Cyclic cholane carboxylate derivative, preparation method and uses thereof

A technology for cyclocholane carboxylate and derivatives, which is applied in the field of industrial preparation of 25-hydroxycholesterol, and can solve the problem of unclear sources of 24-dehydrocholesterol derivatives, unmarked chiral carbon stereo configuration, and the need for additional preparations, etc. problems, to achieve the effects of reliable commercial sources, favorable industrial production, and mild reaction conditions

Inactive Publication Date: 2018-12-18
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In route two, although the starting materials are cheap and easy to obtain, there are relatively large deficiencies in the construction of the 17-position side chain of 25-hydroxycholesterol (1): first, tetrahydropyranyl (THP)-protected 3-methyl Base-1-butyn-3-alcohol (13) requires additional preparation; Second, the coupling reaction uses a special dangerous reagent n-butyllithium; moreover, the resulting coupling product (14) still needs to pass through 10% palladium carbon Catalytic hydrogenation, acidic hydrolysis deprotection to obtain 25-

Method used

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  • Cyclic cholane carboxylate derivative, preparation method and uses thereof
  • Cyclic cholane carboxylate derivative, preparation method and uses thereof
  • Cyclic cholane carboxylate derivative, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1, the preparation of (3β, 5α, 6β)-6-methoxy-3,5-cyclocholane-24-carboxylic acid methyl ester (Ia)

[0054]

[0055] Nickel chloride hexahydrate (0.6g, 2.5mmol), methyl acrylate (0.86g, 10.0mmol) and pyridine (4.5ml) were placed in a reaction flask, and zinc powder (0.7g, 10.0mmol) was added under stirring; Under nitrogen protection, heat to 65°C and stir for 30min. After cooling to room temperature, a solution of Va (1.0 g, 2.2 mmol) in pyridine (4.5 ml) was added dropwise, then stirred at room temperature for 2.5 h. Filter under diatomaceous earth filter, add ethyl acetate (50ml) to the filtrate, wash with 0.5mol / L sulfuric acid aqueous solution to pH 2~3, then use ethylenediaminetetraacetic acid (EDTA) aqueous solution (preparation method: EDTA (80g) and sodium bicarbonate (80g) were dissolved in water (1L) (40ml), washed with saturated brine (40ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue wa...

Embodiment 2

[0056] Embodiment 2, the preparation of (3β, 5α, 6β)-6-methoxy-3,5-cyclocholane-24-carboxylic acid ethyl ester (Ib)

[0057]

[0058] Nickel chloride hexahydrate (1.0g, 4.2mmol), ethyl acrylate (2.23g, 22mmol) and pyridine (9ml) were placed in a reaction flask, and zinc powder (1.3g, 20mmol) was added under stirring; , heated to 65°C and stirred for 30min. After cooling to room temperature, a solution of Va (2.0 g, 4.4 mmol) in pyridine (9 ml) was added dropwise, then stirred at room temperature for 2.5 h. Filtrate under diatomite filter, add ethyl acetate (50ml) to the filtrate, wash with 0.5mol / L sulfuric acid aqueous solution to pH 2~3, then wash with EDTA aqueous solution (50ml) and saturated brine (50ml) successively, Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The resulting residue was purified by flash preparative chromatography (eluent: ethyl acetate-n-hexane, gradient elution: ethyl acetate 1% to 2%), and dried in vacuo to give a col...

Embodiment 3

[0059] Embodiment 3, the preparation of (3β, 5α, 6β)-6-methoxyl-3,5-cyclocholane-24-carboxylic acid propyl ester (Ic)

[0060]

[0061] Nickel chloride hexahydrate (0.6g, 2.5mmol), propyl acrylate (1.1g, 9.6mmol) and pyridine (4.5ml) were placed in a reaction flask, and zinc powder (0.7g, 10.0mmol) was added under stirring; Under nitrogen protection, heat to 65°C and stir for 30min. After cooling to room temperature, a solution of Va (1.0 g, 2.2 mmol) in pyridine (4.5 ml) was added dropwise, then stirred at room temperature for 2.5 h. Filtrate under diatomite filter, add ethyl acetate (30ml) to the filtrate, wash with 0.5mol / L sulfuric acid aqueous solution to pH 2~3, then wash with EDTA aqueous solution (30ml) and saturated brine (30ml) successively, Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The resulting residue was purified by flash preparative chromatography (eluent: ethyl acetate-n-hexane, gradient elution: ethyl acetate 1% to 2%), and...

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PUM

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Abstract

The present invention provides a cyclic cholane carboxylate derivative and a preparation method thereof, and uses of the cyclic cholane carboxylate derivative in industrial preparation of 25-hydroxycholesterol (1), wherein R1 in the cyclic cholane carboxylate derivative represented by a formula I is straight chain or branched chain C1-C12 alkyl, R2 is methyl or ethyl, and the formula (I) is defined in the specification. According to the present invention, the starting raw material stigmasterol of the 25-hydroxycholesterol (1) synthesis process route has characteristics of low price, easy obtaining and reliable commercial source; and particularly during the constructing of the 17-position side chain of 25-hydroxycholesterol (1), the reaction conditions are mild, the reaction steps are simple, the special and dangerous reagents are not required, the harsh reaction conditions are not required, the redundant reaction steps are not required, the chromatographic separation and purification is not required, the industrial production is easily achieved, and the significant progress is achieved compared to the prior art.

Description

technical field [0001] The invention provides a class of cyclocholane carboxylate derivatives, a preparation method thereof, and an application thereof in the industrial preparation of 25-hydroxycholesterol (1). Background technique [0002] 25-Hydroxycholesterol (1) is a key intermediate for the preparation of many important vitamin D derivatives. The vitamin D derivatives include but not limited to idecalcitol (2), calcitriol (3) and calcifediol (4). [0003] Eldecalcitol, chemical name (5Z,7E)-9,10-broken cholesterol-5,7,10(19)-triene-1α,3β,25-triol, other name ED-71, the chemical structural formula is shown in formula 2. Idecalcitol is a vitamin D drug, clinically used for the treatment of osteoporosis. [0004] [0005] Calcitriol, chemical name (5Z,7E)-9,10-broken cholesterol-5,7,10(19)-triene-1α,3β,25-triol, other name 1α ,25-Dihydroxyvitamin D 3 , the chemical structural formula is shown in formula 3. Calcitriol as Vitamin D 3 The active metabolite is clini...

Claims

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Application Information

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IPC IPC(8): C07J53/00C07J9/00
CPCC07J9/00C07J53/004
Inventor 张庆文唐飞李晴晴余汝意任杰齐丽春
Owner SHANGHAI INST OF PHARMA IND
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