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Maxacalcitol synthesizing intermediate and preparation method and application thereof

A technology of maxacalcitol and compounds, which is applied in the field of drug synthesis and can solve problems such as low efficiency

Inactive Publication Date: 2014-01-15
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] JP20111573261 uses vitamin D2 as the starting material and obtains compound X according to the method of patent US4866048. Compound X obtains compound V′ (S configuration) and V″ (R configuration) under the action of lithium aluminum hydride, and their ratio is 35 : 65, compound V′ (S configuration) is the desired configuration (the yield is only 24%), and the synthesis efficiency is too low

Method used

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  • Maxacalcitol synthesizing intermediate and preparation method and application thereof
  • Maxacalcitol synthesizing intermediate and preparation method and application thereof
  • Maxacalcitol synthesizing intermediate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Preparation of compound III-1

[0121]

[0122] Compound II-1 (50.7g, 100mmol) was dissolved in DMF (500mL), and triethylenediamine (11.2g, 100mmol), 2,2-bipyridine (3.12g, 20mmol) and copper acetate (3.64 g, 20mmol). After the addition was complete, it was heated to 45°C under an oxygen atmosphere, and stirring was continued at this temperature for 5 hours. After the reaction was complete, ethyl acetate was added, and the insoluble matter was removed by suction filtration. The filtrate was washed 3 times with water. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting oil was separated and purified to obtain Compound III-1 (39.9 g, yield 81%). This compound is a mixture of two configurations (caused by sulfur dioxide protection), which can be directly used in the next reaction. After a small amount of separation and purification, a compound of configuration 1 (large Rf value) and a compound of configuration 2 (small ...

Embodiment 2

[0127] Preparation of Compound IV-1

[0128]

[0129] Compound III-1 (49.2g, 100mmol) was dissolved in 400ml of anhydrous THF, and (R)-2-methyl-CBS-oxazoborin (1M, 100ml) was slowly added at -20oC, followed by Slowly add BH dropwise 3 ·THF solution (1M, 60ml), continue to stir for 1 hour after the addition, slowly rise to room temperature, add 50ml of saturated aqueous ammonium chloride solution, extract with ethyl acetate, concentrate to dryness under reduced pressure to obtain 49.5g of oil. The resulting oil is a mixture of two configurations (caused by sulfur dioxide protection, C-20 is a single S configuration). After a small amount of separation and purification, a compound of configuration 1 (large Rf value) and a compound of configuration 2 (small Rf value) were obtained.

[0130] The two isomers of compound IV-1 1 H NMR, 13 C NMR and MS measurement data are as follows:

[0131] Isomers with small Rf values: 1H NMR (400MHz, d-CHCl3) δ: -0.01and-0.00(each,s,6H),0...

Embodiment 3

[0134] Preparation of Compound V-1

[0135]

[0136] The crude compound IV-1 obtained in the previous step reaction was dissolved in 400ml of 95% ethanol, 50g of sodium bicarbonate was added under stirring, heated to reflux, and the reaction was continued at this temperature for 2 to 3 hours. After the reaction was complete, the ethanol was removed under reduced pressure and extracted with ethyl acetate. The resulting oil was separated and purified to obtain 36.4 g of compound V-1, with a yield of 84%.

[0137] Compound V-1 1 H NMR, 13 C NMR and MS measurement data are as follows:

[0138] 1 H NMR (400MHz, CDCl 3 )δ: -0.03(s,6H,2SiCH 3 ),0.50(s,3H,CH 3 ),0.82(s,9H,3SiCH 3 ),1.16(d,J=6Hz,3H,CH 3 ),1.18-1.23(m,2H),1.35-2.22(m,13H),2.38-2.43(m,1H),2.57-2.61(m,1H),2.79-2.83(m,1H),3.64-3.67 (m,1H,CHOH),3.78-3.81(m,1H,CHOH),4.58(s,1H,=CH 2 ),4.86(s,1H,=CH 2 ),5.81(d,J=11.6Hz,1H,=CH),6.40(d,J=11.6Hz,1H,=CH); 13 C NMR (75MHz, CDCl 3 )δ: -4.7, -4.6, 12.7, 18.2, 22.2, 2...

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Abstract

The invention provides a new method for synthesizing maxacalcitol and an intermediate thereof. According to the method, the maxacalcitol is creatively synthesized through the steps of taking vitamin D2 as an initial raw material, obtaining a compound shown as a formula II, oxidizing, chirally reducing, connecting a side chain, introducing a hydroxyl group to a C-1 position, photochemically overturning and the like.

Description

technical field [0001] The present invention relates to a kind of synthetic method of medicine, more specifically, the present invention relates to the synthetic method of maxacalcitol, novel reaction intermediate and the synthetic method of this intermediate and use thereof. Background technique [0002] Maxacalcitol (Maxacalcitol, CAS No.: 103909-75-7) English chemical formula is: 22-Oxacalcitriol; (1R,3S,5Z)-4-Methylene-5-[(2E)-2-[(1S ,3aS,7aS)-octah ydro-1-[(1S)-1-(3-hydroxy-3-Methylbutoxy)ethyl]-7a-Methyl-4H-inden-4-ylidene]ethylidene]-1,3-cyclohexanediol , is the third-generation active vitamin D3 drug developed by Japan Chugai Pharmaceutical Co., Ltd., which was launched in Japan in 2000. Its injection (trade name Oxarol) is used to treat secondary hyperparathyroidism in patients with renal dialysis ( SHPT); its ointment (trade name Oxarol) is used for the treatment of psoriasis and other psoriasis skin diseases. The current patents related to synthesis include WO20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/72C07F7/18C07D303/26C07D301/00C07C401/00
CPCC07C401/00C07D301/00C07D303/26C07D333/72C07F7/1804C07C2602/24C07D303/22C07C2601/14Y02P20/55A61P17/06A61P5/14
Inventor 郑国君王亚平冯时
Owner ZHEJIANG HISUN PHARMA CO LTD
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