CN115724849A - Preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane - Google Patents
Preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane Download PDFInfo
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- GEKNCWQQNMEIMS-UHFFFAOYSA-N 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane Chemical compound C1OC(C)(C)OCC2OC21 GEKNCWQQNMEIMS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 30
- OZCRKDNRAAKDAN-UHFFFAOYSA-N but-1-ene-1,4-diol Chemical compound O[CH][CH]CCO OZCRKDNRAAKDAN-UHFFFAOYSA-N 0.000 claims abstract description 16
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
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- 238000010791 quenching Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000007363 ring formation reaction Methods 0.000 abstract description 5
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- CPGCVOVWHCWVTP-LJAQVGFWSA-N (S)-nonacosan-10-ol Chemical compound CCCCCCCCCCCCCCCCCCC[C@@H](O)CCCCCCCCC CPGCVOVWHCWVTP-LJAQVGFWSA-N 0.000 description 4
- CPGCVOVWHCWVTP-UHFFFAOYSA-N celidoniol Natural products CCCCCCCCCCCCCCCCCCCC(O)CCCCCCCCC CPGCVOVWHCWVTP-UHFFFAOYSA-N 0.000 description 4
- -1 hydrogen ions Chemical class 0.000 description 4
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
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- 150000002500 ions Chemical class 0.000 description 2
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane which is a medical intermediate, the method takes 1,4-butenediol and 2,2-dimethoxypropane as raw materials, and the raw materials are subjected to catalytic cyclization reaction under acidic conditions to generate 4,7-dihydro-2,2-dimethyl-1,3-dioxazepine; then oxidizing with hydrogen peroxide to obtain 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane; the method is simple to operate, mild in condition and suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a pharmaceutical intermediate 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane.
Background
Gadobutrol injection is a contrast medium for contrast-enhanced magnetic resonance imaging, which can increase the sensitivity of Magnetic Resonance Imaging (MRI) after intravenous injection, and is therefore frequently used for detecting tumors, inflammation and demyelinating diseases of the central nervous system. The ginbuconazole serving as a novel strong magnetic resonance contrast agent has the advantages of high concentration, high relaxation rate and the like, and has low risk of generating renal systemic fibrosis which is unique in untoward effect of the ginbuconazole-containing contrast agent.
The epoxy side chain is an important intermediate in the preparation method of the ginnol, the quality of the epoxy side chain is 4,4-dimethyl-3,5,8-trioxabicyclo [5,1,0] octane (CAS: 57280-22-5), the yield and the purity of the ginnol are directly and obviously influenced, and the ginnol serving as a diagnostic agent, particularly an MRI diagnostic agent, has higher requirements on the purity of the raw material drug of the ginnol. Therefore, the preparation method for developing the epoxy side chain intermediate with good economy, high yield and high purity has better application prospect and practical significance.
The existing synthesis method of the epoxy side chain intermediate takes 1,4-butylene glycol, 2,2-dimethoxypropane and the like as raw materials, and the epoxy side chain intermediate is prepared by a first step of cyclization and a second step of epoxidation. The epoxy side chain intermediate prepared by the method has low purity and only 53% of total yield, the use of concentrated sulfuric acid increases the discharge of waste acid in a post-treatment stage, and the benzoic acid byproduct generated after the oxidation of the m-chloroperoxybenzoic acid also increases the treatment capacity of hazardous waste, so the environmental friendliness is poor. At present, a catalytic cyclization reaction by using resin is also reported, but the catalytic reaction is difficult to complete, and the yield and the product purity can not meet the requirements of industrial production. In addition, in the existing preparation method, the p-toluenesulfonic acid is catalyzed and cyclized and the hydrogen peroxide is epoxidized, but the p-toluenesulfonic acid is not quenched and is removed, so that the yield is seriously influenced.
Disclosure of Invention
Aiming at the problems of low product yield and easy environmental pollution of intermediate products, the application provides a method for preparing 4,7-dihydro-2,2-dimethyl-1,3-dioxane by using 1,4-butenediol and 2,2-dimethoxypropane as raw materials and carrying out catalytic cyclization reaction under an acidic condition; then using hydrogen peroxide to oxidize, and preparing a synthetic route of a final product 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane through distillation; the method is simple to operate, mild in condition and suitable for large-scale industrial production.
Specifically, the above object is achieved by the following technical route:
a preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane, which comprises the following specific steps;
1) Adding 1,4-butylene glycol and 2,2-dimethoxypropane into a reaction device, adding p-toluenesulfonic acid, reacting at 20-30 ℃, and adding organic base to quench the reaction after the reaction is finished (the controlled content in 1,4-butylene glycol GC is less than 1%);
then silica gel is paved for suction filtration of reaction liquid, a filter cake is rinsed by an organic solvent I, and the filtrate is concentrated to constant weight at 50 ℃, so that 4,7-dihydro-2,2-dimethyl-1,3-dioxane (an intermediate I) is obtained, wherein the purity of the intermediate I is 97-98.5%.
The purpose of adding silica gel in the step is to remove residual p-toluenesulfonic acid and prevent ether bonds in 4,7-dihydro-2,2-dimethyl-1,3-dioxane from breaking and product deterioration under acidic conditions in the concentration process at 50 ℃.
The organic base comprises at least one of sodium carbonate and sodium bicarbonate;
the organic solvent I used for rinsing is prepared by mixing methanol and dichloromethane in a volume ratio of 12:1, mixing to obtain; the purpose of the rinse with organic solvent I was to remove 4,7-dihydro-2,2-dimethyl-1,3-dioxane residue while ensuring that no p-toluenesulfonic acid entered the filtrate.
2) Placing 4,7-dihydro-2,2-dimethyl-1,3-dioxane obtained in the step 1) in a solvent II, adding a sodium hydroxide solution to adjust the pH value of the solution to be 8-9, dropwise adding 30% hydrogen peroxide at the temperature of 20-30 ℃ (the hydrogen peroxide is difficult to react due to too low concentration), dropwise adding a sodium hydroxide solution to adjust the pH value of a reaction solution to be 9-10 after dropwise adding, adding a solvent III to extract after the reaction is finished, concentrating to evaporate the solvent III, acetonitrile and methanol, and distilling a substrate to obtain 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane;
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;
4,7-dihydro-2,2-dimethyl-1,3-dioxane to solvent II mass ratio is preferably 1;
the solvent III used comprises at least one of ethyl acetate and dichloromethane, preferably dichloromethane.
Further, in the step 1), the molar ratio of 1,4-butenediol to 2,2-dimethoxypropane is preferably 2.0 to 2.5:1.
further, in the step 1), the molar ratio of the p-toluenesulfonic acid to the 1,4-butenediol to be added is preferably 0.09 to 0.13.
Further, in the step 1), the mass ratio of the silica gel to 1,4-butenediol is 1.0 to 1.5.
Further, in the step 2), the molar ratio of 30% by mass of hydrogen peroxide to 4,7-dihydro-2,2-dimethyl-1,3-dioxane is preferably 3.5 to 3.8:1.
further, the sodium hydroxide aqueous solution added in the step 2) is 5 to 10% by mass, preferably 5% by mass.
The above reaction involves the following chemical equation:
the reaction principle of the application is as follows: in the first step: under acidic conditions, ether bonds in 2,2-dimethoxypropane are firstly broken at one end with more carbon atoms to form methoxy positive ions, the methoxy positive ions are combined with hydrogen ions in the hydroxyl group of a (alcohol with more carbon atoms) middle alcohol to form methanol, the methoxy in 2,2-dimethoxypropane is lost to form acetonylidene, the acetonylidene is used as a nucleophilic reagent to attack oxygen anions in the hydroxyl group of 1,4-butenediol which are lost to form 4,7-dihydro-2,2-dimethyl-1,3-dioxane; 2,2-dimethoxypropane as solvent and feed, 1,4-butenediol as feed, and p-toluenesulfonic acid as catalyst. In the second step, methanol, acetonitrile and water are used as a solvent (solvent II), the methanol and acetonitrile also play a role of a phase transfer catalyst, so that 4,7-dihydro-2,2-dimethyl-1,3-dioxa Zhuo Rongjie is in the solvent II, the reaction system is homogeneous, hydrogen peroxide is used as an oxidizing agent to oxidize double bonds in 4,7-dihydro-2,2-dimethyl-1,3-dioxan, and sodium hydroxide provides an alkaline condition to catalyze the decomposition of hydrogen peroxide.
Compared with the existing preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane, the preparation method provided by the application has the following beneficial effects:
1) In the synthetic route, 1,4-butenediol and 2,2-dimethoxypropane are used as raw materials, and are subjected to catalytic cyclization reaction on p-toluenesulfonic acid to generate 4,7-dihydro-2,2-dimethyl-1,3-dioxane; wide raw material source, high yield, high (GC) purity and good effect when being directly used in the second step.
2) 4,7-dihydro-2,2-dimethyl-1,3-dioxane is oxidized by hydrogen peroxide, extracted by dichloromethane, concentrated and distilled to obtain 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane; the whole synthesis route has simple operation, mild condition and high yield, and is suitable for large-scale industrial production.
Drawings
Fig. 1 is a central control gas chromatogram of intermediate I prepared in example 1.
FIG. 2 is a gas chromatogram of the objective product prepared in example 1.
Fig. 3 is a controlled gas chromatogram of intermediate I prepared in example 2.
FIG. 4 is a gas chromatogram of the objective product prepared in example 2.
Fig. 5 is a controlled gas chromatogram of intermediate I prepared in example 3.
FIG. 6 is a gas chromatogram of the objective product prepared in example 3.
Detailed Description
Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available.
The raw materials 1,4-butenediol, 2,2-dimethoxypropane and hydrogen peroxide (30% by mass) used in the examples were purchased from Shanghai Bigdi pharmaceutical science and technology Co., ltd.
The silica gel is purchased from Qingdao Ponkayi advanced technology materials Co., ltd, model 300 mesh.
The gas chromatography detection mode in the examples is: chromatography column AC5:30m 320 μm 1 μm, injection port temperature: 250 ℃, detector temperature: the column oven was heated at 300 ℃ without splitting at 50 ℃ and 50 ℃ for 5 minutes, at 40 ℃/minute at 150 ℃ and 150 ℃ for 5 minutes, at 50 ℃/minute at 250 ℃ and 250 ℃ for 3 minutes.
Example 1
1) Adding 132.2g (1.5 mol) of 1,4-butenediol and 462.5g (3.3 mol) of 2,2-dimethoxypropane into a 1000ml reaction bottle, controlling the temperature to be 20-30 ℃, adding 28.5g (150 mmol) of p-toluenesulfonic acid in 3 batches, wherein 1/3 of p-toluenesulfonic acid is added (in the specific embodiment, the batch times and the adding amount of p-toluenesulfonic acid can be selected according to actual conditions); after one hour, performing gas chromatography control, wherein the consumption of 1,4-butylene glycol is less than 1% (mass percent) of (GC), after the reaction is finished, adding 16.4g (195 mmol) of sodium bicarbonate, stirring for 30 minutes, and quenching the reaction;
laying 132g of silica gel, suction-filtering the reaction solution, rinsing a filter cake with an organic solvent I (obtained by mixing dichloromethane and methanol according to a volume ratio of 12.
2) A3L reaction flask was charged with 167g (1.17 mol) of 4,7-dihydro-2,2-dimethyl-1,3-dioxane (intermediate I) obtained in step 1), solvent II (518 g) was added, the pH of the reaction solution was adjusted to 8.5 with 5% (mass percent, the same applies hereinafter) aqueous sodium hydroxide solution, and the amount of the aqueous sodium hydroxide solution used was about 15.66g.
In the step, the solvent II is obtained by mixing 184g of water, 167g of acetonitrile and 167g of methanol, and the mass ratio of the three components is 1.1.
After dropping 30% (mass percentage, the same below) of 398g (3.51 mol) of hydrogen peroxide at a controlled temperature of 20-30 ℃ for about 1h, then adjusting the pH to 9.8 (measured by pH agent) by using 17g of 5% sodium hydroxide aqueous solution, controlling the intermediate I to be less than 2% in the gas chromatogram after 6 h, adding 835ml of methylene chloride (solvent III) for each time, extracting for 3 times, concentrating to be not dropping under vacuum at 50 ℃, then placing to be not dropping under vacuum at 120 ℃, obtaining 3534 g of the final product 3534 zxft, yield 84% (molar yield) and purity 99.7% at 140 ℃, wherein the gas chromatogram of the final product obtained in the example is shown in FIG. 2, wherein 14.240-14.385min is the final product, peak area of 1540.322, 3432 zxft S is corresponding to the peak area of the standard gas chromatogram of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane, and the peak area of the standard gas chromatogram of the bicycle [ 4234.1.0 ] octane is confirmed by the corresponding to the reaction route of 4264 zxft 4234 zft 4234.
The organic base used in this embodiment is sodium bicarbonate, and in specific implementation, at least one of sodium bicarbonate and sodium carbonate can be added into the reaction system; in specific implementation, the solvent III may be at least one selected from ethyl acetate and dichloromethane.
Example 2
1,4-butylene glycol 13.2g (150 mmol), 2,2-dimethoxypropane 46.3g (330 mmol), controlling the temperature to be 20-30 ℃, adding p-toluenesulfonic acid 2.85g (15 mmol) in 3 batches, controlling the gas chromatography after reacting at 20-30 ℃ for 1h, controlling the consumption of 1,4-butylene glycol to be less than 1%, adding sodium bicarbonate 1.64g (19.5 mmol) after the reaction is finished, stirring for 30 minutes, laying silica gel 13.2g on a pad filter paper, performing suction filtration, rinsing a filter cake by using 13.2ml of organic solvent I (obtained after mixing dichloromethane and methanol in a volume ratio of 12).
2) A3L reaction flask was charged with 4,7-dihydro-2,2-dimethyl-1,3-dioxane 16.7g (117 mmol), methanol 16.7g, water 18.4g, and acetonitrile 16.7g, and the pH was adjusted to 8 to 9 with 5% aqueous sodium hydroxide 1.57 g.
Controlling the temperature to be 20-30 ℃, dropwise adding 39.8g (351 mmol) of 30 mass percent hydrogen peroxide, adjusting the pH value to be 9-10,6 hours by using 1.7g of 5% sodium hydroxide aqueous solution after dropwise adding for 1 hour, controlling the intermediate I to be less than 2% in gas chromatography, adding 83.5 ml/each time of dichloromethane, extracting for 3 times, concentrating to be not dropwise under the vacuum condition of 50 ℃, then placing the mixture to be 120 ℃ to be concentrated to be not dropwise, obtaining a final product of 15.4g at 140 ℃, ensuring the molar yield to be 83% and the purity to be 98.6%, and obtaining a final product chromatogram as shown in figure 4, wherein a curve of 10.008-12.179min is the final product, the peak height is 158849.834pA, the peak area is 11200178.272, 3752 zxft 3254, 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0].
Example 3
1) 1,4-butenediol 396.66g (4.5 mol), 2,2-dimethoxypropane 1387g (9.9 mol) are put into a 3000ml reaction bottle, the temperature is controlled at 20-30 ℃, 85.5g (450 mmol) of p-toluenesulfonic acid is added in 3 portions, the reaction is controlled in a gas chromatograph after one hour at 20-30 ℃, after 1,4-butenediol consumption is less than 1%, sodium bicarbonate 49.14g (585 mmol) is added, stirring is carried out for 30 minutes, 397g of silica gel is spread for suction filtration, and the filter cake is filtered by an organic solvent I (dichloromethane and methanol in a volume ratio of 12:1 obtained after mixing) 396g of rinsing, and concentrating under vacuum at 50 ℃ until no drop occurs to obtain 500g of intermediate I, the yield is 87%, the purity of gas chromatography is 98.99%, and the gas chromatography is shown in figure 5, wherein 8.087-8.664min is intermediate I, peak height 275794.419pA, peak surface 3013418.177 pA. S, peak area 98.992%, and 4,7-dihydro-2,2-dimethyl-1,3-dioxane is proved to be obtained.
2) 4,7-dihydro-2,2-dimethyl-1,3-dioxane 500g (3.51 mol) prepared in step 1), methanol 500g, water 550g, and acetonitrile 500g were charged into a 10L reaction flask, and the pH was adjusted to 8 to 9 with 47g of 5% sodium hydroxide aqueous solution.
Controlling the temperature to be 20-30 ℃, dropwise adding 1164g (10.53 mol) of 30% hydrogen peroxide, adjusting the pH value to be less than 2% after 10,6 h by using 51g of 5% sodium hydroxide aqueous solution after dropwise adding, adding 2505ml of dichloromethane for each time, extracting for 3 times, concentrating to be not dropwise under the vacuum of 50 ℃, concentrating to be not dropwise under the vacuum of 120 ℃, obtaining a final product 473g at 140 ℃, obtaining a yield of 83% and purity of 98.35%, wherein a chromatogram of the final product obtained in the embodiment is shown in fig. 6, wherein a 10.085-12.025min curve is a final product, and the peak area is 149636.232pA, 9258555.651 pA.S, the peak area is 98.356; 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] was demonstrated.
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only examples of the present invention, and should not be construed as limiting the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane is characterized by comprising the following specific steps;
1) Mixing 1,4-butylene glycol and 2,2-dimethoxypropane, adding p-toluenesulfonic acid, reacting at 20-30 ℃, and adding organic base to quench the reaction after the reaction is finished; then, silica gel is paved for pumping and filtering the reaction liquid, a filter cake is rinsed by a solvent I, and the filtrate is concentrated to constant weight at 50 ℃ to obtain an intermediate I;
the solvent I is prepared by mixing methanol and dichloromethane in a volume ratio of 12:1, mixing to obtain;
the molar ratio of 1,4-butenediol to 2,2-dimethoxypropane added is 2.0 to 2.5:1;
the molar ratio of the added p-toluenesulfonic acid to 1,4-butenediol is 0.09-0.13;
2) Putting the intermediate I obtained in the step 1) into a solvent II, adjusting the pH of the solution to 8~9, dropwise adding hydrogen peroxide at 20-30 ℃, adjusting the pH of a reaction solution to 9-10 after dropwise adding, then adding a solvent III, performing vacuum concentration at 50 ℃, and distilling to obtain the 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane;
the solvent II is obtained by mixing water, acetonitrile and methanol;
the solvent III used comprises 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, wherein the organic base used in step 1) comprises at least one of sodium carbonate and sodium bicarbonate.
3. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane according to claim 1, wherein in step 1), the mass ratio of silica gel to 1,4-butenediol is 1.0 to 1.5.
4. The preparation method of 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane as claimed in claim 1, wherein in step 2), the mass ratio of the intermediate I to the solvent II is 1.
5. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane according to claim 1, wherein in step 1), the mass ratio of silica gel to 1,4-butenediol is 1.0 to 1.5.
6. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane as claimed in claim 1, wherein in the step 2), the molar ratio of hydrogen peroxide to 4,7-dihydro-2,2-dimethyl-1,3-dioxane is 3.5-3.8: 1.
7. the method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane as claimed in claim 1, wherein the step 2) adjusting the pH of the solution to 8~9 means adjusting the pH of the solution to 8~9 by sodium hydroxide solution with the mass percent of 5% -10%; the pH value of the reaction liquid is adjusted to be 9 to 10 by using a sodium hydroxide solution with the mass percent of 5 to 10 percent.
8. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane according to claim 1, wherein in the solvent II in the step 2), the mass ratio of water, acetonitrile and methanol is 1.1.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020049337A1 (en) * | 1995-09-26 | 2002-04-25 | Takashi Inaba | 4-(2-amino-1-hydroxyethyl)oxazoline derivative and method for producing same |
| JP2005058995A (en) * | 2003-07-30 | 2005-03-10 | Ishikawajima Harima Heavy Ind Co Ltd | Water treatment apparatus and water treatment equipment |
| WO2008094957A1 (en) * | 2007-01-31 | 2008-08-07 | Dow Global Technologies Inc. | Method of producing alkyl polyalkylene glycol alkyl aldehydes |
| CN103351396A (en) * | 2013-07-29 | 2013-10-16 | 太仓市茜泾化工有限公司 | Preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5, 1, 0] octane |
| CN106967083A (en) * | 2017-04-26 | 2017-07-21 | 穆云 | The process of preparing of Gadobutrol epoxy side chain intermediate |
| CN109251209A (en) * | 2018-10-23 | 2019-01-22 | 湖北天舒药业有限公司 | A kind of preparation process of Gadobutrol intermediate |
| CN112409370A (en) * | 2020-12-10 | 2021-02-26 | 四川新迪医药化工有限公司 | Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol |
-
2022
- 2022-11-28 CN CN202211508386.8A patent/CN115724849A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020049337A1 (en) * | 1995-09-26 | 2002-04-25 | Takashi Inaba | 4-(2-amino-1-hydroxyethyl)oxazoline derivative and method for producing same |
| JP2005058995A (en) * | 2003-07-30 | 2005-03-10 | Ishikawajima Harima Heavy Ind Co Ltd | Water treatment apparatus and water treatment equipment |
| WO2008094957A1 (en) * | 2007-01-31 | 2008-08-07 | Dow Global Technologies Inc. | Method of producing alkyl polyalkylene glycol alkyl aldehydes |
| CN103351396A (en) * | 2013-07-29 | 2013-10-16 | 太仓市茜泾化工有限公司 | Preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5, 1, 0] octane |
| CN106967083A (en) * | 2017-04-26 | 2017-07-21 | 穆云 | The process of preparing of Gadobutrol epoxy side chain intermediate |
| CN109251209A (en) * | 2018-10-23 | 2019-01-22 | 湖北天舒药业有限公司 | A kind of preparation process of Gadobutrol intermediate |
| CN112409370A (en) * | 2020-12-10 | 2021-02-26 | 四川新迪医药化工有限公司 | Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol |
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