Pyrazolo(1,5-alpha)pyrimidinyl derivatives useful as corticotropin-releasing factor (crf) receptor antagonists
A C1-C6, alkyl technology, applied in the field of pyrazolo[1,5-α]pyrimidinyl derivatives as corticotropin releasing factor (CRF) receptor antagonists, can solve the lack of stable oral Activity, weakening of CRF pharmacological response, etc.
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0301] Reagent [5-(7-chloro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-4-methyl-pyridin-2-yl]-dimethyl- Synthesis of Amine
[0302]
[0303] Step 1A:
[0304] Within 2 hours at 0℃, add 2-amino-4-methylpyridine (33g), NaBH 3 Acetic acid (60 ml) was added dropwise to a mixture of CN (57 g) and formaldehyde (37% aqueous solution, 240 mL) in acetonitrile (1 L) and water (200 mL). The resulting solution was stirred at room temperature for 7 days and then concentrated in vacuo. The residue was basified to pH 10 with solid NaOH, and then extracted with hexane (3×700 mL). The combined extracts were washed with 1 N NaOH aqueous solution and brine, and washed with Na 2 SO 4 Drying, followed by evaporation in vacuum, gave 2-dimethylamino-4-methylpyridine (Compound 1a, 36 g, 88%) as a colorless oil. 1 H NMR(CDCl 3 ): 2.26 (s, 3H), 3.07 (s, 6H), 6.33 (s, 1H), 6.40 (d, 1H), 8.02 (d, 1H); MS (CI) m / e137 (MH + ).
[0305] Step 1B:
[0306] At 0℃, in 0.5 hours, to compound 1a (32g), Na 2 CO 3...
Embodiment 2
[0320] Synthesis of Reagent (2,4-Dimethoxy-Phenyl)-Acetonitrile
[0321]
[0322] Step 2:
[0323] At -30°C (dry ice / acetone bath), add a solution of TosMIC (58.8g) in DME (150mL) dropwise to the suspension of t-BuOK (47.3g) in DME (150mL), keeping the temperature of the mixture Below -30°C. The solution was stirred and cooled to -60°C within 10 minutes, and then a solution of 2,4-dimethoxybenzaldehyde (50gl) in DME (150mL) was added dropwise, keeping the temperature of the reaction mixture below -50 ℃. The reaction mixture was stirred at -50 to -60°C for 1 hour, and then methanol (200 mL) was added. The mixture was heated to reflux for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water with the addition of acetic acid (40 mL). The aqueous layer was extracted with another portion of ethyl acetate, and then the combined ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated. The r...
Embodiment 3
[0325] Synthesis of reagent 2-chloro-4-methoxy-benzaldehyde and (2-chloro-4-methoxy-phenyl)-acetonitrile
[0326]
[0327] Step 3A:
[0328] 2-chloro-4-hydroxybenzaldehyde (9.56g) and K 2 CO 3 (25.3 g) was stirred with DMF (30 mL) at room temperature for 30 min. Iodomethane (4.0 mL) was added, the reactor was sealed, and the mixture was stirred at room temperature for 16 hours. 300 mL of 2:1 hexane / ethyl acetate was added, and the mixture was washed three times with water and then once with brine. The organic layer was dried over sodium sulfate, filtered, and then evaporated to a volume of about 50 mL. The formed precipitate was filtered and washed with hexane to obtain compound 3a (6.0 g) as a brown solid.
[0329] Step 3B:
[0330] According to the method of step 2, using t-BuOK and TosMIC in DME, acetonitrile compound 3b was prepared.
PUM
| Property | Measurement | Unit |
|---|---|---|
| Wavelength | aaaaa | aaaaa |
Abstract
Description
Claims
Application Information
Login to View More