Method for preparing 3,5-ring,6-ether structure steroid compound from sterol compound

Abstract

The invention discloses a method for preparing a steroid compound with a 3,5-ring, 6-ether structure from a steroid compound, wherein the steroid compound shown in formula I is reacted in a solvent under the action of a halogen-containing Lewis acid, and then R is added to the reaction solution. 1 OH and an organic base are reacted to obtain a 3,5-ring, 6-ether structure steroid compound A; the present invention does not require complicated purification and separation during the reaction process, and a one-pot method is used to synthesize a 3,5-ring, 6-ether structure steroid compound A, which is simple to operate and has a high yield. No sulfonyl chloride and solvent pyridine are used, which is more environmentally friendly. In addition, the reaction conditions are mild, the reaction time is short, the atomic utilization rate is high, and it is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of steroid synthesis, and in particular relates to a method for preparing a steroid compound with a 3,5-ring, 6-ether structure from a sterol compound. Background Art

[0002] Sterol compounds, also known as sterols, are hydroxyl-containing cyclopentane polyhydrophenanthrene derivatives. There are many types of sterol compounds, which are widely distributed in the biological world. For example, cholesterol is an important component of higher animal cells. Another example is phytosterol, which is an important component of plant cells and can be extracted from soybean meal and wood pulp. It is currently widely used as a starting material for steroid drug molecules and has formed a huge industry.

[0003]

[0004] In its structure, the A and B rings mostly contain 3-hydroxyl groups and 5-double bonds (the carbon atom numbers of the steroid rings are as follows, the four rings from left to right are A, B, C, and D rings).

[0005]

[0006] In the application of sterol compounds, this structure can undergo a chemical reaction to form a three-membered ring structure (Compound A). Compound A can further form a lactone structure of the B ring after introducing a 6-hydroxyl group through oxidation, peroxidation and other steps, thereby synthesizing the important plant growth hormone molecules of the brassinolide series.

[0007]

[0008] The known synthesis method of compound A uses pyridine as a solvent and an acid-binding agent, and a sterol reacts with toluenesulfonyl chloride to form a sulfonyl ester. After adding water to precipitate a solid and separating the pure product, the solid reacts with an alcohol to form a 6-ether under alkaline conditions (adding an inorganic base), and crystallizes to obtain compound A. The inventors have studied that this method has the following defects:

[0009] 1. Pyridine must be used as a solvent for the sulfonate to form smoothly. The reaction conditions are harsh and a large amount of sulfur- and nitrogen-containing wastewater is produced during the reaction, causing serious pollution.

[0010] 2. It is difficult to separate the sulfonate, and the reaction solution of the sulfonate needs to be poured into a large amount of ice water to precipitate the solid, which is a cumbersome operation. If the pure sulfonate is not separated and the second step reaction is directly carried out, the presence of tosyl chloride will affect the yield of the second step.

[0011] 3. The reaction has low atom utilization and long reaction time. Summary of the invention

[0012] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide a method for preparing 3,5-ring, 6-ether structure steroid compounds from sterol compounds, which is simple to operate, green and environmentally friendly, and has a high yield.

[0013] In order to solve the above technical problems, the technical solution proposed by the present invention is:

[0014] A method for preparing a 3,5-ring, 6-ether structure steroid compound from a sterol compound comprises the following steps: reacting the sterol compound represented by formula I in a solvent under the action of a halogen-containing Lewis acid, and then adding R 1 OH and organic base, continue to react to obtain 3,5-ring, 6-ether structure steroid compound A;

[0015]

[0016] Where R is C 5 ~C 8 Hydrocarbon, R 1 C 1 ~C 6 Alkyl or aryl, Indicates a single bond or a double bond.

[0017] As a further improvement, R includes

[0018] R 1 Included are substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl or benzyl.

[0019] As a further improvement, the halogen-containing Lewis acid includes at least one of anhydrous ferric chloride, anhydrous cupric chloride, anhydrous aluminum chloride, anhydrous zinc chloride, titanium tetrachloride, copper bromide or ferric bromide.

[0020] As a further improvement, the halogen-containing Lewis acid is anhydrous ferric chloride.

[0021] As a further improvement, the solvent includes at least one of dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene.

[0022] As a further improvement, the solvent is 1,2-dichloroethane.

[0023] As a further improvement, the organic base includes at least one of triethylamine, pyridine, N-methylmorpholine, DMAP or DBU.

[0024] As a further improvement, the organic base is N-methylmorpholine.

[0025] As a further improvement, R is R1 OH is methanol, represents a single bond; the solvent is a mixed solvent of dichloromethane and 1,2-dichloroethane, and the organic base is N-methylmorpholine.

[0026] As a further improvement, the reaction temperature is maintained at 35 to 80 degrees Celsius, the reaction is carried out under the action of a halogen-containing Lewis acid for 4 to 8 hours, and R is added 1 OH and organic base and continue the reaction for 3 to 4 hours.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. During the reaction process, there is no need for complicated purification and separation, and the one-pot synthesis of 3,5-ring, 6-ether structure steroid compound A is achieved, which is simple to operate and has a high yield.

[0029] 2. The present invention does not use sulfonyl chloride and solvent pyridine, which is more environmentally friendly. In addition, the reaction conditions are mild, the reaction time is short, the atomic utilization rate is high, and it is more suitable for industrial production.

[0030] 3. Since the present invention uses a halogen-containing Lewis acid and is a one-pot reaction, it has specific requirements for the solvent and the base. By screening the organic base and solvent used in the reaction, the overall yield can be greatly improved. DETAILED DESCRIPTION

[0031] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and carefully in combination with preferred embodiments below, but the protection scope of the present invention is not limited to the following specific embodiments.

[0032] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0033] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0034] The method for preparing a 3,5-ring,6-ether structure steroid compound from a sterol compound of the present invention comprises reacting the sterol compound represented by formula I in a solvent under the action of a halogen-containing Lewis acid, and then adding R 1 OH and an organic base react to obtain a 3,5-cyclic, 6-ether structure steroid compound A, and the reaction formula is as follows:

[0035]

[0036] The sterol compound represented by formula I, wherein the side chain R is C 5~C 8 Hydrocarbon groups, such as In the formula Represents a single bond or a double bond. Exemplary sterol compounds include:

[0037]

[0038] R 1 OH can be alcohol or phenol, R 1 C 1 ~C 6 Alkyl or aryl, for example substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl or benzyl.

[0039] In some embodiments, the halogen-containing Lewis acid comprises at least one of anhydrous ferric chloride, anhydrous cupric chloride, anhydrous aluminum chloride, anhydrous zinc chloride, titanium tetrachloride, copper bromide or ferric bromide, preferably anhydrous ferric chloride. In some embodiments, the molar ratio of the halogen-containing Lewis acid to the sterol compound is 0.5 to 1.5:1.

[0040] In some embodiments, the reaction solvent includes at least one of dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene, preferably 1,2-dichloroethane. When the organic base used is N-methylmorpholine, a mixed solvent of dichloromethane and 1,2-dichloroethane (volume ratio 0.5-1.5:1) is more preferably used, which has the highest yield.

[0041] In some embodiments, the reaction with the halogen Lewis acid can be carried out under reflux, preferably at a temperature of 35 to 80 degrees Celsius, more preferably 38 to 60 degrees Celsius, and preferably for 4 to 8 hours.

[0042] After the reaction with the halogen-containing Lewis acid is completed, it is best to perform a simple filtration to filter out the precipitate (mainly the metal halide as the halogen-containing Lewis acid) so as not to affect the subsequent reaction. The filtration can be performed using the simplest operation, such as filtration with diatomaceous earth. In industrial production, it is only necessary to introduce the reaction solution into the filtration device and then introduce the filtrate into the reactor, which can be carried out continuously. In some embodiments, the reaction solution is filtered and R is added to the filtrate. 1 OH and the organic base continue to react. Only simple filtration is required in the middle to achieve a one-pot synthesis of 3,5-ring, 6-ether structure steroid compound A. At the same time, the reaction conditions are mild, the reaction time is short, and the yield is high.

[0043] In some embodiments, the organic base includes at least one of triethylamine, pyridine, N-methylmorpholine, DMAP (4-dimethylaminopyridine) or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), preferably N-methylmorpholine, which can significantly increase the total yield. In some embodiments, the molar ratio of the organic base to the sterol compound is 3 to 5:1.

[0044] In some embodiments, R 1 The reaction of OH can be carried out under reflux, preferably at a temperature of 35 to 80 degrees Celsius, more preferably 38 to 60 degrees Celsius, and preferably for 3 to 4 hours.

[0045] In some embodiments, after the reaction is completed, the reaction solvent is evaporated, and optionally, the organic solvent is dissolved with an organic solvent, washed with water, and then the organic solvent is evaporated, and then a solvent (such as methanol or ethanol) is added to dissolve, the solid is precipitated by cooling, and the compound A is obtained by filtration. Alternatively, after the reaction is completed, water is added to wash the separated liquid, and then the organic phase is evaporated, and then a solvent (such as methanol or ethanol) is added to dissolve, the solid is precipitated by cooling, and the compound A is obtained by filtration.

[0046] Example 1

[0047]

[0048] 100 mL of dichloromethane and 25 g of anhydrous ferric chloride were added to a three-necked flask, and 50 g of cholesterol was added under stirring. The temperature was raised to reflux reaction for 8 h, cooled to room temperature, and stirring was stopped. A layer of diatomaceous earth was laid on the funnel, and the reaction solution was filtered. The filter cake was washed with 50 mL of dichloromethane, the filtrate was combined, 100 mL of methanol was added, and 50 mL of N-methylmorpholine was added dropwise under stirring for 20 min. The temperature was continued to be raised to 40 degrees Celsius and reflux reaction was carried out for 4 h. After the reaction was completed, the solvent was concentrated to dryness, 100 mL of methanol was added, the solid was stirred evenly, the temperature was lowered to 0-10 degrees Celsius and filtered, 150 mL of water was added to the filter cake for slurrying for 1 h, filtered, and dried at 50 degrees Celsius to obtain 47.2 g of compound A1 with a weight yield of 94.4% and a purity of 98% detected by HPLC.

[0049] NMR data of compound A1: 1 H NMR (400 MHz, CDCl 3 )δ3.32(s,3H),2.75-2.78(m,1H),2.00-1.68(m,5H),1.62-0.96(m,24H ),0.91-0.82(m,10H)0.71(s,3H),0.65-0.63(m,1H),0.44-0.41(m,1H).

[0050] In order to study the influence of various factors on the reaction, the following comparative experiment was conducted. The method of the comparative experiment is the same as that of Example 1, and only the differences are listed in the table below.

[0051]

[0052]

[0053] It can be seen that the best halogen-containing Lewis acid is anhydrous ferric chloride, the best reaction solvent is 1,2-dichloroethane, and the organic base is better than the inorganic base, and the best is N-methylmorpholine. N-methylmorpholine combined with 1,2-dichloroethane as a solvent has a more obvious improvement in yield. If a mixed solvent of dichloromethane and 1,2-dichloroethane is used, the yield is the highest.

[0054] Example 2

[0055]

[0056] 100 mL of chloroform and 30 g of anhydrous copper bromide were added to a three-necked flask, and 50 g of phytosterol was added under stirring. The temperature was raised to 60 degrees Celsius and refluxed for 4 hours. The temperature was lowered to room temperature, and stirring was stopped. A layer of diatomaceous earth was laid on the funnel, and the reaction solution was filtered. The filter cake was washed with 50 mL of chloroform. The filtrate was combined, 50 g of phenol was added, and 50 mL of N-methylmorpholine was added dropwise under stirring for 20 minutes. The temperature was continued to be raised to 60 degrees Celsius and refluxed for 4 hours. After the reaction was completed, the solvent was concentrated to dryness, dissolved in 100 mL of chloroform, and separated with 100 mL of water. 100 mL of water was added to the organic phase to wash the separated liquid again. The organic phase was concentrated to dryness, 50 mL of methanol was added, and stirred evenly. The temperature was lowered to 0-5 degrees Celsius, filtered, and dried to obtain 45.5 g of compound A2 with a yield of 91.0%.

[0057] Example 3

[0058]

[0059] 100 mL of dichloromethane and 30 g of anhydrous copper bromide were added to a three-necked flask, and 50 g of ergosterol was added under stirring. Under nitrogen protection, the temperature was raised to 40 degrees Celsius and refluxed for 4 hours. The temperature was lowered to room temperature, and stirring was stopped. A layer of diatomaceous earth was laid on the funnel, and the reaction solution was filtered. The filter cake was washed with 50 mL of dichloromethane. The filtrate was combined, 100 mL of ethanol was added, and 50 mL of N-methylmorpholine was added dropwise under stirring for 20 minutes. The temperature was continued to be raised to 40 degrees Celsius and refluxed for 3 hours. After the reaction was completed, 200 mL of water was added, and the liquids were separated. 100 mL of water was added to the organic phase to wash the separated liquid again. The organic phase was concentrated to dryness, 50 mL of ethanol was added, stirred evenly, cooled to 0-5 degrees Celsius, filtered, and dried to obtain 43.3 g of compound A3 with a yield of 86.6%.

[0060] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing a 3,5-ring, 6-ether structure steroid compound from a sterol compound, It is characterized in that The method comprises the following steps: reacting the sterol compound represented by formula I in a solvent under the action of a halogen-containing Lewis acid, and then adding R 1 OH and organic base, continue to react to obtain 3,5-ring, 6-ether structure steroid compound A; Where R is C 5 ~C 8 Hydrocarbon, R 1 C 1 ~C 6 Alkyl or aryl, represents a single bond or a double bond; The halogen-containing Lewis acid is at least one of anhydrous ferric chloride, anhydrous cupric chloride, cupric bromide or ferric bromide; The solvent is at least one of dichloromethane, chloroform or 1,2-dichloroethane; The organic base is at least one of triethylamine, pyridine, N-methylmorpholine or DMAP.

2. The method for preparing a 3,5-ring,6-ether structure steroid compound from a sterol compound according to claim 1, It is characterized in that R is selected from R 1 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl or phenyl.

3. The method for preparing a 3,5-ring, 6-ether structure steroid compound from a sterol compound according to claim 1, It is characterized in that The halogen-containing Lewis acid is anhydrous ferric chloride.

4. The method for preparing a 3,5-ring,6-ether structure steroid compound from a sterol compound according to claim 1, It is characterized in that The solvent is 1,2-dichloroethane.

5. The method for preparing a 3,5-ring,6-ether structure steroid compound from a sterol compound according to claim 1, It is characterized in that The organic base is N-methylmorpholine.

6. The method for preparing a 3,5-ring, 6-ether structure steroid compound from a sterol compound according to claim 1, It is characterized in that R is R 1 OH is methanol, represents a single bond; the solvent is a mixed solvent of dichloromethane and 1,2-dichloroethane, and the organic base is N-methylmorpholine.

7. The method for preparing a 3,5-ring, 6-ether structure steroid compound from a sterol compound according to claim 1 or 2, It is characterized in that The reaction temperature is maintained at 35 to 80 degrees Celsius, and the reaction is carried out for 4 to 8 hours under the action of the halogen-containing Lewis acid. 1 OH and organic base and continue the reaction for 3 to 4 hours.

Images