In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles. 28539-02-8, 1-(Hydroxymethyl)benzotriazole, other downstream synthetic routes, hurry up and to see.
Electric Literature of 28539-02-8 ,Some common heterocyclic compound, 28539-02-8, molecular formula is C7H7N3O, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route.
Preparation 5: 4-(5-Cyclopentyl-8-(ethoxycarbonyl)-7,7-difluoro-6,7-dihydro- 5H-imidazo[l,5-d]pyrimido[4,5-b][l,4]diazepin-3-ylamino)-3-methoxybenzoic acid; [0096] lH-Benzotriazole-1 -methanol (51.0 g, 0.342 mol) was weighed into a round bottom flask and solubilized in EtOH (800 mL). Dibenzylamine (67.5 g, 0.342 mol) was added slowly (over 5 min) to the rapidly stirred solution. Formation of a white precipitate was observed shortly after starting addition. The solution was abandoned to stir for 24 h. At this time the reaction is judged complete by NMR (product fragments on LCMS to show only benzotriazole). The majority of the solvent was removed by rotovap and diethyl ether (1 L) was added to the residue with vigorous stirring. This mixture was filtered, the filtrand washed with ether and dried under vacuum to yield N- (dibenzylaminomethyl)benzotriazole as a fluffy white solid (112 g, quat. yield). 1H NMR in CDCl3: (400 MHz) delta ppm 3.80 (s, 4 H) 5.48 (s, 2 H) 7.21 (d, J=8.34 Hz, 1 H) 7.34 – 7.43 (m, 11 H) 7.49 (d, 1 H) 8.09 (d, J=7.83 Hz, 1 H). MS (ES) [M+H] found 329. To a suspension of zinc dust (2.7 g, 41.6 mmol) in dry THF (75 mL), stirred under argon atmosphere, was added chlorotrimethylsilane (2.63 mL, 20.8 mmol) followed, 10 min later, by ethyl dibromo-fluoroacetate (3.92 g, 20.8 mmol). After 10 min a slight exotherm was detected. The reaction was left to activate for 1 hour, whereupon it was cooled in an ice bath and a solution of N-(Dibenzylaminomethyl)benzotriazole (6.83 g, 20.8 mmol) in THF (50 mL) was added drop wise (over 30 minutes) and then the reaction mixture was allowed to warm to room temperature. After 18 h at r.t, NaHCO3 (sat., 50 mL) was added, let stir for 20 minutes, the reaction was filtered on Celite, and the filter pad was washed with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3chi50 mL). The organic layers were combined and washed with IN HCl (70 mL), brine (70 mL), then dried over MgSO4. After evaporation of the solvent, the residue was poured into rapidly stirring ether (100 mL); the solid formed was removed by filtration and discarded. The ether was evaporated from the filtrate to yield a dark yellow syrup. This crude residue was purified on silica gel column chromatographically (0-10% EtOAc :Hexanes) to yield ethyl 3-(dibenzylamino)-2,2-difluoropropanoate as a clear liquid (3.6 g, 50 % yield). 1H NMR in CDCl3: (400 MHz) delta ppm 1.18 (t, J=7.07 Hz, 3 H) 3.14 (t, J=13.26 Hz, 2 H) 3.69 (s, 4 H) 4.14 (q, J=7.16 Hz, 2 H) 7.14 – 7.33 (m, 10 H). MS (ES) [M+H] found 334.[0097] In a round bottom flask, ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.72 g, 5.2 mmol) was solubilized in EtOH (25 mL) and TFA added (0.4 mL, 5.5 mmol). Under an atmosphere of nitrogen Pd(OH)2ZC (170 mg of 20% Pd by wt. wet) was added. The reaction mixture was repeatedly purged with nitrogen and then left under hydrogen overnight. At this point the reaction was deemed complete by LCMS, filtered through a pad of Celite, the pad washed with EtOH and the filtrate concentrated without heating to yield ethyl 3-amino-2,2-difluoropropanoate-TFA salt as a foggy syrup which starts to crystallize upon standing (1.31 g, 94 % yield). 1U NMR in J6-DMSO (400 MHz) delta ppm 1.29 (t, J=7.20 Hz, 3 H) 3.72 (t, J=16.17 Hz, 2 H) 4.34 (q, J=7.24 Hz, 2 H). MS (ES) [M+H] found 154.To a round bottom flask was added ethyl 3-amino-2,2-difluoropropanoate (1.31 g, 4.9 mmol), THF (50 mL), cyclopentanone (0.46 mL, 5.1 mmol), and NaOAc (400 mg, 4.9 mmol). To this mixture was added sodium triacetoxyborohydride (1.6 g, 7.3 mmol) portion wise over 15 minutes. The reaction was left to stir overnight. It was then added slowly to a stirring solution of ice (30 mL), NaHCO3 (sat., 10 mL), and EtOAc (100 mL) cooled in an ice-salt bath. The layers were then separated and the aqueous pH further adjusted to 11 using 25% NaOH while cooling in the bath. The aqueous layer was washed with EtOAc (2 x 50 mL), the organic extracts combined, washed with cold NaHCO3, (sat. 20 mL x 2) brine (20 mL), dried over MgSO4, filtered and concentrated to yield ethyl 3- (cyclopentylamino)-2,2-difluoropropanoate as a clear syrup (960 mg, 89 %). 1H NMR in J6-DMSO (400 MHz) delta ppm 1.25 (t, J=7.07 Hz, 2 H) 1.34 – 1.74 (m, 8 H) 3.00 (q, 1 H) 3.11 (t, J=14.15 Hz, 2 H) 4.27 (q, J=7.07 Hz, 2 H). MS (ES) [M+H] found 222. [0098] Ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate (396 mg, 1.79 mmol) was solubilized in acetone (40 mL, dry). The solution was cooled in an ice salt bath under a nitrogen atmosphere and K2CO3 (495 mg, 3.58 mmol) added. To this, a solution of 2,4- dichloro-5-nitropyrimidine (378 mg, 1.97 mmol) in acetone (10 mL, dry) was added dropwise. Upon completion of addition the reaction mixture abandoned and allowed to slowly warm to room temperature and stir overnight. The mixture was then filtered through paper, the filter pad washed with acetone, and the filtrate concentrated. The concentrate was then solubilized in…
In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles. 28539-02-8, 1-(Hydroxymethyl)benzotriazole, other downstream synthetic routes, hurry up and to see.
Reference:
Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; CAO, Sheldon X.; ICHIKAWA, Takashi; KIRYANOV, Andre, A.; MCBRIDE, Christopher; NATALA, Srinivasa, Reddy; KALDOR, Stephen, W.; STAFFORD, Jeffrey, A.; WO2010/25073; (2010); A1;,
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