CN105348353B - The preparation method of 24 ketone group steroids - Google Patents

The preparation method of 24 ketone group steroids Download PDF

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Publication number
CN105348353B
CN105348353B CN201510640421.5A CN201510640421A CN105348353B CN 105348353 B CN105348353 B CN 105348353B CN 201510640421 A CN201510640421 A CN 201510640421A CN 105348353 B CN105348353 B CN 105348353B
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steroid
autoclave
ketone group
mol ratio
transition metal
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CN201510640421.5A
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CN105348353A (en
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陈新志
赵倩
钱超
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Zhejiang University ZJU
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Zhejiang University ZJU
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention discloses a kind of preparation method of 24 ketone group steroid, comprise the following steps:1), first by steroid and 2,2,6,6 tetramethyl piperidine nitrogen oxides, nitrite tert-butyl, transition metal salt and solvent are added in autoclave, kettle are closed, first with the air in inert gas replacement autoclave, oxygen is re-filled with until pressure is 0.1~1.0Mpa, react at room temperature, when the pressure in autoclave no longer changes, terminate reaction;2), by step 1) gained reaction solution solvent evaporated, recrystallized using methyl alcohol, obtain 24 ketone group steroids.24 ketone group steroids are prepared using the method for the present invention, gentle with rational technology, reaction condition, high income is simple to operate, the features such as environment-friendly.

Description

The preparation method of 24- ketone group steroids
Technical field
The present invention relates to a kind of method that 24- ketone group steroids are prepared by 24- hydroxy steroids.
Background technology
24- ketone group steroids are isolated a kind of materials from organism, with important physiologically active, no Only it is to prepare vitamin D3The important as precursors of derivative, be also prepare it is a series of with 24- methylene based structures marine steroids chemical combination The important as precursors of thing, wherein, the marine steroids compound with 24- methylene based structures be widely used in it is antitumor, antibacterial with And during the preventing and treating of cardiovascular and cerebrovascular disease, the important as precursors synthesized accordingly, as it, the synthesis of 24- ketone group steroids Technique can largely restrict the condition of production of such compound.
In the prior art, the main method of synthesis 24- ketone group steroids is the C-24 hydroxyls oxidation based on chromium reagent Technique, conventional chromium reagent such as (Steroids, 2009,74,81-87.J.Chem.Research such as Jones reagents, PCC (S),1998,206-207.Russ.J.Bioor.Chem.2002,28,284-288).When using chromium reagent as oxidant, Although with yield higher, chromium reagent toxicity is big, and toxic wastewater welding does not meet the principle of Green Chemistry, together yet When, post processing is also complex, economical big with environmentally limitation.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of rational technology, reaction condition gently, high income, operation letter Singly, the preparation method of environment-friendly 24- ketone group steroids.
In order to solve the above-mentioned technical problem, a kind of preparation method of 24- ketone groups steroid of present invention offer, including with Lower step:
1), first by steroid and 2,2,6,6- tetramethyl piperidine-nitrogen-oxide (TEMPO) shown in formula (II), Nitrite tert-butyl (TBN), transition metal salt and solvent are added in (sequentially adding) autoclave, close kettle, first use inert gas Air in displacement autoclave, is re-filled with oxygen up to pressure is 0.1~1.0Mpa, reacts at room temperature, treats autoclave When interior pressure no longer changes, terminate reaction;
Shown steroid is 1 with the mol ratio of 2,2,6,6- tetramethyl piperidines-nitrogen-oxide (TEMPO):0.01~ 0.2, shown steroid is 1 with the mol ratio of nitrite tert-butyl (TBN):0.01~0.2, shown steroid and mistake The mol ratio for crossing slaine is 1:0.01~0.2;
2), by step 1) gained reaction solution solvent evaporated, recrystallized using methyl alcohol, obtain the 24- ketone groups described in formula (I) Steroid;
Steroid shown in formula (II), as:3- acetyl group -24- hydroxy cholesterols.
24- ketone group steroids described in formula (I), as:3- acetyl group -24- ketone group cholesterol.
Remarks explanation:
Step 1) gained reaction solution solvent evaporated after gains, mainly include product 24- ketone group steroids it is (insoluble In methyl alcohol), the catalyst (being dissolved in methyl alcohol) also including TEMPO, the TBN as residual components etc..
Room temperature generally refers to 15~25 DEG C.
During the course of the reaction, the pressure in autoclave can decline, and when pressure no longer declines, terminate reaction.
As the improvement of the preparation method of 24- ketone groups steroid of the invention:Transition metal salt is iron chloride (trichlorine Change iron), ferric sulfate, ferric nitrate, ferrous sulfate, copper chloride.
As the further improvement of the preparation method of 24- ketone groups steroid of the invention:Step 1) in solvent be Dichloromethane, dichloroethanes, ethyl acetate, acetonitrile, toluene, chlorobenzene (preferably dichloroethanes, less preferred dichloromethane).
As the further improvement of the preparation method of 24- ketone groups steroid of the invention:
The oxygen pressure is 0.4~1.0Mpa,
The steroid is 1 with the mol ratio of 2,2,6,6- tetramethyl piperidines-nitrogen-oxide:0.05~0.2,
The steroid is 1 with the mol ratio of nitrite tert-butyl:0.04.
As the further improvement of the preparation method of 24- ketone groups steroid of the invention:
The transition metal salt is CuCl2Or FeCl3, the steroid and FeCl3Mol ratio be 1:0.05~ 0.2, the steroid and CuCl2Mol ratio be 1:0.05.
In the present invention, it is however generally that, the steroid shown in formula (II) per 5mmol, 20~30mL's of adapted is molten Agent.
The preparation method of 24- ketone groups steroid of the invention has following technical advantage:
1), by the use of oxygen as oxidant, green, environmental protection, oxidant is inexpensive, and source is wide for the present invention, the original of whole reaction Subeconomy is high, and the accessory substance of reaction is only water, environment-friendly, with preferable prospects for commercial application;
2), reaction can be carried out at ambient temperature, and reaction condition is gentle, simple to operate;
3) suitable catalyst, is have selected, so as to obtain preferable yield.
Specific embodiment
Embodiment 1, a kind of preparation method of 24- ketone groups cholesterol, follow the steps below successively:
By 2.22g (5mmol) 3- acetyl group -24- hydroxy cholesterols, 0.04gTEMPO (0.25mmol), 0.02gTBN (0.2mmol), 0.04g ferric trichlorides (0.25mmol) are added sequentially in autoclave, while addition 20mL dichloroethanes (as Solvent), kettle is closed, using oxygen is filled with after nitrogen displacement three times, make its initial pressure for 0.4MPa, stirring is opened, at room temperature Reaction, when pressure gauge registration no longer declines, reaction terminates, pressure release, drives kettle.
After reaction terminates, solvent is removed using Rotary Evaporators, product 3- second can be obtained after absolute methanol (50ml) recrystallization Acyl group -24- ketone group cholesterol 1.88g, yield:86.2%, purity is 99%.Fusing point:126-128℃.1H NMR(CDCl3, 400MHz):δ 5.30 (d, J=4.2Hz, 1H), 4.53 (m, 1H), 1.96 (s, 3H), 0.95 (s, 3H), 0.85 (d, J= 6.5Hz,3H),0.61(s,3H).13C NMR(CDCl3,100MHz):δ214.41,169.51,138.63,121.59,72.95, 55.65,54.87,48.99,41.35,39.82,38.70,37.10,36.19,35.98,35.57,34.35,30.85, 28.83,27.10,26.76,23.24,20.41,20.01,18.29,17.50,17.36,17.29,10.86。
Embodiment 2~7:
Change the species and consumption (as shown in table 1) of transition metal salt, remaining is equal to embodiment 1, obtains embodiment 2~7; The yield of products therefrom is as shown in table 1 below:
Table 1
Embodiment Transition metal salt/mmol Yield
2 Fe(NO3)3.9H2O/0.25 38.5
3 Fe2(SO4)3.6H2O/0.25 30.0
4 FeSO4.7H2O/0.25 29.8
5 CuCl2/0.25 80.0
6 FeCl3/0.05 45.5
7 FeCl3/1.0 80.1
Embodiment 8~11:Change the consumption of TEMPO and TBN, remaining is equal to embodiment 1, obtains embodiment 8~11;Institute The yield for obtaining product is as shown in table 2 below:
Table 2
Embodiment TBN/mmol TEMPO/mmol Yield
8 0.2 0.05 20.9
9 0.2 1.0 85.9
10 0.05 0.25 15.8
11 1.0 0.25 59.8
Embodiment 12~15:
Change oxygen pressure, remaining is equal to embodiment 1, obtains embodiment 12~15;The yield of products therefrom such as table 3 below institute Show:
Table 3
Embodiment Oxygen pressure/MPa Yield
12 0.2 62.8
13 0.6 85.5
14 0.8 86.0
15 1.0 85.2
Embodiment 16~20
Change solvent used, remaining is equal to embodiment 1, obtains embodiment 16~20;The yield of products therefrom such as table 4 below It is shown:
Table 4
Embodiment Solvent Yield
16 Dichloromethane 80.0
17 Ethyl acetate 20.0
18 Acetonitrile 25.8
19 Toluene 40.9
20 Chlorobenzene 58.0
Comparative example 1 is serial, make the TEMPO in embodiment 1 into NHPI, 4-OH-TEMPO, and remaining is equal to embodiment 1, The yield of products therefrom is as shown in table 5 below:
Table 5
Comparative example The substitute of TEMPO Yield
1-1 NHPI 0
1-2 4-OH-TEMPO 52.4
Comparative example 2 is serial, make the TBN in embodiment 1 into NaNO2、Fe(NO3)3.9H2O, remaining is equal to embodiment 1, The yield of products therefrom is as shown in table 6 below:
Table 6
Comparative example The substitute of TBN Yield
2-1 NaNO2 40.7
2-2 Fe(NO3)3.9H2O 48.3
Comparative example 3, the use for cancelling " 0.04g ferric trichlorides (0.25mmol) " in embodiment 1, accordingly by TEMPO's Consumption makes 0.5mmol into by 0.25mmol, and remaining is equal to embodiment 1, and the yield of products therefrom is 30.1%.
Comparative example 4, the use for cancelling " 0.04g ferric trichlorides (0.25mmol) " in embodiment 1, accordingly by the use of TBN Amount makes 0.45mmol into by 0.2mmol, and remaining is equal to embodiment 1, and the yield of products therefrom is 37.2%.
Finally, in addition it is also necessary to it is noted that listed above is only some specific embodiments of the invention.Obviously, the present invention Above example is not limited to, there can also be many deformations.One of ordinary skill in the art can be straight from present disclosure The all deformations derived or associate are connect, protection scope of the present invention is considered as.

Claims (2)

  1. The preparation method of 1.24- ketone group steroids, it is characterised in that comprise the following steps:
    1), first by steroid and 2,2,6,6- tetramethyl piperidine-nitrogen-oxide, the tertiary fourth of nitrous acid shown in formula (II) Ester, transition metal salt and solvent are added in autoclave, close kettle, first with the air in inert gas replacement autoclave, are re-filled with Oxygen is 0.4~1.0Mpa up to pressure, is reacted at room temperature, when the pressure in autoclave no longer changes, knot Shu Fanying;
    Shown steroid is 1 with the mol ratio of 2,2,6,6- tetramethyl piperidines-nitrogen-oxide:0.05~0.2, shown steroid Class compound is 1 with the mol ratio of nitrite tert-butyl:0.04, shown steroid is 1 with the mol ratio of transition metal salt: 0.01~0.2;The transition metal salt is iron chloride, copper chloride, and the solvent is dichloromethane, dichloroethanes;
    2), by step 1) gained reaction solution solvent evaporated, recrystallized using methyl alcohol, obtain the 24- ketone group steroids described in formula (I) Compound;
  2. 2. the preparation method of 24- ketone groups steroid according to claim 1, it is characterised in that:
    The transition metal salt is CuCl2Or FeCl3, the steroid and FeCl3Mol ratio be 1:0.05~0.2, institute State steroid and CuCl2Mol ratio be 1:0.05.
CN201510640421.5A 2015-10-01 2015-10-01 The preparation method of 24 ketone group steroids Expired - Fee Related CN105348353B (en)

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CN108084040B (en) * 2018-01-04 2020-09-08 浙江大学 Synthesis method of N, N, N '-trimethyl-N' -hydroxyethyl bisaminoethylether

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387251A (en) * 2014-11-10 2015-03-04 江西仁明医药化工有限公司 Method for synthesizing 2-norbornane ketone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387251A (en) * 2014-11-10 2015-03-04 江西仁明医药化工有限公司 Method for synthesizing 2-norbornane ketone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A facile synthesis of C-24 and C-25 oxysterols by in situ generated ethyl(trifluoromethyl)dioxirane;Shoujiro Ogawa et al.;《steroids》;20081019;第74卷;81-87 *

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