CN111138512A - Method for synthesizing 25-hydroxycholesterol intermediate - Google Patents
Method for synthesizing 25-hydroxycholesterol intermediate Download PDFInfo
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- CN111138512A CN111138512A CN201911373347.XA CN201911373347A CN111138512A CN 111138512 A CN111138512 A CN 111138512A CN 201911373347 A CN201911373347 A CN 201911373347A CN 111138512 A CN111138512 A CN 111138512A
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- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/001—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class spiro-linked
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Abstract
The invention provides a method for synthesizing a 25-hydroxycholesterol intermediate, which comprises the steps of mixing a compound III, triphenylphosphine and imidazole in a nonpolar organic solvent, and then adding elementary iodine in batches at-20-40 ℃ to perform a synthesis reaction to synthesize a compound V, wherein the compound III is 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-ol or 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-ol, and the compound V is 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-iodine or 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-iodine.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a method for synthesizing a 25-hydroxycholesterol intermediate.
Background
25-hydroxycholesterol is a key intermediate in the preparation of a number of important vitamin D derivatives, such as eldercalciferol, calcitriol and calcifediol. The structural formula of 25-hydroxycholesterol is shown below:
and the target product 25-hydroxycholesterol is obtained by taking stigmasterol as a starting raw material and carrying out sulfonylation, ozonization and other multi-step reactions.
Chinese patent application with application number of CN2017104337408, application date of 2017, 6 and 9 and invention name of 'cyclocholane carboxylate derivative and preparation method and application thereof' discloses a method for synthesizing 25-hydroxycholesterol by using stigmasterol as a starting material, which comprises the following steps:
the iodide V is prepared by taking stigmasterol (6) as an initial raw material, and firstly reacting with paratoluensulfonyl chloride to obtain a compound 7; compound 7 with R in the Presence of Potassium acetate2OH(R2Methyl or ethyl) to obtain 3 α,5 α -cyclic stigmasterol compound II, carrying out ozone oxidation reaction and reduction by using a reducing agent MH on the 3 α,5 α -cyclic stigmasterol compound II to obtain a compound III, reacting the compound III with a compound WCl to obtain a compound IV, carrying out iodination on the compound IV by using an iodide AI to obtain an iodide V, wherein the reaction process is as follows:
synthesizing a cholestyryl carboxylic ester derivative I iodide V and acrylic ester, and performing conjugate addition under the mediation of zero-valent nickel (Ni (0)) to obtain a cholestyryl carboxylic ester derivative I; the chemical reaction formula of the step is as follows:
synthesis of 25-hydroxycholesterol Cyclocholane carboxylate derivative I and Grignard reagent CH3Carrying out Grignard reaction on MgX to obtain a compound VI; compound VI is deprotected by reverse-i-rearrangement reaction in an aqueous organic solvent under the catalysis of acid to obtain 25-hydroxycholesterol (1), and the reaction process of the step is as follows:
therefore, in the process of synthesizing 25-hydroxycholesterol by taking stigmasterol as a starting material, the compound III and the compound V are produced, and the compound V can be synthesized from the compound III through two steps of reactions, so that the synthetic route of the 25-hydroxycholesterol is relatively long, and the product yield is influenced.
Disclosure of Invention
In view of the above, it is necessary to provide a method for synthesizing a 25-hydroxycholesterol intermediate, so as to solve the above problems.
Therefore, the invention provides a method for synthesizing a 25-hydroxycholesterol intermediate, which comprises the following steps: and (2) mixing and dissolving the compound III, triphenylphosphine and imidazole in a non-polar organic solvent, and then adding elemental iodine at the temperature of-20-40 ℃ for synthetic reaction to synthesize a compound V.
Wherein the structural formula of the compound III is as follows:
wherein the group R2Represents methyl or ethyl, i.e. compound III is 6 β -methoxy-3 β,5 a-cyclobisnor choline-22-ol or 6 β -ethoxy-3 β,5 a-cyclobisnor choline-22-ol;
the structural formula of the compound V is as follows:
wherein the group R2Represents methyl or ethyl, i.e. compound V is 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-iodo or 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-iodo.
In the above method provided by the present invention, the route for synthesizing compound V using compound III as a raw material is as follows:
the method for synthesizing the 25-hydroxycholesterol intermediate comprises the following steps: dissolving the compound III in the nonpolar organic solvent, adding triphenylphosphine and imidazole after the compound III is dissolved, and then adding elemental iodine in batches at the temperature of-20-40 ℃ to perform synthetic reaction for 1-3 hours to synthesize the compound V, wherein the molar ratio of the compound III to the triphenylphosphine to the imidazole is 1: 0.5-3: 0.5 to 3; the molar ratio of the compound III to the iodine is 1: 0.5 to 3.
Based on the above, the nonpolar organic solvent is dichloromethane, dichloroethane, acetone, chloroform, toluene or petroleum ether.
The method for synthesizing the 25-hydroxycholesterol intermediate further comprises the following steps: after the synthesis reaction is finished, the synthesized compound V is subjected to a separation and purification step.
Based on the above, the step of separating and purifying the synthesized compound V comprises: after the synthesis reaction is finished, obtaining a compound V mixture, removing the solvent in the compound V mixture by adopting a reduced pressure distillation method, and then preparing a pure product of the compound V by adopting a column chromatography method and a reduced pressure distillation method in sequence. Preferably, after the mixture of the compound V is subjected to the first vacuum distillation, petroleum ether is used as an eluent to perform separation and purification by using silica gel column chromatography, thin layer chromatography (namely, TLC method) is used as an indication and combined with the eluent only containing the product, and then the eluent is removed by vacuum distillation to obtain a pure product of the target compound V.
Besides the separation and purification method of the compound V, the existing separation method can be adopted, for example, after the synthesis reaction is finished, a sodium carbonate solution is added into the reaction system, the mixture is stirred for 10-30 min, and the mixture is kept stand and separated to obtain the organic layer mixture; concentrating the organic layer mixture until the organic layer mixture is dried to obtain an intermediate semi-finished product, pulping the intermediate semi-finished product, standing and extracting to obtain an organic layer solution, and performing spin drying treatment on the organic layer solution to obtain a pure product of a target product compound V.
Compared with the prior art, in the method for synthesizing the 25-hydroxycholesterol intermediate, triphenylphosphine, imidazole and elemental iodine form a nitrogen iodide phosphorus compound, iodine anions in the compound substitute hydroxyl in a compound III to generate an iodide to obtain a target compound V, so that the target compound V can be synthesized in one step by using the compound III as a raw material, reaction steps are reduced, the yield is high, and the yield can reach 96%. The synthesis method provided by the invention is carried out at low temperature, the reaction condition is mild, the preparation method is simple and feasible, and the cost is low.
Furthermore, the method adopts the step of adding the iodine simple substance in batches at the low temperature of-20-40 ℃ mainly because the synthesis reaction is an exothermic reaction, and if the reaction is too fast, other impurities are generated due to overhigh temperature, so that the product yield is influenced.
In addition, the invention adopts a column chromatography method to separate and purify the target compound, which is beneficial to improving the purity of the target compound.
Therefore, the method for synthesizing the 25-hydroxycholesterol intermediate provided by the invention has the characteristics of few synthesis steps, high yield, mild reaction, simplicity and feasibility, low cost and the like.
Detailed Description
The technical solution of the present invention is further described in detail by the following embodiments.
Example 1
This example provides a method for synthesizing 25-hydroxycholesterol intermediate, i.e., a method for synthesizing compound 6 β -methoxy-3 β,5 a-cyclobis-norcholine-22-iodide, comprising:
synthesizing an intermediate, namely dissolving 1g of a compound 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-alcohol in toluene, adding 1.5 g of triphenylphosphine and 0.4 g of imidazole into a reaction system after the dissolution is finished, then adding 1.2 g of elemental iodine into the reaction system in 5 batches at the temperature of minus 20 ℃, reacting for 3 hours, and obtaining an intermediate mixture after the reaction is finished;
after the separation and purification reaction, the solvent was removed by distillation under reduced pressure, the product was separated and purified by silica gel column chromatography using petroleum ether as eluent, TLC method was used as indication and eluent containing only the product was combined, and the eluent was removed by distillation under reduced pressure to obtain 1.25g of the target compound 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-iodine in 95% yield, and the result of nuclear magnetic detection of the target product obtained in this step was 1H NMR (400MHz, CDCl)3) δ 3.3(s,3H), δ 3.1 (m,2H), δ 2.8(t,1H), δ 1.1(m,6H), δ 0.8(s,3H), δ 1.3 to 1.5(m,22H), and thus the structural formula of the target compound, 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-iodine, can be determined.
Example 2
This example provides a method for synthesizing 25-hydroxycholesterol intermediate, i.e., a method for synthesizing compound 6 β -methoxy-3 β,5 a-cyclobis-norcholine-22-iodide, comprising:
1g of compound 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-alcohol is dissolved in dichloroethane, 2 g of triphenylphosphine and 0.5 g of imidazole are added into a reaction system after the dissolution is finished, then 4g of elemental iodine is added into the reaction system in 10 batches at 5 ℃, the reaction is carried out for 2 hours, and an intermediate mixture is obtained after the reaction is finished;
after the completion of the separation and purification reaction, the solvent was removed by distillation under reduced pressure, separation and purification were carried out by silica gel column chromatography using petroleum ether as an eluent, TLC method was used as an indicator and eluent containing only the product was combined, and the eluent was removed by distillation under reduced pressure to obtain 1.27g of the target compound 6 β -methoxy-3 β,5 a-cyclobis-norcholine-22-iodine with a yield of 96%.
Example 3
This example provides a method for synthesizing 25-hydroxycholesterol intermediate, i.e., a method for synthesizing compound 6 β -methoxy-3 β,5 a-cyclobis-norcholine-22-iodide, comprising:
1g of compound 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-alcohol is dissolved in dichloroethane, 0.4 g of triphenylphosphine and 0.2 g of imidazole are added into a reaction system after the dissolution is finished, then 0.8 g of elemental iodine is added into the reaction system in 3 batches at 30 ℃, the reaction is carried out for 2 hours, and an intermediate mixture is obtained after the reaction is finished;
after the completion of the separation and purification reaction, the solvent was removed by distillation under reduced pressure, separation and purification were carried out by silica gel column chromatography using petroleum ether as an eluent, TLC method was used as an indicator and eluent containing only the product was combined, and the eluent was removed by distillation under reduced pressure to obtain 1.21g of the target compound 6 β -methoxy-3 β,5 a-cyclobis-norcholine-22-iodine with a yield of 92%.
Example 4
This example provides a method for synthesizing a 25-hydroxycholesterol intermediate, i.e., a method for synthesizing compound 6 β -ethoxy-3 β,5 a-cyclobis-norcholine-22-iodide, comprising:
the intermediate synthesis comprises the steps of dissolving 1.04 g of a compound 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-alcohol in dichloroethane, adding 1.6 g of triphenylphosphine and 0.3 g of imidazole into a reaction system after the dissolution is finished, adding 2.4g of elemental iodine into the reaction system in 3 batches at 10 ℃, reacting for 2 hours, and obtaining an intermediate mixture after the reaction is finished;
after the completion of the separation and purification reaction, the solvent was removed by distillation under reduced pressure, separation and purification were carried out by silica gel column chromatography using petroleum ether as an eluent, TLC method was used as an indicator and eluent containing only the product was combined, and the eluent was removed by distillation under reduced pressure to obtain 1.28g of the target compound 6 β -ethoxy-3 β,5 a-cyclobis-norcholine-22-iodine with a yield of 94%.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.
Claims (5)
1. A method for synthesizing a 25-hydroxycholesterol intermediate comprises the steps of mixing and dissolving a compound III, triphenylphosphine and imidazole in a nonpolar organic solvent, and then adding elementary iodine at the temperature of-20-40 ℃ to perform a synthesis reaction to synthesize a compound V, wherein the compound III is 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-ol or 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-ol, and the compound V is 6 β -methoxy-3 β,5 a-cyclobisnorcholine-22-iodine or 6 β -ethoxy-3 β,5 a-cyclobisnorcholine-22-iodine.
2. The method of synthesizing a 25-hydroxycholesterol intermediate as claimed in claim 1, comprising: dissolving the compound III in the nonpolar organic solvent, adding triphenylphosphine and imidazole after the compound III is dissolved, and then adding elemental iodine in batches at the temperature of-20-40 ℃ to perform synthetic reaction for 1-3 hours to synthesize the compound V, wherein the molar ratio of the compound III to the triphenylphosphine to the imidazole is 1: 0.5-3: 0.5 to 3; the molar ratio of the compound III to the iodine is 1: 0.5 to 3.
3. The method of synthesizing a 25-hydroxycholesterol intermediate according to claim 1 or 2, wherein the non-polar organic solvent is dichloromethane, dichloroethane, acetone, chloroform, toluene, or petroleum ether.
4. The method of synthesizing a 25-hydroxycholesterol intermediate as in claim 1 or 2, further comprising: after the synthesis reaction is finished, the synthesized compound V is subjected to a separation and purification step.
5. The method of claim 4, wherein the step of isolating and purifying the synthesized compound V comprises: after the synthesis reaction is finished, obtaining a compound V mixture, removing the solvent in the compound V mixture by adopting a reduced pressure distillation method, and then preparing a pure product of the compound V by adopting a column chromatography method and a reduced pressure distillation method in sequence.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3822254A (en) * | 1973-05-21 | 1974-07-02 | Hoffmann La Roche | Synthesis of 25-hydroxycholesterol |
| CN106866772A (en) * | 2017-01-11 | 2017-06-20 | 武汉大学 | A kind of cholesterol molecule probe and its preparation method and application |
| CN109021059A (en) * | 2017-06-09 | 2018-12-18 | 郑州泰丰制药有限公司 | Ring cholane carboxylic ester derivative and its preparation method and application |
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- 2019-12-27 CN CN201911373347.XA patent/CN111138512A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3822254A (en) * | 1973-05-21 | 1974-07-02 | Hoffmann La Roche | Synthesis of 25-hydroxycholesterol |
| CN106866772A (en) * | 2017-01-11 | 2017-06-20 | 武汉大学 | A kind of cholesterol molecule probe and its preparation method and application |
| CN109021059A (en) * | 2017-06-09 | 2018-12-18 | 郑州泰丰制药有限公司 | Ring cholane carboxylic ester derivative and its preparation method and application |
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