Method for enantioselective synthesis of tacalcitol

A technology of enantioselectivity and tacalcitol, which is applied in the field of preparation of enantioselective synthesis of tacalcitol, can solve the problems of costing a lot of manpower and material resources and equipment costs, and achieve the requirements of loose reaction conditions and high production efficiency. High efficiency and simple operation

Inactive Publication Date: 2016-03-30
NANJING UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Literature 2 (OkamotoM, FujiiT, TanakaT. The first convergent synthesis of 1α, 24(R)-dihydroxyvitaminD 3 viadiastereoselectiveisopropylationandalkylativeenynecyclization.[J].Tetrahedron.1995,51(19):5543-5556); Literature 3 (FallY,TorneiroM,CastedoL,etal.Aefficientstereoselectivesynthesisof1α,24(R)-dihydroxyvitaminD 3 bythedienyneroute.[J].Tetrahedron.1997,53(13):4703-4714) through the coup

Method used

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  • Method for enantioselective synthesis of tacalcitol
  • Method for enantioselective synthesis of tacalcitol
  • Method for enantioselective synthesis of tacalcitol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the synthesis of compound 2

[0043] Under nitrogen protection, 2M tetrahydrofuran solution (0.2mL) of borane tetrahydrofuran complex was added dropwise to 1M (R)-2-methyl-CBS-oxazolidine solution (0.2mL) in toluene, at room temperature The reaction was stirred for 2 hours, cooled to -20°C, and a toluene solution of compound 1 (128mg, 0.2mmol) was slowly added, then stirred at -20°C for 0.5 hours, TLC showed that the reaction was complete, and ammonium chloride was added to the reaction system. aqueous solution, moved to room temperature and stirred for 0.5 hours, then poured the reaction system into an aqueous solution of ammonium chloride (30mL), extracted with ethyl acetate (3×20mL), washed the organic layer with water (2×20mL), and washed with saturated brine (2× 20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was separated by Pre-HPLC to obtain enol 2 as a colorless solid (91 mg, 71%) after distilling off the solvent. 1 HNMR (5...

Embodiment 2

[0044] Embodiment 2: the synthesis of compound 3

[0045] Compound 2 (1.29g, 2mmol) and 9-acetylanthracene (222mg, 1mmol) were dissolved in toluene (80mL), stirred and reacted under 365nm ultraviolet light irradiation at 20°C for 1.5 hours, after the completion of the reaction as detected by TLC, the reaction solution was concentrated in vacuo , and the residue was subjected to column chromatography (SiO 2 , V(PE):V(EA)=20:1) Compound 3 (0.92g, 71%) was isolated as a white solid. 1 HNMR (500MHz, CDCl 3 )δ6.24(d, J=11.2Hz, 1H), 6.02(d, J=11.3Hz, 1H), 5.18(s, 1H), 4.87(s, 1H), 4.37(m, 1H), 4.19( m,1H),3.32(m,1H),0.92(m,9H),0.88(s,18H),0.54(s,3H),0.07(s,12H).

Embodiment 3

[0046] Embodiment 3: the synthesis of compound 4

[0047] Compound 3 (645mg, 1mmol) was dissolved in tetrahydrofuran (30mL), and 1MTBAF solution in tetrahydrofuran (5mL, 5mmol) was added under the protection of argon, and the reaction was stirred at 60°C for 3 hours. After the reaction was detected by TLC, saturated Aqueous sodium bicarbonate solution (100mL), extraction with ethyl acetate (3×40mL), organic layer washed with water (2×30mL), washed with saturated brine (2×30mL), dried over anhydrous magnesium sulfate, filtered, spin-dried, and the residue Column chromatography (SiO 2 , V(PE):V(EA)=1:1) Compound 4 (tacalcitol) was obtained as a white solid (279 mg, 67%) after separation. 1 HNMR (500MHz, CDCl 3 )δ6.37(d, J=11.2Hz, 1H), 6.02(d, J=11.1Hz, 1H), 5.32(s, 1H), 4.99(s, 1H), 4.42(m, 1H), 4.22( m,1H),3.32(m,1H),0.92(m,9H),0.55(s,3H). 13 CNMR (125MHz, CDCl 3 )δ147.7, 143.1, 133.0, 124.9, 117.1, 111.8, 77.4, 70.7, 66.8, 56.3, 45.9, 45.2, 42.8, 40.5, 36.0, 33.6, 33.2, 3...

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Abstract

The invention discloses a method for enantioselective synthesis of tacalcitol and relates to the field of chemical synthesis of psoriasis treatment drug tacalcitol. The method has simple processes, purifying convenience and a high yield. The method comprises that in the presence of chiral oxazaborolidine and a borane complex system as catalysts, a prochiral ketone compound 1(S), 3(R)-bis(t-butyldimethylsilyloxy)-20(R)-(3'-isopropyl-3'-oxo)alkenyl-9, 10-semipregna-5, 7 (E), 10 (19)-triene is subjected to asymmetric catalytic reduction, the reduction product is subjected to photocatalysis double bond isomerization, a t-butyldimethylsilane-based protective group is removed and tacalcitol is obtained. The method is economic, can be operated simply, realize high optical purity and chemical purity and can be industrialized easily.

Description

technical field [0001] The invention belongs to vitamin D 3 The field of synthesis of active metabolite analogue tacalcitol, in particular relates to a preparation method for enantioselective synthesis of tacalcitol. Background technique [0002] Tacalcitol (Tacalcitol,4) is an analogue of the active metabolite of vitamin D3, the chemical name is (+)-(5Z,7E,24R)-9,10-cyclocholesterol-5,7,10( 19)-Triene-1α,3β,24-triol, chemical formula C 27 h 44 o 3 , CAS accession number 57333-96-7; is a drug for the treatment of psoriasis (psoriasis). In 1993, it was launched by Japan's Teijin Pharmaceutical Co., Ltd. (Teijin) Biomedical Research Institute, and the product name is Mengerfu. Because tacalcitol has a good drug effect and can be used for the treatment of psoriasis of facial infection, it has become the main topical drug for the treatment of psoriasis (psoriasis). [0003] Document 1 (MorisakiM, KoizumiN, IkekawaN, etal. Synthesis of active forms of vitamin D. Part IX. Sy...

Claims

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Application Information

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IPC IPC(8): C07C401/00
CPCY02P20/55
Inventor 方志杰郭威张衡瑞潘峰刘娅楠李红亮汪熙
Owner NANJING UNIV OF SCI & TECH
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