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A method for preparing intermediate compound ii of vitamin D and its analogs

A technology of compounds and analogues, which is applied in the field of compound preparation, can solve the problems of non-commercialization of prenol benzoate raw materials, difficult costs, and easy danger, so as to reduce the risk of preparation, easy to scale up preparation, and reduce cost effect

Active Publication Date: 2016-01-06
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There are many deficiencies in this synthetic route: 1) the methyl deuterated prenol benzoate raw material used in the synthesis is not commercialized, and cannot be cheap and easy to obtain; 2) the tertiary compound used in the first step of synthesis The butyllithium reagent has strict requirements on the reaction conditions, and at the same time, it is prone to danger during the scale-up operation
Based on the above two points, it is not only difficult but also costly to realize the mass production of the products 25,26-deuteromethyl vitamin D3 and 25,26-deuteromethyl alphacalcidol

Method used

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  • A method for preparing intermediate compound ii of vitamin D and its analogs
  • A method for preparing intermediate compound ii of vitamin D and its analogs
  • A method for preparing intermediate compound ii of vitamin D and its analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of compound VIII

[0037]

[0038] Pyridine (300mL), NiCl 2.6H 2 O (21g, 73.31mmol) and ethyl acrylate (36.65g, 320mmol, 4.4eq) were added into a 1L three-necked flask, and the temperature was raised to 60°C. After the reaction solution turned reddish brown, the temperature was kept constant and stirred for 4 hours, and then The reaction solution was cooled to room temperature, and 20 mL of a pyridine solution of IX (32 g, 73.31 mmol) was added dropwise, and the temperature was kept stirring after dropping.

[0039] 40 minutes after the raw material was added dropwise, TLC detected that the raw material spot disappeared, indicating that the reaction was complete. Quench the reaction with 1mol / L hydrochloric acid solution (1L), extract with ethyl acetate, combine the organic phases, wash with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate to obtain 31g brown oily liquid crude product. Silica gel column chromatography gave 2...

Embodiment 2

[0041] Embodiment 2: the preparation of compound VII

[0042]

[0043] Dissolve VIII (22g, 53.5mmol) in THF (250mL), cool down to 10°C in an ice bath, and add LiAlH in batches 4 (3g, 80.3mmol), after the addition, the ice room temperature reaction was removed. After 40 minutes, TLC observed that the raw material spots disappeared, and the reaction was completed, and the aqueous solution of 1mol / LNaOH was added dropwise to the excess LiAlH 4 Just quenched. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 20 g of crude yellow oil. Silica gel column chromatography gave 18 g of colorless oil VII, with a yield of 91%.

[0044] 1H-NMR (CDCl3, δ): 3.98 (1H, brs), 3.63 (2H, t, J=6.85Hz), 1.93 (1H, m), 1.87-1.75 (3H, m), 1.58-1.40 (5H, m), 1.35-1.28 (7H, m), 1.40-1.09 (2H, m), 0.97 (3H, d, J=6.8), 0.94 (3H, s), 0.89 (9H, s), 0.025 (6H, s); HRMS(ESI-TOF): calcdfor[C 22 h 44...

Embodiment 3

[0045] Embodiment 3: the preparation of compound VI

[0046]

[0047] Dissolve VII (18g, 48.82mmol) in 360mLTHF, add imidazole (10.5g, 146.46mmol) and triphenylphosphine (25.6g, 97.64mmol), cool down to 5°C, add iodine (24.8g, 97.64mmol) dropwise 10 mL of THF solution. After 30 minutes, TLC observed that the raw material spots disappeared, added 1L of water to quench, extracted with ethyl acetate, combined organic phases, washed with saturated NaCl, anhydrous NaCl 2 SO 4 Drying and concentration gave 40 g of crude yellow oil. Silica gel column chromatography gave 21 g of light yellow oil VI, with a yield of 90%.

[0048] 1HNMR (400MHz, CDCI3) δ3.99(1H, s), 2.60(2H, t, J=7.46Hz), 1.90(1H, d, J=12.8Hz), 1.84-1.76(2H, m), 1.66( 1H, d, J=13.6Hz), 1.59-1.41(5H, m), 1.40-1.08(8H, m), 0.98(3H, d, J=5.2Hz), 0.94(3H, s), 0.88(9H , s), -0.00(3H, s), -0.02(3H, s); HRMS (ESI-TOF): calcdfor[C 22 h 43 IOSi+H]+478.21, found 478.21.

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Abstract

The invention discloses a method for preparing an intermediate compound II of vitamin D and an analogue thereof. The method comprises the following steps: carrying out addition reduction on a compound IX taken as a starting material and ethyl acrylate, and then carrying out reduction, iodization, substitution, alkylation, reduction and a deprotection reaction on the compound so as to obtain the compound II. The invention further discloses a method for preparing the compound II by virtue of multi-step continuous operations without the need of individual separation and purification. By taking the cheap raw material as a starting point, the method is simple, convenient, safe and suitable for industrial production. The structural formulae of the compounds IX and II are as shown in the specification.

Description

technical field [0001] The present invention relates to a preparation method of a compound, in particular to an intermediate for preparing vitamin D and its analogs 25,26-deuteromethyl vitamin D3 and 25,26-deuteromethyl alphacalcidol II's method. Background technique [0002] Vitamin D (vitaminD) 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 vitam...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C35/32C07C29/09
CPCC07B59/001C07B2200/05C07C29/09C07C2602/46C07F7/08C07C35/32
Inventor 郑保富高强张宪恕丁福斗李洪坤
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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