The preparation method of 5r-benzyloxyaminopiperidine-2s-formic acid ester
A technology of benzyloxyaminopiperidine and formate, which is applied in the field of preparation of 5R-benzyloxyaminopiperidine-2S-formate, can solve the problem of increasing chemical resolution steps and costs, and inconsistency in product diastereoselectivity. high, reduce ceftazidime resistance and other issues, to achieve the effect of good diastereoselectivity, favorable for industrialization and high safety
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[0038] The invention provides a kind of preparation method of 5R-benzyloxyaminopiperidine-2S-formic acid ester, comprising the following steps:
[0039] Mixing compound A, low boiling point organic acid and reducing agent to carry out reduction reaction;
[0040] Among them, the reducing agent is R 1 R 2 R 3 SiH; R 1 , R 2 with R 3 Each independently selected from: a straight-chain alkyl group having 1 to 20 C atoms, a branched or cyclic alkyl group having 3 to 20 C atoms, an aromatic group having 6 to 20 carbon atoms;
[0041] The structure of compound A is shown in formula (1):
[0042]
[0043] Formula 1);
[0044] The structure of the 5R-benzyloxyaminopiperidine-2S-carboxylate is shown in formula (2):
[0045]
[0046] Formula (2);
[0047] R 4 selected from linear alkyl groups having 1 to 10 C atoms, branched or cyclic alkyl groups having 3 to 10 C atoms, aromatic groups having 6 to 20 carbon atoms, aromatic groups having 5 to 20 carbon atoms atom heteroa...
Embodiment 1
[0067] This embodiment provides a preparation method of 5R-benzyloxyaminopiperidine-2S-ethyl carboxylate, the specific steps are as follows:
[0068] At a temperature of 0 degrees Celsius and under nitrogen protection, to a solution of ethyl 5-benzyloxyiminopiperidine-2S-carboxylate (276.3 mg, 1.0 mmol) in trifluoroacetic acid (1 mL), slowly drop three Ethylsilane (127.9 mg, 1.1 mmol). The reaction was at 0°C and stirring was continued for 3 hours. After the reaction, the reaction system was distilled under reduced pressure to recover trifluoroacetic acid, and the crude product was purified by column chromatography to obtain 253.3 mg of 5R-benzyloxyaminopiperidine-2S-ethyl carboxylate with a yield of 91%. The enantiomer ratio is (5R-benzyloxyaminopiperidine-2S-carboxylate):(5S-benzyloxyaminopiperidine-2S-carboxylate)=80:20.
[0069] The prepared product was characterized, and the characterization results are as follows:
[0070] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.37-7.28 (m...
Embodiment 2
[0072] This embodiment provides a preparation method of 5R-benzyloxyaminopiperidine-2S-ethyl carboxylate, the specific steps are as follows:
[0073] At 0 °C under nitrogen protection, to a solution of ethyl 5-benzyloxyiminopiperidine-2S-carboxylate (276.3 mg, 1.0 mmol) in trifluoroacetic acid (1 mL), slowly add dimethylbenzene dropwise Dimethylsilane (149.9 mg, 1.1 mmol). The reaction was continued to stir for 3 h at 0°C. After the reaction was over, trifluoroacetic acid was recovered by distillation under reduced pressure, and the crude product was purified by column chromatography to obtain 236.5 mg of ethyl 5R-benzyloxyaminopiperidine-2S-formate with a yield of 85%. Diastereoisomers The ratio is (5R-benzyloxyaminopiperidine-2S-carboxylate):(5S-benzyloxyaminopiperidine-2S-carboxylate)=85:15.
[0074] The prepared product was characterized, and the characterization results are as follows:
[0075]1 H NMR (400 MHz, DMSO-d 6 ): δ7.37-7.28 (m, 5H), 4.59 (s, 2H), 4.22-4.15(m...
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