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A derivative of (z)-2-((3r,4r,5r)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylenecyclohexyl)ethanol a Preparation

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: 2017-03-22
SHANGHAI HAOHONG SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 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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  • A derivative of (z)-2-((3r,4r,5r)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylenecyclohexyl)ethanol a Preparation
  • A derivative of (z)-2-((3r,4r,5r)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylenecyclohexyl)ethanol a Preparation
  • A derivative of (z)-2-((3r,4r,5r)-3,5-dihydroxy-4-(3-hydroxy-propoxy)-2-methylenecyclohexyl)ethanol a Preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Preparation of Compound 2

[0062]

[0063] Dissolve compound 1 (500g, 2.66mol) and imidazole (542.5g, 7.97mol) in DMF (5.0L), add tert-butyldimethylchlorosilane (1000g, 6.65mol) in batches at room temperature, continue after adding Reaction for 4.0h. TLC detects that the raw material spots disappear, and the reaction is complete. The reaction was quenched by adding aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and anhydrous Na 2 SO 4 Dry and concentrate to obtain crude product as pale yellow oil. The crude product was chromatographed on a silica gel column to obtain 940 g of compound 2 as a pale yellow oil, with a yield of 85%.

[0064] 1H NMR (400MHz, CDCl3): 6.75 (s, 1H), 4.40 (d, 1H, J = 12.1Hz), 4.05 (d, 1H, J = 3.1 Hz), 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),0.0...

Embodiment 2

[0065] Example 2: Preparation of Compound 3

[0066]

[0067] Dissolve compound 2 (300g, 721mmol) in DMF (3.0L), add potassium tert-butylate (121g, 1.08mol) in batches under ice-water bath, stir under ice-water bath for 0.5h, add (3-bromopropyl ) Tert-butyldimethylsilane (726g, 2.88mol). Continue the incubation reaction for 12 hours, TLC detects that the raw material spots disappear, and the reaction is complete. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, and anhydrous Na 2 SO 4 Dry and concentrate to obtain crude product as pale yellow oil. The crude product was chromatographed on a silica gel column to obtain 310 g of compound 3 as a pale yellow oil, with a yield of 73%.

[0068] 1H NMR (400MHz, CDCl3): 6.85 (s, 1H), 3.95 (d, 1H, J = 10.1 Hz), 3.85 (s, 1H), 3.80 (s, 1H), 3.76 (s, 3H), 3.71 ( m, 4H), 2.44 (dd, 2H, J = 8.1 Hz), 2.26 (m, 2H), 0.887-0.916 ...

Embodiment 3

[0069] Example 3: Preparation of Compound 4

[0070]

[0071] Compound 3 (200g, 334mmol) was dissolved in ethanol (2.0L), and an aqueous solution (1.0L) of potassium permanganate (528g, 3.34mol) was added dropwise at zero. After the addition is complete, keep the temperature and react until the spots of the raw material disappeared by TLC observation, add water to quench, filter, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl, and anhydrous Na 2 SO 4 Dry and concentrate to obtain a crude red product. Silica gel column chromatography gave 146 g of colorless oil 4 with a yield of 70%.

[0072] 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

[0001] Technical field: [0002] The present invention relates to a preparation method of a compound, in particular to a key intermediate of alcalcidol (Z)-2-((3R,4R,5R)-3,5-dihydroxy-4-(3- A new preparation method of the derivative A of hydroxy-propoxy)-2-methylenecyclohexyl)ethanol. [0003] Background technique: [0004] Vitamin D (vitamin D) is a sterol derivative with anti-rickets effect, also known as anti-rickets vitamin. It is currently considered that vitamin D is also a steroid hormone. The most important members of the vitamin D family are VD2 (ergocalciferol) and VD3 (cholecalciferol). Vitamin D is the derivative of different pro-vitamin D after ultraviolet irradiation. A 40-year study by American scientists found that taking a daily dose of vitamin D can reduce the risk of breast, colon and ovarian cancer by half. Sunlight on the skin, the body will produce vitamin D, this part of vitamin D accounts for 90% of the body's vitamin D supply. [0005] In recent years, more...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
CPCY02P20/55
Inventor 丁福斗刘树芳张宪恕高强郑保富
Owner SHANGHAI HAOHONG SCI CO LTD
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