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Preparation method for medical intermediate N-Boc-cis-4-hydroxy-L-proline

A technology of n-boc- and intermediates, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of long route, difficult purification, high production cost, etc., and achieve good reaction selectivity, low preparation cost, and high ee value Effect

Inactive Publication Date: 2017-03-29
SHANGHAI QINGSONG PHARMA
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  • Abstract
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  • Claims
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Problems solved by technology

Disadvantages: This method is difficult to purify, and generally needs to be purified by column chromatography, the cost is high, and it is not suitable for industrialization
Disadvantages: This method has a long route and high production costs

Method used

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  • Preparation method for medical intermediate N-Boc-cis-4-hydroxy-L-proline
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  • Preparation method for medical intermediate N-Boc-cis-4-hydroxy-L-proline

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Embodiment Construction

[0027] The following description serves to disclose the present invention to enable those skilled in the art to carry out the present invention. The preferred embodiments described below are only examples, and those skilled in the art can devise other obvious variations.

[0028] The synthesis method comprises using L-hydroxyproline as a raw material, protecting it with Boc, then oxidizing the hydroxyl group to obtain N-Boc-4-oxo-L-proline, finally dissolving it in a solvent, and reducing it at a certain temperature reagent reduction and purification to obtain the product. This process is shown in Equation 7:

[0029]

[0030] Specific steps are as follows:

[0031] Step 1: Preparation of intermediate 2 (tras-F-1)

[0032] L-Hydroxyproline (65.6 g, 0.5 mol, 1.0 e.q.) was added to NaOH solution (1.0 M, 525 mL, 8.0X) and dioxane (525 mL, 8.0X). Cool down to 0-5C, slowly drop Boc2O (120g, 0.55mol, 1.1e.q.) into it, keep warm at 0-5C and stir after dropping, monitor the rea...

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Abstract

The invention provides a preparation method for a medical intermediate N-Boc-cis-4-hydroxy-L-proline. The preparation method comprises the following steps: with L-hydroxyproline as a raw material, subjecting the raw material to Boc protection; then carrying out hydroxyl radical oxidation so as to obtain N-Boc-4-oxo-L-proline; dissolving N-Boc-4-oxo-L-proline in a solvent and successively carrying out reduction with a reducing agent and purification at a certain temperature so as to obtain the product N-Boc-cis-4-hydroxy-L-proline. The method has the advantages of good reaction selectivity, high product ee value and low preparation cost.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate N-Boc-cis-4-hydroxyl-L-proline. Background technique [0002] N-Boc-cis-4-hydroxy-L-proline is an important pharmaceutical intermediate, many marketed drugs and active molecular structures contain this fragment, for example: FK888①, Microcolin A and B②, BI201335③ Ciluprevir (BILN-2061)③, Danoprevir (ITMN-191, Phase II)③, Simeprevir (simeprevir, already on the market in the United States and Japan)③, Vaniprevir (Phase III)③, VHL-1④, VHL-2④, 4S, 36R, 38R-Microcolin A⑤ etc. [0003] [0004] [0005] [0006] At present, the intermediate mainly has the following three preparation methods: [0007] Method 1: Bioorganic & Medicinal Chemistry (2006), 14, (7), 2253-2265. Bioorganic & Medicinal Chemistry (2009), 17(1), 251-259. With N-Boc-4-oxo-L proline as raw material, methanol and water as solvent, sodium borohydride reduction (Formula 3), the disadvantage of the re...

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Application Information

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IPC IPC(8): C07D207/16
CPCC07B2200/07C07D207/16
Inventor 张健陈晓娜高军峰张树斌谭宙宏段星星
Owner SHANGHAI QINGSONG PHARMA
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