acetic acid and the resulting solution was heated to 70 C and allowed to stir at this temperature for 1 hour. The reaction mixture was diluted with EtOAc (100 mL), cooled to 0 C and saturated aqueous Na C03 solution was added slowly until the solution reached pH 8. The organic layer was then separated and the aqueous layer was extracted with EtOAc (250 mLx 2). The combined organic layers were washed with water, then brine, dried over M S04, filtered and concentrated in vacuo to provide Compound Int-2 (3.75 g, 38 %) which was used without further purification. LCMS: M " = 308.
Step 1 : Trifluoroethylamine hydrochloride salt (275 mg, 2.03 mmol) was suspended in THF (3 mL) followed by addition of DIPEA (1.7 mL, 10.2 mmol) and the resulting solution was cooled to O0C. Thiophosgene (156 uL, 2.03 mmol) was added to the solution by syringe and the mixture was allowed to stir 15 min. at O0C followed by addition of 4-bromobenzene-l,2-diamine (380 mg, 2.03 mmol). The mixture was allowed to warm to room temperature and stirred an additional 30 min. then concentrated. The residue was taken into ethyl acetate and washed twice with 10% aqueous citric acid then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then taken into THF (10 mL) followed by addition of solid mercury (II) oxide (500 mg, 2.3 mmol) and the mixture was brought to reflux for 12 h. On cooling to room temperature the solution was filtered through a bed of celite and the filtrate concentrated to give 5-bromo-N-(2,2,2-trifluoroethyl)-lH-benzo[d]imidazol-2-amine that was used without further purification. MS (EI) for C9H7BrF3N3: 294, 296 (MH+, Br isotope pattern).
//-Benzyl proline (10.2 g, 50 mmol) and triethylamine (50 mmol) were dissolved in THF (250 mL) and cooled to O0C. To this solution was added ethyl chloroformate (ClCOOEt, 50 mmol) dropwise over 15 minutes and stirred for an additional30 minutes. To this solution was added 4-bromobenzene-l,2-diamine (75 mmol) over 15 minutes. The reaction mixture was stirred at O0C for 1 hour, then was allowed to reach room temperature and stirred for 16 hours, then refluxed for 3 hours. After completion of this reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (3 x 70 mL). The organic layers were combined, dried (magnesium sulfate), the solids were removed by filtration and the solvents of the filtrate were evaporated under reduced pressure. The residue was purified by columnchromatography (hexanes/ethyl acetate : 7/3) to afford H g of intermediate.H g of intermediate was dissolved in acetic acid (50 mL) at 2O0C and stirred for 15 hours. The solvent was removed under reduced pressure and then NaHCO3 (saturated, aqueous, 200 mL) was added. The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were concentrated and the residue was purified by column chromatography to afford 3 g of HA
General procedure: A solution of 2 (242 mg, 1.0 mmol) and 4-bromobenzene-1,2-diamine (187 mg, 1.0 mmol) in DMSO (5 mL) was stirred at room temperature for 3 h. After the reaction was complete, 50 mL of ice water was added and the mixture was extracted with CHCl3 (3 × 10 mL). The organic layer was dried over MgSO4. After the solvent was removed, the residue was purified by silica gel chromatography to afford 3 (120 mg, 36.7%). 1H NMR (400 MHz, CDCL3) delta 9.26 (s, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.9, 2.2 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 3.08 (s, 6H). MS (APCI): m/z calcd for C16H14BrN3 327.04; found 328.00 (M+H+).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 19h;
A solution of Compound Int-2a (7.35g, 39.3 mmol), Compound Int-8b (9.88 g, 39.3 mmol) and diisopropylethylamine (10 mL, 57.5 mmol) in DMF-(40 mL) was cooled to 0 C. HATU (15.0 g, 39.45 mmol) was added slowly, then the reaction mixture was allowed to warm to room temperature and stirred for 1 hours. The reaction mixture was -then diluted with ethyl acetate (300. mL) and washed with brine (3 x 100 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residure obtained was purified using a 330 g ISCO silica column (0-5% methanol in dichloromethane as eluent) to provide Compound Int-8c as a brown gel (1 .1 g, 91%).
91%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 19h;
Step A - Synthesis of Intermediate Compound Int-21c (0366) A solution of Compound Int-21a (7.35g, 39.3 mmol), Compound Int-21b (9.88 g, 39.3 mmol) and diisopropylethylamine (10 mL, 57.5 mmol) in DMF (40 mL) was cooled to 0 C. HATU (15.0 g, 39.45 mmol) was added slowly to the cooled solution and the resulting reaction was allowed to warm to room temperature on its own, then stirred at room temperature for 19 hours. The reaction mixture was then diluted with ethyl acetate (300 mL) and washed with brine (3 x 100 mL), and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residure obtained was purified using a 330 g ISCO silica column (0-5% methanol in dichloromethane as eluent) to provide Compound Int-21c as a brown gel (15.1 g, 91%).
To a solution of compound 12-3 (2.7 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (25 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 C. After stirring at 0 C for 0.5 hr, compound 2-10 (2.22 g, 11.9 mmol) was added in a portionwise manner. At the end of the addition, the mixture was stirred at rt for 4.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), the THF solvent was removed, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL), and the solution was stirred at 40 C overnight. After the reaction was completedd, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The mixture was washed with Na2C03 aqueous solution (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (2.14 g, 50%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 403.5 [M+H]+; and H NMR (400 MHz, CDC13) delta (ppm): 7.71-7.70 (m, 1H), 7.33, 7.30 (d, d, 1H), 7.19, 7.17 (d, d, 1H), 5.13-5.08 (m, 1H), 4.18-4.04 (m, 1H), 3.91-3.78 (m, 1H), 3.00-2.82 (m, 1H), 2.61-2.41 (m, 1H), 1.41 (s, 9H).
Commercial 4-bromo-1,2-phenylenediamine (561 mg) and 3-(4-chlorophenyl)-glutaric anhydride (674 mg) were dissolved in THF (1 ml) with heating. The dark solution was stirred at rt for 1 h. Then the solution was decolourised with activated carbon and filtered. The filtrate was concentrated and the solid residue dried in vacuo. The solid was dissolved in a mixture of acetic acid (4 ml) and conc. HCl (2 ml) and stirred under reflux for 3 h. All volatiles were removed at the water aspirator and the residue was recrystallised from ethanol /EtOAc 1:3 to give a crude (0.47 g). The impure crude was again refluxed with acetic acid /conc. HCl 2:1 for 1 h to leave after concentration and acetone trituration 4-(5-bromo-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid?HCl (0.3 g) as light greyish solid.1H-NMR (500 MHz, DMSO-d6): delta (ppm)=2.72 (dd, J=16.2, 8.6 Hz, 1H), 2.83 (dd, J=16.3, 8.2 Hz, 1H), 3.43 (dd, J=14.9, 9.2 Hz, 1H), 3.55 (dd, J=14.9, 6.9 Hz, 1H), 3.85 (m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.60 (dd, J=8.7, 1.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H).13C-NMR and DEPT (125 MHz, DMSO-d6): delta (ppm)=32.66 (CH2), 39.19 (CH), 39.60 (CH2), 115.57 (CH), 116.42 (CH), 117.34 (C), 128.14 (CH), 128.34 (2CH), 129.14 (2CH), 130.26 (C), 131.44 (C), 132.32 (C), 140.69 (C), 153.07 (C), 172.12 (CO).MS (+ESI): m/z=393 (M+H).
With triethylamine; HATU; In dichloromethane; at 20℃;
To a solution of 4-bromobenzene-l ,2-diamine (10) (0.281g, 1.5mmol) , <strong>[5267-07-2]2-(pyrimidin-5-yl)acetic acid</strong> (11) (0.207g, 1.5mmol), and HATU (0.741g, 1.95mmol) in DCM (50ml) was added triethylamine (0.63ml, 4.5mmol). The reaction mixture was stirred at room temperature overnight. The solution was washed with saturated sodium bicarbonate (50ml) and brine (50ml). The DCM solution was dried over sodium sulfate and concentrated. The residue was purified by automated column chromatography columned using DCM and methanol as eluents. Yield 0.4g, 87%. MS: m/z 306.9 (M+H+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 1 : Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-3H- benzo[2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-benzo[d]imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 1 ): Step 1 : Mixture of tert-butyl ((1 R,2S)-2-((2-amino-4-bromophenyl)carbamoyl)cyclopentyl) carbamate AND tert-butyl ((1 R,2S)-2-((2-amino-5-bromophenyl)carbamoyl)cyclopentyl) carbamate (1 a): (1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid [synthesized using procedures described in Tetrahedron: Asymmetry, 2008, 19, 2796-2803] (1 .52 g, 6.62 mmol) was dissolved in DMF (12 mL) and Hunig's base (1 .73 ml_, 9.93 mmol) was added followed by EDCI hydrochloride (1 .91 g, 9.93 mmol). To this stirred mixture at room temperature was added HOBT (1 .01 g, 6.62 mmol) after 10 min. followed by 4- bromobenzene-1 ,2-diamine (1 .36 g, 7.28 mmol) after another 10 min. The brown mixture was allowed to stir overnight after which ice cold water was added and the organics were extracted with ethyl acetate (100 mL) twice. The combined ethyl acetate extracts were dried over Na2S04 and concentrated under reduced pressure to obtain a brown mass which was purified by column chromatography by gradient elution with ethyl acetate- hexane (20-30%) to obtain a mixture of two regio-isomers (1 .16 g, 46%). 1 H NMR (400 MHz, DMSO-D6): delta 8.93 (br s, 2H), 7.13-6.97 (m, 2H), 6.74-6.71 (m, 2H), 6.68-6.60 (m, 4H), 5.15-5.02 (m, 2H), 4.18-4.13 (m, 2H), 3.01 -2.93 (m, 2H), 1 .95-1 .34 (m, 12H), 1 .26 (s, 18H). m/z 398.10 (M+) and 400.10 (M++2).
(S)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.45 g
Preparation 9 (SHerf-Butyl (1 -(5-bromo-1 H-benzo[d1imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)- carbamate To a solution of (S)-2-((fe/ -butoxycarbonyl)amino)-4-oxo-4-(tritylamino)butanoic acid (4.25 g, 8.96 mmol) in anhydrous tetrahydrofuran (20 mL, 200 mmol) cooled in an ice water bath was added 4-methylmorpholine (1 .48 mL, 13.4 mmol) and isobutyl chloroformate (1 .28 mL, 9.85 mmol). The reaction mixture was stirred for 1 hour at 0C and then 4-bromo-1 ,2-benzenediamine (1 .68 g, 8.96 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours and stirred at room temperature for additional 2 hours. The reaction mixture was concentrated in vacuo and dried under vacuum for 18 hours to give the intermediate product. Acetic acid (48 mL, 850 mmol) was added to the above intermediate and heated at 65C for 2 hours. The reaction solution was concentrated and the residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to half of the original volume. A solid precipitated out during concentration and was collected by filtration to give 2.48 g of the title compound as a pale pink solid. The filtrate was concentrated onto celite and was purified using silica gel column chromatography eluting with 0% to 100% ethyl acetate in dichloromethane to afford additional compound (0.97 g, pale tan solid). A total of 3.45 g of the product was obtained. LCMS Rt =1 .47 minutes MS m/z 625 [M+H]+
Preparation 11 (SHe/t-Butyl (1 -(5-bromo-1 H-benzo[d1imidazol-2-yl)butyl Carbamate To a solution of Boc-NVA-OH (4.5 g, 21 mmol) in acetonitrile (68 ml_) and 4- methylmorpholine (2.41 ml_, 21 .9 mmol) cooled to -20°C was added isobutyl chloroformate (2.7 ml_, 21 mmol) dropwise. The mixture was stirred for 120 minutes at -20°C and then 4-bromo-1 ,2-benzenediamine (3.87 g, 20.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (20 ml_, 400 mmol) and stirred at 70°C for 6 hours. The acetic acid was removed in vacuo and the mixture was redissolved in ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was redissolved in dichloromethane, treated with activated carbon and filtered through a plug of celite. Purification by silica gel column chromatography eluting with a 0-100percent ethyl acetate/hexanes gradient to afford the title compound (5.95 g, 78percent) as a white solid. 1H NMR (400MHz, CDCI3): delta ppm 0.92 (t, 3H), 1 .41 (m, 1 1 H), 1 .90 (m, 1 H), 2.1 1 (m, 1 H), 4.85 (m, 1 H), 5.65 (m,1 H), 7.1 1 (m, 0.5H), 7.25 (m, 0.5H), 7.31 (m, 0.5H), 7.37 (m, 0.5H), 7.52 (m, 0.5H), 7.80 (m, 0.5H), 1 1 .20 (m, 1 H). LCMS Rt = 1 .19 minutes MS m/z 366, 368 [79Br, 81Br M+H]+
Example 77 2-{2-[( 1 R,2R)-1 -Amino-2-methoxypropyl1-1 H-benzimidazol-5-yl)benzonitrile To 4-bromo-1 ,2-benzenediamine (2.3 g, 12.3 mmol) and N-boc-O-methyl-L-threonine (2.9 g, 12.3 mmol) was added DCM (100 ml_) followed by DIEA (3 ml_, 17.5 mmol) and HATU (4.7 g, 12.3 mmol). The reaction was stirred at 30C for 16 hours before concentrating in vacuo. To the residue was added AcOH (120 ml_) and the reaction heated to 50C for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with a 2M solution of LiOH in water (250 ml_). The aqueous layer was extracted with EtOAc (2 x 150 ml_), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane to obtain a 0.075M solution. To an aliquot of this solution (1 ml_) was added cesium carbonate (75 mg, 225 pmol), 2-cyanophenylboronic acid (1 12.5 muomicronIota), water (30 muIota_), and nitrogen was bubbled through for 30 seconds. Pd(dppf)CI2 (6 mg, 7.5 pmol) was then added and the reaction shaken at 90C for 16 hours before cooling and filtering. MeOH (200muIota_) was then added followed by 4M HCI in dioxane (300 muIota_) and the reaction shaken at 30C for 16 hours. The reaction was concentrated in vacuo and purified using preparative HPLC (Boston Symmetrix ODS-H; 150 x 30 mm x 5 mu; mobile phase A: Acetonitrile, mobile phase B: 0.225% TFA in water; eluting with a gradient of 22-52% organic, over 10 minutes with a flow rate of 30 mL/min) to afford the title compound as the TFA salt. LCMS Rt = 2.42 minutes MS m/z 307 [M+H]+
Preparation 23 tert-Butyl {(1 S,2R)-1 -[(2-amino-4-bromophenyl)carbamoyl1-2- methoxypropyDcarbamate To a solution of N-(fe/t-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 4 g, 17.15 mmol) in anhydrous THF (150 mL) was added NMM (2.43 g, 24.01 mmol) and isobutyl chloroformate (2.58 g, 18.86 mmol) at -78C and the reaction was stirred at this temperature for 1 hour. This solution was then added to a solution of 4- bromophenyl-1 ,2-diamine (3.85 g, 20.58 mmol) in THF ( 50 mL) at -78C and the reaction was stirred warming to room temperature for 18 hours. The reaction was quenched by the addition of water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-60% acetonitrile in 0.1 % formic acid in water to afford the title compound (6.60 g, 96%). 1H NMR (400MHz, MeOD): delta ppm 0.95-1 .20 (m, 3H), 1 .45 (s, 9H), 3.38 (s, 3H), 3.85 (m, 1 H), 4.20 (m, 1 H), 6.60-7.20 (m, 3H).
Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). Intermediate 14-a and 14-b (I-14a) and (I-14b) (l-14a) (l-14b) 2-Chloro-6-fiuorobenzoic acid (0.698 g, 4 mmol) in DMF (20 mL) and DIPEA (1.072 mL, 6.22 mmol) was treated with HBTU (1.52 g, 4 mmol) and the r.m. was stirred for 15 min at r.t. Then a mixture of intermediates (I-13a) and (I-13b) (0.9 g, 3.56 mmol) in DMF (20 mL) was added and the stirring was prolonged for further 16 h at the same temperature. The r.m. was then poured onto ice/H20 (0.5 L) and the solid thus obtained was collected by filtration. The solid was then diluted with DCM (0.1 L) and treated with 1 M NaOH aq. solution (20 mL). The organic layers were separated, washed with 1M HC1 (20 mL), then with 1M NaOH (20 mL), dried (MgS04), filtered and the solvent concentrated in vacuo. The crude mixture was purified by column chromatography (silica; MeOH in DCM 0: 100 to 5:95) to give an off white solid which was recrystallized from Heptane/EtOAc (~15 mL/~5 mL) yielding finally a mixture of intermediates (I-14a) and (I-14b) as off white solid (0.75 g, 51%). Ci6HiiBrClFN40, LCMS: 5.18 (co-elution of the two peaks), m/z 409 [M + H]+ (method 7).
Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). Intermediate 14-a and 14-b (I-14a) and (I-14b) (l-14a) (l-14b) 2-Chloro-6-fiuorobenzoic acid (0.698 g, 4 mmol) in DMF (20 mL) and DIPEA (1.072 mL, 6.22 mmol) was treated with HBTU (1.52 g, 4 mmol) and the r.m. was stirred for 15 min at r.t. Then a mixture of intermediates (I-13a) and (I-13b) (0.9 g, 3.56 mmol) in DMF (20 mL) was added and the stirring was prolonged for further 16 h at the same temperature. The r.m. was then poured onto ice/H20 (0.5 L) and the solid thus obtained was collected by filtration. The solid was then diluted with DCM (0.1 L) and treated with 1 M NaOH aq. solution (20 mL). The organic layers were separated, washed with 1M HC1 (20 mL), then with 1M NaOH (20 mL), dried (MgS04), filtered and the solvent concentrated in vacuo. The crude mixture was purified by column chromatography (silica; MeOH in DCM 0: 100 to 5:95) to give an off white solid which was recrystallized from Heptane/EtOAc (~15 mL/~5 mL) yielding finally a mixture of intermediates (I-14a) and (I-14b) as off white solid (0.75 g, 51%). Ci6HiiBrClFN40, LCMS: 5.18 (co-elution of the two peaks), m/z 409 [M + H]+ (method 7). Intermediate 15-a and 15b (I- 15a) and (I- 15b) 8-Bromo- l-(2-chloro-6-fluor ophenyl)-4-methyl [ 1 ,2,4] triazolo [4,3-a] quinoxaline A mixture of intermediates (I-14a) and (I-14b) (1 g, 2.44 mmol) in DCE (20 mL) was treated with POCI3 (0.6 mL, 6.5 mmol) and the r.m. was heated at 70 C for 16 h. Then, additional POCI3 (0.6 mL, 6.5 mmol) was added and the mixture heated at the same temperature as before further for 5 h. After this time, again more POCI3 (1.2 mL, 13 mmol) was added and the mixture heated as before for further 16 h. The r.m. was cooled and poured onto ice/aq. NH4OH (150 mL/150 mL) and the layers separated. The organic phase was dried (MgS04), filtered and concentrated in vacuo. The crude compound was purified by chromatography (silica; MeOH in DCM 0/100 to 2/98) to give a mixture of intermediate (I-15a) together with its regioisomer (I-15b) (0.7 g, 75%). A batch of the regioisomeric mixture was separated by column chromatography (silica, EtOAC in CH2CI2, 0/100 to 25/75) to give intermediate (I-15a) as pure isomer. Ci6H9BrClFN4, LCMS: 2.58, m/z 391 [M + H]+ (method 3).
Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). DMF (0.182 mL, 2.34 mmol) was added to a mixture of <strong>[5344-49-0]2-chloro-6-nitrobenzoic acid</strong> (0.473 g, 2.34 mmol) and oxalyl chloride (0.201 mL, 2.34 mmol) in dichloromethane (5 mL).The mixture was stirred for 15 min at RT, then this solution was added dropwise to a stirred mixture of triethylamine (0.544 mL, 1.95 mmol) and intermediate compounds I-13a and I-13b (0.495 g, 1.95 mmol) dissolved in dichloromethane (5 mL) at 0 C. The mixture was then allowed to RT and stirred for further 15 min. Then it was quenched with NaHCC"3 (sat. sol. in water), the organic layer was quickly separated and the solvent evaporated. The residue was treated with ethyl ether to yield a mixture of (I- 21a) and (1-2 lb) as a brown solid (0.814 g, 95%) that was used as such in the next reaction step.
Intermediates 1-a and 1-b ((I-la) and (I-lb)) Methyl pyruvate (8.69 mL, 96.24 mmol) was added to a solution of 4-bromo-l,2- diaminobenzene (15 g, 80 mmol) dissolved in toluene (120 mL) in a round flask, equipped with a Dean-Stark apparatus. Then the r.m. was heated under reflux for 3 h. When the reaction was finished, the solvent was removed in vacuo and the crude product was washed with diethyl ether to give a mixture of intermediates (I-la) and (I- lb) as a pale gray solid that was used as such in the next step (16 g, 83%). LCMS: Rt 1.07 (first isomer), 1.15 (second isomer), m/z 239 [M + H]+ (method 2). A batch of the regioisomeric mixture was separated by suspending the mixture in methanol and ammonium hydroxide (q.s.), warming up to reflux and cooling down to room temperature. The precipitate that formed was filtered, water was added to the filtrate and the precipitate that formed was also recovered by filtration. Two additional cycles were repeated to obtain a precipitate containing a 94:6 mixture of I-la:I-lb. Intermediates 2-a and 2-b ((I-2a) and (I-2b)) (l-2a) (|-2b) The mixture of intermediates (I-la) and (I-lb) (16 g, 66.95 mmol) was dissolved in POCI3 (78 mL), and the r.m. was stirred for 2 h at 120C. The solvent was then evaporated and the mixture was cooled down in an ice bath and gently NH4OH was added dropwise until it reached a basic pH. Once the addition was completed, the formed precipitate was filtered off, washed with H20 and then washed several times with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified by open column chromatography (silica, DCM in heptane 20/80 to 80/20), the desired fractions were collected and concentrated in vacuo to give a mixture of intermediates (I-2a) and (I-2b) as white solid (12 g, 69%). C9H6BrCl 2, LCMS: Rt 2.95 (co-elution of the two peaks), m/z 257 [M + H]+ (method 8). Intermediate 13-a and 13-b (I-13a) and (I-13b) Hydrazine hydrate (60% in H20, 0.52 mL, 9.7 mmol) was added to a mixture of Intermediate (I-2a) and Intermediate (I-2b) (1 g, 3.88 mmol) in MeOH (15 mL) at r.t. The r.m. was then heated at 50 C for 30 min, after that it was diluted with H20 (5 mL) and extracted with DCM (20 mL). The organic layers were separated, dried (MgS04), filtered and concentrated in vacuo to give a mixture of intermediates (I-13a) and (I-13b) (0.92 g, 96%) that was used as such in the next reaction step. LCMS: 4.29 (co-elution of the two peaks), m/z 253 [M + H]+ (method 7). DMF (0.182 mL, 2.34 mmol) was added to a mixture of <strong>[5344-49-0]2-chloro-6-nitrobenzoic acid</strong> (0.473 g, 2.34 mmol) and oxalyl chloride (0.201 mL, 2.34 mmol) in dichloromethane (5 mL).The mixture was stirred for 15 min at RT, then this solution was added dropwise to a stirred mixture of triethylamine (0.544 mL, 1.95 mmol) and intermediate compounds I-13a and I-13b (0.495 g, 1.95 mmol) dissolved in dichloromethane (5 mL) at 0 C. The mixture was then allowed to RT and stirred for further 15 min. Then it was quenched with NaHCC"3 (sat. sol. in water), the organic layer was quickly separated and the solvent evaporated. The residue was treated with ethyl ether to yield a mixture of (I- 21a) and (1-2 lb) as a brown solid (0.814 g, 95%) that was used as such in the next reaction step.A mixture of intermediate compounds I-21a and I-21b (0.402 g, 0.92 mmol) in DCE (5 mL) was treated with POCI3 (0.343 mL, 3.68 mmol) and the r.m. was heated at 160 C for 10 min under microwave irradiation. The solvent was then evaporated and the crude compound purified by chromatography (silica, EtOAc in heptanes 20/80 to 60/40). The desired fractions were collected, the solvent evaporated under vacuum to give I-22a (0.053 g, 13.7%) and I-22b (0.112 g, 29%) as pure isomers.
To a solution of compound 14-1 (2.45 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. After stirring at 0 °C for 0.5 hr, compound 2-10 (2.22 g, 11.9 mmol) was added in a portionwise manner. At the end of the addition, the mixture was stirred at rt for 4.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), the THF solvent was removed, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL), and the solution was stirred at 40 °C overnight. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The mixture was washed with Na2C03 aqueous solution (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (3.24 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 380.5 [M+H]+; and H NMPv (400 MHz, CDC13) delta (ppm): 7.84 (d, 1H, J= 2.9 Hz), 7.44 (d, 1H, J= 15.0 Hz), 7.33 (dd, 1H, J= 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J= 16.9 Hz), 4.27 (dd, 1H, J= 24.8 Hz, 17.3 Hz), 3.14 (dd, 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 1.41 (s, 9H), 0.95 (d, 3H, J= 12.7 Hz).
[001811 To a cooled 0°C solution of compound 2-1(13.3 g, 47.1 mmol), HATU (26.5 g, 69 mmol)in 150 mL of THF was added DIPEA (9 mL, 51.1 mmol) dropwise. After the addition, the mixture was stirred at 0 °C for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (10 g, 53.5 mmol) in THF (20 mL) After the addition, the mixture was stirred at 25 °C for 4.0 hours, quenched with little water, removed the THF and then to the mixture was added water (50 mL). To the residue was added water (50 mL), and the resulting mixture was extracted with EtOAc (60 mLx3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2504 and concentrated in vacuo.The residue was diossloved in 100 mL of acetic acid, and the resulting mixture was stirred at 40 °C for 12 hours. Then the mixture was concentrated in vacuo to remove the acetic acid. To the residue was added saturate aqueous NaHCO3 solution (100 mL), and the resulting mixture was extracted with EtOAc (100 mLx3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a light yellow solid (17.32 g, 85percent). The compound was characterized by the following spectroscopic data:?H NMR (400 MHz, CDC13): oe 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H) ppm.
85%
Step 1) the Preparation of Compound 2-2 (0278) To a cooled 0° C. solution of compound 2-1 (13.3 g, 47.1 mmol), HATU (26.5 g, 69 mmol) in 150 mL of THF was added DIPEA (9 mL, 51.1 mmol) dropwise. After the addition, the mixture was stirred at 0° C. for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (10 g, 53.5 mmol) in THF (20 mL) After the addition, the mixture was stirred at 25° C. for 4.0 hours, quenched with little water, removed the THF and then to the mixture was added water (50 mL). To the residue was added water (50 mL), and the resulting mixture was extracted with EtOAc (60 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in 100 mL of acetic acid, and the resulting mixture was stirred at 40° C. for 12 hours. Then the mixture was concentrated in vacuo to remove the acetic acid. To the residue was added saturate aqueous NaHCO3 solution (100 mL), and the resulting mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a light yellow solid (17.32 g, 85percent). The compound was characterized by the following spectroscopic data: (0279) 1H NMR (400 MHz, CDCl3): delta 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H) ppm.
80%
To a solution of compound 10-1 (2.45 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. The mixture was stirred at this temperature for 0.5 hour and compound 3-16-0 (2.21 g, 11.9 mmol) was added in portions. Then the mixture was stirred at rt for 4 hours. After the reaction was completed, the reaction was quenched with water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The resulting solution was washed with an aqueous solution of sodium carbonate (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (3.24 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 381.3 [M+H]+; and *H NMR (400 MHz, CDC13): delta 7.84 (d, 1H, J= 2.9 Hz), 7.44 (d, 1H, J= 15.0 Hz), 7.33 (dd, 1H, J= 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J= 16.9 Hz), 4.27 (dd, 1H, J= 24.8 Hz, 17.3 Hz), 3.14 (dd, 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 1.41 (s, 9H), 0.95 (d, 3H, J= 12.7 Hz) ppm.
72%
With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 2.5h;Inert atmosphere;
To a mixture of compound N-2 (2 g, 8.7 mmol) and HATU (3.5 g, 9.2 mmol) in THF (30 mL) was added DIPEA (6 mL) at 0 °C under N2. The mixture was stirred at rt for 0.5 hour, and compound N-1 (1.8 g, 9.6 mmol) was added. The mixture was stirred at rt for another 2 hours and quenched with water (10 mL). THF was removed in vacuo, and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine and concentrated in vacuo. To the above residue was added acetic acid (35 mL) and the mixture was stirred at 40 °C overnight. The mixture was then neutralized with NaHCO3 saturated solution and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-3 as a reddish brown solid (2.4 g, 72percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H). [0527] To a mixture of compound N-3 (2.4 g, 6.3 mmol), bis(pinacolato)diboron (1.8 g, 7 mmol), Pd(dppf)Cl2·CH2Cl2 (0.1 g, 0.12 mmol) and KOAc (1.6 g, 16 mmol) was added DME (30 mL) under N2 via syringe. The mixture was stirred at 90 °C in an oil bath for 3 hours and concentrated in vacuo. To the residue was added water (5 mL), and the mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-4 (2.1 g, 78percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H). [0528] To a mixture of compound 11-1 (54 mg, 0.12 mmol), compound N-4 (50 mg, 0.11 mmol), Pd(PPh3)4 (12.7 mg, 0.01 mmol) and potassium carbonate (46 mg, 0.33 mmol) was added DME (5 mL) under N2 via syringe followed by pure water (1 mL). The mixture was stirred at 90 °C overnight and concentrated in vacuo. To the residue was added water (3 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 2/1) to give the title compound 28-2 as a yellow solid (32 mg, 46.9percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.82 (s, 2H), 7.52 (s, 2H), 7.39 (d, J = 8.24 Hz, 2H), 7.11 (d, J = 8.24 Hz, 2H), 4.94 (m, H), 3.78 (m, H), 3.44 (m, 1H), 3.19 (m, 1H), 2.83 (s, 4H), 1.82 (m, 2H), 1.76 (m, 1H), 1.55 (m, 17H), 0.96 (d, 3H).
72%
To a mixture of compound N-2 (2 g, 8.7 mmol) and HATU (3.5 g, 9.2 mmol) in THF (30 mL) was added DIPEA(6 mL) at 0 °C under N2. The mixture was stirred at rt for 0.5 hour, and compound N-1 (1.8 g, 9.6 mmol) was added.The mixture was stirred at rt for another 2 hours and quenched with water (10 mL). THF was removed in vacuo, and theaqueous layer was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine andconcentrated in vacuo. To the above residue was added acetic acid (35 mL) and the mixture was stirred at 40 °Covernight. The mixture was then neutralized with NaHCO3 saturated solution and extracted with EtOAc (50 mL x 3). Thecombined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified bysilica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-3 as a reddish brown solid (2.4 g,72percent). The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m,2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H).
(R)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-(4-methoxyphenyl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
K)-iert-Butyl (1-(5-bromo-1 H-benzo[ ]imidazol-2-yl)-2-(4- methoxyphenyl)ethyl)carbamate: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available (ft)-2-((te/f-butoxycarbonyl)amino)- 3-(4-methoxyphenyl)propanoic acid (2.00 g, 6.4 mmol) in AcCN (36.7 mL) was treated at 0 C with 4-ethylmorpholine (1.68 mL, 12.9 mmol), TBTU (2.07 g, 6.4 mmol) and 4- bromobenzene-1 ,2-diamine (1.20 g, 6.4 mmol). The reaction mixture was stirred at 0 C for 2 h. The reaction mixture was diluted with EA and water. The org. phase was dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in glacial acetic acid (37 mL) and the reaction mixture was stirred at 60 C for 1 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was partitioned between EA (50 mL) and sat. aq. NaHC03 (50 mL). The org. layer was washed with sat. aq. NaHC03 (twice 20 mL), dried over MgS04, filtered, and the solvent was removed under reduced pressure. Purification of the residue by crystallization from EA gave the title compound as beige solid: LC-MS-conditions 07: tR = 0.77 min; [M+H]+ = 446.03.
With lithium hexamethyldisilazane; In tetrahydrofuran; hexane; at 5 - 20℃; for 1.0h;Green chemistry;
General procedure: To a solution of o-aminophenol (400 mg, 3.67 mmol) and NCTS (998 mg, 3.67 mmol) in THF (6 mL), 1 M LiHMDS in hexane (3.67 mL, 3.67 mmol) was added and stirred at 5 C to r.t. for 1h. Then the reaction mixture was poured in ice water and stirred for 15 min. Then extracted with EtOAc, the organic layer was separated. The organic layer was washed with brine solution.Then organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtained pure 2-aminobenzaxozole in 90% yield (471 mg).
[001861 To a cooled 0 °C solution of compound 1-6 (3.8 g, 16.57 mmol) in 50 mL of DCM was added C1COOEt (1.58 mL, 16.57 mmol) and TEA (2.4 mL, 17.36 mmol) dropwise. After the addition, the mixture was stirred at 0 °C for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (2.96 g, 15.78 mmol) in DCM (30 mL). Then the mixture was stirred at 25 °C for 4 hours. To the mixture was added water (20 mL). The resulting mixture was extracted with DCM (100 mLx3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (4.2 g, 10.57 mmol) was dossloved in 50 mL of acetic acid, and the resulting mixture was stirred at 50 °C for 10 h. After the reaction was completed, the mixture was concentrated in vacuo to remove acetic acid. The residue was dissolved in EtOAc (100 mL), and the resulting mixture was washed with aquous NaHCO3 solution (50 mLx 2).The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a light red solid (3.98 g, 66percent). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 381.3 [M+Hfb; and?HNMR (400 MHz, CDC13): 7.71 (br, 1H), 7.43 (br, 1H), 7.30-7.32 (d,J= 8.0 Hz, 1H), 5.07-5.10 (m, 1H), 3.95-3.97 (m, 1H), 2.94 (br, 1H), 2.12-2.26 (m, 2H), 1.86 (br, 1H), 1.49 (s, 9H), 1.14 (d,J= 6.4 Hz, 3H) ppm.
66%
Step 1) the Preparation of Compound 3-1 (0293) To a cooled 0° C. solution of compound 1-6 (3.8 g, 16.57 mmol) in 50 mL of DCM was added ClCOOEt (1.58 mL, 16.57 mmol) and TEA (2.4 mL, 17.36 mmol) dropwise. After the addition, the mixture was stirred at 0° C. for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (2.96 g, 15.78 mmol) in DCM (30 mL). Then the mixture was stirred at 25° C. for 4 hours. To the mixture was added water (20 mL). The resulting mixture was extracted with DCM (100 mL×3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (4.2 g, 10.57 mmol) was dissolved in 50 mL of acetic acid, and the resulting mixture was stirred at 50° C. for 10 h. After the reaction was completed, the mixture was concentrated in vacuo to remove acetic acid. The residue was dissolved in EtOAc (100 mL), and the resulting mixture was washed with aqueous NaHCO3 solution (50 mL×2). The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a light red solid (3.98 g, 66percent). The compound was characterized by the following spectroscopic data: (0294) MS (ESI, pos. ion) m/z: 381.3 [M+H]+; and (0295) 1H NMR (400 MHz, CDCl3): delta 7.71 (br, 1H), 7.43 (br, 1H), 7.30-7.32 (d, J=8.0 Hz, 1H), 5.07-5.10 (m, 1H), 3.95-3.97 (m, 1H), 2.94 (br, 1H), 2.12-2.26 (m, 2H), 1.86 (br, 1H), 1.49 (s, 9H), 1.14 (d, J=6.4 Hz, 3H) ppm.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice;
Step A - Synthesis of Intermediate Compound Int-20b (0361) (0362) To a solution of Int-20a (6.1 g, 32.7 mmol), <strong>[68-95-1]N-acetyl-L-proline</strong> (5.4g, 34.35 mmol) and HATU (13.7 g, 34.35 mmol) in anhydrous DMF (100 mL) was added diisopropylethylamine (16.91 mL, 96.9 mmol) dropwise over 15 minutes at ice temperature The reaction was warmed to room temperature and allowed to stir for 3 hours. The reaction was then diluted with EtOAc (500 mL) and the organic layer washed with water (200 mLx 2). The aqueous layer was back-extracted with EtOAc (100 mLx 2). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified using flash chromatography using a 1% -2 % MeOH/CH2Cl2 as eluent to provide the intermediate amide (4.1 g). The amide was dissolved in glacial acetic acid and was heated at 60 - 70 C for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and cooled in ice bath. Saturated Na2CO3 solution was added slowly until the pH = 8. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mLx 2). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide Compound Int-20b (3.75g, 38 %). LCMS: M+ = 308
5-bromo-2-(2-chloro-3,4-dimethoxyphenyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With sodium metabisulfite; In N,N-dimethyl-formamide; for 4h;Reflux;
General procedure: 4-Bromo-1,2-diaminobenzene (1 mmol) and different substitutedaromatic aldehydes (1 mmol) in N,N-dimethylformamide(10 mL) were taken into a 100 mL round-bottomedflask. Catalytic amount of sodium metabisulfite (Na2S2O5)was added into the reaction mixture and refluxed for 4 h.Reaction progress was carefully monitored by thin layerchromatography. After completion of reaction, it was addedinto chilled distilled water (100 mL). Precipitates wereformed and filtered to afford products. Crude products werecrystallized from ethanol to get pure products in high yields.
5-bromo-2-(4-butoxyphenyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium metabisulfite; In N,N-dimethyl-formamide; for 4h;Reflux;
General procedure: 4-Bromo-1,2-diaminobenzene (1 mmol) and different substitutedaromatic aldehydes (1 mmol) in N,N-dimethylformamide(10 mL) were taken into a 100 mL round-bottomedflask. Catalytic amount of sodium metabisulfite (Na2S2O5)was added into the reaction mixture and refluxed for 4 h.Reaction progress was carefully monitored by thin layerchromatography. After completion of reaction, it was addedinto chilled distilled water (100 mL). Precipitates wereformed and filtered to afford products. Crude products werecrystallized from ethanol to get pure products in high yields.
To a solution of compound 8-1 (2.45 g, 10.7 mmol) and compound HATU (4.88 g,12.84 mmol) in THF (30 mL) at 0 ° C was added DIPEA (1.95 mL, 11.8 mmol) Compound 1-9-2(2.21 g, 11.9 mmol) was added in portions, and after the addition was complete, thereaction was carried out at room temperature for 4.0 hours. After the reaction wascompleted, the reaction was quenched by the addition of water (50 mL), the THF wasremoved, extracted with EtOAc (50 mL x 3), and the organic phases were combined, washedwith brine, dried over anhydrous sodium sulfate and concentrated. The residue wasdissolved in glacial acetic acid (20 mL) at 40 ° C overnight. After completion of thereaction, glacial acetic acid was removed and the residue was dissolved in EtOAc (100 mL), washed with sodium carbonate solution (50 mL x 3), dried over anhydrous sodiumsulfate, concentrated and purified by column chromatography (eluent: PE / EtOAc (v / v)= 1/2) to give the product 3.24 g, yield: 80percent.
With acetic acid; at 0 - 30℃; for 12h;Inert atmosphere;
Methyl 2,2,2-trichloroacetimidate (6.60 g, 37.4 mmol) was added to acetic acid (50.0 mL).A solution of 4-bromobenzene-1,2-diamine (7.00 g, 37.4 mmol) in acetic acid (50.0 mL) was slowly added dropwise at 0 C, then the mixture was stirred at room temperature overnight.After the reaction was completed, water was added and the mixture was extracted twice with ethyl acetate.After combining the organic layers, wash them with water and saturated sodium chloride solution, respectively.Dry with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (100 mL). Evaporate the solvent under reduced pressure.Add ethyl acetate to dissolve, and then use saturated sodium bicarbonate solution,The solution was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to yield intermediate 100a(3.00 g, 11.8 mmol, yield 26%).
Step 536a. The mixture of <strong>[706806-60-2](R)-2-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid</strong> (200 mg, 0.66 mmol) and 4-bromo-1,2-diaminobenzene (135 mg, 0.73 mmol) in acetonitrile (2 mL) was added EDC (138 mg, 0.73 mmol) and 4-dimethylaminopyridine (40 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 1 hour before being partitioned between water and EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated to afford a brown slurry, which was purified by flash column chromatography (silica, hexane-EtOAc) to give the desired product as a light yellow solid (190 mg, 61%). ESIMS m/z=474.18 [M+H]+.; Step 536b. The desired product was prepared from the compound of step 536a using procedures similar to that described in step 1b. ESIMS m/z=456.17 [M+H]+. ; Step 1b. A solution of the crude compound from step 1a (10.7 g, 26.7 mmol at most) in glacial acetic acid (100 mL) was heated at 50 C. for 2 hours. The volatiles were evaporated off and the residue was partitioned (EtOAc-aqueous NaHCO3). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a brown foam (5.78 g, 59%). ESIMS m/z=366.17, 368.17 [M+H]-. 1H NMR (CDCl3) 10.96, 10.93 (2 s, 1H), 7.81, 7.30 (2 s, 1H), 7.53, 7.17 (2d, J=8.5 Hz, 1H), 7.23, 7.03 (2d, J=8.5 Hz, 1H), 5.09, 5.07 (2s, 1H), 3.42-3.49 (m, 2H), 2.75-2.85 (m, 1H), 2.13-2.23 (m, 2H), 1.97-2.00 (m, 1H), 1.48 (s, 9H).
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