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Preparation method of fluorocalciferol

A technology for calcidol and its compounds, which is applied in the field of preparation of fluorocalcidol, can solve the problems of unsuitability for industrial production, long reaction route, complicated operation, etc., and achieve the effect of short synthesis route, less by-products and simple purification

Pending Publication Date: 2022-04-05
CP PHARMA QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention adopts convergent synthetic route for the first time to prepare fluorocalcidol, which solves the problems of long reaction route, complicated operation, low yield and unsuitability for industrial production in traditional synthetic route

Method used

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  • Preparation method of fluorocalciferol
  • Preparation method of fluorocalciferol
  • Preparation method of fluorocalciferol

Examples

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Effect test

preparation example Construction

[0038] Refer figure 1 The reaction route for the preparation method of fluorobyl alcohol, comprising the steps of:

[0039] Step 1: Compound 1 reacts compound 3 in the organic solvent 1 to the oxidant.

[0040]

[0041] Step 2: Compound 3 reacts compound 4 under an organic solvent 2 in alkaline conditions to obtain compound 4;

[0042]

[0043] Step 3: Compound 4 is reacted with the compound 2 in an organic solvent three in alkaline conditions to obtain a compound 5;

[0044]

[0045] Step 4: Compound 5 Deep off in an organic solvent 4 with an acidic reagent or a fluoride-containing ion reagent condition to obtain a compound 6: fluororonyl alcohol

[0046]

[0047] In the step one, the oxidant is one or more of dichloro chloric acid pyridine, chlorocyanic acid pyridine, chromium chromium, trioxide pyridine, and recombationate, and its molecular feed is Compound 1. 1.5 ~ 5 times; one or more of the organic solvent is one of dichloromethane, chloroform, n-heptane, acetone, i...

Embodiment 1

[0054] Example 1: Preparation of Compound 3

[0055]

[0056] Under room temperature conditions, Compound 1 (10 g, 25.6 mmol) and dichloromethane (200 mL) were added to nitrogen-protected three reaction bottles, stirred and dissolved, and PDC (24.1 g, 64.0 mmol) was added, and the system became dark brown, 25 ~ 30 ° C reaction for 3 h, TLC monitoring (expander: PE / EA = 2: 1) raw material reaction is complete. The reaction liquid was filtration, diatomalifoil to filter, washable with dichloromethane, concentrated filtrate, column chromatography purified, eluent: n-hexane / EA = 10: 1 → 5: 1, 25 ~ 30 ° C The vacuum was dried for 30 min to give a white granular solid 9.45 g, and the yield was 95%.

Embodiment 2

[0057] Example 2: Compound 4 (R 1 Preparation of = TMS)

[0058]

[0059] EtOAc (EtOAc) (2.3 g, 15.42 mmol) was added after the addition of 10 to 30 ° C for 12h, TLC monitoring (expandant: PE: EA = 5: 1) raw material substantially. Dilutina (100 mL) diluted reaction solution was added, and the water (50 ml × 2) was washed sequentially washed sequentially with a 20% aqueous solution of hydrochloric acid (50 mL), saturated water (50 ml × 2), and anhydrous sulfate was dried. EtOAc (EtOAc)

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Abstract

The invention belongs to the field of organic chemistry, and discloses a method for preparing fluorocalciferol by adopting a convergent synthesis route, which comprises the following steps: reacting a compound 1 with an oxidant in an organic solvent 1 to obtain a compound 3; reacting the compound 3 with a hydroxyl protecting group reagent containing a silicon group in an organic solvent 2 under an alkaline condition to obtain a compound 4; carrying out coupling reaction on the compound 4 and a compound 2 in an organic solvent 3 under an alkaline condition to obtain a compound 5; and reacting the compound 5 with a desilicication protecting group reagent in an organic solvent IV to obtain the fluorocalciferol. Compared with the traditional synthesis route, the method has the advantages of short synthesis route, few byproducts, simplicity in purification, high yield and suitability for industrial production, avoids the use of highly toxic reagents MOMCl and methanesulfonic acid, is environment-friendly, improves the yield, and improves the total yield to 70% or above.

Description

Technical field [0001] The present invention belongs to the art of organic chemistry, and is related to the preparation method of fluorobyl alcohol. [0002] technical background [0003] Formoliccitriol, is a bonized triol analogue developed by Taisho, Kissei and Da Japanese Sumitomo, with high effectiveness in vivo and in vitro, and has a longer in the body. The role time. This medicine improves orthopedic disease and symptoms due to lack of vitamin D, and can be used to promote change absorption to supplement lack of calcium to prevent osteoporosis. The secondary parathyroidism of patients used in dialysis is hyperthyroidism, parathyroid dielectric degradation, disease and bone softening. [0004] The literature reports that the traditional fluorobyl alcohol synthesis route is prepared by multi-step transformation by cholesterol or vitamin D2 and its derivatives: [0005] (1) Preparation method of a fluorobyl alcohol disclosed in Patent No. 358406, with a cholesterol compound a...

Claims

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Application Information

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IPC IPC(8): C07C401/00
Inventor 马庆童牛建兴邱传龙陈阳生王明刚臧云龙孙桂玉刘晓霞杜昌余王清亭
Owner CP PHARMA QINGDAO CO LTD
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