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A kind of preparation method of alcalcidol intermediate

A technology of saponification and compounding, which is applied in the field of preparation of alcalcitol intermediate 1A, can solve the problems of low raw material utilization rate, influence on product quality, increased workload, etc., and achieve the effect of easy industrial scale-up and improved raw material utilization rate

Active Publication Date: 2019-03-01
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • 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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  • A kind of preparation method of alcalcidol intermediate
  • A kind of preparation method of alcalcidol intermediate
  • A kind of preparation method of alcalcidol intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Preparation of Compounds 1A and 7 from Compound 1

[0034]

[0035]Compound 1 (33 g, 100 mmol) and ethyl acrylate (20 g, 200 mmol) were dissolved in 500 mL of n-hexane, Novozymes lipase 4353 g was added at room temperature, heated to 70 ° C, kept the temperature to react overnight, sampling and filtration HPLC detection, 1B Less than 3%, the reaction is completed. The solid was removed by filtration, the filter cake was washed with 200 mL of n-hexane, 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 17 g of compound 1A with a yield of 52% and a purity of 97%, and compound 716 g 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, 5.0H...

Embodiment 2

[0040] Example 2 Preparation of Compound 1B

[0041]

[0042] Compound 7 (15 g, 40.3 mmol) was dissolved in 100 mL of tetrahydrofuran and 100 mL of methanol, and potassium carbonate (11.1 g, 80.6 mmol) was added under cooling to zero. After the addition, the temperature was naturally raised to room temperature for 3 hours. The reaction was completed until the spots of the raw materials were detected by TLC, and the reaction was completed. 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 chromatographed on a silica gel column 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...

Embodiment 3

[0045] Example 3 Preparation of Compound 1C

[0046]

[0047] Compound 1B (10 g, 30.4 mmol) was dissolved in 100 mL of dry THF, triphenylphosphine (31.8 g, 121.6 mmol), and p-nitrobenzoic acid (20.3 g, 121.6 mmol) were added, and the temperature was lowered to zero in batches. DEAD (21.0 g, 121.6 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was carried out until the spot of the raw material disappeared as observed by TLC, and 300 mL of water was added to quench the reaction. Extract with 100 mL of ethyl acetate three times, combine the organic phases, wash with 200 mL of saturated brine, dry with 200 g of anhydrous Na2SO4, and concentrate 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...

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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 invention relates to a recovery method for enzymatic separation and separation of racemic compounds and by-products, in particular to a new method for preparing alcalcidol intermediate 1A. Background technique: [0002] Vitamin D (vitamin D) is a steroid derivative with anti-rickets effect, also known as anti-rickets vitamin. It is currently 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 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 could cut the risk of breast, colon and ovarian cancer in half. When sunlight hits the skin, the body produces vitamin D, which accounts for 90% of the body's vitamin D supply. [0003] In recent years, there has been increasing evidence that a lack of vitamin D can be extremely harmfu...

Claims

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Application Information

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Patent Type & Authority Patents(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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