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Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof

A compound and hydrogen atom technology, applied in organic chemistry and other fields, to achieve excellent results

Inactive Publication Date: 2006-03-29
SUMITOMO CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to solve the problems of the existing preparation methods such as the use of ozone oxidation or toxic reagents, to provide efficient and industrial scale, low-cost preparation of the formula (XIV) useful as an intermediate of anti-AIDS drugs The method for showing the compound (hereinafter also referred to as compound (XIV)), and the intermediate used in the method and the preparation method thereof, especially provide the method for preparing the compound having the absolute stereostructure shown in formula (XV) without using methods such as optical resolution. Type compound (XIV) and its enantiomer method, and the intermediate used in the method and its preparation method

Method used

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  • Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
  • Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
  • Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof

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preparation example Construction

[0288] Compound (XIX) can usually be prepared in THF, hexane, di-n-butyl ether, MTBE, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1,3-dioxolane, 1, 4 -Carry out in reaction solvents such as dioxane and toluene, preferably in THF or hexane. The amount of the reaction solvent used is usually 1-100L, preferably 3-30L, relative to 1kg of compound (XIII).

[0289] The reaction temperature is usually -100°C to 70°C, preferably -80°C to 40°C; the reaction time is usually 0.5-48 hours, preferably 3-24 hours.

[0290] Formula: R 3 O-CH 2 CH 2 The compound represented by -X can be prepared by a known method. For example, 2-benzyloxyethyl iodide can react 2-benzyloxyethanol with methanesulfonyl chloride in the presence of a catalyst such as triethylamine to obtain 2-benzyloxyethyl methanesulfonate, which can be reacted with sodium iodide To prepare by reaction, 2-tert-butoxyethyl iodide can be prepared by using 2-tert-butoxyethanol instead of the aforementioned 2-benzyl...

Embodiment 1

[0399] Example 1 (1’R * , 2S * )-2-[2'-(1,1-Dimethylethoxy)-1'-hydroxyethyl]-4-butyrolactone synthesis (compound with relative stereo configuration shown in formula (VII) )

[0400] Dissolve 4-tert-butoxy ethyl acetoacetate (20.0 g), which can be synthesized according to the method described in Heterocycles 26, 2841 (1987), in methanol (150 mL), and then add sodium borohydride (1.68 g), stir for 1 hour, and then add water (100 mL). Most of the solvent was distilled off, extracted twice with MTBE (150 mL), the organic layer was washed thoroughly with water, and then MTBE was distilled off to obtain ethyl (±)-4-tert-butoxy-3-hydroxybutyrate (16.9 g) . A 1.5M cyclohexane solution (73mL) of lithium diisopropylamide was added to THF (100mL), and (±)-4-tert-butoxy was added to the resulting solution at -58°C to -48°C A solution of ethyl-3-hydroxybutyrate (10.66 g) in THF (30 mL) was then raised to -20°C. In addition, in the presence of p-toluenesulfonic acid monohydrate (10mg), 2-iodoet...

Embodiment 2

[0402] Example 2 (1’R * , 2S * )-2-(1',2'-Dihydroxyethyl)-4-butyrolactone (compound with relative stereo configuration shown in formula (VIII))

[0403] Will (1’R * , 2S * )-2-[2'-(1,1-Dimethylethoxy)-1'-hydroxyethyl]-4-butyrolactone (1.3g) was added to trifluoroacetic acid (4mL) and placed on ice After stirring in the bath for 90 minutes, the trifluoroacetic acid was directly distilled off under reduced pressure to obtain the title compound (1.0 g).

[0404] 1 H-NMR(CDCl 3 , Δppm): 2.10-2.20(1H, m), 2.37-2.44(1H, m), 2.80-2.87(1H, m), 3.6-3.8(1H(-OH), br), 3.67(1H, dd, J=12Hz, J=6Hz), 3.75 (1H, dd, J=12Hz, J=3Hz), 3.86-3.90 (1H, m), 4.24-4.30 (1H, m), 4.43 (1H, dt, J= 9Hz, J=3Hz), 4.4-4.5(1H(-OH), br).

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Abstract

A process for efficiently producing compound (XIV) being useful as a drug intermediate on an industrial scale at low cost without the need to use ozonization and highly toxic agents; and an intermediate for use in the process. In particular, a process for producing a compound having the absolute configuration of the formula (XV) or an enantiometric isomer thereof without the need to use means such as optical resolution; and an intermediate for use in the process. (1) Compound (XIV) is produced by deriving compound (I) from compound (XIII) as a starting material and sequentially performing introduction of a protective group, reduction and cyclization. Particularly, compound (XIV) is produced by deriving compound (I) through compound (XX) from compound (XIII) as a starting material. Compound having the absolute configuration of the formula (XV) or the like is produced in high stereoselectivity from optically active compound (XIII) as a starting material. (2) Compound (XXVI) is produced by deriving compound (XXII) from compound (XXI) as a starting material through stereoselective reduction thereof and sequentially performing introduction of a protective group, reduction and cyclization. Compound (XV) is produced by inverting hydroxyl of the compound (XXVI). (1) (2) wherein symbols are as defined in the description.

Description

Technical field [0001] The present invention relates to a method for preparing a hexahydrofurofuranol derivative represented by the following formula (XIV) as a pharmaceutical intermediate, particularly the following formula (XV), and the following formula ( The compounds shown in A), (B) and (C) and their preparation methods. Background technique [0002] Formula (XIV): [0003] [0004] Especially the formula (XV): [0005] [0006] The compounds shown are compounds useful as intermediates of anti-AIDS drugs (refer to International Publication No. 01 / 25240 Pamphlet and International Publication No. 99 / 67254 Pamphlet). Known methods for synthesizing compounds represented by formula (XIV) or (XV) include: International Publication No. 01 / 25240 Pamphlet, European Patent Application Publication No. 539192 Specification, Tetrahedron Letters, Volume 27, p3715 (1986) and The method described in Tetrahedron Letters, Volume 4, p505 (1995), but using ozone oxidation or highly toxic t...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D407/04C07D307/32
Inventor 池本哲哉朴东国
Owner SUMITOMO CHEM CO LTD
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