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Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine

A technology of alkoxycarbonyl and alkylsiloxy, which is applied in the field of chemistry, can solve the problem of unsatisfactory selectivity of synthetic routes, and achieve the effects of high yield, low synthesis cost, and simple operation and separation

Inactive Publication Date: 2007-11-07
NORTHWEST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, the selectivity of the two synthetic routes of this research group is not ideal

Method used

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  • Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine
  • Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine
  • Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] 1: Compound 2——Synthesis of (S)-2-amino-5-(benzyloxy)carboxy-pentanoic acid

[0054] Under nitrogen protection, compound 1——L-glutamic acid (33.8mmol) was dissolved in concentrated sulfuric acid (150mL), benzyl alcohol (33.8mmol) was added, and the reaction was continued at 0-100°C for 2-10 hours. It can be obtained after extraction, drying, concentration and silica gel column chromatography. The reaction system was diluted with water, extracted three times with ethyl acetate, the organic layer was washed three times with saturated brine, anhydrous Na 2 SO 4 It was dried and concentrated to obtain compound 2 (yield 50.0%).

[0055] 2: Compound 3——Synthesis of (S)-2-hydroxy-5-(benzyloxy)carboxy-pentanoic acid

[0056] Compound 2 (20.7mmol) was dissolved in 150mL of anhydrous acetic acid, sodium nitrite (24.8mmol) was added, and the reaction was continued at 0°C to rt. for 2 to 10 hours. After concentration, it was diluted with water and extracted three times with ethy...

Embodiment 2

[0080] The synthesis of compounds 2-4 in steps 1-3 is the same as in Example 1.

[0081] Step 4, Compound 5——Synthesis of (S)-2-tert-butyldiphenylsilyloxy-5-(benzyloxy)carboxy-valeric acid methyl ester

[0082] Compound 4 (3.76 mmol) was dissolved in DMF (50 mL), tert-butyldiphenylchlorosilane (5.64 mmol) was added at rt., and stirring was continued for 5-20 hours. Diluted with water, separated, extracted with ethyl acetate, washed the organic phase three times with saturated sodium carbonate, washed with Na 2 SO 4 After drying and concentration, the crude product was purified by silica gel column chromatography to obtain compound 5 (yield 88.3%).

[0083] The synthesis of compounds 6-7 in steps 5-6 is the same as in Example 1.

[0084] Step 7, Compound 8——Synthesis of (S)-2-tert-butyldiphenylsilyloxy-5-(methanesulfonyl)oxy-pentanoic acid methyl ester

[0085] Compound 7 (1.86mmol) was dissolved in CH 2 Cl 2 (30mL), add p-methanesulfonyl chloride (2.05mmol) at 0°C, Et 3...

Embodiment 3

[0092] The synthesis of compounds 2-10 in steps 1-9 is the same as that described in Example 1.

[0093] Step 10, Compound 11——Synthesis of (S)-3-tert-butyldimethylsilyloxy-1-tert-butoxycarbonyl-2-piperidone

[0094] Compound 10 (2.27mmol) was dissolved in CH 2 Cl 2 (50mL), add (Boc) at 0°C 2 O (3.75mmol) and Et 3 N (4.54mmol), continuous reaction for 2-10 hours. Saturated NaHCO 3 The reaction was quenched, separated, the aqueous phase was extracted three times with dichloromethane, the organic phase was washed three times with saturated sodium chloride, washed with Na 2 SO 4 After drying and concentration, the crude product was purified by silica gel column chromatography to obtain compound 11 (yield 80.4%).

[0095] The synthesis of compounds 12-14 in steps 11-13 was the same as that described in Example 1.

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Abstract

The present invention provides process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine as one key intermediate for synthesizing antimalarial febrifugin and RU-19110. The present invention synthesizes (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine with cheap facile material (L)-glutamic acid as main material and common reagent as assistant. The synthesizing process is convenient and short, and has high selectivity, high yield and low cost.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to the asymmetric synthesis of piperidine compounds, in particular to a piperidine compound (2R, 3S)-3 alkylsilyloxy-2-allyl-1-alkoxy Synthetic method of carbonyl-piperidine. Background technique [0002] (2R,3S)-3Hydroxy-2-allylpiperidine is a Chinese medicinal plant hematine with antimalarial activity and a drug developed by the French company Roussel-Uclaf that has entered Phase II clinical trials for the treatment of scleroderma, The key intermediate of anti-fibrosis drug RU-19110. Because of its drug resistance is 100 times that of quinine, hemosine has not been popularized and used because of its clinical side effects such as vomiting, but its structural modification to reduce side effects such as vomiting has not stopped. Although hirsepine was isolated by Shanghai Pharmaceuticals in the 1950s, its structure was not determined by Japanese chemists through asymmetric synthesis until 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
Inventor 王进贤马景毅魏邦国
Owner NORTHWEST NORMAL UNIVERSITY
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