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Preparation method of derivative A of (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylene cyclohexyl) ethanol

A technology of dioxane and compound is applied in the field of compound preparation, and achieves the effects of reduced cost, low cost and simple operation

Active Publication Date: 2015-04-29
上海皓鸿生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In summary, there are factors restricting industrial scale-up production in the synthetic routes of the key intermediate A of Alcalcitol reported so far.

Method used

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  • Preparation method of derivative A of (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylene cyclohexyl) ethanol
  • Preparation method of derivative A of (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylene cyclohexyl) ethanol
  • Preparation method of derivative A of (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylene cyclohexyl) ethanol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the preparation of compound 2

[0058]

[0059] Compound 1 (500g, 2.66mol) and imidazole (542.5g, 7.97mol) were dissolved in DMF (5.0L), and tert-butyldimethylsilyl chloride (1000g, 6.65mol) was added in portions at room temperature. Reaction 4.0h. TLC detects that the raw material spot disappears, and the reaction is complete. Add aqueous sodium bicarbonate solution to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to give the crude product as a pale yellow oil. The crude product was chromatographed on a silica gel column to obtain 940 g of compound 2 as a light yellow oil, with a yield of 85%.

[0060] 1H NMR (400MHz, CDCl3): 6.75(s, 1H), 4.40(d, 1H, J=12.1Hz), 4.05(d, 1H, J=3.1Hz), 3.83(m, 1H), 3.75(s, 3H),2.49(dd,1H,J=14.1Hz),2.26(d,2H,J=6.1Hz),0.885(s,9H),0.855(s,9H),0.125(s,3H),0.114( s,3H),0.089(s,3H),0.0614(s,3H).LC-MS(ESI-TOF):calcd for[C 20 ...

Embodiment 2

[0061] Embodiment 2: the preparation of compound 3

[0062]

[0063] Dissolve compound 2 (300g, 721mmol) in DMF (3.0L), add potassium tert-butyl alkoxide (121g, 1.08mol) in batches under ice-water bath, stir for 0.5h under ice-water bath, add (3-bromopropyl ) tert-butyldimethylsilane (726 g, 2.88 mol). Continue to incubate for 12 hours, TLC detects that the raw material spots disappear, and the reaction is complete. Add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, combine the organic phases, wash with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to give the crude product as a pale yellow oil. The crude product was chromatographed on a silica gel column to obtain 310 g of compound 3 as a light yellow oil, with a yield of 73%.

[0064] 1H NMR (400MHz, CDCl3): 6.85(s, 1H), 3.95(d, 1H, J=10.1Hz), 3.85(s, 1H), 3.80(s, 1H), 3.76(s, 3H), 3.71( m,4H),2.44(dd,2H,J=8.1Hz),2.26(m,2H),0.887-0.916(m,27H),0.066-0.074(m,...

Embodiment 3

[0065] Embodiment 3: the preparation of compound 4

[0066]

[0067] Compound 3 (200 g, 334 mmol) was dissolved in ethanol (2.0 L), and an aqueous solution (1.0 L) of potassium permanganate (528 g, 3.34 mol) was added dropwise at zero temperature. After the dropwise addition, keep the temperature and react until the spots of raw materials observed by TLC disappear, add water to quench, filter, extract with ethyl acetate, combine organic phases, wash with saturated NaCl, anhydrous NaCl 2 SO 4 Dry and concentrate to give a red crude product. Silica gel column chromatography gave 146 g of colorless oil 4, with a yield of 70%.

[0068] 1H NMR (400MHz, CDCl3): 4.55(d, 1H, J=6.3Hz), 4.51(s, 1H,), 4.08(s, 1H), 3.75(m, 4H), 3.62(dd, 2H, J= 9.3Hz), 3.45(t, 2H), 2.59(dd, 1H, J=4.3Hz), 2.12(t, 1H), 1.69(t, 2H, J=6.2Hz), 1.61(t, 1H), 0.86 -0.94(m,27H),0.18(d,6H,J=5.6Hz),0.061-0.10(m,12H).LC-MS(ESI-TOF):calcd for[C 29 h 62 o 8 Si 3 +H] + 623.38, found 623.38

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Abstract

The invention discloses a new preparation method of a derivative A of a key Ayr calciferol intermediate (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylene cyclohexyl) ethanol. The method comprises the following steps: performing 3,5-hydroxy protection on a compound 1 serving as a starting material, then reacting the protected compound 1 with R2O(CH2)3X to protect 4-hydroxy, oxidizing with a permanganate to obtain 1,2-hydroxy, performing further oxidation and wittig reaction to obtain 2-methylene, reducing, oxidizing, reacting the oxidized product with trimethyl silicon-based ethyl acetate, and performing DiBAL-H reduction to obtain a compound A. Compared with the prior art, illumination reaction is not used in the new route, so that the operation is simple and amplification is facilitated; and the used raw materials are cheap and readily available natural products, and all chiral centers are introduced from the raw materials, so the cost is low and the quality of the compound A is easy to control.

Description

Technical field: [0001] The present invention relates to a preparation method of a compound, in particular to a key intermediate (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3- Novel preparation of derivative A of hydroxy-propoxy)-2-methylenecyclohexyl)ethanol. Background technique: [0002] Vitamin D (vitamin D) is a sterol derivative with anti-rickets effect, also known as anti-rickets vitamin. At present, it is considered that vitamin D is also a steroid hormone, and the most important members of the vitamin D family are VD2 (ergocalciferol) and VD3 (cholecalciferol). Vitamin D is a derivative of different provitamin D after ultraviolet irradiation. A 40-year study by American scientists found that taking a daily dose of vitamin D can cut the risk of breast, colon and ovarian cancer in half. When the sun shines on the skin, the body produces vitamin D, which accounts for 90% of the body's vitamin D supply. [0003] In recent years, more and more evidence has shown that a lack o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCY02P20/55
Inventor 丁福斗刘树芳张宪恕高强郑保富
Owner 上海皓鸿生物医药科技有限公司
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