2-((1s3ar7ar)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid

Abstract

The invention relates to a preparation method of 2-((1S3aR7aR)-5-tert-butyloxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. The preparation method comprises 11 steps: carrying out esterification on a dicarboxylic acid piperidine compound 1 in thionyl chloride to obtain a diester compound 2; then reducing a pyridine ring by utilizing palladium carbon to obtain a compound 3; then taking the compound 3 to react with Boc acid anhydride to obtain a Boc protected compound 4; hydrolyzing the compound 4 by utilizing lithium hydroxide to obtain a dicarboxylic acid compound 5; carrying out ring closure in acetic anhydride to obtain a compound 6; carrying out reduction and ring opening by utilizing NaBH4 to obtain a mixture of position isomerism compounds 7A and 7B; carrying out the ring closure in the presence of iodomethane and potassium carbonate to generate position isomerism lactone 8A and 8B; step 8, reducing the 8A, obtained by column passing separation, by utilizing DIBAH (Diisobutylaluminum Hydride) to obtain a compound 9; carrying out Wittig reaction to obtain a compound 10; carrying out Michael addition under an alkaline condition to obtain a compound 11; finally, hydrolyzing the compound 11 under the alkaline condition to obtain a final compound.

Description

technical field

[0001] The invention relates to a method for synthesizing compound 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. Background technique

[0002] Compound 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid (CAS: 646518-35-6 ) and related derivatives are widely used in medicinal chemistry and organic synthesis. application. At present, there is no literature report on the synthesis method of 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. Therefore, it is necessary to develop a synthetic method that is easy to obtain raw materials, easy to operate, easy to control the reaction, suitable for overall yield, and suitable for industrial production. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1) with raw materials that are easy to get, easy to operate, easy...

Examples

Embodiment 1

[0013] At zero degrees, SOCl 2 (400 mL) was slowly added dropwise into methanol (2.0 L). After the dropwise addition, the solution was stirred at room temperature for 15 minutes. Compound 1 (200 g, 1.2 mol) was added to the above solution in batches, and then 2, 2-Dimethoxypropane (400 mL). After the dropwise addition, the reaction solution was refluxed overnight. TLC (dichloromethane / methanol volume ratio 10:1) showed the reaction was complete. The reaction solution was concentrated under reduced pressure, ethyl acetate (2.0 L) was added to the residue, and the pH value was adjusted to 8 with dimethylamine. The mixture was washed with water three times, each time with 1.0 L of water, the separated organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the finally obtained residue was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate volume ratio From 10 / 1 to 5 / 1 to 2 / 1) to obtain pure compound 2 as ...

technical field

[0001] The invention relates to a method for synthesizing compound 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. Background technique

[0002] Compound 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid (CAS: 646518-35-6 ) and related derivatives are widely used in medicinal chemistry and organic synthesis. application. At present, there is no literature report on the synthesis method of 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1)acetic acid. Therefore, it is necessary to develop a synthetic method that is easy to obtain raw materials, easy to operate, easy to control the reaction, suitable for overall yield, and suitable for industrial production. Contents of the invention

[0003] The purpose of the present invention is to develop a kind of 2-((1S3aR7aR)-5-tert-butoxycarbonyltetrahydrofuro[3,4]piperidine-1) with raw materials that are easy to get, easy to operate, easy...

Examples

Embodiment 1

[0013] At zero degrees, SOCl 2 (400 mL) was slowly added dropwise into methanol (2.0 L). After the dropwise addition, the solution was stirred at room temperature for 15 minutes. Compound 1 (200 g, 1.2 mol) was added to the above solution in batches, and then 2, 2-Dimethoxypropane (400 mL). After the dropwise addition, the reaction solution was refluxed overnight. TLC (dichloromethane / methanol volume ratio 10:1) showed the reaction was complete. The reaction solution was concentrated under reduced pressure, ethyl acetate (2.0 L) was added to the residue, and the pH value was adjusted to 8 with dimethylamine. The mixture was washed with water three times, each time with 1.0 L of water, the separated organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the finally obtained residue was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate volume ratio From 10 / 1 to 5 / 1 to 2 / 1) to obtain pure compound 2 as ...

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