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Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative

A technology of ethyl trihydroxyhexanoate and its derivatives, applied in the direction of organic chemistry, can solve the problems of inconvenient large-scale preparation, increase of operation process and reagent cost, etc., and achieve simple operation, short route and high atom economy Effect

Inactive Publication Date: 2013-02-06
SHANGHAI INST OF PHARMA IND CO LTD
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Problems solved by technology

[0010] When the above-mentioned method prepares unprotected (3R, 5S)-3,5,6-trihydroxyhexanoate derivatives at the 6-position hydroxyl group, it is necessary to selectively protect the 3,5-dihydroxyl group, and then remove the 6- The -position hydroxyl protecting group is prepared through a two-step reaction, which increases the operation process and reagent cost, and is not convenient for large-scale preparation

Method used

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  • Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative
  • Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative
  • Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative

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Embodiment 1

[0032] 1) Preparation of ethyl (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoate

[0033] The (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoic acid ethyl ester in the present invention can be referred to Tararov et al. [WO2005047276, 2005-05-26; Adv. Synth Catal., 2006, 348(18): 2633-2644.]. The synthesis process is shown in the following formula:

[0034]

[0035] Use Ru[(R)-BINAP]Cl 2 ·NEt 3 Asymmetric catalytic hydrogenation of the compound represented by chemical formula X to (3R,5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoic acid ethyl ester, the de% is greater than 99; wherein the compound X is The preparation method can refer to Chinese Patent 200610025601.3 (2006-04-11).

[0036] 2) Preparation of (3R,5S)-3,5,6-trihydroxyhexanoic acid ethyl ester derivative

[0037] The (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoate (de%=99, 3.0g, 12.9mmol) obtained in step 1), CSA (Camphorsulfonic acid, 0.30g) and benzaldehyde (Compound R of formula IV 1 =H, 3.45g, 3...

Embodiment 2

[0039] In this embodiment, the preparation method of (3R,5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoate may refer to step 1) of embodiment 1. Then the prepared (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoate (de%=99, 3.0g, 12.9mmol), p-toluenesulfonate Acid (0.20g) and benzaldehyde dimethyl acetal (compound R of formula III 1 =H, R 2 =CH 3 , 3.93g, 25.8mmol) was dissolved in dichloromethane (50ml), stirred at room temperature for 30 hours, and then used saturated NaHCO 3 Wash the aqueous solution (40ml), extract the aqueous layer with dichloromethane (30ml×2), combine the organic layers and wash with saturated brine and anhydrous MgSO 4 Drying, concentration, silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 2.87 g of the compound represented by formula II (R 1 =H), the yield is 79.3%. [α] D 21 -15.60°(c1.00, EtOH); ESI-MS m / z: [M+Na] + 303.1; 1 H-NMR(CDCl 3 ): δ1.26(t, 3H, CO 2 CH 2 C H 3 ), 1.55-1.69(m, 2H, CHC H 2 CH), 1.95...

Embodiment 3

[0041] 1) Preparation of ethyl (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoate

[0042] The (3R,5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoic acid ethyl ester of the present invention can also be modified with tartaric acid Raney-Ni[(R , R)-TA-NaBr-MRNi-U] asymmetric catalytic hydrogenation of compound X to (3R,5S)-5,6-O-isopropylidene-3,5,6-trihydroxyhexanoic acid ethyl ester, The de% is 48.

[0043] Preparation of catalyst (R, R)-TA-NaBr-MRNi-U:

[0044] Preparation of Raney-Ni-U: Dissolve 45.0g of sodium hydroxide in 200ml of water, add 19.0g of nickel-aluminum alloy (nickel content: 40-50%) in batches under an ice-water bath, add it in about 15 minutes, and stir until bubbles are released After the speed becomes slow, the temperature is raised to 100°C and stirred for 1 hour, cooled to room temperature, the water layer is poured out with the help of a magnet, and then the catalyst is washed with distilled water, 300ml each time, until neutral. The obtained Raney-Ni...

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Abstract

The invention provides a preparation method of a (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative. In the method, (3R, 5S)-5,6-O-isopropylidene-3,5,6-3-hydroxy-ethyl hexanoate reacts with a benzaldehyde derivative in the presence of acid to prepare the (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative. The invention has the advantages of simple and short route, simple and convenient operation and high atom economy.

Description

Technical field [0001] The present invention relates to a preparation method of (3R,5S)-3,5,6-trihydroxyhexanoic acid ethyl ester derivative Background technique [0002] The 6-position hydroxyl unprotected (3R,5S)-3,5,6-trihydroxyhexanoic acid ethyl ester derivative is an intermediate for the synthesis of statins. Its chemical structure is shown in formula II, and the literature reports that it is similar There are several types of synthetic methods as follows. [0003] [0004] In 1990, Wess et al. [Tetrahedron Lett., 1990, 31(18): 2545-2548] In the synthesis of cerivastatin, (3R, 5S)-3,5-dihydroxy compound V was subjected to 2,2-dimethyl The VI was prepared by protecting the oxypropane, and the 6-hydroxyl unprotected (3R,5S)-3,5,6-trihydroxyhexanoate derivative VII was prepared by the desiliconization of the VI via tetrabutylammonium fluoride. . [0005] [0006] In 1995, Beck et al. [Synthesis, 1995(8): 1014-1018] reported that (3R, 5S)-3,5-dihydroxy compound VIII was protecte...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
Inventor 张福利邱友春张椿年
Owner SHANGHAI INST OF PHARMA IND CO LTD
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