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Stage #1: With aluminum (III) chloride In chlorobenzene at 20 - 30℃; for 0.166667 h; Stage #2: With boron trichloride In chlorobenzene at 0 - 100℃; Stage #3: With water In isopropyl alcohol; toluene at 50℃;
Step 3; Bromoanisidine.HCl (5.73g, 24.0 mmol), Aluminumtrichloride (3.52g) and chlorobenzene (15.0 mL) are charged into an oven dried 100 mL three necked flask at rt (temperature rise to 300C). The resulting mixture is then stirred for 10 min then cooled to 0-50C followed by slow addition of acetonitrile (1.89 mL, 36.0 mmol) followed by addition of BCl3 (2.82g), transferred as gas (or liquid) into the reaction mixture, keeping the temperature below 5 0C. The resulting mixture is then stirred at rt for 20 min then heated to 85-1000C for 16h. HPLC indicate completion of the reaction (SM<0.5percent at 220nm). The mixture is cooled down to 500C then Toluene (15mL) was added followed by slow addition of IPA (11.ImL) then slow addition of water (32mL) at 500C. The resulting mixture stirred for additional 2h at this temperature then 3g Celite was added and the stirred mixture cooled to rt. Filtration then wash of the organic fraction with water lxl5mL, 2xl5m: 5percentNaHCO3, lxl5mL water then concentration under reduced pressure provided 3.92-4.4g of the desired product in 68- 72percent isolated yield. 1H NMR (400 MHz, CDCl3)δ: 7.72 (d, / = 9.0 Hz, IH), 7.1 (br s, 2H), 6.28 (d, / = 9.1 Hz, IH), 3.94 (s, 3H), 2.55 (s, 3H).
thiazole-2-carboxylic acid chloride hydrochloride[ No CAS ]
[ 923289-31-0 ]
Yield
Reaction Conditions
Operation in experiment
60%
Intermediate 38 (11.2 g, 45.9 mmol) was added under nitrogen to a suspension of thiazole-2-carboxylic chloride .HCl (1.5 eq, 68.8 mmol) in dry dioxane (500 mL). After 12 h at room temperature, the reaction mixture was concentrated under reduced pressure. Then, ether (200 mL) was added and the resulting mixture was cooled down to 0 C. The precipitate was filtered off and washed with ether to give a solid fraction A. The filtrate was concentrated under reduced pressure. The residue was partitioned between AcOEt and IN NaHCO3, dried (Na2SO4), and evaporated. Purification by column chromatography (heptane/AcOEt, 1:1) provided 9.8 g (60%) of the target product 39 as a yellow powder: m/z = 355, 357.
Step 14: Preparation of Lambdaf-(6-acetyl-2-bromo-3-methoxyphenyl)-4- isopropylthiazole-2-carboxamide 75h. Compound 75h was synthesized from compound 73h, <n="122"/>following procedure described in WO 2007/014919.
2-bromo-3-methoxyphenylamine hydrochloride[ No CAS ]
[ 75-05-8 ]
[ 923289-30-9 ]
Yield
Reaction Conditions
Operation in experiment
72%
Step 3; Bromoanisidine.HCl (5.73g, 24.0 mmol), Aluminumtrichloride (3.52g) and chlorobenzene (15.0 mL) are charged into an oven dried 100 mL three necked flask at rt (temperature rise to 300C). The resulting mixture is then stirred for 10 min then cooled to 0-50C followed by slow addition of acetonitrile (1.89 mL, 36.0 mmol) followed by addition of BCl3 (2.82g), transferred as gas (or liquid) into the reaction mixture, keeping the temperature below 5 0C. The resulting mixture is then stirred at rt for 20 min then heated to 85-1000C for 16h. HPLC indicate completion of the reaction (SM<0.5% at 220nm). The mixture is cooled down to 500C then Toluene (15mL) was added followed by slow addition of IPA (11.ImL) then slow addition of water (32mL) at 500C. The resulting mixture stirred for additional 2h at this temperature then 3g Celite was added and the stirred mixture cooled to rt. Filtration then wash of the organic fraction with water lxl5mL, 2xl5m: 5%NaHCO3, lxl5mL water then concentration under reduced pressure provided 3.92-4.4g of the desired product in 68- 72% isolated yield. 1H NMR (400 MHz, CDCl3)delta: 7.72 (d, / = 9.0 Hz, IH), 7.1 (br s, 2H), 6.28 (d, / = 9.1 Hz, IH), 3.94 (s, 3H), 2.55 (s, 3H).
Step 4; Oxalyl chloride (8.15 mL) is added dropwise to the cold mixture (10+/-5 0C) of Thiazole acid 8 (20.18 g) is dissolved in THF (300 mL) and DMF (300 muL) over a period of ~5 min keeping the internal temperature at 10+/-5C. The reaction mixture becomes yellow and homogenous. The cooling bath is removed and the mixture is allowed to reach ambient temperature over a period of -30 min. Gas evolution is observed. The mixture is stirred at ambient temperature for 30 min to 1 hour. A solution of aniline 7 (19.8 g), DMAP (140 mg) and THF (35 mL) was added at 10+/-5C. Et3N (13.2 mL) was added in portions at 10+50C over a period of 10 min. The ice bath was removed and mixture was heated to 65+/-2C and stirred overnight (18 h). The mixture was allowed to reach ambient temperature, diluted with EtOAc (150 mL) and washed with water (150 mL). NaHCO3 (5%, 225 mL) was added to the organic portion and the mixture was stirred at ambient temperature for 30 min. The organic portion was concentrated under reduced pressure at approx. 400C. EtOAc (150 mL) was added to the resulting material and the residual water was removed and the mixture was concentrated under reduced pressure at approx. 40 0C (to azeotrope water). EtOAc (94 mL) was added and the resulting slurry was stirred for 2-6 h and filtered. The solid was washed with EtOAc (30 mL) followed by heptane (30 mL) and air dried for 1 h to give the desired product in 70% yield.1H NMR (400 MHz, CDCl3) delta: 1.32 (d, 6H, / = 7.8 Hz), 2.58 (s, 3H), 2.65-2.72 (m, IH), 3.98 (s, 3H), 6.83 (d, IH, / = 8.7 Hz), 7.70 (d, IH, / = 8.7 Hz), 7.86 (s, IH), 8.98 (bs, IH), 10.13 (bs, IH).
I. Charge the thiazole compound III and NMP to a reactor. 2. Charge thionyl chloride after 15 min., keeping the temperature below 25 C.3. Stir batch at 25 C for 0.5h. Check HPLC with PrNH2 to confirm formation of acid chloride is complete (2 drops sample is added to 1 ml MeCN + 0.1 ml PrNH2, Rt = 5.05 min for propyl amide, Rt = 4.16 min for remaining acid, target <; 1 %).4. Charge solution of the aniline compound II in MeTHF at 25 C and stir for 12h at 30 C until HPLC shows <; 2% of the aniline compound.5. Charge 15% NaOH solution slowly keeping inside temperature below 22 C. Quench is exothermic. Set the jacket temperature at 0 C. The pH of the aqueous layer is measured to about 7.6. Charge MeTHF and then add water and stir for 5 min and then allow the layers to separate at 400C.7. Wash with 5wt% NaHCO3 and brine and separate the layers at 22 C.8. Distill MeTHF and switch solvent to THF to adjust the final volume to about 310 ml.9. Charge t-BuOH and heat the contents to internal temperature 65 C.10. Charge 50 wt% KOH solution at 65 C and stir for 12-14 h until HPLC shows Compound IV is <; 1 %.I 1. Charge benzenesulfonyl chloride (TsCl) at 10 C over minimum of 1 h and then stir at 22C for 0.5h.12. Charge suspension of benzenesulphinic acid Na salt in water at 22 C followed by 2MHCl and stir at 54-56 C for 12-14h until HPLC shows tosylate is <; 1%. 13. Cool to 22 C and charge 5wt% NaHCO3 and brine and separate the layers.14. Distill THF and switch solvent to DMF and then charge water at 50 C over 30 min and slowly cool the batch to 22 C over 2h.15. Charge IM NaOH and stir for 30 min at 22 C.16. Filter the slurry, rinse with 1.5:1 DMF/water and dry under vacuum at 50C for 12-15 h to afford 32.4 g of solid purple solid of compound I (as mono solvate of DMF) (70% isolated yield).
1. Add Compound III. Add MeCN. Add DMF. Cool the batch to 100C.2. Add oxalyl chloride after 15 min., keeping temperature at 10-150C and gas bubbling under control. Addition time could be longer in larger scale if it is necessary for control of bubbling. Stir batch at 27C for 5h. A clear solution is obtained. Check HPLC with PrNH2 to confirm formation of acid chloride is complete (2 drops sample is added to 1 ml MeCN + 0.1 ml PrNH2, Rt = 4.3 min for propyl amide, Rt = 2.6 min for remaining acid, target <; X0Io).3. Add solid Compound II at 0-50C, stir for Ih at 100C. 4. Add Et3N at 10-130C in 40-60 min., stir at 13C for 6 h and 23C for overnight (11 h). Check HPLC to make sure Compound II (Rt =7.9 min) is <; 1% area. It is recommended to apply agitation at fast speed several times in the middle of this period for good mixing effect.5. Cool to 100C. 6. Add 20 1 water, keeping inside temperature below 2 C. Exotherm is very minor.7. Add about 4.0 1 Et3N, keeping inside temperature at 20-250C. Note mild exotherm, expect temperature rising about 5C. Stir slurry at 22C for Ih. Check pH is 7-8.8. Filter slurry, and rinse with 18 1 acetonitrile-water (1:2).9. Compound IV Yield: 75%. 4.56 Kg.
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