A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane

Abstract

The invention provides a preparation method of a pharmaceutical intermediate, namely 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane. The method uses 1,4-butenediol and 2,2-dimethoxypropane as raw materials, catalyzes a cyclization reaction under acidic conditions to generate 4,7-dihydro-2,2-dimethyl-1,3-dioxapine; and then uses hydrogen peroxide to oxidize 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane. The method has simple operation, mild conditions and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, in particular to a method for preparing a pharmaceutical intermediate 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane. Background Art

[0002] Gadobutrol injection is a contrast agent used for contrast-enhanced magnetic resonance imaging. After intravenous injection, it can increase the sensitivity of magnetic resonance imaging (MRI), so it is often used to detect tumors, inflammation and demyelinating diseases of the central nervous system. As a new type of powerful magnetic resonance contrast agent, gadobutrol has the advantages of high concentration and high relaxation rate, and has a low risk of nephrogenic systemic fibrosis, an adverse reaction unique to contrast agents.

[0003] The epoxy side chain is an important intermediate in the preparation of zabutrol. Its chemical name is 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane (CAS: 57280-22-5). The quality of the epoxy side chain directly and significantly affects the yield and purity of zabutrol. As a diagnostic agent, especially an MRI diagnostic agent, zabutrol has higher requirements for the purity of zabutrol API. Therefore, developing a method for preparing an epoxy side chain intermediate with good economy, high yield and high purity has good application prospects and practical significance.

[0004] The existing synthesis method of epoxy side chain intermediates is to use 1,4-butenediol and 2,2-dimethoxypropane as raw materials, undergo the first step of cyclization and the second step of epoxidation to prepare epoxy side chain intermediates. Among them, the existing method is to use concentrated sulfuric acid to catalyze the cyclization and meta-chloroperbenzoic acid to epoxidize the epoxy side chain intermediates. The epoxy side chain intermediates prepared by this method have low purity and a total yield of only 53%. The use of concentrated sulfuric acid increases the waste acid discharge in the post-treatment stage, and the benzoic acid by-product produced after the oxidation of meta-chloroperbenzoic acid also increases the amount of hazardous waste treatment, which is environmentally friendly. There are also reports of using resins to catalyze cyclization reactions, but the catalytic reaction is difficult to react completely, and the yield and product purity do not meet the requirements of industrial production. In addition, in the existing preparation method, p-toluenesulfonic acid catalyzes the cyclization and hydrogen peroxide epoxidation, but the p-toluenesulfonic acid is not quenched and then removed, which seriously affects the yield. Summary of the invention

[0005] In view of the problems of low yield of the above-mentioned products and easy environmental pollution of intermediate products, the present application provides a synthetic route which uses 1,4-butenediol and 2,2-dimethoxypropane as raw materials, catalyzes a cyclization reaction under acidic conditions to generate 4,7-dihydro-2,2-dimethyl-1,3-dioxacyclopentane; then oxidizes it with hydrogen peroxide, and then prepares the final product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane through distillation; the method is simple to operate, has mild conditions, and is suitable for large-scale industrial production.

[0006] Specifically, the above invention objectives are achieved through the following technical routes:

[0007] A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, the specific steps of which are as follows;

[0008] 1) Add 1,4-butenediol and 2,2-dimethoxypropane to a reaction device, add p-toluenesulfonic acid, react at 20° C. to 30° C., and after the reaction is completed (the GC control content of 1,4-butenediol is less than 1%), add an organic base to quench the reaction;

[0009] Then, the reaction liquid was filtered through silica gel, the filter cake was rinsed with organic solvent I, and the filtrate was concentrated at 50° C. to constant weight to obtain 4,7-dihydro-2,2-dimethyl-1,3-dioxapine (intermediate I) with a purity of 97-98.5%.

[0010] The purpose of adding silica gel in this step is to remove residual p-toluenesulfonic acid and prevent the ether bond in 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline from breaking under acidic conditions during the concentration process at 50°C, thereby preventing the product from deteriorating.

[0011] The organic base used includes at least one of sodium carbonate and sodium bicarbonate;

[0012] The organic solvent I used for rinsing is obtained by mixing methanol and dichloromethane in a volume ratio of 12:1; the purpose of rinsing with the organic solvent I is to remove the residual 4,7-dihydro-2,2-dimethyl-1,3-dioxapine and ensure that no p-toluenesulfonic acid enters the filtrate.

[0013] 2) placing the 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline obtained in step 1) in solvent II, adding sodium hydroxide solution to adjust the solution pH to 8-9, adding 30% by mass hydrogen peroxide at 20° C. to 30° C. (if the concentration is too low, the reaction will be difficult), and after the addition is completed, adding sodium hydroxide aqueous solution to adjust the reaction solution pH to 9-10. After the reaction is completed, adding solvent III for extraction, concentrating and distilling off solvent III, acetonitrile and methanol, and then distilling the substrate to obtain 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane;

[0014] The solvent II is obtained by mixing water, acetonitrile and methanol; the mass ratio of water, acetonitrile and methanol is preferably 1.1:1:1;

[0015] The mass ratio of 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline to solvent II is preferably 1:3.1-6.2;

[0016] The solvent III used includes at least one of ethyl acetate and dichloromethane, preferably dichloromethane.

[0017] Furthermore, in the above step 1), the molar ratio of 1,4-butenediol to 2,2-dimethoxypropane is preferably 2.0 to 2.5:1.

[0018] Furthermore, in the above step 1), the molar ratio of the added p-toluenesulfonic acid to 1,4-butenediol is preferably 0.09 to 0.13:1.

[0019] Furthermore, in the above step 1), the mass ratio of silica gel to 1,4-butenediol is 1.0 to 1.5:1.

[0020] Furthermore, in the above step 2), the molar ratio of 30% by mass hydrogen peroxide to 4,7-dihydro-2,2-dimethyl-1,3-dioxapine is preferably 3.5-3.8:1.

[0021] Furthermore, the mass percentage of the sodium hydroxide aqueous solution added in the above step 2) is 5-10%, preferably 5%.

[0022] The chemical equations involved in the above reactions are as follows:

[0023]

[0024] The reaction principle of the present application is as follows: in the first step: under acidic conditions, the ether bond in 2,2-dimethoxypropane is broken first at the end with more carbon atoms to form a methoxyl cation, which combines with the hydrogen ion in the hydroxyl group of the alcohol (alcohol with more carbon atoms) to form methanol, and 2,2-dimethoxypropane loses the methoxy group to form an acetone fork, which acts as a nucleophile to attack the oxygen anion in the hydroxyl group of 1,4-butenediol that loses the hydrogen ion to form 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline; 2,2-dimethoxypropane is used as a solvent and raw material, 1,4-butenediol is used as a raw material, and p-toluenesulfonic acid is used as a catalyst. In the second step: methanol, acetonitrile and water are used as solvents (solvent II). Methanol and acetonitrile also act as phase transfer catalysts to dissolve 4,7-dihydro-2,2-dimethyl-1,3-dioxazone in solvent II, making the reaction system homogeneous. Hydrogen peroxide is used as an oxidant to oxidize the double bonds in 4,7-dihydro-2,2-dimethyl-1,3-dioxazone, and sodium hydroxide provides alkaline conditions to catalyze the decomposition of hydrogen peroxide.

[0025] Compared with the existing preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, the preparation method provided in this application has the following beneficial effects:

[0026] 1) The synthetic route of the present application uses 1,4-butenediol and 2,2-dimethoxypropane as raw materials, and performs a cyclization reaction catalyzed by p-toluenesulfonic acid to generate 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline; the raw materials have a wide source, high yield, high (GC) purity, and can be directly used in the second step for good effect.

[0027] 2) 4,7-dihydro-2,2-dimethyl-1,3-dioxacyclopentane is oxidized with hydrogen peroxide, extracted with dichloromethane, concentrated, and distilled to obtain 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane; the overall synthetic route is simple to operate, mild in conditions, high in yield, and suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the gas chromatogram of the intermediate I prepared in Example 1.

[0029] Figure 2 This is the gas chromatogram of the target product prepared in Example 1.

[0030] Figure 3 This is the gas chromatogram of the intermediate I prepared in Example 2.

[0031] Figure 4 This is the gas chromatogram of the target product prepared in Example 2.

[0032] Figure 5 This is the gas chromatogram of the intermediate I prepared in Example 3.

[0033] Figure 6 This is the gas chromatogram of the target product prepared in Example 3. DETAILED DESCRIPTION

[0034] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available.

[0035] The raw materials 1,4-butenediol, 2,2-dimethoxypropane and hydrogen peroxide (30% mass concentration) used in the examples were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0036] Silica gel was purchased from Qingdao Bangkai High-tech Materials Co., Ltd., model 300 mesh.

[0037] The gas chromatography detection method in the embodiment is: chromatographic column AC5: 30m*320μm*1μm, injection port temperature: 250°C, detector temperature: 300°C, no splitting, column oven temperature increased by 50°C and maintained at 50°C for 5 minutes, increased by 40°C / min to 150°C and maintained at 150°C for 5 minutes, increased by 50°C / min to 250°C and maintained at 250°C for 3 minutes.

[0038] Example 1

[0039] 1) Add 132.2 g (1.5 mol) of 1,4-butenediol and 462.5 g (3.3 mol) of 2,2-dimethoxypropane into a 1000 ml reaction bottle, control the temperature at 20°C to 30°C, add 28.5 g (150 mmol) of p-toluenesulfonic acid in 3 batches, and add 1 / 3 each time (in a specific embodiment, the number of batches and the amount added each time can be selected according to actual conditions); one hour later, the gas chromatography control shows that the consumption of 1,4-butenediol is less than (GC) 1% (mass percentage). After the reaction is completed, add 16.4 g (195 mmol) of sodium bicarbonate and stir for 30 minutes to quench the reaction;

[0040] 132 g of silica gel was spread and the reaction liquid was filtered, the filter cake was rinsed with organic solvent I (mixed with dichloromethane and methanol in a volume ratio of 12:1), and then the rinsed filtrate was concentrated to constant weight under vacuum at 50°C to obtain 167 g of intermediate I with a yield of 88% and a purity of 99%. The gas chromatography test results are as follows: Figure 1 As shown, Figure 1 In the experiment, 2-4 min is the peak of dilute intermediate I dichloromethane, 8.507 min is the peak of intermediate I, the peak height is 198370.324 pA, the peak area is 1824526.619 pA·S, and the peak area is 99.760%, which corresponds to the purchased standard bottle, confirming that the intermediate I obtained is 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline.

[0041] 2) 167 g (1.17 mol) of 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline (intermediate I) obtained in step 1) was added to a 3 L reaction bottle, and solvent II (518 g) was added. The pH of the reaction solution was adjusted to 8.5 with 5% (mass percentage, the same below) sodium hydroxide aqueous solution. The amount of sodium hydroxide aqueous solution used was about 15.66 g.

[0042] In this step, solvent II is obtained by mixing 184 g of water, 167 g of acetonitrile, and 167 g of methanol, and the mass ratio of the three is 1.1:1:1.

[0043] The temperature was controlled at 20°C to 30°C, 398g (3.51mol) of 30% (mass percentage, the same below) hydrogen peroxide was added dropwise, and the addition was completed in about 1h. Then, 17g of 5% sodium hydroxide aqueous solution was used to adjust the pH to 9.8 (pH agent measurement). After 6 hours, the intermediate I was controlled to be less than 2% in the gas chromatography. 835ml of dichloromethane (solvent III) was added each time, extracted 3 times, concentrated under vacuum at 50°C until no dripping, and then concentrated under vacuum at 120°C until no dripping. 157.79g of the final product was obtained at 140°C, with a yield of 84% (molar yield) and a purity of 99.7%. The gas chromatogram of the final product obtained in this embodiment is as follows Figure 2As shown, 14.240-14.385min is the final product, the peak height is 1540.322pA, and the peak area is 3694.060pA·S, which corresponds to the gas chromatogram of the 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane standard, confirming that the reaction route of this example obtains 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane.

[0044] The organic base used in this embodiment is sodium bicarbonate. In a specific implementation, at least one of sodium bicarbonate and sodium carbonate can be added to the reaction system. In a specific implementation, the solvent III can be at least one of ethyl acetate and dichloromethane.

[0045] Example 2

[0046] In a 100 ml reaction bottle, 13.2 g (150 mmol) of 1,4-butenediol and 46.3 g (330 mmol) of 2,2-dimethoxypropane were added. The temperature was controlled at 20°C to 30°C. 2.85 g (15 mmol) of p-toluenesulfonic acid was added in three batches. After reacting at 20°C to 30°C for 1 hour, the consumption of 1,4-butenediol was controlled by gas chromatography. After the reaction was completed, 1.64 g (19.5 mmol) of sodium bicarbonate was added and stirred for 30 minutes. 13.2 g of silica gel was placed on filter paper and filtered. The filter cake was rinsed with 13.2 ml of organic solvent I (obtained by mixing dichloromethane and methanol in a volume ratio of 12:1). The filter cake was concentrated at 50°C in vacuum until no dripping occurred to obtain intermediate I, 16.7 g, with a yield of 88% and a gas chromatographic purity of 98.55%. The gas chromatographic detection results are as follows: Figure 3 As shown, 8.164-8.645min is intermediate I, with a peak height of 182553.651pA, a peak area of ​​1574111.898pA·S, and a peak area of ​​98.558%, proving that 4,7-dihydro-2,2-dimethyl-1,3-dioxepin was obtained.

[0047] 2) In a 3 L reaction bottle, add 16.7 g (117 mmol) of 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline, 16.7 g of methanol, 18.4 g of water, and 16.7 g of acetonitrile, and adjust the pH to 8-9 with 1.57 g of 5% sodium hydroxide solution.

[0048] The temperature was controlled at 20°C to 30°C, 39.8 g (351 mmol) of 30% hydrogen peroxide was added dropwise, and after 1 hour of addition, 1.7 g of 5% sodium hydroxide aqueous solution was used to adjust the pH to 9 to 10. After 6 hours, the intermediate I was controlled to be less than 2% in the gas chromatography, and 83.5 ml of dichloromethane was added each time, extracted 3 times, concentrated under vacuum at 50°C until no dripping, and then concentrated under vacuum at 120°C until no dripping, and the final product was 15.4 g at 140°C, with a molar yield of 83% and a purity of 98.6%. The chromatogram of the final product obtained in this embodiment is as follows: Figure 4 As shown, the 10.008-12.179 min curve is the final product, the peak height is 158849.834 pA, and the peak area is 11200178.272 pA·S, which proves that 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] is obtained.

[0049] Example 3

[0050] 1) 396.66 g (4.5 mol) of 1,4-butenediol and 1387 g (9.9 mol) of 2,2-dimethoxypropane were added to a 3000 ml reaction bottle, and the temperature was controlled at 20°C to 30°C. 85.5 g (450 mmol) of p-toluenesulfonic acid was added in three batches. After reacting at 20°C to 30°C for one hour, the gas chromatography was controlled to show that the consumption of 1,4-butenediol was less than 1%. After completion, 49.14 g (585 mmol) of sodium bicarbonate was added and stirred for 30 minutes. 397 g of silica gel was spread and filtered. The filter cake was rinsed with 396 g of organic solvent I (obtained by mixing dichloromethane and methanol in a volume ratio of 12:1), and concentrated under vacuum at 50°C until no dripping occurred, to obtain 500 g of intermediate I, with a yield of 87% and a gas chromatographic purity of 98.99%. The gas chromatographic purity was as follows: Figure 5 As shown, 8.087-8.664min is intermediate I, with a peak height of 275794.419pA, a peak surface of 3013418.177pA·S, and a peak area of ​​98.992%, proving that 4,7-dihydro-2,2-dimethyl-1,3-dioxepin was obtained.

[0051] 2) Into a 10L reaction bottle, add 500 g (3.51 mol) of 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline prepared in step 1), 500 g of methanol, 550 g of water, and 500 g of acetonitrile, and adjust the pH to 8-9 with 47 g of 5% sodium hydroxide solution.

[0052] The temperature was controlled at 20°C to 30°C, 1164g (10.53mol) of 30% hydrogen peroxide was added dropwise, and after the addition was completed, 51g of 5% sodium hydroxide aqueous solution was used to adjust the pH to 9-10. After 6 hours, the gas chromatographic control band of intermediate I was less than 2%, and 2505ml of dichloromethane was added each time, extracted 3 times, concentrated under vacuum at 50°C until no dripping, concentrated under vacuum at 120°C until no dripping, and concentrated at 140°C to obtain 473g of the final product, with a yield of 83% and a purity of 98.35%. The chromatogram of the final product obtained in this embodiment is as follows Figure 6 As shown, the 10.085-12.025min curve is the final product, with a peak height of 149636.232pA, a peak area of ​​9258555.651pA·S, and a peak area of ​​98.356%, proving that 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] is obtained.

[0053] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, characterized in that: The specific steps are as follows; 1) 1,4-butenediol and 2,2-dimethoxypropane were mixed, p-toluenesulfonic acid was added, and the mixture was reacted at 20°C to 30°C. After the reaction was completed, an organic base was added to quench the reaction. Then, the reaction liquid was filtered through silica gel, the filter cake was rinsed with solvent I, and the filtrate was concentrated at 50°C to a constant weight to obtain intermediate I. The solvent I is obtained by mixing methanol and dichloromethane in a volume ratio of 12:1; The molar ratio of the added 1,4-butenediol to 2,2-dimethoxypropane is 2.0-2.5:1; The molar ratio of the added p-toluenesulfonic acid to 1,4-butenediol is 0.09-0.13:1; The organic base includes at least one of sodium carbonate and sodium bicarbonate; The mass ratio of silica gel to 1,4-butenediol used is 1.0 to 1.5:1; Said adding of p-toluenesulfonic acid means adding p-toluenesulfonic acid in 3 batches, adding 1 / 3 each time; 2) placing the intermediate I obtained in step 1) in solvent II, adjusting the solution pH to 8-9, adding hydrogen peroxide dropwise at 20°C-30°C, adjusting the reaction solution pH to 9-10 after the addition is complete, then adding solvent III, concentrating under vacuum at 50°C, and distilling to obtain the 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane; The molar ratio of the added hydrogen peroxide to 4,7-dihydro-2,2-dimethyl-1,3-dioxazoline is 3.5-3.8:1; The solvent II is obtained by mixing water, acetonitrile and methanol in a mass ratio of 1.1:1:1; the mass ratio of the added intermediate I to the solvent II is 1:3.1-6.2; The solvent III used includes at least one of ethyl acetate and dichloromethane.

2. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: Step 2) The pH value of the solution is adjusted to 8-9, which means that the pH value of the solution is adjusted to 8-9 with a sodium hydroxide solution having a mass percentage of 5%-10%; the pH value of the reaction solution is adjusted to 9-10, which means that the pH value of the reaction solution is adjusted to 9-10 with a sodium hydroxide solution having a mass percentage of 5%-10%.

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