6-(tert-butoxycarbonyl) octahydro-furo [2,3-c] pyridine-4-carboxylic acid synthetic method

A technology of tert-butoxycarbonyl and octahydrofuran, which is applied in the field of synthesis of 6-(tert-butoxycarbonyl) octahydrofuran [2,3-c] pyridine-4-carboxylic acid, can solve the problem that there is no suitable industrial synthesis method and other problems, to achieve the effect of convenient large-scale production, short synthetic route and simplified operation process

A technology of tert-butoxycarbonyl and octahydrofuran, which is applied in the field of synthesis of 6-(tert-butoxycarbonyl) octahydrofuran [2,3-c] pyridine-4-carboxylic acid, can solve the problem that there is no suitable industrial synthesis method and other problems, to achieve the effect of convenient large-scale production, short synthetic route and simplified operation process

CN105669686AActive Publication Date: 2016-06-15SHANGHAI SYNTHEALL PHARM CO LTD
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  • 6-(tert-butoxycarbonyl) octahydro-furo [2,3-c] pyridine-4-carboxylic acid synthetic method
  • 6-(tert-butoxycarbonyl) octahydro-furo [2,3-c] pyridine-4-carboxylic acid synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] Example 1: Compound 1 (4g, 0.03mol) and furfural (2.8g, 0.03mol) were dissolved in ethanol (30mL), stirred at 30°C for 3hr, and then sodium cyanoborohydride (3.6g, 0.05 mol)), after the addition, the reaction was stirred at room temperature for 2 days. TLC (dichloromethane: methanol volume ratio=20 / 1, R f =0.1) shows that the reaction is complete, the reaction mixture is concentrated to remove the ethanol solvent, then add water (30mL), extract with ethyl acetate (30mLx3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate, the crude product is purified by column chromatography , the eluent ratio was (petroleum ether: ethyl acetate = 20:1~10:1~2:1), and after removing the solvent, compound 2 (1.8g) was obtained as a yellow oil with a yield of 23%.

[0011] Compound 2 (7.6g, 0.042mol) and triethylamine (8.48g, 0.084mol) were dissolved in dichloromethane (100mL), and ethyl chloroformate (5.03g, 0.046mol) was added dropwise at 0...

Embodiment 2

[0021] Example 2: Compound 1 (40g, 0.286mol) and furfural (28.9g, 3.01mol) were dissolved in ethanol (0.7L), 30 o C was stirred for 3 hr, then sodium cyanoborohydride (36.1 g, 0.573 mol) was added in batches, and after the addition was complete, the reaction was stirred at room temperature for 2 days. TLC (dichloromethane: methanol volume ratio=20 / 1, R f=0.1) shows that the reaction is complete, the reaction mixture is concentrated to remove the ethanol solvent, then added water (500mL), extracted with ethyl acetate (300mLx3), the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue is purified by column chromatography For purification, the eluent ratio was (petroleum ether: ethyl acetate = 20:1~10:1~2:1), and after removal of the solvent, a yellow oily compound 2 (19 g) was obtained with a yield of 22%.

[0022] Compound 2 (76.9g, 0.42mol) and triethylamine (84.8g, 0.84mol) were dissolved in dichloromethane (1L),...

Embodiment 3

[0032] Example 3: Compound 1 (400g, 2.86mol) and furfural (289g, 3.01mol) were dissolved in ethanol (7L), 30 o C was stirred for 3 hr, then sodium cyanoborohydride (361 g, 5.73 mol) was added in batches, and after the addition was complete, the reaction was stirred at room temperature for 2 days. TLC (dichloromethane: methanol volume ratio=20 / 1, R f =0.1) shows that the reaction is complete, the reaction mixture is concentrated to remove the ethanol solvent, then add water (1L), extract with ethyl acetate (500mLx3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate, the residue is analyzed by column chromatography For purification, the eluent ratio was (petroleum ether: ethyl acetate = 20:1~10:1~2:1), and after removal of the solvent, a yellow oily compound 2 (192 g) was obtained with a yield of 23%.

[0033] Compound 2 (769g, 4.2mol) and triethylamine (848.8g, 8.4mol) were dissolved in dichloromethane (10L), and ethyl chloroformat...

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Abstract

The present invention relates to a 6-(tert-butoxycarbonyl) octahydro-furo [2,3-c] pyridine-4-carboxylic acid synthetic method and mainly solves a technical problem that currently no suitable industrial synthetic method exists. The synthetic method comprises ten steps as follows: firstly a compound 1 is subjected to a reductive amination with a furfural to obtain a compound 2; then the compound 2 is subjected to alkylation to produce a compound 3; the compound 3 is hydrolyzed to obtain a hydrolyzate 4; the hydrolyzate 4 is subjected to an intramolecular Friedel-Crafts reaction to obtain a compound 5; the compound 5 is subjected to a hydrogenation reduction to obtain a compound 6; a trifluoromethanesulfonyl is bond to a ketone group of the compound 6 to obtain a compound 7; a carbonyl group inserted to the compound 7 to obtain a compound 8; the compound 8 is subjected to a double bond hydrogenation reduction to obtain a compound 9; the compound 9 is subjected to ethoxycarbonyl removing by a strong acid; and the ethoxycarbonyl removed compound 9 is reacted with a Boc anhydride to obtain a final compound 11. The reaction formulas are described as follows.

Description

Technical field [0001] The compounds of the present invention 6- (beadoxyl) alcoholic 八 呋 [2,3-C] pyridine-4-carboxylic acid synthesis method. Background technique [0002] Compounds 6- (Schidin oxygen) octa hydrogen sarf [2,3-c] pyridine-4-carboxylic acid (CAS: 1314392-08-9) and related derivatives are widely used in pharmaceutical chemistry and organic synthesis,The market sales are better.At present, the synthesis of the synthesis of the synthesis of the eight-hydrogen bearing [2,3-C] pyridine-4-carboxylic acid is more difficult.Therefore, it is necessary to develop a raw material, convenient operation, easy to control, and the overall income is suitable. It is suitable for industrialized production. Invention content [0003] The purpose of the present invention is to develop a 6- (2,3-c] pyridine-4-carboxylic acid with high income with easy to obtain raw materials, convenient operations, easy reaction, and high revenue.resolve resolution.It mainly solves technical problems ...

Claims

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Application Information

Patent Timeline
15 Jun 2016
Publication
CN105669686A
IPC
C07D491/048
Inventors
赵东; 张金宝