CN109053855B - Synthesis method of 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone - Google Patents
Synthesis method of 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone Download PDFInfo
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- CN109053855B CN109053855B CN201811166826.XA CN201811166826A CN109053855B CN 109053855 B CN109053855 B CN 109053855B CN 201811166826 A CN201811166826 A CN 201811166826A CN 109053855 B CN109053855 B CN 109053855B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, and discloses a preparation method of rocuronium bromide important intermediate 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone, which comprises the following steps of (1) adding 17-acetoxy androstane-2 α,16 α -diepoxide, pyrrolidine and silica gel into a ball milling tank, and reacting under a certain mechanical grinding frequency, and (2) carrying out post-treatment and recrystallization on a reaction mixture to obtain 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone.
Background
Rocuronium bromide is a novel non-depolarizing sterol muscle relaxant, has the advantages of quick response, no accumulation in vivo, no histamine release, weak inhibition effect on cardiovascular system, no anaphylactoid reaction and the like, and becomes a novel anesthetic drug for replacing succinylcholine.
In the prior art, 17-acetoxyandrostane-2 α,16 α -diepoxide is used as a raw material, and the 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone (WO2007033348A2) is prepared by two steps of hydrolysis and pyrrolidine ring opening under an alkaline condition.
The mechanical ball milling method not only can greatly reduce the use of solvents in the reaction process, but also can solve the problems of long reaction time, poor selectivity, low yield, troublesome post-treatment and the like of the traditional synthetic method to a certain extent.
Disclosure of Invention
The invention aims to overcome the defects of poor selectivity, difficult separation of impurities, large waste liquid amount and the like of the conventional method for synthesizing 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone, and provides a novel method for synthesizing 16 β -tetrahydropyrrole androstane-2 α -epoxy-17-ketone, which has high yield, little environmental pollution, simplicity and high efficiency.
In order to achieve the purpose of the invention, the invention specifically adopts the following technical scheme:
a preparation method of 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone shown as a formula II is characterized by comprising the following steps:
(1) adding 17-acetoxyandrostane-2 α,16 α -diepoxide shown in formula I, pyrrolidine, stainless steel balls and silica gel into a ball milling tank, and setting the operating frequency of the ball mill within the range of 5-20Hz to perform mechanical grinding reaction;
(2) carrying out post-treatment and recrystallization on the reaction mixture to obtain 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone shown in a formula II;
the feeding molar ratio of the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula (I) to the pyrrolidine is 1: 0.8-20;
the feeding mass ratio of the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula I to the silica gel is 1: 2-20.
Preferably, the feeding molar ratio of the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula I to the pyrrolidine is 1: 1-8.
Preferably, the 17-acetoxyandrostane-2 α,16 represented by formula I
α -the feeding mass ratio of the diepoxide to the silica gel is 1: 2-10.
Preferably, the operating frequency of the ball mill is set within the range of 8-16 Hz.
Preferably, the total time of the mechanical ball milling reaction is 10 to 60 minutes.
Preferably, the recrystallization solvent is one or a mixture of two or more of methanol, ethanol, isopropanol, ethyl acetate, acetone, n-hexane, petroleum ether and water.
The post-treatment method of the reaction mixture comprises the following steps: after the reaction is finished, transferring the reaction mixture from the ball milling tank to a beaker, adding a small amount of organic solvent for soaking, filtering, and directly concentrating the filtrate to be dry.
Preferably, the soaking solvent in the post-treatment process is one or a mixed solvent of more than two of ethyl acetate, dichloromethane, acetone, n-hexane, toluene, tetrahydrofuran and petroleum ether.
Preferably, the volume mass ratio of the soaking solvent to the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula (I) is 5-10: 1.
Compared with the prior art, the invention has the beneficial effects that:
1) the reaction steps are reduced from two steps to one step, the reaction selectivity is good, and the yield is high.
2) Organic solvent is not needed in the mechanical grinding reaction process, so that the use of the organic solvent in the preparation process is greatly reduced.
3) Simple operation and simple post-treatment, and compared with the prior separation technology of elutriation products, the separation and purification of the products by recrystallization can greatly reduce the amount of three wastes.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1
3.46g (10mmol) of 17-acetoxyandrostane-2 α,16 α -diepoxide, 6g (50mmol) of pyrrolidine and 17.3g of silica gel are added into a ball mill pot, the operation frequency of the ball mill is set to be 15Hz, the mechanical grinding is stopped after 20 minutes, the whole reaction mixture is transferred from the grinding pot to a 50mL beaker, 20mL of dichloromethane is added for soaking for 1 hour, the filtration is carried out, the filtrate is concentrated to be dry, and a mixed solvent (10:1) of methanol and water is added for recrystallization, so that 3.21g of white solid 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone is obtained, and the yield is 90%.
The specific characteristics of the product were determined as follows:
melting point: 167.2-168.9 ℃ of the total weight of the mixture,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.
example 2
The procedure is followed as in example 1, except that in step (1) the molar ratio of 17-acetoxyandrost-2 α,16 α -diepoxide to pyrrolidine is adjusted to 1:3, giving a yield of 78%.
Example 3
The procedure is followed as in example 1, except that in step (1) the molar ratio of 17-acetoxyandrost-2 α,16 α -diepoxide to pyrrolidine is adjusted to 1:8, giving a yield of 94%.
Example 4
The procedure is as in example 1, except that in step (1) the mass ratio of 17-acetoxyandrost-2 α,16 α -diepoxide to silica gel is adjusted to 1:3, giving a yield of 80%.
Example 5
The procedure is as in example 1, except that in step (1) the mass ratio of 17-acetoxyandrost-2 α,16 α -diepoxide to silica gel is adjusted to 1:10, giving a yield of 88%.
Example 6
The method and procedure of example 1 were followed except that the mechanical ball milling reaction time was adjusted to 10 minutes in the step (1) and the yield was 81%.
Example 7
The method and procedure of example 1 were followed except that the mechanical ball milling reaction time was adjusted to 50 minutes in the step (1) and the yield was 91%.
Example 8
The procedure and steps of example 1 were followed except that the recrystallization solvent was changed to ethanol in step (1), and the yield was 65%.
Example 9
The method and procedure of example 1 were followed, except that in step (1) the recrystallization solvent was changed to n-hexane: ethyl acetate (10:1) yield 78%.
Example 10
The procedure and steps of example 1 were followed, except that in step (1) the recrystallization solvent was changed to acetone: water (10:1) in 76% yield.
Example 11
The procedure and procedure of example 1 were followed, except that the immersion solvent in the work-up procedure in step (1) was changed to ethyl acetate, yielding 92%.
Example 12
The procedure and steps of example 1 were followed except that the immersion solvent in the post-treatment in step (1) was changed to acetone, resulting in a yield of 89%.
Claims (9)
1. A preparation method of 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone shown as a formula II is characterized by comprising the following steps:
(1) adding 17-acetoxyandrostane-2 α,16 α -diepoxide shown in formula I, pyrrolidine, stainless steel balls and silica gel into a ball milling tank, and setting the operating frequency of the ball mill within the range of 5-20Hz to perform mechanical grinding reaction;
(2) carrying out post-treatment and recrystallization on the reaction mixture to obtain 16 β -tetrahydropyrrolyl androstane-2 α -epoxy-17-ketone shown in a formula II;
the feeding molar ratio of the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula (I) to the pyrrolidine is 1:0.8-20, and the feeding mass ratio of the 17-acetoxyandrostane-2 α,16 α -diepoxide shown in the formula (I) to the silica gel is 1: 2-20.
2. The preparation method of claim 1, wherein the molar ratio of 17-acetoxyandrost-2 α,16 α -diepoxide represented by formula (I) to pyrrolidine is 1: 1-8.
3. The preparation method of claim 1, wherein the feeding mass ratio of the 17-acetoxyandrost-2 α,16 α -diepoxide represented by the formula (I) to the silica gel is 1: 2-10.
4. The method according to claim 1, wherein the operation frequency of the ball mill is set to 8 to 16 Hz.
5. The method of claim 1, wherein the total time of the ball milling reaction is 10 to 60 minutes.
6. The method according to claim 1, wherein the recrystallization solvent is one or a mixture of two or more of methanol, ethanol, isopropanol, ethyl acetate, acetone, n-hexane, petroleum ether, and water.
7. The process according to claim 1, wherein the post-treatment of the reaction mixture comprises: after the reaction is finished, transferring the reaction mixture from the ball milling tank to a beaker, adding a small amount of organic solvent for soaking, filtering, and directly concentrating the filtrate to be dry.
8. The method according to claim 7, wherein the organic solvent is one or more of ethyl acetate, dichloromethane, acetone, n-hexane, toluene, tetrahydrofuran, and petroleum ether.
9. The preparation method of claim 7, wherein the volume-to-mass ratio of the organic solvent to the 17-acetoxyandrostane-2 α,16 α -diepoxide represented by formula I is 5-10: 1.
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