Synthetic method of 3-tert-butyldimethylsiloxy-3-(furan-2-yl)-propionaldehyde

Abstract

The invention relates to the field of pharmaceutical chemicals, and particularly discloses a synthesis method of 3-tertiary butyl dimethyl siloxy-3-(furan-2-yl)-propionaldehyde. The preparation method comprises the following steps: reacting 1-tert-butyldimethylsiloxy-1-(furan-2-yl)-butyl-3-ene with an aqueous solution of permanganate in the presence of ethylene glycol to generate an o-dihydroxyl intermediate, and then reacting the o-dihydroxyl intermediate with sodium periodate to prepare the 3-tert-butyldimethylsiloxy-3-(furan-2-yl)-propionaldehyde. The 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propionaldehyde is synthesized by adopting the method disclosed by the invention, so that the defects that the cost is too high, the environmental protection property is poor and large-scale industrial production cannot be realized in the traditional production process are overcome.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical chemistry, and more specifically, it relates to a method for synthesizing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal. Background Art

[0002] 3-tert-Butyldimethylsilyloxy-3-(furan-2-yl)propanal is a key intermediate for the preparation of prostatic active compounds and an important synthetic raw material in the process of drug synthesis, and it has broad market prospects.

[0003] U.S. Patent US20090259058 describes a method for preparing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal as shown in the following formula:

[0004]

[0005] The synthesis method shown in the above reaction formula uses the precious metal catalyst potassium osmate dihydrate, the chiral ligand hydroquinine 1,4-(2,3-phthalazine) diether, and N-methylmorpholine-N-oxide. The raw materials are very expensive and difficult to recycle and reuse during the reaction process, resulting in extremely high raw material costs and inability to carry out large-scale industrial production. At the same time, potassium osmate dihydrate is a highly toxic chemical, and there are safety hazards during use. If used in large quantities, it will have a huge negative impact on the human body and the environment.

[0006] In view of the fact that 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal is a key intermediate for the preparation of prostatic active compounds, it is imperative to find a synthesis method with green environmental protection, strong controllability, and low cost. Summary of the Invention

[0007] The purpose of the present invention is to provide a new method for synthesizing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal to solve the defects such as high cost, poor environmental protection, and limited industrial production in the traditional synthesis process.

[0008] This application provides a method for synthesizing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal, adopting the following technical scheme:

[0009] A method for synthesizing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal, characterized in that 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)but-3-ene reacts with an aqueous solution of permanganate in the presence of ethylene glycol to form an o-dihydroxy intermediate, and then the o-dihydroxy intermediate reacts with sodium periodate to obtain 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal.

[0010] By adopting the above technical solution, the double bond of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene undergoes an oxidative addition reaction and combines with the oxygen atom of potassium permanganate to form a vicinal diol intermediate. Compared with the traditional synthesis method, the synthesis method of this application does not require the use of expensive noble metal catalysts and chiral ligand catalysts, is easy to operate, safe, green and environmentally friendly, significantly reduces the production cost, the product purity is comparable to the existing process, and it is more suitable for industrial production.

[0011] Preferably, it specifically includes the following steps:

[0012] Step 1, prepare the vicinal diol intermediate. Below 0 °C, dissolve 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in acetone, add ethylene glycol, and oxidize it with an aqueous solution of permanganate to form the vicinal diol intermediate;

[0013] Step 2, at a temperature of 10 - 30 °C, react the vicinal diol intermediate with sodium periodate to obtain 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal.

[0014] By adopting the above technical solution, in Step 1, the experimental temperature is controlled below 0 °C, and the product is the vicinal diol intermediate. If the temperature is high, the raw material will be over-oxidized to acid and the next-step experiment cannot be carried out. In Step 2, at room temperature, the energy loss is the least, and the reaction yield and efficiency are also the best.

[0015] Preferably, in Step 1, the reaction temperature is -10 - 0 °C.

[0016] By adopting the above technical solution, if the temperature is too low, the cost of temperature control will increase, and at the same time, the reaction rate will decrease. Controlling the temperature within the above range ensures the formation of the vicinal diol intermediate in the reaction, while controlling the cost and reaction rate.

[0017] Preferably, the aqueous solution of permanganate is one of sodium permanganate or potassium permanganate aqueous solution.

[0018] By adopting the above technical solution, considering from the perspectives of cost and raw material properties, sodium permanganate or potassium permanganate aqueous solution is selected. The oxidation abilities of potassium permanganate and sodium permanganate are similar, and the oxidation effect is due to the permanganate ion. Experiments have proved that choosing any one of the two in the technical solution of this application is beneficial to improving the experimental accuracy and product yield.

[0019] Preferably, the concentration of the sodium permanganate aqueous solution is 35% - 45%; the concentration of the potassium permanganate aqueous solution is 35% - 45%.

[0020] By adopting the above technical solution, at room temperature, the maximum water solubility of potassium permanganate and sodium permanganate is about 40%. Considering the convenience of actual operation and the product yield, this concentration range is selected.

[0021] Preferably, the weight ratio of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene, ethylene glycol and the aqueous solution of permanganate is 1:1:2.

[0022] By adopting the above technical solution, it is beneficial to improve the reaction rate and the yield of the vicinal dihydroxy intermediate.

[0023] Preferably, the weight ratio of the vicinal dihydroxy intermediate to sodium periodate is 1:0.8.

[0024] By adopting the above technical solution, it is beneficial to improve the reaction rate and the yield of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal.

[0025] In summary, the beneficial technical effects of this application are as follows:

[0026] 1. When using the method of this application to synthesize 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal, it is not necessary to use expensive noble metal catalyst potassium osmate dihydrate, chiral ligand catalyst hydroquinine 1,4-(phthalazine) diether and N-methyl morpholine-N-oxide. The operation is simple, safe, green and environmentally friendly, significantly reducing the production cost. The product purity and yield are not much different from the existing process, and it is more suitable for industrial production.

[0027] 2. When preparing the vicinal dihydroxy intermediate, after the reaction is completed, there will be residual oxidant sodium permanganate in the reaction. Sodium bisulfite is used to reduce the residual sodium permanganate to ensure the safety of the post-treatment. Specific Embodiments

[0028] The following further elaborates on this application with reference to examples. In the following examples, those not specified in detail are carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples are all available from ordinary commercial sources.

[0029] This application provides a method for synthesizing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal. Dissolve 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in acetone, cool it to below 0 °C, add an appropriate amount of ethylene glycol, oxidize it with an aqueous solution of permanganate to form a vicinal dihydroxy intermediate, and then react with sodium periodate at 10 - 30 °C to obtain 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal. The principle is as follows:

[0030]

[0031] The process for preparing 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal is safe, green, environmentally friendly, low in cost, and the product purity and yield are comparable to those of the existing process, making it more suitable for industrial production.

[0032] Example 1

[0033] Step 1: At room temperature, dissolve 100 g of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)but-3-ene in 2000 ml of acetone, cool it to -10 °C using a laboratory circulating freezer, add 100 g of ethylene glycol, and dropwise add 80 g of an aqueous sodium permanganate solution with a concentration of 40%. The addition is completed within 2 hours, and the reaction is continued under insulation for 1 hour. GC detection shows that the content of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)but-3-ene is less than 1%. Then, dropwise add 250 g of saturated sodium bisulfite solution, filter by suction, wash the filter cake with 100 ml of acetone, concentrate the filtrate under reduced pressure until more than 90% of the acetone is removed, extract twice with 300 g of ethyl acetate, wash the organic phase twice with 200 g of saturated brine, and then dry and concentrate to obtain 120 g of crude oil of the vicinal dihydroxy intermediate.

[0034] Step 2: Mix 120 g of the crude oil of the vicinal dihydroxy intermediate prepared in Step 1 with 280 g of acetone to obtain an acetone solution of the crude oil of the vicinal dihydroxy intermediate. At room temperature, dissolve 100 g of sodium periodate in 360 g of water, control the temperature at 25 ± 5 °C, and dropwise add the acetone solution of the crude oil of the vicinal dihydroxy intermediate. The addition is completed within 2 hours. After the addition is completed, the reaction is continued under insulation for 1 hour. GC detection shows that the content of the vicinal dihydroxy intermediate is less than 1%. Filter by suction, wash the filter cake with 200 g of petroleum ether, let it stand for layering, and the sample is divided into two layers. The upper layer is the petroleum ether organic layer, and the lower layer is the water layer mixed with water and acetone. After extracting the water layer with 200 g of petroleum ether again, combine the organic phases, wash with 100 g of saturated brine, dry, and concentrate under reduced pressure to obtain 96 g of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal, with a GC-detected purity of 92%.

[0035] Example 2

[0036] Step 1: At room temperature, dissolve 100 g of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in 2000 ml of acetone. Use a laboratory circulating freezer to cool the solution to 0 °C, add 100 g of ethylene glycol, and slowly drip 80 g of 40% aqueous sodium permanganate solution. Finish the dripping in 2 hours, then continue the reaction at the same temperature for 1 hour. When the content of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene detected by GC is less than 1%, add 250 g of saturated sodium bisulfite solution. Filter by suction, wash the filter cake with 100 ml of acetone, then concentrate the filtrate under reduced pressure to remove more than 90% of the acetone. Extract twice with 300 g of ethyl acetate, wash the organic phase twice with 200 g of saturated brine, and then dry and concentrate to obtain 120 g of crude oil of vicinal dihydroxy intermediate;

[0037] Step 2: Mix 120 g of the crude oil of vicinal dihydroxy intermediate prepared in Step 1 with 280 g of acetone to obtain an acetone solution of the crude oil of vicinal dihydroxy intermediate. At room temperature, dissolve 100 g of sodium periodate in 360 g of water, control the temperature at 25±5 °C, and slowly drip the acetone solution of the crude oil of vicinal dihydroxy intermediate. Finish the dripping in 2 hours, then continue the reaction at the same temperature for 1 hour. When the content of the raw material vicinal dihydroxy intermediate detected by GC is less than 1%, filter by suction, wash the filter cake with 200 g of petroleum ether, let it stand for layering, and the sample is divided into two layers. The upper layer is the organic layer of petroleum ether, and the lower layer is the aqueous layer of a mixture of water and acetone. After extracting the aqueous layer with 200 g of petroleum ether again, combine the organic phases, wash with 100 g of saturated brine, dry, and concentrate under reduced pressure to obtain 96 g of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal, and the purity detected by GC is 92%.

[0038] Example 3

[0039] Step 1: At room temperature, dissolve 100 g of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in 2000 ml of acetone. Use a laboratory circulating freezer to cool the solution to -10 °C, add 100 g of ethylene glycol, and slowly drip 180 g of 40% aqueous potassium permanganate solution. Finish the dripping in 2 hours, then continue the reaction at the same temperature for 1 hour. When the content of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene detected by GC is less than 1%, add 250 g of saturated sodium bisulfite solution. Filter by suction, wash the filter cake with 100 ml of acetone, then concentrate the filtrate under reduced pressure to remove more than 90% of the acetone. Extract twice with 300 g of ethyl acetate, wash the organic phase twice with 200 g of saturated brine, and then dry and concentrate to obtain 123 g of crude oil of vicinal dihydroxy intermediate;

[0040] Step 2: At room temperature, take 120 g of the crude oil of the vicinal dihydroxy intermediate prepared in Step 1 and mix it with 280 g of acetone to obtain an acetone solution of the crude oil of the vicinal dihydroxy intermediate; dissolve 100 g of sodium periodate in 360 g of water, control the temperature at 25 ± 5 °C, and dropwise add the acetone solution of the crude oil of the vicinal dihydroxy intermediate. Finish dropping in 2 hours. After dropping, keep the temperature for reaction for 1 hour. When the vicinal dihydroxy intermediate detected by GC is less than 1%, filter by suction. Wash the filter cake with 200 g of petroleum ether, let it stand for layering, and it is divided into two layers. The upper layer is the petroleum ether organic layer, and the lower layer is the water layer mixed with water and acetone; after the water layer is extracted with 200 g of petroleum ether again, combine the organic phases, wash with 100 g of saturated brine, dry, and concentrate under reduced pressure to obtain 98 g of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal. The purity detected by GC is 93%.

[0041] Example 4

[0042] Step 1: At room temperature, dissolve 100 g of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in 2000 ml of acetone, cool it to 0 °C using a laboratory circulating freezer, add 100 g of ethylene glycol, and dropwise add 180 g of 40% aqueous potassium permanganate solution. Finish dropping in 2 hours. Continue to keep the temperature for reaction for 1 hour. When 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene detected by GC is less than 1%, dropwise add 250 g of saturated sodium bisulfite solution, filter by suction. After washing the filter cake with 100 ml of acetone, concentrate the filtrate under reduced pressure to remove more than 90% of the acetone, extract twice with 300 g of ethyl acetate, wash the organic phase twice with 200 g of saturated brine, and then dry and concentrate to obtain 123 g of the crude oil of the vicinal dihydroxy intermediate;

[0043] Step 2: Take 120 g of the crude oil of the vicinal dihydroxy intermediate prepared in Step 1 and mix it with 280 g of acetone to obtain an acetone solution of the crude oil of the vicinal dihydroxy intermediate; at room temperature, dissolve 100 g of sodium periodate in 360 g of water, control the temperature at 25 ± 5 °C, dropwise add the acetone solution of the crude oil of the vicinal dihydroxy intermediate. Finish dropping in 2 hours. After dropping, keep the temperature for reaction for 1 hour. When the vicinal dihydroxy intermediate detected by GC is less than 1%, filter by suction. Wash the filter cake with 200 g of petroleum ether, let it stand for layering, and the sample is divided into two layers. The upper layer is the petroleum ether organic layer, and the lower layer is the water layer mixed with water and acetone; after the water layer is extracted with 200 g of petroleum ether again, combine the organic phases, wash with 100 g of saturated brine, dry, and concentrate under reduced pressure to obtain 98 g of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal. The purity detected by GC is 93%.

[0044] Comparative Example 1

[0045] The method in US Patent US20090259058 was adopted to prepare 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal, and the purity detected by GC was 95%.

[0046] Compared with the comparative example, the purity of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal prepared in the example decreased by about 2.1% - 3.2% detected by GC, and the difference was small; however, the example does not need to use expensive noble metal catalyst potassium osmate dihydrate, chiral ligand catalyst hydroquinine 1,4-(2,3-phthalazine) diether and N-methyl morpholine-N-oxide. The operation is simple, safe, green and environmentally friendly, significantly reducing the production cost and being suitable for factory batch production.

[0047] Comparative Example 2

[0048] The difference from Example 1 is that: in Step 1, the temperature was not lowered before adding diethanol, and as a result, the crude oil of the vicinal dihydroxy intermediate could not be obtained.

[0049] Comparative Example 3

[0050] The difference from Example 3 is that: in Step 1, the temperature was not lowered before adding diethanol, and as a result, the crude oil of the vicinal dihydroxy intermediate could not be obtained.

[0051] The above are all the preferred embodiments of this application. The protection scope of this application is not limited accordingly. Therefore, all equivalent changes made according to the structure, shape and principle of this application should be covered within the protection scope of this application.

Claims

1. A method for synthesizing 1.3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal, characterized in that, It includes the following steps: React 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene with an aqueous solution of permanganate in the presence of ethylene glycol to form an o-dihydroxy intermediate, and then react the o-dihydroxy intermediate with sodium periodate to obtain 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal.

2. The synthesis method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 1, characterized in that: Specifically, it includes the following steps: Step 1, prepare the o-dihydroxy intermediate. Below 0 °C, dissolve 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene in acetone, add ethylene glycol, and oxidize it with an aqueous solution of permanganate to form the o-dihydroxy intermediate; Step 2, at a temperature of 10-30 °C, react the o-dihydroxy intermediate with sodium periodate to obtain 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)-propanal.

3. The synthesis method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 2, characterized in that: In Step 1, the reaction temperature is -10-0 °C.

4. The synthesis method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 2, characterized in that: The aqueous solution of permanganate is one of sodium permanganate or potassium permanganate aqueous solution.

5. The synthesis method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 4, characterized in that: The concentration of the sodium permanganate aqueous solution is 35%-45%.

6. The synthesis method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 4, characterized in that: The concentration of the potassium permanganate aqueous solution is 35%-45%.

7. The synthetic method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl) propionaldehyde according to any one of claims 1-6, characterized in that: The weight ratio of 1-tert-butyldimethylsilyloxy-1-(furan-2-yl)-but-3-ene, ethylene glycol and the aqueous solution of permanganate is 1:1:

2.

8. The synthetic method of 3-tert-butyldimethylsilyloxy-3-(furan-2-yl)propanal according to claim 7, characterized in that: The weight ratio of the o-dihydroxy intermediate to sodium periodate is 1:0.8.

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