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CAS No. : | 1007882-04-3 | MDL No. : | MFCD19982645 |
Formula : | C18H22BrN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SEJWRHUDDTVGHP-HNNXBMFYSA-N |
M.W : | 392.29 | Pubchem ID : | 56605031 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302-H317 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonium acetate; In xylene; at 150℃; for 5h;sealed reactor; | Intermediate 8: 1 ,1-dimeth<strong>[1007881-98-2]y</strong>leth<strong>[1007881-98-2]y</strong>l(2S)-2-[4-(4-bromophen<strong>[1007881-98-2]y</strong>l)-1 /-/-imidazol-2-<strong>[1007881-98-2]y</strong>ll-1-A mixture of 1 ,1-dimeth<strong>[1007881-98-2]y</strong>leth<strong>[1007881-98-2]y</strong>l(2S)-2-([2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2- oxoeth<strong>[1007881-98-2]y</strong>l]amino}carbon<strong>[1007881-98-2]y</strong>l)-1 -p<strong>[1007881-98-2]y</strong>rrolidinecarbox<strong>[1007881-98-2]y</strong>late (7) (40. Og, 97.2mmol) and NH4OAc (60g, 0.778mol) in x<strong>[1007881-98-2]y</strong>lene (400ml_) was heated to 150 C for 5 hrs in a sealed reactor. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (500 mL) and washed with aqueous NaHC03 and brine. The organic phase was dried over Na2S04, concentrated to dr<strong>[1007881-98-2]y</strong>ness. The crude product was purified b<strong>[1007881-98-2]y</strong> chromatograph<strong>[1007881-98-2]y</strong> on silica gel (petroleum ether / eth<strong>[1007881-98-2]y</strong>l acetate =1/1 ) to give 1 , 1 -dimeth<strong>[1007881-98-2]y</strong>leth<strong>[1007881-98-2]y</strong>l(2S)-2-[4-(4-bromophen<strong>[1007881-98-2]y</strong>l)-1 /-/-imidazol-2-<strong>[1007881-98-2]y</strong>l]-1 - p<strong>[1007881-98-2]y</strong>rrolidinecarbox<strong>[1007881-98-2]y</strong>late (Intermediate 8) (34g, <strong>[1007881-98-2]y</strong>ield: 89%) as brown solid. 1H NMR (300 MHz, CDCI3) delta ppm 7.52 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 7.20(s, 1 H), 5.58-5.71 (m, 1 H), 3.38-3.42 (m, 1 H), 2.80-2.87 (m, 2H), 2.03-2.06 (m, 2H), 1.88-2.00 (m, 2H), 1.49 (s, 9H). ES LC-MS m/z =392, 394 (M+H)+ . |
76% | With ammonium acetate; sodium hydrogencarbonate; In 5,5-dimethyl-1,3-cyclohexadiene; | Preparation of (S)-2-[5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-imidazol-2-<strong>[1007881-98-2]y</strong>l]-p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>lic acid tert-but<strong>[1007881-98-2]y</strong>l ester 5. Compound 4 (19.16 mmol) and NH4OAc (95.75 mmol) were mixed together in x<strong>[1007881-98-2]y</strong>lene (96 mL). The reaction mixture was stirred at 140 C. for 2 hrs. The reaction mixture was then cooled down to room temperature and concentrated under vacuum. The residue was diluted with EtOAc (20 mL) and water (20 mL). A saturated NaHCO3 solution was added. The organic la<strong>[1007881-98-2]y</strong>ers were separated, washed sequentiall<strong>[1007881-98-2]y</strong> with water (180 mL) and brine (180 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified b<strong>[1007881-98-2]y</strong> silica gel chromatograph<strong>[1007881-98-2]y</strong> (PE/EtOAc) to give compound 5 as an orange solid in 76% <strong>[1007881-98-2]y</strong>ield. 1H NMR (DMSO-d6, 400 MHz) delta (ppm) 1.38 (s, 9H), 1.84-2.31 (m, 4H), 3.29 (s, 2H), 3.51 (brs, 1H), 4.75 (m, 1H), 7.74 (d, J=7.90 Hz, 2H), 7.91 (d, J=7.90 Hz, 2H), 12.18 (brs, 1H). |
76% | With ammonium acetate; HATU; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 2h; | Compound4 (19.16 mmol) and NH4OAc (95.75 mmol) were mixed together in x<strong>[1007881-98-2]y</strong>lene (96 mL). The reaction mixture wasstirred at 140 C for 2 hrs. The reaction mixture was then cooled down to room temperature and concentrated undervacuum. The residue was diluted with EtOAc (20 mL) and water (20 mL). A saturated NaHCO3 solution was added. Theorganic la<strong>[1007881-98-2]y</strong>ers were separated, washed sequentiall<strong>[1007881-98-2]y</strong> with water (180 mL) and brine (180 mL), dried over Na2SO4, andconcentrated in vacuo. The residue was purified b<strong>[1007881-98-2]y</strong> silica gel chromatograph<strong>[1007881-98-2]y</strong> (PE/EtOAc) to give compound 5 as anorange solid in 76% <strong>[1007881-98-2]y</strong>ield. 1H NMR (DMSO-d6, 400 MHz) delta (ppm) 1.38 (s, 9H), 1.84-2.31 (m, 4H), 3.29 (s, 2H), 3.51(brs, 1H), 4.75 (m, 1H), 7.74 (d, J = 7.90 Hz, 2H), 7.91 (d, J = 7.90 Hz, 2H), 12.18 (brs, 1H). |
74% | With ammonium acetate; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 4h;Sealed tube; | A mixture of (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2-oxoeth<strong>[1007881-98-2]y</strong>lcarbamo<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine- 1 - carbox<strong>[1007881-98-2]y</strong>late (2.50 g, 6.08 mmol) and ammonium acetate (2.34 g, 30.4 mmol) in x<strong>[1007881-98-2]y</strong>lenes (10 mL) was heated in a sealed tube at 140C for 4 h. The reaction was then cooled to room temperature and diluted with eth<strong>[1007881-98-2]y</strong>l acetate. The organic fraction was washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified b<strong>[1007881-98-2]y</strong> ISCO flashchromatograph<strong>[1007881-98-2]y</strong> (Teled<strong>[1007881-98-2]y</strong>ne Isco RediSep Flash Column 40 g; (00%> to 100% eth<strong>[1007881-98-2]y</strong>lacetate/hexane) to afford, (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-lH-imidazol-2-<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-l- carbox<strong>[1007881-98-2]y</strong>late as a <strong>[1007881-98-2]y</strong>ellow solid, (1.77g, 74%): ESI-LRMS m/e calcd for [M+] 392, found 393 [M+H+]. |
70% | With ammonium acetate; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 4h;Sealed tube; | A mixture of the keto amide BB1-C (45 g, 109.8 mmol) and NH4OAc (42.2 g, 548.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (500 ml) was heated in a sealed tube at 140 C. After 4 h, the volatile component was removed in vacuo and the residue carefull<strong>[1007881-98-2]y</strong> partitioned between EtOAc and water, whereafter a saturated solution of NaHC03 was added until slightl<strong>[1007881-98-2]y</strong> basic pH. The la<strong>[1007881-98-2]y</strong>ers were separated, the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an EtOAc, and the combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The resulting solid was purified b<strong>[1007881-98-2]y</strong> flash chromatograph<strong>[1007881-98-2]y</strong> (p. ether: EtOAc 5: 1) which gave the title compound (30 g 70%) as a light-brown solid. MS (ESI): 392 [M+H]+ and MS (ESI): 394 [M+H]+. |
52% | With ammonium acetate; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; | Add x<strong>[1007881-98-2]y</strong>lene (160 ml) to a 500 mL one-neck round bottom flask and add to the x<strong>[1007881-98-2]y</strong>lene(S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2-oxoeth<strong>[1007881-98-2]y</strong>lamino)p<strong>[1007881-98-2]y</strong>rrole-1 -carbox<strong>[1007881-98-2]y</strong>lic acid tert-but<strong>[1007881-98-2]y</strong>l ester(17.6 g, 0.428 mol) and ammonium acetate (16.5 g, 0.214 mol). A water separator and a reflux condenser are connected to the reaction flask. The reaction mixture was heated to reflux for 2.5 hours and then rotar<strong>[1007881-98-2]y</strong> to remove x<strong>[1007881-98-2]y</strong>lene.The residue was taken up in 200 ml of eth<strong>[1007881-98-2]y</strong>l acetate and 50 ml of water and stirred until all dissolved.The pH of the solution was adjusted to 8 with a saturated aqueous solution of sodium h<strong>[1007881-98-2]y</strong>drogencarbonate and the organic phase was separated. The aqueous phase was extracted with 150 ml of eth<strong>[1007881-98-2]y</strong>l acetate.Dr<strong>[1007881-98-2]y</strong> over anh<strong>[1007881-98-2]y</strong>drous sodium sulfate.Purified b<strong>[1007881-98-2]y</strong> column chromatograph<strong>[1007881-98-2]y</strong>((S)-2-(5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-1H-imidazol-2-<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>lic acid tert-but<strong>[1007881-98-2]y</strong>l ester) 8.7 g,The <strong>[1007881-98-2]y</strong>ield was 52%. |
43% | With ammonium acetate; In xylene; for 16h;Reflux; | Step 2; A mixture of intermediate XXIII (60 g, 0.14 mol) and ammonium acetate (89 g, 1.4 mol) in x<strong>[1007881-98-2]y</strong>lene (800 mL) was heated at reflux for 16 hours. The reaction mixture was partitioned between eth<strong>[1007881-98-2]y</strong>l acetate (700 mL) and saturated NaHC03 solution (500 mL). The la<strong>[1007881-98-2]y</strong>ers were separated and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with additional eth<strong>[1007881-98-2]y</strong>l acetate (2 x 300 mL). The organic la<strong>[1007881-98-2]y</strong>ers were combined, washed with brine (500 mL), dried over MgS04, the solids removed via filtration and the solvents of the filtrate were evaporated under reduced pressure. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/petroleum ether to afford a <strong>[1007881-98-2]y</strong>ellow solid, Villa, 25 g (43%).1H NMR: (CD3OD 400 MHz): delta 7.62 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.31-7.36 (m, 1H), 4.93-4.98 (m, 1H), 3.66-3.70 (m, 1H), 3.48- 3.54 (m, 1H), 2.29-2.41 (m, 1H), 1.93-2.17 (m. 3H), 1.48 (s, 3H), 1.27 (s, 6H). |
43% | With ammonium acetate; In xylene; for 16h;Reflux; | 1.10 Preparation of I-12; A mixture of intermediate I-11 (60 g, 0.14 mol) and ammonium acetate (89 g, 1.4 mol) in x<strong>[1007881-98-2]y</strong>lene (800 mL) was heated at reflux for 16 hours. The reaction mixture was partitioned between eth<strong>[1007881-98-2]y</strong>l acetate (700 mL) and saturated NaHCO3 solution (500 mL). The la<strong>[1007881-98-2]y</strong>ers were separated and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with additional eth<strong>[1007881-98-2]y</strong>l acetate (2×300 mL). The organic la<strong>[1007881-98-2]y</strong>ers were combined, washed with brine (500 mL), dried over MgSO4, the solids removed via filtration and the solvents of the filtrate were evaporated under reduced pressure. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/petroleum ether to afford a <strong>[1007881-98-2]y</strong>ellow solid, I-12, 25 g (43%).1H NMR (400 MHz, MeOD) delta ppm 1.23 (s, 6H) 1.46 (s, 3H) 1.84-2.10 (m, 3H) 2.36 (m, J=5.80 Hz, 1H) 3.50 (m, J=10.40, 5.10 Hz, 1H) 3.60-3.73 (m, 1H) 4.94-5.00 (m, 1H) 7.28-7.39 (m, 1H) 7.49 (d, J=8.28 Hz, 2H) 7.61 (d, J=8.03 Hz, 2H) |
A mixture of ketoamide 1b (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole 1c as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole 1c. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. I): RT=1.71 min; >98% homogeneit<strong>[1007881-98-2]y</strong> index; LC/MS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959.The optical purit<strong>[1007881-98-2]y</strong> of the two samples of 1c was assessed using the chiral HPLC conditions noted below:Column: Chiralpak AD, 10 um, 4.6×50 mmSolvent: 2% ethanol/heptane (isocratic) Flow rate: 1 mL/min Wavelength: either 220 or 254 nm Relative retention time: 2.83 minutes (R), 5.34 minutes (S) Result: ee>99% for the combined crops; ee=96.7% for the sample from flash chromatograph<strong>[1007881-98-2]y</strong> | ||
With ammonium acetate; acetic acid; In xylene; at 20 - 160℃; for 3h; | Example 15 Preparation of (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-1H-imidazol-2-<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>late (19a) To the solution of (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2-oxoeth<strong>[1007881-98-2]y</strong>lcarbamo<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>late (compound 18a, 5.0 g, 12.2 mmol) in x<strong>[1007881-98-2]y</strong>lene (75 ml) were added ammonium acetate (23.4 g, 304 mmol) and acetic acid (5 ml) at room temperature. The reaction mixture was placed in an oil bath and heated to 160 C. with water being azeotroped into a Dean-Stark trap. After 3 hours, the resulting mixture was cooled to room temperature and then extracted with eth<strong>[1007881-98-2]y</strong>l acetate and distillated water. The organic la<strong>[1007881-98-2]y</strong>er was dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified with column chromatograph<strong>[1007881-98-2]y</strong> (100% eth<strong>[1007881-98-2]y</strong>l acetate) to <strong>[1007881-98-2]y</strong>ield the pure product 19a (4.4 g). | |
With ammonium acetate; In xylene; at 140℃; for 2h; | A mixture J.6 (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2-oxoeth<strong>[1007881-98-2]y</strong>lcarbamo<strong>[1007881-98-2]y</strong>l)- p<strong>[1007881-98-2]y</strong>rrolidine- 1 -carbox<strong>[1007881-98-2]y</strong>late (12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCC solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgS04), filtered, and concentrated. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of J.7 (S)-tert- but<strong>[1007881-98-2]y</strong>l 2-(5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-lH-imidazol-2-<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-l-carbox<strong>[1007881-98-2]y</strong>late, 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g. XH NMR(DMSO-d6, delta = 2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond.-Jl): RT = 1.71 min; LC/MS: Anal. Calcd. For [M+H]+ Ci8H23Br 302: 392.10; found 391.96. HRMS: Anal. Calcd. For [M+H]+ Ci8H23Br 302: 392.0974; found 392.0959. | |
With ammonium acetate; In xylenes; at 140℃; for 2h;Sealed tube; | Exam le D-l, step bA mixture of D-la (12.8 g, 31.12 mmol) and H4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCCh solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgS04), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole D-lb as a light-<strong>[1007881-98-2]y</strong>ellow, dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>lacetate/hexanes) to provide an additional 2.23 g of Example D-lb. lH NMR (500 MHz, DMSO-d6) delta ppm 1.40/1.15 (app br s, 9 H), 2.30-1.75 (m, 4 H), 3.36 (m, 1 H), 3.52 (app br s, 1 H), 4.86-4.70 (m, 1 H), 7.72-7.46/7.28 (m, 5 H), 12.17/11.92/11.86 (m, 1 H). LC (Cond. 7): RT = 1.71 min; LRMS: Anal. Calcd. for [M+H]+ Ci8H23Br 302: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ Ci8H23Br 302: 392.0974; found 392.0959. | |
With ammonium acetate; In xylene; at 140℃; for 4h; | A mixture of (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(2-(4-bromophen<strong>[1007881-98-2]y</strong>l)-2-oxoeth<strong>[1007881-98-2]y</strong>lcarbamo<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>late (2.50 g, 6.08 mmol) and ammonium acetate (2.34 g, 30.4 mmol) in x<strong>[1007881-98-2]y</strong>lenes (10 mL) was heated in a sealed tube at 140 C. for 4 h. The reaction was then cooled to room temperature and diluted with eth<strong>[1007881-98-2]y</strong>l acetate. The organic fraction was washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified b<strong>[1007881-98-2]y</strong> ISCO flash chromatograph<strong>[1007881-98-2]y</strong> (Teled<strong>[1007881-98-2]y</strong>ne Isco RediSep Flash Column 40 g; (00% to 100% eth<strong>[1007881-98-2]y</strong>l acetate/hexane) to afford, (S)-tert-but<strong>[1007881-98-2]y</strong>l 2-(5-(4-bromophen<strong>[1007881-98-2]y</strong>l)-1H-imidazol-2-<strong>[1007881-98-2]y</strong>l)p<strong>[1007881-98-2]y</strong>rrolidine-1-carbox<strong>[1007881-98-2]y</strong>late as a <strong>[1007881-98-2]y</strong>ellow solid, (1.77 g, 74%): ESI-LRMS m/e calcd for C18H22BrN3O2 [M+] 392, found 393 [M+H+]. | |
With ammonium acetate; In xylene; at 140℃; for 2h; | A mixture of ketoamide 1a (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole 1b as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole 1b. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT=1.71 min; >98% homogeneit<strong>[1007881-98-2]y</strong> index; LC/MS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959 | |
With ammonium acetate; In xylenes; at 140℃; for 2h; | A mixture of ketoamide I a (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole 1 b as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole 1b. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT=1.71 min; >98% homogeneit<strong>[1007881-98-2]y</strong> index; LC/MS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959The optical purit<strong>[1007881-98-2]y</strong> of the two samples of 1b were assessed using the chiral HPLC conditions noted below (ee >99% for the combined crops; ee=96.7% for the sample from flash chromatograph<strong>[1007881-98-2]y</strong>): Column: Chiralpak AD, 10 um, 4.6×50 mm Solvent: 2% ethanol/heptane (isocratic) Flow rate: 1 mL/min Wavelength: either 220 or 254 nm Relative retention time: 2.83 minutes (R), 5.34 minutes (S) | |
A mixture of ketoamide 1a (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole 1b as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole 1b. 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT=1.71 min; >98% homogeneit<strong>[1007881-98-2]y</strong> index; LC/MS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959The optical purit<strong>[1007881-98-2]y</strong> of the two samples of 1b were assessed using the chiral HPLC conditions noted below (ee>99% for the combined crops; ee=96.7% for the sample from flash chromatograph<strong>[1007881-98-2]y</strong>):Column: Chiralpak AD, 10 um, 4.6×50 mmSolvent: 2% ethanol/heptane (isocratic)Flow rate: 1 mL/minWavelength: either 220 or 254 nmRelative retention time: 2.83 minutes (R), 5.34 minutes (S) | ||
With ammonium acetate; In xylenes; at 140℃; for 2h;Sealed tube; | A mixture of ketoamide (36) (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 0C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic <n="42"/>after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole (28) as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole (28). 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, IH), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, IH), 3.52 (app br s, IH), 3.36 (m, IH), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC/MS: Anal. Calcd. for [M+H]+ Ci8H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ Ci8H23BrN3O2: 392.0974; found 392.0959.The optical purit<strong>[1007881-98-2]y</strong> of the two samples of (28) were assessed using the chiral HPLC conditions noted below (ee > 99% for the combined crops; ee=96.7% for the sample from flash chromatograph<strong>[1007881-98-2]y</strong>):Column: Chiralpak AD, 10 um, 4.6 x 50 mm Solvent: 2% ethanol/heptane (isocratic) Flow rate: 1 mL/min Wavelength: either 220 or 254 nm Relative retention time: 2.83 minutes (R), 5.34 minutes (S) | |
Example 1, Step b1b A mixture of ketoamide Ia (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 0C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCtheta3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with an additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole Ib as a light-<strong>[1007881-98-2]y</strong>ellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of imidazole Ib. 1H NMR (DMSO- <n="112"/>d6, delta = 2.5 ppm, 400 MHz): delta 12.17/11.92/11.86 (m, IH), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, IH), 3.52 (app br s, IH), 3.36 (m, IH), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT = 1.71 min; >98% homogeneit<strong>[1007881-98-2]y</strong> index; LC/MS: Anal. Calcd. for [M+H]+ Ci8H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ Ci8H23BrN3O2: 392.0974; found 392.0959 | ||
With ammonium acetate; In xylenes; at 140℃; for 2h;Sealed tube; | Example D-I, step b; A mixture of D-Ia (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in x<strong>[1007881-98-2]y</strong>lenes (155 mL) was heated in a sealed tube at 140 0C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefull<strong>[1007881-98-2]y</strong> between eth<strong>[1007881-98-2]y</strong>l acetate and water, whereb<strong>[1007881-98-2]y</strong> enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightl<strong>[1007881-98-2]y</strong> basic after the shaking of the biphasic s<strong>[1007881-98-2]y</strong>stem. The la<strong>[1007881-98-2]y</strong>ers were separated, and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with additional eth<strong>[1007881-98-2]y</strong>l acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/hexanes to provide two crops of imidazole D-Ib as a light-<strong>[1007881-98-2]y</strong>ellow, dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatograph<strong>[1007881-98-2]y</strong> (silica gel; 30% eth<strong>[1007881-98-2]y</strong>l acetate/hexanes) to provide an additional 2.23 g of Example D-Ib. 1H NMR (500 MHz, DMSO-dbeta) delta ppm 1.40/1.15 (app br s, 9 H), 2.30-1.75 (m, 4 H), 3.36 (m, 1 H), 3.52 (app br s, 1 H)5 4.86-4.70 (m, 1 H), 7.72-7.46/7.28 (m, 5 H), 12.17/11.92/11.86 (m, 1 H). LC (Cond. 7): RT - 1.71 min; LRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959.The optical purit<strong>[1007881-98-2]y</strong> of the two samples of Example D-Ib was assessed according to the chiral HPLC conditions noted below (ee >; 99% for the combined crops; ee - 96.7% for the sample from flash chromatograph<strong>[1007881-98-2]y</strong>): Column: Chiralpak AD, 10 um, 4.6 x 50 mm Solvent: 2% ethanol/heptane (isocratic) Flow rate: 1 mL/min Wavelength: either 220 or 254 nm Relative retention time: 2.83 minutes (R), 5.34 minutes (S). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 80℃; for 5.75h; | Example 1, Step d di-tert-butyl (2S,2'S)-2,2'-(4,4'-biphenyldiylbis(]H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate) Pd(Ph3P)4 (59.9 mg, 0.0518 mmol) was added to a mixture of bromide 1b (576.1 mg, 1.469 mmol), boronate 1c (621.8 mg, 1.415 mmol), NaHCO3 (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 C. for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned between 20% methanol/CHCl3 (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl3 (30 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer id, contaminated with Ph3PO, as an off-white solid (563 mg). 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): 6 12.21-12-16/11.95-11.78 (m, 2H), 7.85-7.48/7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10 (m, 18H). LC (Cond. 1b): RT=1.77 min; LC/MS: Anal. Calcd. for [M+H]+C36H45BN6O4: 625.35; found 625.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 5.75h; | Pd(Ph3P)4 (59.9 mg, 0.0518 mmol) was added to a mixture of bromide 1b (576.1 mg, 1.469 mmol), boronate 1c (621.8 mg, 1.415 mmol), NaHCO3 (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 C. for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned between 20% methanol/CHCl3 (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl3 (30 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer 1d, contaminated with Ph3PO, as an off-white solid (563 mg). 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.21-12-16/11.95-11.78 (m, 2H), 7.85-7.48/7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10 (m, 18H). LC (Cond. 1b): RT=1.77 min; LC/MS: Anal. Calcd. for [M+H]+ C36H45BN6O4: 625.35; found 625.48. | |
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 5.75h;Product distribution / selectivity; | Pd(Ph3P)4 (59.9 mg, 0.0518 mmol) was added to a mixture of bromide 1b (576.1 mg, 1.469 mmol), boronate 1c (621.8 mg, 1.415 mmol), NaHCO3 (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 C. for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned between 20% methanol/CHCl3 (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl3 (30 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer 1d, contaminated with Ph3PO, as an off-white solid (563 mg). 1H NMR (DMSO-d6, delta=2.5 ppm, 400 MHz): delta 12.21-12-16/11.95-11.78 (m, 2H), 7.85-7.48/7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10 (m, 18H). LC (Cond. 1b): RT=1.77 min; LC/MS: Anal. Calcd. for [M+H]+ C36H45BN6O4: 625.35; found 625.48. | |
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 5.75h; | Example 1, Step d di-tert-butyl (2S, 2 'S)-2, 2 '-(4,4'-biphenyldiylbis(lH-imidazole-5, 2-diyl))di(l- pyrrolidinecarboxylate)Pd(Ph3P)4 (59.9 mg, 0.0518 mmol) was added to a mixture of bromide Ib (576.1 mg, 1.469 mmol), boronate Ic (621.8 mg, 1.415 mmol), NaHCO3 (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 0C for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned <n="119"/>between 20% methanol/ CHCI3 (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl3 (30 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer Id, contaminated with Ph3PO, as an off-white solid (563 mg). 1H NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz): delta 12.21-12- 16/11.95-11.78 (m, 2H), 7.85-7.48/ 7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10 (m, 18H). LC (Cond. Ib): RT = 1.77 min; LC/MS: Anal. Calcd. for [M+H]+ C36H45BN6O4: 625.35; found 625.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In xylene; for 16h;Reflux; | Preparation of 1-12A mixture of intermediate 1-11 (60 g, 0.14 mol) and ammonium acetate (89 g, 1.4 mol) in x<strong>[1007881-98-2]y</strong>lene (800 mL) was heated at reflux for 16 hours. The reaction mixture was partitioned between eth<strong>[1007881-98-2]y</strong>l acetate (700 mL) and saturated NaHCOs solution (500 mL). The la<strong>[1007881-98-2]y</strong>ers were separated and the aqueous la<strong>[1007881-98-2]y</strong>er was extracted with additional eth<strong>[1007881-98-2]y</strong>l acetate (2 x 300 mL). The organic la<strong>[1007881-98-2]y</strong>ers were combined, washed with brine (500 mL), dried over MgSO4, the solids removed via filtration and the solvents of the filtrate were evaporated under reduced pressure. The resulting material was recr<strong>[1007881-98-2]y</strong>stallized from eth<strong>[1007881-98-2]y</strong>l acetate/petroleum ether to afford a <strong>[1007881-98-2]y</strong>ellow solid, 1-12, 25 g (43%).1H NMR (400 MHz, MeOD) delta ppm 1.23 (s, 6 H) 1.46 (s, 3 H) 1.84 - 2.10 (m, 3 H) 2.36 (m, J=5.80 Hz, 1 H) 3.50 (m, J=10.40, 5.10 Hz, 1 H) 3.60 - 3.73 (m, 1 H) 4.94 - 5.00 (m, 1 H) 7.28 - 7.39 (m, 1 H) 7.49 (d, J=8.28 Hz, 2 H) 7.61 (d, J=8.03 Hz, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium chloride In 1,4-dioxane at 80℃; for 3h; Inert atmosphere; Sealed pressure tube; | M1a Pd(Ph3P)4 (0.1 15 g, 0.099 mmol) was added to a mixture oftributyl(ethynyl)stannane (1.539 g, 4.88 mmol), (S)-tert-butyl 2-(4-(4-bromophenyl)- lH-imidazol-2-yl)pyrrolidine-l-carboxylate (0.965 g, 2.46 mmol; for its preparation, see PCT Publication No. WO 2008/021927) and LiCl (0.277 g, 6.53 mmol) in dioxane (20 mL) in a sealed pressure tube. The mixture was purged with nitrogen, sealed and heated at 80 °C for 3 hr. After it was allowed to cool to ambient temperature, the volatile component was removed in vacuo and the residue was partitioned between CH3CN and hexanes (2: 1 ratio in volume). The hexane layer was washed with an equal volume of CH3CN. The combined CH3CN phase was rotervaped, and the resultant crude material was purified with a BIOTAGE (100 g silica gel; 40-50% EtOAc/hexanes) to afford Intermediate Mia as a dull orange solid (591 mg). lH NMR (DMSO-d6, δ = 2.50 ppm, 400 MHz): 12.21/1 1.95/ 1 1.88 (three 'br s', 1H), 7.74 (d, J = 8.3, 1.6H), 7.66-7.47 (m, 1.66H), 7.41 (d, J = 8.3, 1.6H), 7.32 (m, 0.14H), 4.84-4.75 (m, 1H), 4.19/4.12 (two 's', 1H), 3.52 (m, 1H), 3.39-3.29 (m, 1H), 2.28-1.77 (m, 4H), 1.39/1.15 (two 's', 9H). LC/MS: Anal. Calcd. for (M+H)+ C2oH24N302: 338.18; found, 338.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | Preparation 20: fert-Butyl (2S)-2-{5-[4-(6-chloropyridin-3-yl)phenyl]-1H-imidazol-2-yl}pyrrolidine-1- carboxylateTo ieri-butyl (2S)-2-[5-(4-bromophenyl)-1 H-imidazol-2-yl]pyrrolidine-1 -carboxylate obtained from Preparation 2 (200 mg, 0.510 mmol) and 2-chloro-5-pyridine boronic acid (88 mg, 0.561 mmol) in 1 ,4-dioxane (2 ml_), were added Pd2(dba)3 (5 mg, 0.005 mmol) and tricyclohexylphosphine (4 mg, 0.012 mmol). A solution of potassium phosphate (184 mg, 0.867 mmol) in water (683 muIota_) was added and the resulting mixture was heated at 100 C for 16 hours under nitrogen. After this time, the resulting mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (heptane : ethyl acetate, 70:30 to 10:90) to give the title compound as a yellow solid (183 mg).LCMS (run time = 2 minutes, System A): Rt = 1.24 minutes; m/z 425, 427 [MH+]H NMR (400 MHz, CDCI3): delta = 8.63 (d, 1 H), 7.86 (dd, 1 H), 7.77 (m, 2H), 7.56 (d, 2H), 7.40 (d, 1 H), 7.30 (s, 1 H), 5.01 (d, 1 H), 3.48-3.41 (m, 2H), 3.09-2.98 (m, 1 H), 2.25-2.13 (m, 2H), 2.05-1.96 (m, 1 H), 1.51 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 3.2: 4 h / 25 - 30 °C 4.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 4.2: 7 h / 0 - 30 °C | ||
Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: sodium phosphate dodecahydrate; tetrabutylammomium bromide; palladium 10% on activated carbon / methanol / 5 h / 25 - 70 °C / Inert atmosphere 3.2: 6 h / 5 - 10 °C 4.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 4.2: 7 h / 0 - 30 °C | ||
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 4 h / 25 - 65 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 1.75 h / 0 - 20 °C 2.2: 14 h / 0 - 20 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 15 h / 25 - 85 °C 4.1: potassium carbonate / 1,4-dioxane; water / 15 h / 25 - 85 °C 4.2: 4 h / 25 - 30 °C 5.1: sodium carbonate / dichloromethane; water / 0.25 h / 25 - 30 °C 5.2: 7 h / 0 - 30 °C |
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 2.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 3.2: 22.75 h / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 16.5 h / 80 °C 2.1: sodium hydrogencarbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 5.75 h / 80 °C 3.1: hydrogenchloride / methanol / 23 h / 20 - 50 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / acetonitrile / 1 h / 20 °C 4.2: 22.75 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With ammonium acetate In dimethyl sulfoxide at 60℃; for 2h; | 5 Example 5 Preparation of DSV02 Intermediate Compound DSV103 (0.36 g) and dimethyl sulfoxide (5 ml) were added to a 50 ml three-necked flask, and reacted at 30 ° C for 24 h.Add ammonium acetate (301 mg),L-Boc guanylaldehyde (260mg),The reaction was carried out at 60 ° C for 2 h. Add 50ml of water,Extract with dichloromethane (30ml*3),The organic phase was washed with saturated brine (50 ml).Concentrated under reduced pressure,Column chromatography separated 463 mg of DSV02.The yield is 91%.The purity is 94%. |
Tags: 1007882-04-3 synthesis path| 1007882-04-3 SDS| 1007882-04-3 COA| 1007882-04-3 purity| 1007882-04-3 application| 1007882-04-3 NMR| 1007882-04-3 COA| 1007882-04-3 structure
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