CN109320494B - Raloxifene derivative and preparation method thereof - Google Patents
Raloxifene derivative and preparation method thereof Download PDFInfo
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- CN109320494B CN109320494B CN201811329107.5A CN201811329107A CN109320494B CN 109320494 B CN109320494 B CN 109320494B CN 201811329107 A CN201811329107 A CN 201811329107A CN 109320494 B CN109320494 B CN 109320494B
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- raloxifene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
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Abstract
The invention discloses a raloxifene derivative, the molecular structural formula of which is
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a raloxifene derivative and a preparation method thereof.
Background
Raloxifene is used as a selective estrogen receptor modulator and an anti-tubulin agent and is mainly used for treating female postmenopausal osteoporosis. Its derivative DRL527 was found to be a mutation-selective antagonist for ERA (E353A) and ERb (E305A). Other relevant information has also been reported for raloxifene derivatization as polymerization inhibitors and as inhibitors of acetyl-coa carboxylase.
Given their importance in medicinal chemistry, the development of efficient methods for synthesizing raloxifene derivatives is of great importance to chemists. Classical methods for the synthesis of raloxifene rely on intermolecular Friedel-Crafts acylation6But are generally limited in the formation of environmentally harmful HCl, poor regioselectivity and functional group tolerance. The synthesis of raloxifene derivatives therefore often requires complex reaction starting materials.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the raloxifene derivative with simple raw materials and reaction conditions.
In order to achieve the purpose, the invention provides the following technical scheme:
a raloxifene derivative is provided,
the molecular structural formula is
As another object of the present invention, there is provided a method for producing raloxifene derivatives,
the method comprises the following steps:
reacting a compound I and a compound II in a solvent under the action of an Ag catalyst and an oxidant to obtain a compound III;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
the structural formula of the compound III is as follows:
step two:
reacting the compound III with NaSEt in a solvent to obtain a compound IV;
the structural formula of the compound IV is as follows:
step three:
reacting the compound IV with 1- (2-chloroethyl) piperidine, CsCO3 and KI to obtain a raloxifene derivative;
the raloxifene derivative has a structural formula of
As a further improvement of the invention:
the oxidant in the step one is K2S2O8。
As a further improvement of the invention:
the catalyst in the first step is silver nitrate.
As a further improvement of the invention:
the solvent in the first step is CH with the volume ratio of 1: 13CN and H2A mixture of O.
As a further improvement of the invention:
the first step is carried out in a nitrogen atmosphere, the reaction temperature is 60-80 ℃, and the reaction time is 8-12 hours.
As a further improvement of the invention:
the solvent in the second step is DMF;
as a further improvement of the invention:
and the reaction temperature of the second step is 70-90 ℃.
As a further improvement of the invention:
and the reaction time of the second step is 3-5 hours.
As a further improvement of the invention:
and the third step is carried out at room temperature for 12-16 hours.
In the invention, mainly provides a
The raloxifene derivative prepared by the method has the advantages of simple raw materials, easily-achieved reaction conditions, high yield and no harmful substances generated in the reaction process, and is the raloxifene derivative with simple raw materials and reaction conditions.
Detailed Description
Example (b):
the method comprises the following steps:
reacting the compound I and the compound II in a solvent under the action of an Ag catalyst and an oxidant to obtain a compound II;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
the structural formula of the compound III is as follows:
step two:
reacting the compound III with NaSEt in a solvent to obtain a compound IV;
the structural formula of the compound IV is as follows:
step three:
mixing compound IV with 1- (2-chloroethyl) piperidine and CsCO3Performing a reaction on KI to obtain a raloxifene derivative;
the raloxifene derivative has a structural formula of
The oxidant in the step one is K2S2O8。
The catalyst in the first step is silver nitrate.
The solvent in the first step is CH with the volume ratio of 1: 13CN and H2A mixture of O.
The first step is carried out in a nitrogen atmosphere, the reaction temperature is 60-80 ℃, and the reaction time is 8-12 hours.
The solvent in the second step is DMF;
and the reaction temperature in the second step is 70-90 ℃.
And the reaction time in the second step is 3-5 hours.
And reacting at room temperature for 12-16 hours in the third step.
The specific reaction equation is as follows:
wherein, the dosage of each substance in the step one is as follows:
a compound I: 0.2mol of
Compound II: 0.6mol
Silver nitrate: 0.02mmol
K2S2O8：0.6mmol
CH with volume ratio of 1: 13CN and H21.2mL of a mixture of O;
the dosage of each substance in the step two:
NaSEt: 1.5 equivalents
DMF: excess;
the dosage of each substance in the step three is as follows:
1- (2-chloroethyl) piperidine: 1.1 equivalent
CsCO3: 2.0 equivalent
KI：2mol％。
The structural data of the compound III confirmed by nuclear magnetic resonance are as follows:
Following the general procedure，using petroleum ether/AcOEt(10∶1)asthe eluant to afford yellow soild(79％yield).1H NMR(500MHz，DMSO-d6)δ7.69(d，J＝9.0Hz，2H)，7.63(s，1H)，7.34-7.30(m，3H)，7.00-6.98(m，1H)，6.91-6.86(m，4H)，3.83(s，3H)，3.75(s，3H)，3.69(s，3H)；13C NMR(125MHz，DMSO-d6)δ192.3，163.6，159.5，157.4，140.8，139.4，133.2，131.8，130.2，129.6，125.2，123.3，115.0，114.3，114.0，105.1，55.5，55.5，55.1.
the structural data of compound IV confirmed by nuclear magnetic resonance were:
Following the general procedure，using petroleum ether/AcOEt(2∶1)asthe eluant to afford yellow soild(89％yield).1H NMR(500MHz，Acetone-d6)δ7.68(d，J＝9.0Hz，2H)，7.53-7.52(m，1H)，7.45(d，J＝9.0Hz，1H)，7.37(d，J＝8.5Hz，2H)，7.01-6.98(m，1H)，6.84(d，J＝8.5Hz，2H)，6.79(d，J＝8.5Hz，2H)，3.88(s，3H)，3.73(s，3H)；13CNMR(125MHz，Acetone-d6)δ193.2，163.4，160.9，158.8，141.9，140.8，134.8，133.1，131.9，130.8，130.3，126.8，124.5，116.1，115.7，115.0，105.5，56.0，55.6.
the raloxifene derivative is confirmed to have structural data by nuclear magnetic resonance as follows:
Following the general procedure，using petroleum ether/AcOEt/triethylamine(2∶1∶0.1)as the eluant to afford yellow soild(90％yield).1H NMR(500MHz，Acetone-d6)δ7.73(d，J＝9.0Hz，2H)，7.56-7.55(m，1H)，7.45(d，J＝9.0Hz，1H)，7.37(d，J＝9.0Hz，2H)，7.01-6.99(m，1H)，6.90-6.85(m，4H)，4.11(t，J＝7.0Hz，2H)，3.89(s，3H)，3.75(s，3H)，2.66(t，J＝7.0Hz，2H)，2.43(s，4H)，1.53-1.48(m，4H)，1.40-1.38(m，2H)；13C NMR(125MHz，Acetone-d6)δ193.2，164.2，160.9，158.9，142.2，140.9，134.7，132.8，131.8，131.2，130.9，126.8，124.6，115.8，115.2，115.0，105.6，67.3，58.4，56.0，55.6，26.8，25.0.
in the invention, under the action of an Ag catalyst and an oxidant, the compound I and the compound II break a trivalent bond in the compound I to respectively generate a carbon ring with a-SCH 3 group and a-COOH group in the compound II, so that the first step of chemical reaction is formed.
In step two, one-OCH is removed by further reaction3In (C-CH)3To obtain a compound II, and finally reacting the compound III with 1- (2-chloroethyl) piperidine in the third step to obtain the final raloxifene derivative.
In the examples of the present invention, the yield of compound III in step one can reach 79%, the yield of compound IV in the further reaction in step two reaches 89%, and the yield of raloxifene derivative in step three reaches 90%. The raloxifene derivative prepared by the method has the advantages of simple raw materials, easily-achieved reaction conditions, high yield and no harmful substances generated in the reaction process, and is the raloxifene derivative with simple raw materials and reaction conditions.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (7)
1. A preparation method of raloxifene derivatives is characterized by comprising the following steps:
the method comprises the following steps:
reacting a compound I and a compound II in a solvent under the action of an Ag catalyst and an oxidant to obtain a compound III;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
the structural formula of the compound III is as follows:
step two:
reacting the compound III with NaSEt in a solvent to obtain a compound IV;
the structural formula of the compound IV is as follows:
step three:
reacting the compound IV with 1- (2-chloroethyl) piperidine, CsCO3 and KI to obtain a raloxifene derivative;
the raloxifene derivative has a structural formula of
Oxygen in the first stepThe agent is K2S2O8；
The catalyst in the first step is silver nitrate.
2. The process for preparing a raloxifene derivative according to claim 1, wherein:
the solvent in the first step is a solvent with a volume ratio of 1: 1 CH3CN and H2A mixture of O.
3. The process for the preparation of raloxifene derivatives according to claim 2, wherein:
the first step is carried out in a nitrogen atmosphere, the reaction temperature is 60-80 ℃, and the reaction time is 8-12 hours.
4. The process for preparing a raloxifene derivative according to claim 1, wherein:
and the solvent in the second step is DMF.
5. The process for preparing a raloxifene derivative according to claim 1, wherein: and the reaction temperature of the second step is 70-90 ℃.
6. The process for preparing a raloxifene derivative according to claim 1, wherein: and the reaction time of the second step is 3-5 hours.
7. The process for preparing a raloxifene derivative according to claim 1, wherein:
and the third step is carried out at room temperature for 12-16 hours.
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| CN201811329107.5A CN109320494B (en) | 2018-11-09 | 2018-11-09 | Raloxifene derivative and preparation method thereof |
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| CN109320494B true CN109320494B (en) | 2020-05-22 |
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