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Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative

A compound, dicarbonic acid technology, applied in the direction of organic chemistry, can solve the problems of long steps, low yield, incapable of large-scale production, etc., and achieve the effect of mild reaction conditions, simple operation and easy operation

Active Publication Date: 2012-10-17
SHANDONG DIAI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly solve the technical problems of the existing compound I such as long steps, low yield, and inability to produce on a large scale

Method used

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  • Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative
  • Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative
  • Method for preparing 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Preparation of Intermediate Compound XIII

[0019] Synthesis of Compound XII

[0020]

[0021] Add compound XI (740.0g, 4.88mol, 1.0eq.) in 4L water, add 4L ethyl acetate, 2L H 2 O, stirring under ice-water bath, adding NaHCO in batches 3 (820.6g, 9.77mol, 2.0eq.), then add Boc 2 O (1064.8g, 4.88mol, 1.0eq.), stirred at room temperature for 8h, separated after the reaction, extracted once with EA, combined the organic phases, washed with brine, dried over anhydrous sodium sulfate, concentrated to obtain compound XII colorless oil 793.0 g, yield: 75.5%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.10-4.12 (d, J=7.6 Hz, 4H), 3.77 (s, 3H), 3.33-3.40 (m, 1H), 1.46 (s, 9H). Synthesis of Compound XIII

[0022]

[0023] Put compound XII (80.0g, 0.37mol, 1.0eq.), N-fluorobisbenzenesulfonamide (NFSI) (175.8g, 0.557mol, 1.5eq.) into a 2L four-neck flask, add THF500mL, after dissolution, Cool down to about -78°C, add LiHMDS (1M, 670mL, 1.8eq.) dropwise, and keep the reaction fo...

Embodiment 2

[0025] Synthesis of Compound I

[0026]

[0027] Put compound XIII (50.0g, 0.214mol, 1.0eq.) into a 1L four-neck flask, add 2M NaOH 214mL and methanol 100mL, react at 20°C for 4 hours, adjust the pH to acidic with 2N HCl, concentrate, and dichloromethane (500mL×3) extraction, the combined organic phases were dried over anhydrous sodium sulfate, and spin-dried to obtain 46.4g of compound I as a white solid, with a yield of 99.0% and a purity of 98%. 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.54 (b, 1H), 4.41-4.49 (q, 2H), 4.20-4.28 (q, 2H), 1.48 (s, 9H).

Embodiment 3

[0029] Preparation of Intermediate Compound XIII

[0030] Synthesis of Compound XII

[0031]

[0032] Add compound XI (740.0g, 4.88mol, 1.0eq.) in 4L water, add 4L THF, 2L H 2 O, stirring under ice-water bath, adding Na in batches 2 CO 3 (1553g, 14.655mol, 3.0eq.), then add Boc 2 O (1597.2g, 7.32mol, 1.5eq.), stirred at room temperature for 10h, separated after the reaction, extracted once with EA, combined the organic phases, washed with brine, dried over anhydrous sodium sulfate, concentrated to obtain compound XII colorless oil 740.4 g, yield: 70.5%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 4.10-4.12 (d, J=7.6 Hz, 4H), 3.77 (s, 3H), 3.33-3.40 (m, 1H), 1.46 (s, 9H). Synthesis of Compound XIII

[0033]

[0034] Put compound XII (80.0g, 0.37mol, 1.0eq.), N-fluorobisbenzenesulfonamide (NFSI) (175.8g, 0.557mol, 1.5eq.) into a 2L four-neck flask, add THF500mL, after dissolution, Cool down to about -78°C, add NaHMDS (1M, 745mL, 2.0eq.) dropwise, and keep the reaction for 4h ...

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Abstract

The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative (I), and a preparation method of an intermediate of the 1-carboxylic acid tert-butyl ester-3-fluoro-azetidine derivative. The method comprises the steps of using a compound IV as raw material, performing reaction of the compound IV with di-tert-butyl dicarbonate under an alkaline condition; then under the effect of alkali, performing fluoronation with N-fluorobenzenesulfonimide to obtain the intermediate. The intermediate is hydrolyzed under the alkaline condition to obtain the derivative (I). The preparation method provided by the invention is milder in reaction condition, simple in operation and higher in yield of each step, and the total yield of the intermediate reaches 74%. The total yield of the compound (I) prepared by the intermediate is 99%.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 1-tert-butyl carboxylate-3-fluoro-azetidine derivatives. Background technique [0002] Fluorine-substituted azetidines are widely used in the field of drug research and development due to their unique physical and chemical properties and in vivo metabolism characteristics, such as dipeptidyl peptidase IV inhibitors, cannabinoid receptor modulators and other structures that contain fluorine substitution Fragments of Azetidine. The synthesis of these active compounds is mainly connected with 3-fluoro-substituted azetidines through different substituents, therefore, 1-tert-butyl carboxylate-3-fluoro-azetidine derivatives will be a kind of Pharmaceutical intermediates with great market potential. [0003] For the preparation of 1-tert-butyl carboxylate-3-fluoro-azetidine derivatives (I), the related compound methods reported in the li...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04
Inventor 周西朋祝兴勇郑兴旺杨民民吴希罕
Owner SHANDONG DIAI BIOTECH CO LTD
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