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Preparation method of eldecalcitol intermediate

A saponification and compound technology, applied in the field of preparation of alcalcidol intermediate 1A, can solve the problems of affecting product quality, low utilization rate of raw materials, increased workload, etc., and achieve the effect of improving utilization rate of raw materials and easy industrial amplification

Active Publication Date: 2015-08-12
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Since 1A and 1B do not go through the separation process in the synthetic route but are converted into the key A ring fragment compound 3 or 5 and then separated, there are inevitable defects in these two routes: 1. Due to the existence of compound 1B , resulting in a low utilization rate of raw materials; 2. Since 1B will also participate in the corresponding reaction to prepare compound 3 or 5, it will inevitably increase the workload of the preparation reaction, and at the same time increase the consumption of other materials and reagents; 3. Due to The separation step is placed at the end, and the residue of the diastereoisomer of the key A ring fragment compound 3 or 5 produced by compound 1B is bound to affect the quality of the final product
However, there is no corresponding literature report on the separation of compounds 1A and 1B, only the separation reports of isomers with different chiral structures

Method used

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  • Preparation method of eldecalcitol intermediate
  • Preparation method of eldecalcitol intermediate
  • Preparation method of eldecalcitol intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Preparation of Compounds 1A and 7 Using Compound 1 as a Raw Material

[0034]

[0035]Dissolve compound 1 (33g, 100mmol) and ethyl acrylate (20g, 200mmol) in 500mL of n-hexane, add Novozyme lipase 4353g at room temperature, heat to 70°C, keep the temperature and react overnight, sample and filter for HPLC detection, 1B Less than 3%, the reaction is complete. The solid was removed by filtration, the filter cake was washed with 200 mL of n-hexane, and the filtrate was collected and concentrated to obtain 35 g of crude product. The crude product was subjected to silica gel column chromatography to obtain 17g of compound 1A with a yield of 52% and a purity of 97%, and compound 716g with a yield of 48% and a purity of 95%.

[0036] Compound 1A: 1H NMR (400MHz, CDCl3) δ = 5.93 (ddd, 1H, J = 17.4, 10.7, 6.2Hz), 5.34 (dt, 1H, J = 17.4, 1.5Hz), 5.23 (dt, 1H, J = 10.2, 1.5Hz), 4.29–4.09(m, 4H), 4.00(dd, 1H, J=8.4, 6.3Hz), 3.79–3.65(m, 3H), 3.30(dd, 2H, J=6.0, 5.0Hz...

Embodiment 2

[0040] The preparation of embodiment 2 compound 1B

[0041]

[0042] Compound 7 (15g, 40.3mmol) was dissolved in 100mL tetrahydrofuran and 100mL methanol, and potassium carbonate (11.1g, 80.6mmol) was added after cooling down to zero. After the addition, the temperature was naturally raised to room temperature for 3 hours. React until the spots of raw materials detected by TLC disappear, and the reaction is complete. The reaction was quenched by adding 300 mL of water. Extracted three times with 100 mL of ethyl acetate, combined the organic phases, washed with 200 mL of saturated brine, dried with 200 g of anhydrous Na2SO4, and concentrated to obtain 14 g of crude product. The crude product was subjected to silica gel column chromatography to obtain 12.5 g of compound 1B with a yield of 93.9% and a purity of 95%.

[0043] 1B: 1H NMR (400MHz, CDCl3) δ = 5.89 (ddd, 1H, J = 17.4, 10.7, 6.2Hz), 5.35 (dt, 1H, J = 17.4, 1.5Hz), 5.24 (dt, 1H, J = 10.2 ,1.5Hz),4.29–4.09(m,4H),4....

Embodiment 3

[0045] The preparation of embodiment 3 compound 1C

[0046]

[0047] Compound 1B (10g, 30.4mmol) was dissolved in 100mL of dry THF, triphenylphosphine (31.8g, 121.6mmol) and p-nitrobenzoic acid (20.3g, 121.6mmol) were added, and the temperature was lowered to zero in batches Add DEAD (21.0 g, 121.6 mmol), naturally warm to room temperature and stir for 3 hours. After the reaction was observed by TLC, the spots of the starting material disappeared, and 300 mL of water was added to quench the reaction. Extracted three times with 100 mL of ethyl acetate, combined the organic phases, washed with 200 mL of saturated brine, dried with 200 g of anhydrous Na2SO4, and concentrated to obtain 44 g of crude product. The crude product was subjected to silica gel column chromatography to obtain 13.5 g of compound 1C with a yield of 90.9%.

[0048] 1H NMR (400MHz, CDCl3): δ = 8.40-8.20 (4H, m), 6.8-6.74 (1H, m), 6.43-6.37 (1H, dd, J = 1.5, 17.37Hz), 5.80-5.76 (1H, dd,J=1.5,10.5Hz),4.22...

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Abstract

The invention relates to a method of preparing a compound 1A through enzymatic resolution. In particular, the enantiomer separating and recycling method includes steps of treating a compound 1 or a compound 9 with an enzyme to obtain the compound 1A and a compound 7, performing selective saponification to the compound 7, performing a Mitsunobu reaction, and performing selective saponification again to obtain the compound 1A. The method achieves enantiomer resolution with recycling utilization.

Description

technical field [0001] The present invention relates to a recovery method for enzymatic resolution and separation of racemic compounds and by-products, in particular to a new method for preparing alcalcitol intermediate 1A. 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 of vitamin D can be extremely ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P17/04C07D317/22
Inventor 丁福斗李洪坤杨旭慧张宪恕高强郑保富
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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