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Novel synthesis method of calcipotriol

A technology of calcipotriol and its synthetic method, which is applied in the new technical field of calcipotriol synthesis, can solve the problems of unindustrialized reports, etc., and achieve the effects of short route, high yield and easy operation

Active Publication Date: 2016-06-01
TIANJIN JINYAO GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, in my country, only Chongqing Huabang Shengkai Pharmaceutical Co., Ltd. obtained the production approval of calcipotriol at the end of 2012, but there is still no report of industrialization.

Method used

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  • Novel synthesis method of calcipotriol
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  • Novel synthesis method of calcipotriol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1: step 1 biological hydroxylation

[0070] Embodiment 1-1 put 100ml containing glucose 1%, corn steep liquor 1%, potassium dihydrogen phosphate 0.05%, the culture medium of pH6.5 (hydrochloric acid adjustment) is put into fermenter, inserts Penicillium oxalicum P.oxalicumAS3 after sterilization .7766 seed solution, ventilated and stirred, cultivated at 26.5°C for 2 days, added compound 2 to 0.1% Tween 80 solution to make a suspension, and added it to the fermenter, the substrate feeding concentration was 5g / L, continued After 3 days of fermentation, after the reaction was terminated, the fermentation broth was extracted with ethyl acetate, and the layers were left to stand. The organic layer was concentrated under reduced pressure to obtain the crude product of compound 3, and then repeatedly recrystallized with a mixed solvent of toluene and chloroform to obtain the refined product of compound 3 (content 95 %, yield 55%).

[0071] Embodiment 1-2 100ml cont...

Embodiment 2

[0074] Example 2: Step 2

[0075] Example 2-1 Compound 3 (42.9g, 0.1mol) was dissolved in 200ml of DMF, then imidazole (29.9g, 0.44mol) and TBDMSCl (33.2g, 0.22mol) were added, stirred at 15°C for 2 hours, and concentrated under reduced pressure A minimum amount was poured into 50ml of ethanol, cooled to room temperature and diluted in ice water, filtered, the filter cake was washed with water and then dried to obtain 61.6g of compound 4 with a yield of 95.8%.

[0076] Example 2-2 Compound 3 (42.9g, 0.1mol) was dissolved in 200ml of DMSO, then imidazole (29.9g, 0.44mol) and TBDMSCl (33.2g, 0.22mol) were added, stirred at 35°C for 1.5 hours, then concentrated under reduced pressure A minimum amount was poured into 50ml of ethanol, cooled to room temperature and diluted in ice water, filtered, the filter cake was washed with water and then dried to obtain 62.5g of compound 4 with a yield of 95.2%.

[0077] Example 2-3 Compound 3 (42.9g, 0.1mol) was dissolved in 200mlTHF, then t...

Embodiment 3

[0079] Example 3: Step 3

[0080] Example 3-1 Compound 4 (65.7g, 0.1mol) was added to pyridine (200ml), stirred and dissolved, then cooled to -35°C, and O 3 gas, undergoes an oxidation reaction. TLC followed the reaction and stopped feeding O 3 gas, into which N 2 Will O 3 After cleaning, it was raised to room temperature, washed successively with saturated sodium bicarbonate solution and water, and concentrated to dryness under reduced pressure to obtain light yellow oily compound 5 (48.2 g). (yield 83.9%)

[0081] Example 3-2 Compound 4 (65.7g, 0.1mol) and triethylamine (50ml) were added to chloroform (500ml), stirred and dissolved, then cooled to -15°C, and O 3 gas, undergoes an oxidation reaction. TLC followed the reaction and stopped feeding O 3 gas, into which N 2 Will O 3 After cleaning, it was raised to room temperature, washed successively with saturated sodium bicarbonate solution and water, and then concentrated to dryness under reduced pressure to obtain l...

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Abstract

The invention discloses a novel preparation method of calcipotriol. According to the preparation method, stigmasterol-2 is adopted as a starting material, alpha hydroxyl and tert-butyldimethylsilyl chloride are introduced in through microbial fermentation for carrying out seven steps of reactions including hydroxy protection, O3 oxidation, witting reaction, reduction, illumination isomerization, deprotection of hydroxys, and the like, so as to obtain calcipotriol.

Description

Technical field: [0001] The invention relates to a new process for synthesizing calcipotriol. Background technique: [0002] Calcipotriol, a synthetic vitamin D derivative, is used in adult patients with psoriasis vulgaris (psoriasis) and is a first-line topical treatment for psoriasis. Calcipotriol was launched in Europe in 1991, and is currently on the market in more than 80 countries and regions including the United States, China, Europe, and Japan. [0003] Calverley first reported in 1987 that vitamin D2 was used as the starting material to synthesize calcipotriol through 12 steps (Tetrahedron, 1987, vol.43, #20p.4609-4619). After that, other researchers made process improvements or route adjustments on the basis of this route. The synthesis route of the drug is long, and the synthesis process involves the formation of one or more chiral centers and configuration transformation, which has certain synthesis difficulty and technical requirements, and the yield is not hi...

Claims

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Application Information

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IPC IPC(8): C12P7/22C12R1/80C12R1/66
Inventor 李岩峰王淑丽
Owner TIANJIN JINYAO GRP
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