CN107746396B - Novel compound 6, 6-dimethyl tetrahydropyrane-2-methanol and preparation method thereof - Google Patents
Novel compound 6, 6-dimethyl tetrahydropyrane-2-methanol and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a novel compound 6, 6-dimethyl tetrahydropyran-2-methanol and a preparation method thereof, namely, benzyloxyethanol is prepared by a sodium alkoxide method; oxidizing the benzyloxyethanol to benzyloxyacetaldehyde by using a swern oxidation method; then reacting the allyl tributyltin prepared by the Grignard reaction with benzyloxyacetaldehyde to obtain 1- (benzyloxy) pent-4-en-2-ol; catalyzing 1- (benzyloxy) pent-4-ene-2-ol with trimethylchlorosilane and potassium iodide, cyclizing the product and acetone to prepare 4-iodine-6, 6-dimethyltetrahydropyran-2-methanol, and hydrogenating and deiodinating the 4-iodine-6, 6-dimethyltetrahydropyran-2-methanol to obtain the target product 6, 6-dimethyltetrahydropyran-2-methanol. The preparation method provided by the invention has relatively mild reaction, and the product is easy to treat and purify and is suitable for batch preparation, so that the preparation method of 6, 6-dimethyltetrahydropyran-2-methanol has important application value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a novel compound 6, 6-dimethyl tetrahydropyran-2-methanol and a preparation method thereof.
Background
The pyranomethanol compounds have very various uses, the structures have very good pharmacological activity, some medicaments for treating hypertension and medicaments for treating cardiovascular and nervous system degenerative diseases contain the pyranomethanol structures or fragments, and the pyranomethanol also exists in a plurality of natural product molecules, so that the pyranomethanol derivatives are important organic and medicinal intermediates. However, the pyran methanol compound is not easy to synthesize, and most of the common preparation methods have long steps, expensive raw materials, difficult operation and low yield, which greatly limits the requirements on efficient preparation and application of the pyran methanol compound. The types and the synthesis methods of tetrahydropyran-2-methanol are rarely reported, the synthesis method of 6, 6-dimethyltetrahydropyran-2-methanol is not reported so far, the CAS number of 6, 6-dimethyltetrahydropyran-2-methanol is not published so far, the novel degree of the substance is met, the research on the synthesis of the substance is not made clear, and the synthesis route disclosed by the invention is short; the preparation method is simple and convenient to operate, and is a cheap method suitable for mass preparation. Because the compounds are valuable pharmaceutical intermediates, the content disclosed by the invention has important research and practical values, and can greatly promote the preparation of other similar derivatives.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel compound 6, 6-dimethyl tetrahydropyran-2-methanol and a preparation method thereof, the reaction condition is mild, the product is easy to treat and purify, and the method is suitable for batch preparation.
In order to solve the technical problems, the invention adopts the following technical scheme:
a novel compound 6, 6-dimethyl tetrahydropyran-2-methanol, wherein the structural formula of the 6, 6-dimethyl tetrahydropyran-2-methanol is shown in the specification
The preparation method of the novel compound 6, 6-dimethyl tetrahydropyran-2-methanol comprises the following steps:
(1) adding ethylene glycol into tetrahydrofuran solution, adding sodium, reacting for 0.5h at 50 ℃, then dropwise adding benzyl bromide, refluxing the mixture for 12-14h, extracting, washing and drying to obtain benzyloxyethanol;
(2) adding oxalyl chloride into a dichloromethane solution, cooling to minus 50 to minus 60 ℃, dropwise adding the dichloromethane solution of dimethyl sulfoxide, dropwise adding benzyloxyethanol, dropwise adding triethylamine after 0.5h, stirring at the temperature of minus 50 to minus 60 ℃ for 1h, extracting, washing with acid water, and drying to obtain benzyloxyacetaldehyde;
(3) adding magnesium chips into anhydrous ether solution under the protection of nitrogen, then dropwise adding allyl bromide, reacting for 1.5h at 36-38 ℃ after the addition is finished, then adding tributyl tin oxide, refluxing for 1.5h after the addition is finished, and then adding water for quenching, extracting, washing and drying to obtain allyl tributyl tin;
(4) dropwise adding boron trifluoride diethyl etherate into a dichloromethane solution of benzyloxyacetaldehyde and allyl tributyltin at 0 ℃, reacting at room temperature for 0.5h, adjusting the pH to be neutral by using an aqueous solution of sodium bicarbonate after the reaction is finished, extracting, washing with brine, and drying to obtain 1- (benzyloxy) pent-4-en-2-ol;
(5) adding 1- (benzyloxy) pent-4-ene-2-ol into a mixed solution of acetonitrile, acetone and sodium iodide, then dropwise adding trimethylchlorosilane, reacting for 0.5h at 0-5 ℃, and then washing and drying by extraction, a sodium thiosulfate solution and a sodium bicarbonate solution to obtain a compound 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol;
(6) adding triethylamine and palladium carbon into an ethyl acetate solution of a compound 4-iodine-6, 6-dimethyltetrahydropyran-2-methanol, reacting for 10-12 h in a hydrogen atmosphere, and then filtering, washing and drying to obtain the compound 6, 6-dimethyltetrahydropyran-2-methanol;
the specific preparation reaction route is as follows:
the molar ratio of the ethylene glycol to the sodium to the benzyl bromide in the step (1) is 5.0-5.3: 1.0-1.3: 1.
In the step (2), the molar ratio of oxalyl chloride to dimethyl sulfoxide to benzyloxyethanol to triethylamine is 1.1: 2.0-2.2: 1: 6.
the molar ratio of the magnesium chips, the allyl bromide and the tributyl tin oxide in the step (3) is 4.8-5: 2.8-3.0: 1.
In the step (4), the molar ratio of boron trifluoride diethyl etherate, allyl tributyltin and benzyloxyacetaldehyde 2 is 1:2: 2.
In the step (5), the molar ratio of acetone, sodium iodide, trimethylchlorosilane to 1- (benzyloxy) pent-4-en-2-ol 3 is 2.5:2.5:2.5: 1.
The molar ratio of the triethylamine in the step (6) to the 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol 4 is 2-3: 1.
The invention has the beneficial effects that: 6, 6-dimethyl tetrahydropyrane-2-methanol is a novel compound, and the synthesis of the compound is not reported in documents at present. The preparation method provided by the invention has relatively mild reaction, and the product is easy to treat and purify and is suitable for batch preparation, so that the preparation method of 6, 6-dimethyltetrahydropyran-2-methanol has important application value.
Detailed Description
The present invention will be further described with reference to the following examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention, which is to be given numerous insubstantial modifications and adaptations by those skilled in the art based on the teachings set forth above.
The specific preparation reaction route of the invention is as follows:
example 1
The 6, 6-dimethyltetrahydropyran-2-methanol of this example was prepared as follows:
(1) synthesis of benzyloxyethanol 1
To a solution of ethylene glycol 30g (0.5 mol) in tetrahydrofuran (100 mL) was added sodium 2.3g (0.1 mol) and the temperature was controlled at 50 ℃. The resulting mixture was stirred under reflux for 0.5 hour, and then 17.1g (0.1 mol) of benzyl bromide was added dropwise, followed by reflux overnight. The next day 100mL of water was added, most of the solvent was removed by rotary evaporator, 80mL of ethyl acetate was added, the organic phase was separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, and 70 deg.c (2 mmHg) fractions were collected to give 12.1g of the product in 80% yield.
MS：m/z: [M+Na]
+:176；
1H NMR (400 MHz, CDCl
3): 7.48 (d, 2H), 7.37 (m, 2H), 7.21 (m, 1H),4.45 (s, 2H), 3.86 (t, 2H), 3.10 (t, 2H), 2.33 (br, 1H)；
Elemental analysis C
9H
12O
2Theoretical values (%): C, 71.03; H, 7.95; measured values: C:71.24; H: 7.72.
(2) Synthesis of benzyloxyacetaldehyde 2
Oxalyl chloride (2.92 g, 0.023 mol) was dissolved in 50mL of dichloromethane, cooled to-50 to-60 ℃, and then a mixture of 10mL of dichloromethane and 2.3g of dimethyl sulfoxide (0.046 mol) was added dropwise. After 30 minutes, 3.5g (0.023 mol) of benzyloxyethanol 1 were added dropwise, the temperature being kept at-50 ℃ to-60 ℃. After 15 minutes, 14g of triethylamine (0.138 mol) were added while keeping the temperature at-50 ℃ to-60 ℃. After stirring for 1h, 70mL of water were added, the aqueous layer was separated and extracted 2 times with dichloromethane. The combined organic layers were washed with 3% hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, collecting 80 ℃ (2 mmHg) fractions to give 2.4g of product in 70% yield.
MS：m/z: [M+1]
+:150；
1H NMR (400 MHz, CDCl
3): 9.70（s, 1H），7.45 (d, 2H), 7.31 (m, 2H), 7.28(m, 1H) , 4.84 (s, 2H), 4.44 (d, 2H)；
Elemental analysis C
9H
10O
2Theoretical values (%): C, 71.98; H, 6.71; measured values: C,71.92; H: 6.77.
(3) Synthesis of allyl tributyltin
A dry three-neck flask equipped with mechanical stirring is added with 7.2g (0.30 mol) of magnesium chips, 100mL of anhydrous ether and a small amount of iodine, a dropping funnel is filled with 21.17g (0.175 mol) of allyl bromide and 15mL of anhydrous ether, the whole system is protected by nitrogen, 1-1.2 mL of allyl bromide solution is slowly dropped, then the temperature of the system gradually rises, and the reaction is initiated. The remaining allyl bromide solution was continuously added dropwise, keeping the system at slow reflux. After the addition, the mixture was refluxed for 1.5 hours, and then heating was stopped and 15mL of a mixture of anhydrous ether and 19g (0.062 mol) of tributyltin oxide was added, and the reaction was carried out while maintaining the reaction temperature at 36 to 38 ℃. After the addition was complete, the reaction mixture was refluxed for 1.5 hours, stirred at room temperature overnight, and then saturated aqueous ammonium chloride was added and extracted with n-hexane 3 times. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the residual oil after removing most of the solvent was distilled under reduced pressure to collect 19.3g (94%) of a fraction as a colorless oil.
MS：m/z: [M+1]
+:332；
1H NMR (400 MHz, CDCl
3): 5.8 (m, 1H), 4.8 (d, 2H), 1.82 (d, 2H), 1.58(m, 6H), 1.34 (m, 6H), 0.90 (m, 15H)。
(4) Synthesis of 1- (benzyloxy) pent-4-en-2-ol 3
To a solution of 9g of benzyloxyacetaldehyde 2 (0.06 mol) and allyl tributyltin 19.86g (0.06 mol) in dichloromethane (80 mL) was added boron trifluoride diethyl etherate 4.3g (0.03 mol) dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After adjusting the pH to neutrality with aqueous sodium bicarbonate solution, the organic phase was separated and the aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-5/1 as eluent to give 10.25g of the product as a colorless oil in 89% yield.
MS：m/z: [M+1]
+:193
(5) Synthesis of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol 4
2g of 1- (benzyloxy) pent-4-en-2-ol 3 (0.01 mol), 0.14g of acetone (0.025 mol), and 3.75g of sodium iodide (0.025 mol) were dissolved in 20mL of an acetonitrile solution, and then 2.71g of trimethylchlorosilane (0.025 mol) was added dropwise thereto while cooling on ice. The mixture was stirred for 30 min. Then, ethyl acetate was added to the reaction mixture, and the organic layer was washed with a sodium thiosulfate solution and a sodium bicarbonate solution, respectively, dried over anhydrous sodium sulfate, and after concentration, the residue was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to obtain the product as a white solid 2.2g in a yield of 81%.
MS：m/z: [M+1]
+:271；
1H NMR (400 MHz, CDCl
3): 3.8-3.51 (m, 3H), 2.28 (m, 2H) , 1.84 (m,2H), 1.24 (s, 6H)；
Elemental analysis C
8H
15IO
2Theoretical value (%) < C, 35.57 >, H, 5.60, < I,46.98, measured C,35.52, H, 5.63, I, 47.01;
(6) synthesis of 6, 6-dimethyltetrahydropyran-2-methanol 5
To a solution of 1.2g (0.0045 mol) of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol in ethyl acetate (20 mL) were added 0.91g (0.009 mol) of triethylamine and 10% Pd/C (0.12 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. Then, filtration was carried out, the filter cake was washed with ethyl acetate, the filtrate was washed with 1M hydrochloric acid 1 time, the aqueous layer was extracted with ethyl acetate (80 mL) 1 time, the combined organic layers were dried and concentrated, and the residue after concentration was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to give the product 0.6g as a colorless oil in 92% yield.
Example 2
The 6, 6-dimethyltetrahydropyran-2-methanol of this example was prepared as follows:
(1) synthesis of benzyloxyethanol 1
Ethylene glycol 31.6g (0.51 mol) was added to a tetrahydrofuran (100 mL) solution followed by sodium 2.53g (0.11 mol) and the temperature was controlled at 50 ℃. The resulting mixture was then stirred at reflux for 0.5h, 17.1g (0.1 mol) of benzyl bromide was added dropwise, and the mixture was then refluxed overnight. Then 100mL of water was added, most of the solvent was removed by rotary evaporator, 80mL of ethyl acetate was added, the organic phase was separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, and 70 ℃ (2 mmHg) fractions were collected to give 12.4g of product in 82% yield.
(2) Synthesis of benzyloxyacetaldehyde 2
Oxalyl chloride (2.92 g, 0.023 mol) was dissolved in 50mL of dichloromethane, cooled to-50 to-60 ℃, and then a mixture of 10mL of dichloromethane and 2.4g of dimethyl sulfoxide (0.048 mol) was added dropwise. After 30 minutes, 3.5g (0.023 mol) of benzyloxyethanol 1 were added dropwise, the temperature being kept at-50 ℃ to-60 ℃. After 15 minutes, 14g of triethylamine (0.138 mol) were added while keeping the temperature at-50 ℃ to-60 ℃. After stirring for 1h, 70mL of water were added, the aqueous layer was separated and extracted 2 times with dichloromethane. The combined organic layers were washed with 3% hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, collecting 80 ℃ (2 mmHg) fractions to give 2.47g of product in 72% yield.
(3) Synthesis of allyl tributyltin
A dry three-neck flask equipped with mechanical stirring is added with 7.2g (0.30 mol) of magnesium chips, 100mL of anhydrous ether and a small amount of iodine, a dropping funnel is filled with 21.5g (0.177 mol) of allyl bromide and 15mL of anhydrous ether, the whole system is protected by nitrogen, 1-1.2 mL of allyl bromide solution is slowly dropped, then the temperature of the system gradually rises, and the reaction is initiated. The remaining allyl bromide solution was continuously added dropwise, keeping the system at slow reflux. After the addition, the mixture was refluxed for 1.5 hours, and then heating was stopped and 15mL of a mixture of anhydrous ether and 19g (0.062 mol) of tributyltin oxide was added, and the reaction was carried out while maintaining the reaction temperature at 36 to 38 ℃. After the addition was complete, the reaction mixture was refluxed for 1.5 hours, stirred at room temperature overnight, and then saturated aqueous ammonium chloride was added and extracted with n-hexane 3 times. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the residual oil after removing most of the solvent was distilled under reduced pressure to collect 19.5g (95%) of a fraction as a colorless oil.
(4) Synthesis of 1- (benzyloxy) pent-4-en-2-ol 3
To a solution of 9g of benzyloxyacetaldehyde 2 (0.06 mol) and allyl tributyltin 19.86g (0.06 mol) in dichloromethane (80 mL) was added boron trifluoride diethyl etherate 4.3g (0.03 mol) dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After adjusting the pH to neutrality with aqueous sodium bicarbonate solution, the organic phase was separated and the aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-5/1 as eluent to give 10.25g of the product as a colorless oil in 89% yield.
(5) Synthesis of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol 4
2g of 1- (benzyloxy) pent-4-en-2-ol 3 (0.01 mol), 0.14g of acetone (0.025 mol), and 3.75g of sodium iodide (0.025 mol) were dissolved in 20mL of an acetonitrile solution, and then 2.71g of trimethylchlorosilane (0.025 mol) was added dropwise thereto while cooling on ice. The mixture was stirred for 30 min. Then, ethyl acetate was added to the reaction mixture, and the organic layer was washed with a sodium thiosulfate solution and a sodium bicarbonate solution, respectively, dried over anhydrous sodium sulfate, and after concentration, the residue was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to obtain the product as a white solid 2.2g in a yield of 81%.
(6) Synthesis of 6, 6-dimethyltetrahydropyran-2-methanol 5
To a solution of 1.2g (0.0045 mol) of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol in ethyl acetate (20 mL) were added 1.14g (0.011 mol) of triethylamine and 8% Pd/C (0.1 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. Then, filtration was carried out, the filter cake was washed with ethyl acetate, the filtrate was washed with 1M hydrochloric acid 1 time, the aqueous layer was extracted with ethyl acetate (80 mL) 1 time, the combined organic layers were dried and concentrated, and the residue after concentration was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to give the product 0.61g as a colorless oil in 93% yield.
Example 3
The 6, 6-dimethyltetrahydropyran-2-methanol of this example was prepared as follows:
(1) synthesis of benzyloxyethanol 1
Ethylene glycol 32.8g (0.53 mol) was added to a tetrahydrofuran (100 mL) solution, followed by sodium 3.0g (0.13 mol) and the temperature was controlled at 50 ℃. The resulting mixture was then stirred at reflux for 0.5h, 17.1g (0.1 mol) of benzyl bromide was added dropwise, and the mixture was then refluxed overnight. Then 100mL of water was added, most of the solvent was removed by rotary evaporator, 80mL of ethyl acetate was added, the organic phase was separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, collecting the 70 deg.c (2 mmHg) fraction to give 12.86g of the product in 85% yield.
(2) Synthesis of benzyloxyacetaldehyde 2
Oxalyl chloride (2.92 g, 0.023 mol) was dissolved in 50mL of dichloromethane, cooled to-50 to-60 ℃, and then a mixture of 10mL of dichloromethane and 2.5g of dimethyl sulfoxide (0.05 mol) was added dropwise. After 30 minutes, 3.5g (0.023 mol) of benzyloxyethanol 1 were added dropwise, the temperature being kept at-50 ℃ to-60 ℃. After 15 minutes, 14g of triethylamine (0.138 mol) were added while keeping the temperature at-50 ℃ to-60 ℃. After stirring for 1h, 70mL of water were added, the aqueous layer was separated and extracted 2 times with dichloromethane. The combined organic layers were washed with 3% hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated, which was purified by distillation, collecting 80 ℃ (2 mmHg) fractions to give 2.57g of product in 75% yield.
(3) Synthesis of allyl tributyltin
A dry three-neck flask with mechanical stirring is added with 7.2g (0.30 mol) of magnesium chips, 100mL of anhydrous ether and a small amount of iodine, a dropping funnel is filled with 21.78g (0.18 mol) of allyl bromide and 15mL of anhydrous ether, the whole system is protected by nitrogen, 1-1.2 mL of allyl bromide solution is slowly dropped, then the temperature of the system gradually rises, and the reaction is initiated. The remaining allyl bromide solution was continuously added dropwise, keeping the system at slow reflux. After the addition, the mixture was refluxed for 1.5 hours, and then heating was stopped and 15mL of a mixture of anhydrous ether and 19g (0.062 mol) of tributyltin oxide was added, and the reaction was carried out while maintaining the reaction temperature at 36 to 38 ℃. After the addition was complete, the reaction mixture was refluxed for 1.5 hours, stirred at room temperature overnight, and then saturated aqueous ammonium chloride was added and extracted with n-hexane 3 times. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the residual oil after removing most of the solvent was distilled under reduced pressure to collect 19.7g (96%) of a fraction as a colorless oil.
(4) Synthesis of 1- (benzyloxy) pent-4-en-2-ol 3
To a solution of 9g of benzyloxyacetaldehyde 2 (0.06 mol) and allyl tributyltin 19.86g (0.06 mol) in dichloromethane (80 mL) was added boron trifluoride diethyl etherate 4.3g (0.03 mol) dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After adjusting the pH to neutrality with aqueous sodium bicarbonate solution, the organic phase was separated and the aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate 10/1-5/1 as eluent to give 10.25g of the product as a colorless oil in 89% yield.
(5) Synthesis of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol 4
2g of 1- (benzyloxy) pent-4-en-2-ol 3 (0.01 mol), 0.14g of acetone (0.025 mol), and 3.75g of sodium iodide (0.025 mol) were dissolved in 20mL of an acetonitrile solution, and then 2.71g of trimethylchlorosilane (0.025 mol) was added dropwise thereto while cooling on ice. The mixture was stirred for 30 min. Then, ethyl acetate was added to the reaction mixture, and the organic layer was washed with a sodium thiosulfate solution and a sodium bicarbonate solution, respectively, dried over anhydrous sodium sulfate, and after concentration, the residue was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to obtain the product as a white solid 2.2g in a yield of 81%.
(6) Synthesis of 6, 6-dimethyltetrahydropyran-2-methanol
To a solution of 1.2g (0.0045 mol) of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol in ethyl acetate (20 mL) were added 1.36g (0.0135 mol) of triethylamine and 5% Pd/C (0.06 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 h. Then, filtration was carried out, the filter cake was washed with ethyl acetate, the filtrate was washed with 1M hydrochloric acid 1 time, the aqueous layer was extracted with ethyl acetate (80 mL) 1 time, the combined organic layers were dried and concentrated, and the residue after concentration was separated and purified by column chromatography with petroleum ether/ethyl acetate =5/1 as an eluent, to give the product 0.6g as a colorless oil in 93% yield.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
- A preparation method of 6, 6-dimethyl tetrahydropyran-2-methanol is characterized by comprising the following steps:(1) adding ethylene glycol into tetrahydrofuran solution, adding sodium, reacting for 0.5h at 50 ℃, then dropwise adding benzyl bromide, refluxing the mixture for 12-14h, extracting, washing and drying to obtain benzyloxyethanol;(2) adding oxalyl chloride into a dichloromethane solution, cooling to minus 50 to minus 60 ℃, dropwise adding dimethyl sulfoxide and the dichloromethane solution, dropwise adding benzyloxyethanol, dropwise adding triethylamine after 0.5h, stirring at the temperature of minus 50 to minus 60 ℃ for 1h, extracting, washing with acid water, and drying to obtain benzyloxyacetaldehyde;(3) adding magnesium chips into anhydrous ether solution under the protection of nitrogen, then dropwise adding allyl bromide, reacting for 1.5h at 36-38 ℃ after the addition is finished, then adding tributyl tin oxide, refluxing for 1.5h after the addition is finished, and then adding water for quenching, extracting, washing and drying to obtain allyl tributyl tin;(4) dropwise adding boron trifluoride diethyl etherate into a dichloromethane solution of benzyloxyacetaldehyde and allyl tributyltin at 0 ℃, reacting at room temperature for 0.5h, adjusting the pH to be neutral by using an aqueous solution of sodium bicarbonate after the reaction is finished, extracting, washing with brine, and drying to obtain 1- (benzyloxy) pent-4-en-2-ol;(5) adding 1- (benzyloxy) pent-4-ene-2-ol into a mixed solution of acetonitrile, acetone and sodium iodide, then dropwise adding trimethylchlorosilane, reacting for 0.5h at 0-5 ℃, and then washing and drying by extraction, a sodium thiosulfate solution and a sodium bicarbonate solution to obtain a compound 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol;(6) adding triethylamine and palladium carbon into an ethyl acetate solution of a compound 4-iodine-6, 6-dimethyltetrahydropyran-2-methanol, reacting for 10-12 h in a hydrogen atmosphere, and then filtering, washing and drying to obtain the compound 6, 6-dimethyltetrahydropyran-2-methanol; the structural formula of the 6, 6-dimethyl tetrahydropyran-2-methanol is shown in the specification;In the step (5), the molar ratio of acetone, sodium iodide, trimethylchlorosilane to 1- (benzyloxy) pent-4-en-2-ol is 2.5:2.5:2.5: 1.
- 2. The method for producing 6, 6-dimethyltetrahydropyran-2-methanol according to claim 1, characterized in that: the molar ratio of the ethylene glycol to the sodium to the benzyl bromide in the step (1) is 5.0-5.3: 1.0-1.3: 1.
- 3. The method for producing 6, 6-dimethyltetrahydropyran-2-methanol according to claim 1, characterized in that: the molar ratio of oxalyl chloride, dimethyl sulfoxide, benzyloxyethanol and triethylamine in the step (2) is 1.1: 2.0-2.2: 1: 6.
- 4. The method for producing 6, 6-dimethyltetrahydropyran-2-methanol according to claim 1, characterized in that: the molar ratio of the magnesium chips, the allyl bromide and the tributyl tin oxide in the step (3) is 4.8-5: 2.8-3.0: 1.
- 5. The method for producing 6, 6-dimethyltetrahydropyran-2-methanol according to claim 1, characterized in that: in the step (4), the molar ratio of boron trifluoride diethyl etherate, allyl tributyltin and benzyloxyacetaldehyde is 1:2: 2.
- 6. The method for producing 6, 6-dimethyltetrahydropyran-2-methanol according to claim 1, characterized in that: in the step (6), the molar ratio of triethylamine to 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol is 2-3: 1, and the amount of palladium carbon is 5-10% of the mass of 4-iodo-6, 6-dimethyltetrahydropyran-2-methanol.
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| WO2007111345A1 (en) * | 2006-03-29 | 2007-10-04 | The University Of Tokyo | Reactive oxygen determination reagent |
| TW201629015A (en) * | 2014-11-25 | 2016-08-16 | 第一三共股份有限公司 | Hydronaphthoquinoline derivatives |
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| WO2007111345A1 (en) * | 2006-03-29 | 2007-10-04 | The University Of Tokyo | Reactive oxygen determination reagent |
| TW201629015A (en) * | 2014-11-25 | 2016-08-16 | 第一三共股份有限公司 | Hydronaphthoquinoline derivatives |
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