Methods for preparing glutamic acid derivatives and intermediates thereof
A compound and heteroaryl technology, applied in the field of preparation of glutamic acid derivatives and their intermediates, can solve problems such as difficulty in preventing or limiting homocoupling products, unstable formation of Grignard reagents, difficulty in controlling Grignard steps, etc.
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[0075] Unless otherwise indicated, for compounds of formulas (I) to (XIV) and for all reagents used in their preparation, and throughout this specification, the symbols are defined as follows:
[0076] R 1 is phenyl, heteroaryl, biphenyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl or tricyclic heteroaryl, each of which is optionally modified by one or more R 5 or R 6 replaced, and when R 1 After more than one R 5 or R 6 When substituting, the substituents can be the same or different;
[0077] R 2 is hydrogen, (C 1 -C 6 ) Alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -(CH 2 ) n R 11 , -OH or -O-(C 1 -C 6 )alkyl;
[0078] R 5 is aryl, heteroaryl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O) -(C 1 -C 6 ) alkyl, -C(=O)-aryl, -C(=O)-heteroaryl, -SO 2 -(C 1 -C 6 ) Alkyl, -SO 2 -Aryl, -SO 2 -Heteroaryl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -NHSO 2 -(C 1 -C 6 ) A...
example
[0299] Unless otherwise indicated, the following HPLC conditions, such as those shown below, were used:
[0300] Sample preparation: Final product: 2-3 mg of solid was dissolved in 2 mL of acetonitrile.
[0301] Sample in preparation: Dissolve 1-2 drops of reaction mixture in 2 mL of 50:50 acetonitrile:water (containing 1-2 drops of acetic acid).
[0302] Column: Agilent Eclipse XDB-C8, 5μ, 4.6×150mm
[0303] Temperature = 25°C
[0304] Flow rate: 1.5mL / min
[0305] Mobile phase: solvent A = 95% acetonitrile / 5% H 2 O / 0.05% TFA
[0306] Solvent B = 95% H 2 O / 5% Acetonitrile / 0.05% TFA
[0307] Schedule: Time Solvent A Solvent B
[0308] 0.00 10.0% 90.0%
[0309] 15.00min 100.0% 0.00%
[0310] Stop time = 20.0min
[0311] Post analysis time = 5.0min
[0312] Detector: Signal = 220nm, Bw = 4; Reference = 360nm, Bw = 100
[0313] Peak width>0.1min
[0314] Slit = 4nm
[0315] Injection volume = 5 μl
example 1
[0317] Preparation of 1-(4-fluorophenyl)-2-methyl-1-propanol
[0318] 4-Fluorobenzaldehyde (186.0 g, 1.50 mol) was added dropwise to a solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 molar, 787.8 g, 1.62 mol) maintained at about 0-10°C. After the addition was complete, the reaction mixture was allowed to stir at 0-10°C for about 2 hours.
[0319] The reaction mixture was transferred to a 3-liter, 4-necked round bottom flask (equipped with a mechanical stirrer, temperature probe, and nitrogen inlet) containing aqueous glacial acetic acid (126 ml) (1.06 L) maintained at about 5-15 °C over about 70 minutes. )middle. The flask and transfer line were flushed with THF into a quench vessel. The resulting biphasic mixture was allowed to stir for about 15 minutes at about 5-15°C, and the phases were then separated. The organic phase is then washed with 5% NaCl solution.
[0320] The organic phase was concentrated under reduced pressure. Glacial acetic acid (253 g...
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