Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate

A carbamate, tert-butyl technology, applied in the field of intermediate synthesis, can solve the problems of low stereoselectivity, inconvenient operation, low reaction yield, etc., to simplify the experimental operation process, reduce the reaction time, The effect of cheap and easy to obtain raw materials

Inactive Publication Date: 2016-05-11
EAST CHINA NORMAL UNIV
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The output of natural D-10 is extremely small, and the existing synthetic methods and routes are limited to the laboratory scale, which cannot meet the growing demand
One of the reasons is that the most complex component in D-10, Dil with three chiral centers, cannot be synthesized efficiently and stereoselectively.
[0003] Tetrahedron Letters, 1991, 32 (7) pages 931-934, reported the method of generating β-carbonyl ester first, and then reducing it by sodium borohydride. This method is not high in stereoselectivity
Tetrahedron, 1994,50 (18), the 5345-5360 page, has reported to form allyl ketone by Grignard reagent earlier, utilizes the method for sodium borohydride reduction ketone again, but this reaction requires solvent anhydrous, and reduction reaction stereo poor selectivity
J.Org.Chem.2012, 77, pages 733-738 apply the Reformatsky reaction for stereoselective synthesis of β-hydroxy-γ-amino acids, and control the 3-position chirality by introducing groups with large steric hindrance. This reaction It needs to be carried out at ultra-low temperature -78°C, which is inconvenient to operate
WO2013072813A2, US20130129753A1, etc. have disclosed that β-hydroxy esters are obtained through Aldol condensation reaction. This method also needs to be carried out at ultra-low temperature, and the reaction yield is also very low.

Method used

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  • Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate
  • Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate
  • Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (3.64g, 30mmol), dissolve in dichloromethane (35mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (6.78g, 30mmol) and zinc powder (1.96g, 30mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.73 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 71%.

[0025] 1 HNMR (400MHz, CDCl 3 )δ5.80-5.90(m,1H), 4.98-5...

Embodiment 2

[0027] At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (3.28g, 27mmol), dissolve in dichloromethane (32mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (6.10g, 27mmol) and zinc powder (1.76g, 27mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.65 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 69%.

[0028] 1 HNMR (400MHz, CDCl 3 )δ5.80-5.90(m,1H), 4.98-5...

Embodiment 3

[0030] At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (4.0g, 33mmol), dissolve in dichloromethane (35mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (7.46g, 33mmol) and zinc powder (2.16g, 33mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.69 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 70%.

[0031] 1 HNMR (400MHz, CDCl 3)δ5.80-5.90(m,1H), 4.98-5.1...

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Abstract

The invention discloses a preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate. The preparation method comprises the following steps: using N-tert-butoxycarbonyl-L-isoleucinal and allyl bromide as raw materials to prepare a crude product with a higher diastereoselectivity through a Barbier reaction; then performing column chromatography separation and purification to obtain the tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate. The synthetic product of the invention can be used as an intermediate for synthesizing a key synthon Dil of aplysiatoxin 10; the method of the invention is low in raw material cost, mild in reaction condition, short in reaction time, and easy to operate.

Description

technical field [0001] The invention relates to a synthetic method of an intermediate of a natural product with antitumor activity, in particular to a tert-butyl (3R, 4S, 5S)-5-hydroxyl-3-methyl-7-octene-4- A method for preparing carbamate, the intermediate of Dil, the key synthon (dolaisoleuine) Dil of dolastatin 10. Background technique [0002] Aplysia toxin is a highly active anti-cancer active peptide, which is mainly used for the treatment of solid tumors such as small cell lung cancer, ovarian cancer, melanoma and prostate, especially D-10 has entered phase II clinical trials. Due to its definite mechanism of action and mild toxicity, D-10 is likely to become one of the preferred drugs for combination therapy. The yield of natural D-10 is extremely small, and the existing synthetic methods and routes are limited to laboratory scale, which cannot meet the growing demand. One of the reasons is that the most complex component in D-10, Dil with three chiral centers, cou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/12C07C269/06
CPCY02P20/582
Inventor 胡文浩王信彭丹丹
Owner EAST CHINA NORMAL UNIV
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