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(4S)-N-Boc-4-methoxymethyl-L-proline synthesis method

A technology of -n-boc-4--, -n-boc-4-, applied in the field of medicine, can solve the problems of high raw material cost and production cost, long reaction line, safety problems, etc., and achieve the reduction of raw material cost and saving Economic cost and the effect of reducing environmental pressure

Inactive Publication Date: 2016-07-27
PORTON FINE CHEM
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Problems solved by technology

The synthesis method reported in the literature has L-hydroxyproline as the raw material to obtain the product through multi-step reaction. This method has the disadvantages of long reaction line, high raw material cost and high production cost; Iodomethane has safety and environmental issues
In the document US20130115194, it is disclosed that (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid methyl ester reacts with 1-diazo-2-oxopropyl)phosphonic acid dimethyl ester to obtain ( The method of 2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid has certain potential safety hazards due to the use of diazo compounds

Method used

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preparation example Construction

[0029] A kind of synthetic method of (4S)-N-Boc-4--methoxymethyl-L-proline of the present embodiment comprises the following steps:

[0030] a. Using L-hydroxyproline as a starting material, the step of obtaining N-Boc-L-hydroxyproline through Boc protection;

[0031] b. Dissolve N-Boc-L-hydroxyproline in a solvent and oxidize it with TEMPO (tetramethylpiperidine nitrogen oxide) to obtain (2S)-N-Boc-4-oxopyrrolidine-2-carboxy acid step;

[0032] c. Dissolve (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid and methoxymethyltriphenylphosphonium chloride in a solvent for wittig reaction to prepare (2S)-N-Boc - the step of 4-methoxymethylenepyrrolidine-2-carboxylic acid;

[0033] d. Dissolve (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid and tert-butylamine in water to prepare (4S)-N-Boc-4--methoxymethyl base-L-proline; its synthetic route is:

[0034]

[0035] In this example, in step a, dissolve L-hydroxyproline in water to adjust the pH to 8-9, then heat to 20-2...

Embodiment 1

[0046]In a 2L reaction flask, add 131.13g (1mol) L-hydroxyproline and 500mL water, stir to dissolve it; then add about 240g saturated potassium carbonate solution to adjust the pH to 8-9. The reaction solution was heated to 23°C, and 218.25g (1mol) (Boc) was added dropwise 2 O in 500 mL THF. After the dropwise addition was completed, the reaction was incubated at 23° C. for 18 hours. After the reaction is completed, distill under reduced pressure to remove THF in the system, extract the water phase with 2×250mL methyl tert-butyl ether, then cool to 3°C, adjust to PH=2~3 with 4N HCl, add solid NaCl, and use 1.1L ethyl acetate extracted 3 times. The organic phases were combined, washed with 300 mL of saturated brine, separated, the organic phase was dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to obtain an oil, which became a white solid after standing, weighing 230.0 g, yield 99%.

Embodiment 2

[0048] In a 2L reaction flask, add 131.24g (1mol) L-hydroxyproline and 500mL water, stir to dissolve it; then add about 240g saturated potassium carbonate solution to adjust the pH to 8-9. The reaction solution was heated to 20°C, and 218.18g (1mol) (Boc) was added dropwise 2 O solution in 500mL THF, after the dropwise addition, was incubated at 20°C for 16h. After the reaction was completed, the THF in the system was distilled off by distillation under reduced pressure. The aqueous phase was extracted with 2×250mL methyl tert-butyl ether, then cooled to 0°C, adjusted to pH=2~3 with 4N HCl, added solid NaCl, and extracted three times with 1.1L ethyl acetate. The organic phases were combined, washed with 300 mL of saturated brine, separated, the organic phase was dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was concentrated to obtain an oil, which became a white solid after standing, weighing 223.1 g, yield 96%.

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Abstract

The invention discloses a (4S)-N-Boc-4-methoxymethyl-L-proline synthesis method. The method comprises that 1, L-hydroxyproline as an initial raw material is subjected to Boc protection so that N-Boc-L-hydroxyproline is produced, 2, the N-Boc-L-hydroxyproline is dissolved in a solvent, the solution and 2, 2, 6, 6-tetramethyl-1-piperidinyloxy (TEMPO) undergo an oxidation reaction to produce (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid, 3, the (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid and (methoxymethyl)triphenylphosphonium chloride are dissolved in a solvent and undergo a wittig reaction to produce (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid, and 4, the (2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid and tert-butylamine are dissolved in water and undergo a hydrogenation reaction to produce (4S)-N-Boc-4-methoxymethyl-L-proline. The method shortens reaction processes, is free of severe-toxicity cyanides, improves safety, reduces environmental protection pressure, improves atom economy, reduces waste discharge and greatly reduces a raw material cost.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing (4S)-N-Boc-4-methoxymethyl-L-proline. Background technique [0002] (4S)-N-Boc-4--Methoxymethyl-L-proline is an important intermediate of the anti-hepatitis C drug being researched by Gilead in the United States, and the drug is currently in Phase 2 of clinical trials. The synthesis method reported in the literature has L-hydroxyproline as the raw material to obtain the product through multi-step reaction. This method has the disadvantages of long reaction line, high raw material cost and high production cost; However, methyl iodide has safety and environmental issues. In the document US20130115194, it is disclosed that (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid methyl ester reacts with 1-diazo-2-oxopropyl)phosphonic acid dimethyl ester to obtain ( 2S)-N-Boc-4-methoxymethylenepyrrolidine-2-carboxylic acid method, which has certain potential safety ...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 林文清刘小波朱剑平郑宏杰
Owner PORTON FINE CHEM
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