CN109053855A - A kind of synthetic method of-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane - Google Patents
A kind of synthetic method of-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane Download PDFInfo
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- CN109053855A CN109053855A CN201811166826.XA CN201811166826A CN109053855A CN 109053855 A CN109053855 A CN 109053855A CN 201811166826 A CN201811166826 A CN 201811166826A CN 109053855 A CN109053855 A CN 109053855A
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- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
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Abstract
The present invention relates to pharmaceutical chemistry technical fields, disclose a kind of preparation method of-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane of rocuronium important intermediate, the preparation method the following steps are included: (1) in ball grinder,-2 α of 17- Acetoxyandrost is added together, 16 α-di-epoxide, pyrrolidines and silica gel are reacted under certain mechanical lapping frequency；(2) reaction mixture is post-treated and by being recrystallized to give-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane.Preparation method of the present invention has many advantages, such as that reaction yield is high, the time is short, selectivity is good, easy to operate, pollution is few, is a kind of green chemical synthesis method with preferable popularization and application foreground.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical fields, and in particular to -2 alpha-epoxy-17 of a kind of 16 beta-tetrahydro pyrrole radicals androstane -
The preparation method of ketone.
Background technique
- 2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane is to synthesize the important intermediate of rocuronium.Rocuronium is
A kind of novel non depolarization sterol muscle relaxant, have it is rapid-action, in vivo without accumulation, without histamine release, to cardiovascular system press down
Production has become the novel narcotics for substituting Scoline with weak and without advantages such as anaphylactoid reactions.Clinically, Luo Ku
Bromine ammonium is widely used in operations on cranium and brain, Ophthalmic Emergency operation and the anesthesia of potential renal insufficiency patient etc..
Before the present invention, existing technology be with -2 α of 17- Acetoxyandrost, 16 α-di-epoxide as raw material,
16-2 α of beta-tetrahydro pyrrole radicals androstane-epoxy-is prepared by hydrolyzed under basic conditions and pyrrolidines open loop two-step reaction
17- ketone (WO2007033348A2).The disadvantages of this method is as follows: needing using a large amount of organic solvents, and reacts and need to return in high temperature
It is carried out under the conditions of stream；Reaction selectivity is poor, and impurity separating difficulty is high；The method that the separation of product uses elutriation generates a large amount of
Waste liquid is not easily recycled processing.
An important directions of the mechanico-chemical reaction technology that organic solvent-free participates in as the development of Green Chemistry, have become
For one of the research hotspot of organic synthesis field in recent years.Mechanical attrition method can not only substantially reduce the solvent in reaction process
It uses, can also solve that prior synthesizing method such as reaction time length, poor selectivity, yield is low, post-processing is numb to a certain extent
The problems such as tired.Therefore, a kind of efficient, environmental protection and easily industrialization -2 alpha-epoxy-17 of 16 beta-tetrahydro pyrrole radicals androstane-is developed
Ketone synthetic method, economic and social benefit with higher.
Summary of the invention
The purpose of the present invention is to solve existing-2 alpha-epoxy-17 -one synthetic method institutes of 16 beta-tetrahydro pyrrole radicals androstane
The defects of existing poor selectivity, impurity are not readily separated and waste liquid amount is big provides a kind of high income, low in the pollution of the environment, easy to be high
The new method of-2 alpha-epoxy-17 -one of the 16 beta-tetrahydro pyrrole radicals androstane synthesis of effect.
In order to achieve the above object of the invention, the present invention specifically uses following technical scheme:
A kind of preparation method of-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane shown in Formula II, it is characterised in that institute
The preparation method stated the following steps are included:
(1) in ball grinder, -2 α of 17- Acetoxyandrost shown in Formulas I, 16 α-di-epoxide, pyrroles are added together
Alkane, stainless steel ball and silica gel, setting ball mill running frequency carry out mechanical lapping reaction within the scope of 5-20Hz；
(2) reaction mixture is post-treated and is recrystallized to give 16-2 α of beta-tetrahydro pyrrole radicals androstane-ring shown in Formula II
Oxygen -17- ketone；
- 2 α of 17- Acetoxyandrost shown in the formula (I), the molar ratio of 16 α-di-epoxide and pyrrolidines
For 1:0.8-20；
The mass ratio that feeds intake of -2 α of 17- Acetoxyandrost shown in the Formulas I, 16 α-di-epoxide and silica gel is
1:2-20。
Preferably, -2 α of 17- Acetoxyandrost shown in the Formulas I, 16 α-di-epoxide feed intake with pyrrolidines
Molar ratio is 1:1-8.
Preferably, -2 α of 17- Acetoxyandrost shown in the Formulas I, 16
The mass ratio that feeds intake of α-di-epoxide and silica gel is 1:2-10.
Preferably, the ball mill running frequency setting range is 8-16Hz.
Preferably, the total time of the mechanical ball mill reaction is 10-60 minutes.
Preferably, the recrystallization solvent uses methanol, ethyl alcohol, isopropanol, ethyl acetate, acetone, n-hexane, stone
The mixed solvent of one or more of oily ether, water.
The reaction mixture post-processing approach are as follows: after reaction, reaction mixture is transferred to from ball grinder
Beaker adds a small amount of organic solvent to impregnate, is directly thickened to do by filtrate after filtering.
Preferably, immersion solvent in the last handling process be ethyl acetate, methylene chloride, acetone, n-hexane,
The mixed solvent of one or more of toluene, tetrahydrofuran, petroleum ether.
Preferably, -2 α of 17- Acetoxyandrost shown in the immersion solvent and formula (I), 16 α-di-epoxide
Volume mass ratio is 5-10:1.
The present invention compared with prior art, has the beneficial effect that:
1) reaction step is reduced to a step, good reaction selectivity, high income by two steps.
2) mechanical lapping reaction process is without using organic solvent, to drastically reduce organic solvent in preparation process
Use.
3) easy to operate, post-processing is simple, compares more existing elutriation product isolation technics, is divided by way of recrystallization
Quantity of three wastes can be greatly reduced from purified product.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Embodiment 1
- 2 α of 3.46g (10mmol) 17- Acetoxyandrost, 16 α-di-epoxide, 6g are added in ball grinder
(50mmol) pyrrolidines and 17.3g silica gel set ball mill running frequency as 15Hz, and mechanical lapping stops after twenty minutes.It will be complete
Portion's reaction mixture is transferred in 50mL beaker from grinding pot, and 20mL methylene chloride is added and impregnates 1 hour.Filtering, filtrate is dense
It is reduced to after doing, the mixed solvent (10:1) that methanol and water is added recrystallizes, and obtains 16 beta-tetrahydro pyrrole radicals androstane -2 of white solid
Alpha-epoxy-17 -one 3.21g, yield 90%.
Through detecting, the concrete property of product is as follows:
Fusing point: 167.2-168.9 DEG C,1H NMR(400MHz,CDCl3)δ3.18-3.12(m,2H),2.94-2.90(m,
1H),2.78-2.72(m,2H),2.62-2.60(m,2H),2.17-2.08(m,1H),1.96-1.91(m,2H),1.85-1.71
(m,5H),1.67-0.95(m,13H),0.91(s,3H),0.80(s,3H),0.75-0.68(m,1H).13C NMR(100MHz,
CDCl3)218.7,69.1,54.0,52.3,51.8,50.9,47.6,47.0,38.2,36.3,34.5,33.9,32.0,30.7,
29.0,28.1,26.6,23.2,20.1,14.0,12.9.
Embodiment 2
It is only that in step (1) with step, difference by -2 α of 17- Acetoxyandrost, 16 α-according to the method for embodiment 1
The molar ratio of di-epoxide and pyrrolidines is adjusted to 1:3, yield 78%.
Embodiment 3
It is only that in step (1) with step, difference by -2 α of 17- Acetoxyandrost, 16 α-according to the method for embodiment 1
The molar ratio of di-epoxide and pyrrolidines is adjusted to 1:8, yield 94%.
Embodiment 4
It is only that in step (1) with step, difference by -2 α of 17- Acetoxyandrost, 16 α-according to the method for embodiment 1
The mass ratio of di-epoxide and silica gel is adjusted to 1:3, yield 80%.
Embodiment 5
It is only that in step (1) with step, difference by -2 α of 17- Acetoxyandrost, 16 α-according to the method for embodiment 1
The mass ratio of di-epoxide and silica gel is adjusted to 1:10, yield 88%.
Embodiment 6
According to the method for embodiment 1 and step, difference, which is only that in step (1), is adjusted to 10 for the mechanical ball mill reaction time
Minute, yield 81%.
Embodiment 7
According to the method for embodiment 1 and step, difference, which is only that in step (1), is adjusted to 50 for the mechanical ball mill reaction time
Minute, yield 91%.
Embodiment 8
According to the method for embodiment 1 and step, difference, which is only that in step (1), is changed to ethyl alcohol, yield for recrystallization solvent
It is 65%.
Embodiment 9
According to the method for embodiment 1 and step, difference, which is only that in step (1), is changed to n-hexane for recrystallization solvent: second
Acetoacetic ester (10:1), yield 78%.
Embodiment 10
According to the method for embodiment 1 and step, difference, which is only that in step (1), is changed to acetone for recrystallization solvent: water
(10:1), yield 76%.
Embodiment 11
According to the method for embodiment 1 and step, difference, which is only that, changes the immersion solvent in step (1) in last handling process
For ethyl acetate, yield 92%.
Embodiment 12
According to the method for embodiment 1 and step, difference, which is only that, changes the immersion solvent in step (1) in last handling process
For acetone, yield 89%.
Claims (9)
1. the preparation method of-2 alpha-epoxy-17 -one of 16 beta-tetrahydro pyrrole radicals androstane shown in a kind of Formula II, it is characterised in that described
Preparation method the following steps are included:
(1) in ball grinder, together be added Formulas I shown in -2 α of 17- Acetoxyandrost, 16 α-di-epoxide, pyrrolidines,
Stainless steel ball and silica gel, setting ball mill running frequency carry out mechanical lapping reaction within the scope of 5-20Hz；
(2) reaction mixture is post-treated and is recrystallized to give -2 alpha-epoxy-17 of 16 beta-tetrahydro pyrrole radicals androstane-shown in Formula II
Ketone；
2. preparation method according to claim 1, it is characterised in that 17- Acetoxyandrost -2 shown in the formula (I)
α, 16 α-di-epoxide and pyrrolidines molar ratio are 1:0.8-20, preferably 1:1-8.
3. preparation method according to claim 1, it is characterised in that 17- Acetoxyandrost -2 shown in the formula (I)
The mass ratio that feeds intake of α, 16 α-di-epoxide and silica gel is 1:2-20, preferably 1:2-10.
4. preparation method according to claim 1, it is characterised in that set ball mill running frequency is 5-20Hz, excellent
Select 8-16Hz.
5. preparation method according to claim 1, it is characterised in that the total time of the ball-milling reaction is 10-60 minutes.
6. preparation method according to claim 1, it is characterised in that the recrystallization solvent is using methanol, ethyl alcohol, different
The mixed solvent of one or more of propyl alcohol, ethyl acetate, acetone, n-hexane, petroleum ether, water.
7. preparation method according to claim 1, it is characterised in that the reaction mixture post-processing approach are as follows: reaction
After, reaction mixture is transferred to beaker from ball grinder, a small amount of organic solvent is added to impregnate, it is after filtering that filtrate is directly dense
It is reduced to dry.
8. preparation method according to claim 7, it is characterised in that the organic solvent is ethyl acetate, dichloromethane
The mixed solvent of one or more of alkane, acetone, n-hexane, toluene, tetrahydrofuran, petroleum ether.
9. preparation method according to claim 7, it is characterised in that 17- acetyl oxygen shown in the organic solvent and Formulas I
- 2 α of base androstane, the volume mass ratio of 16 α-di-epoxide are 5-10:1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437169A (en) * | 2022-01-25 | 2022-05-06 | 台州仙琚药业有限公司 | Synthesis method of drospirenone key intermediate bromide |
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| CN1090852A (en) * | 1992-11-02 | 1994-08-17 | 佐尔坦·图巴 | Androstane derivative and pharmaceutical composition thereof and preparation method |
| WO2007033348A2 (en) * | 2005-09-13 | 2007-03-22 | Sicor, Inc. | Process for the synthesis of rocuronium bromide |
| CN101323636A (en) * | 2007-06-15 | 2008-12-17 | 复旦大学 | Preparation of rocuronium |
| CN101381390A (en) * | 2007-09-05 | 2009-03-11 | 王加旺 | Synthetic method of bromamines muscle relaxant |
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2018
- 2018-10-08 CN CN201811166826.XA patent/CN109053855B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1090852A (en) * | 1992-11-02 | 1994-08-17 | 佐尔坦·图巴 | Androstane derivative and pharmaceutical composition thereof and preparation method |
| WO2007033348A2 (en) * | 2005-09-13 | 2007-03-22 | Sicor, Inc. | Process for the synthesis of rocuronium bromide |
| CN101323636A (en) * | 2007-06-15 | 2008-12-17 | 复旦大学 | Preparation of rocuronium |
| CN101381390A (en) * | 2007-09-05 | 2009-03-11 | 王加旺 | Synthetic method of bromamines muscle relaxant |
Non-Patent Citations (2)
| Title |
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| 严昕等: "罗库溴铵重要中间体17β-羟基-16β-四氢吡咯基雄甾-2(3)α-环氧化合物的合成工艺改进", 《复旦大学（医学版）》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114437169A (en) * | 2022-01-25 | 2022-05-06 | 台州仙琚药业有限公司 | Synthesis method of drospirenone key intermediate bromide |
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