25-hydroxy vitamin D2 series medicament side chain and its preparation method

An alkyl and methyl technology, applied in the field of chain phosphorus-containing compounds and their preparation, can solve the problems of difficult synthesis and purification, inconvenient operation, large pollution, etc., and achieve the effects of short route, convenient storage and use, and wide use.

Inactive Publication Date: 2012-02-15
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, when compound 4 is used for the synthesis of a series of similar drugs of compound 2, the yield is very low, and it needs to be constructed by two-step reaction through coupling and desulfurization of Na-Hg, which is inconvenient to operate and pollutes a lot
Compound 5 not only has a low yield when it is used for drug synthesis, but also the synthesis and purification of compound 5 itself is difficult, and its synthesis process also causes some limitations for the protective group R functional group

Method used

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  • 25-hydroxy vitamin D2 series medicament side chain and its preparation method
  • 25-hydroxy vitamin D2 series medicament side chain and its preparation method
  • 25-hydroxy vitamin D2 series medicament side chain and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: compound 1a, its molecular structure is as follows, wherein R 1 =R 2 =-OEt, R=-CH 2 OCH 3 , and its molecular structure is shown in the following formula 6:

[0033]

[0034] Formula 6

[0035] Its synthetic route is shown in the following formula 7:

[0036]

[0037] Formula 7

[0038] Dissolve (S)-2-methyl-3-hydroxypropionic acid methyl ester (11.8g, 100mmol) in diethyl ether, add MeMgBr (3M, 100mL, 300mmol) dropwise into it in an argon atmosphere at zero degrees Celsius, dropwise After that, continue to stir for 6 hours, slowly drop 1M hydrochloric acid into it to quench the reaction, extract with ethyl acetate (300mL each time) three times, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate to obtain colorless oil 11 (10.7g ), yield 90%.

[0039] Structure analysis data: 1H NMR (300MHz, δ, ppm) 0.81 (3H, d, J=6.9Hz), 1.14 (3H, s), 1.22 (3H, s), 1.77 (1H, m), 3.58 (1H, b), 3.66 (2H, m), 3.84 (1H, b). ...

Embodiment 2

[0046] Embodiment two: the synthesis of 1b. where R 1 = R 2 =OMe, R=THP, the molecular structure is shown in formula 8 below:

[0047]

[0048] Formula 8

[0049] Its synthetic route is shown in the following formula 9:

[0050]

[0051] Formula 9

[0052] Compound 11 (40.0 mmol) was dissolved in CH 2 Cl 2 (100mL) and pyridine (4.0g), slowly drop thionyl chloride (5.1g, 50mmol) into it under ice-salt bath cooling, continue to stir for 1 hour, after the raw material disappears, add water to quench the reaction, separate liquid, water The phase was extracted three times with dichloromethane (200 mL), dried over anhydrous sodium sulfate, concentrated by filtration and used directly in the next step.

[0053] The above chloride 13b (11.4 g, 50 mmol) was dissolved in dry CH 2 Cl 2 (100 mL), under cooling in an ice-water bath, p-toluenesulfonic acid (0.5 g) was added thereto, and then dihydropyran (5 g, 60 mmol) was slowly dropped thereinto. After reacting at room te...

Embodiment 3

[0055] Example three: Synthesis of 1c. where R 1 = R 2 =Ph, R=Bz, its molecular structure is shown in formula 10 below:

[0056]

[0057] Formula 10

[0058] Its synthetic route is shown in following formula 11:

[0059]

[0060] Formula 11

[0061] Diol 11 (11.8g) was dissolved in dry diethyl ether (100mL), and anhydrous PBr was added thereto under cooling in an ice-water bath 3 (30g), continue to stir for 1h after adding, quench with water, extract with ether, dry the organic phase with anhydrous magnesium sulfate, filter to remove desiccant, obtain iodide 13c (7g) through silica gel chromatography purification after concentration, yield 70 %.

[0062] 13c (2g) was dissolved in CH 2 Cl 2 (20mL), add pyridine (1g) and DMAP (100mg) to it, then drop benzoyl chloride (1.7g) into it, continue stirring for 2h after adding, add water to quench, after liquid separation, the organic phase is dried , after concentration, the compound 14c (2.3 g) was obtained by silica g...

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PUM

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Abstract

The invention relates to a 25-hydroxy vitamin D2 series medicament side chain and its preparation method. The invention provides a novel compound 1, the structure of which is shown in formula 1, and a synthetic method thereof. The synthetic method provided by the invention comprises the following steps of: using (S)-2-methyl-3-hydroxypropionic acid methyl ester as an initial raw material, performing a reaction between (S)-2-methyl-3-hydroxypropionic acid methyl ester and a methyl metal reagent, carrying out selective halogenation or sulfonate esterification, followed by selective halogenation and protection of tertiary alcohols, and performing a reaction with a metallic compound of diaryl phosphine or trialkoxyl phosphine to obtain the target compound.

Description

technical field [0001] The invention relates to an organic compound and a preparation method thereof, specifically a class of chain phosphorus-containing compounds and a preparation method thereof. Background technique [0002] [0003] Formula 1 [0004] A series of 25-hydroxyvitamin D as shown in formula 1 2 All drugs have a common side chain. These drugs include 25-hydroxyvitamin D2, 1 alpha, 25-dihydroxyvitamin D 2 , paricalcitol, etc. These drugs are regulators of calcium and phosphorus homeostasis in animals and humans 1，2 . Recent studies have also identified their activity in cell recognition 3，4，5 . Therefore, various types of vitamin D analogs have aroused extensive interest of researchers, such as derivatives of vitamin D side chains, analogs of different hydroxyl models, analogs of different stereo configurations, etc., are widely used in many fields. In various types of activity tests, many known compounds of this type have demonstrated good activity ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40C07F9/655C07F9/53C07C401/00
CPCC07F9/5442C07C401/00C07C2601/14C07C2602/24C07F9/4006C07F9/5325C07F9/65515C07F9/6552
Inventor 高强薛吉军郑保富刘荣李海峰
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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