Preparation method of 5-hydroxymethyl tetrahydrofuran-3-alcoholTechnical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of 5-hydroxymethyl tetrahydrofuran-3-ol.
Background
Currently, the preferred treatment for AIDS is the inhibition of HIV Reverse Transcriptase (RT) using modified nucleosides. Thus, AZT, ddC, ddI and BW-1685 compounds, etc., exhibit potent activity against HIV reverse transcriptase and, in some cases, have been used as a first line of defense against AIDS. Recently, it has been found that certain modified nucleosides in the enantiomeric series, such as L-3-TC and L-5-F-ddC, also exhibit activity against HIV RT. Generally, these compounds are much less toxic and therefore have better therapeutic indicators. Except for these modified nucleoside analogs, they all have heterocyclic bases in the normal ectopic position. Examples of such compounds having antiviral activity are D-and L-dideoxyadenosine. 5-hydroxymethyl tetrahydrofuran-3-ol is a key intermediate for synthesizing nucleosides, and is widely focused and studied in recent years.
Synthesis of 5-hydroxymethyltetrahydrofuran-3-ol according to the disclosure of J.Org. chem.1998, 63, 2975-2981 Process one essentially starting from 1, 4-pentadiene, by sharp asymmetric dihydroxylation using (DHQD) 2PHAL with 1, 4-pentadiene prepared by reaction of allyl chloride with magnesium, gives about a 1:1 mixture of optically active tetradienes which are converted into optically active diepoxides by their ditoluic acid. And in the second method, asymmetric reduction and alkali cyclization are carried out on copper salt of 1, 5-dichloropentane-2, 4-dione by using a Node catalyst. The method III comprises the steps of converting d-ribonic acid gamma-lactone into tetraenoic acid with optical activity in six steps, carrying out sulfonylation by TPSCl, and then treating by sodium hydride to obtain the diepoxy compound. The three routes react with acid or alkali to obtain the 5-hydroxymethyl tetrahydrofuran-3-alcohol. However, the optical activity of the intermediate in the first route is 1:1, and the intermediate cannot be separated by any simple method (crystallization, distillation or chromatography), and the second and third methods are expensive in raw materials, so that the cost of the product is high, and the industrial development is limited. The reaction formula is as follows:
According to document M. Tiecco et al/Tetrahedron 63 (2007) 5482-5489, the synthesis of 5-hydroxymethyl tetrahydrofuran-3-ol is mainly prepared by taking (R) -glycidol as a raw material and carrying out five steps of reactions of ring opening, electrophilic addition, reduction, free radical cyclization and TBDPS removal, but the isomerism of the finally obtained 5-hydroxymethyl tetrahydrofuran-3-ol lacks diastereoselectivity, the isomerism ratio is about 1:1, and the 5-hydroxymethyl tetrahydrofuran-3-ol with high purity is not easy to separate, so that the industrial development is limited. The reaction formula is as follows:
In the prior art, the synthesis of 5-hydroxymethyl tetrahydrofuran-3-alcohol is that the final product lacks diastereoselectivity, has higher isomerism and is not easy to separate out high-purity 5-hydroxymethyl tetrahydrofuran-3-alcohol.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of 5-hydroxymethyl tetrahydrofuran-3-alcohol, which remarkably improves diastereoselectivity in the synthesis process, effectively reduces the generation of isomers, so that the high-purity 5-hydroxymethyl tetrahydrofuran-3-alcohol can be more easily separated, the raw materials are more economic and easily obtained based on the synthesis path provided by the invention, the cost of the raw materials is reduced, the synthesis process is simple, the yield and purity of a target product are remarkably improved by precisely controlling the reaction condition and the mole ratio, the process is environment-friendly, the condition is mild, and the method is suitable for the requirement of large-scale industrial production.
The invention is realized by the following technical scheme that on one hand, the invention provides a preparation method of 5-hydroxymethyl tetrahydrofuran-3-alcohol, which comprises the following chiral isomers:
Wherein the molar ratio of the compound shown in the formula (IX) to the compound shown in the formula (X) is 4:1, and the synthetic route of the compound shown in the formula (IX) and the compound shown in the formula (X) is shown in the following route I:
。
further, the method comprises the following steps:
Step 1) the process of formula (I)Reacting with a protecting group and alcohol under alkaline conditions to generate a compound shown in a formula (II);
step 2) reacting a compound shown in a formula (II) with vinyl magnesium bromide to obtain a compound shown in a formula (III);
Step 3) reacting a compound shown in a formula (III) with tetrabutylammonium fluoride to carry out deprotection reaction to obtain a compound shown in a formula (IV);
Step 4) obtaining a mixture of a compound shown in a formula (V) and a compound shown in a formula (VI) from the compound shown in the formula (IV) under the action of iodine and sodium carbonate;
step 5) reacting the mixture of the compound shown in the formula (V) and the compound shown in the formula (VI) with p-nitrobenzoic acid to obtain a mixture of the compound shown in the formula (VII) and the compound shown in the formula (VIII);
Step 6) removing the protecting group from the mixture of the compound shown in the formula (VII) and the compound shown in the formula (VIII) under the action of sodium tert-butoxide to obtain a mixture of the compound shown in the formula (IX) and the compound shown in the formula (X), and purifying the mixture of the compound shown in the formula (IX) and the compound shown in the formula (X) by using a column chromatography method;
wherein in step 1), the molar ratio of the protecting group to the compound of formula (I) is (1-1.5): 1, preferably 1.2:1.
In step 2), a catalyst CuI is also used, the molar ratio of CuI to the compound of formula (II) being (0.1-0.3): 1, preferably 0.3:1.
In the step 3), the molar ratio of the tetrabutylammonium fluoride to the compound shown in the formula (III) is (1-1.5): 1;
in step 4), the molar ratio of iodine to the compound of formula (IV) is (2-3): 1, preferably 2.5:1.
In step 5), the molar ratio of p-nitrobenzoic acid to the compound of formula (V) and the compound of formula (VI) is (4-8): 1, preferably 6:1.
In step 6), the molar ratio of the sodium tert-butoxide to the compound of formula (VII) and the mixture of the compound of formula (VIII) is (6-10): 1, preferably 8:1.
Again, a process for the preparation of 5-hydroxymethyltetrahydrofuran-3-ol is provided, comprising the following chiral isomers:
wherein the molar ratio of the compound of formula (XIX) to the compound of formula (XX) is 4:1.
Further, the synthetic routes of the compound represented by the formula (XIX) and the compound represented by the formula (XX) are shown in the following scheme II:
。
further, the method comprises the following steps:
Step 1) the process of formula (XI)Reacting with a protecting group and alcohol under alkaline conditions to produce a compound shown in a formula (XII);
step 2) reacting a compound shown in a formula (XII) with vinyl magnesium bromide to obtain a compound shown in a formula (XIII);
Step 3) reacting a compound shown in a formula (XIII) with tetrabutylammonium fluoride to carry out deprotection reaction to obtain a compound shown in a formula (XIV);
step 4) obtaining a mixture of the compound shown in the formula (XV) and the compound shown in the formula (XVI) by using the compound shown in the formula (XIV) under the action of iodine and sodium carbonate;
Step 5) reacting the mixture of the compound represented by the formula (XV) and the compound represented by the formula (XVI) with p-nitrobenzoic acid to obtain a mixture of the compound represented by the formula (XVII) and the compound represented by the formula (XVIII);
Step 6) removing the protecting group from the mixture of the compound shown in the formula (XVII) and the compound shown in the formula (XVIII) under the action of sodium tert-butoxide to obtain a mixture of the compound shown in the formula (XIX) and the compound shown in the formula (XX), and purifying the mixture of the compound shown in the formula (XIX) and the compound shown in the formula (XX) by using a column chromatography method;
Wherein in step 1), the molar ratio of the protecting group to the compound of formula (XI) is (1-1.5): 1, preferably 1.2:1.
In step 2), a catalyst CuI is also used, the molar ratio of CuI to the compound of formula (XII) being (0.1-0.3): 1, preferably 0.3:1.
In the step 3), the molar ratio of tetrabutylammonium fluoride to the compound shown in the formula (XIII) is (1-1.5): 1;
In step 4), the molar ratio of iodine to the compound of formula (XIV) is (2-3): 1, preferably 2.5:1.
In step 5), the molar ratio of p-nitrobenzoic acid to the compound of formula (XV), the mixture of compounds of formula (XVI) is (4-8): 1, preferably 6:1.
In step 6), the molar ratio of the sodium tert-butoxide to the compound of the formula (XVII) and the mixture of compounds of the formula (XVIII) is (6-10): 1, preferably 8:1.
Preferably, in step 1), the protecting group is selected from one of TBDPSCl, TESOTf, DTBMSCl.
Finally, a process for the preparation of 5-hydroxymethyltetrahydrofuran-3-ol is provided, comprising the following cis-trans isomers:
Wherein the molar ratio of the compound of formula (XXIX) to the compound of formula (XXX) is 4.1:1.
Further, the synthetic routes of the compound represented by the formula (XXIX) and the compound represented by the formula (XXX) are as shown in the following route three:
。
further, the method comprises the following steps:
Step 1) the compound of formula (XXI)Reacting with vinyl magnesium bromide to obtain a compound represented by formula (XXII);
Step 2) obtaining a compound shown in a formula (XXIII) from the compound shown in the formula (XXII) under the action of Na2CO 3;
step 3) the compound shown in the formula (XXIII) is boiled by heating water at 90 ℃ to obtain the compound shown in the formula (XXXIV);
Step 4) a compound shown in a formula (XXIV) is subjected to the action of iodine and sodium carbonate to obtain a mixture of the compound shown in the formula (XXV) and the compound shown in the formula (XXVI);
Step 5) reacting a mixture of a compound represented by formula (XXV) and a compound represented by formula (XXVI) with p-nitrobenzoic acid to obtain a mixture of a compound represented by formula (XXVII) and a compound represented by formula (XXVIII);
step 6) removing the protecting group from the mixture of the compound shown in the formula (XXVII) and the compound shown in the formula (XXVIII) under the action of sodium tert-butoxide to obtain a mixture of the compound shown in the formula (XXIX) and the compound shown in the formula (XXX), and purifying the compound shown in the formula (XXIX) and the compound shown in the formula (XXX) by using a column chromatography method;
Wherein in step 1), the molar ratio of vinyl magnesium bromide to the compound represented by formula (XXI) is (1.05-1.5): 1;
in the step 2), the molar ratio of Na2CO3 to the compound shown in the formula (XXII) is (1.05-1.5): 1;
In step 4), the molar ratio of iodine to the compound of formula (XXIV) is (2-3): 1;
In the step 5), the molar ratio of the p-nitrobenzoic acid to the compound shown in the formula (XXV) and the mixture of the compound shown in the formula (XXVI) is (4-8): 1;
in the step 6), the molar ratio of the compound represented by the formula (XXVII), the mixture of the compounds represented by the formula (XXVIII) and the sodium tert-butoxide is (6-10): 1.
Advantageous effects
The invention obviously improves diastereoselectivity in the synthesis process by precisely controlling reaction conditions and molar ratio and using specific catalyst and protecting group, and effectively reduces the generation of isomers, thereby separating high-purity 5-hydroxymethyl tetrahydrofuran-3-alcohol more easily.
The synthetic route based on the invention comprises a route one, a route two and a route three, so that four RS isomerism products and two cis-trans isomerism products are obtained, the raw materials are cheap and easy to obtain, the synthetic method is simple, the generation of byproducts is reduced, the subsequent purification steps are simplified, and higher yield and purity are achieved.
The process is environment-friendly, mild in condition and suitable for the requirement of large-scale industrial production.
Drawings
FIG. 1 is a 1HNMR spectrum of a compound of formula (IX);
FIG. 2 is a 1HNMR spectrum of the compound represented by the formula (X).
Detailed Description
The present invention will be described in further detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, proportions or parts are by weight unless otherwise indicated.
The reagents and starting materials used in the examples and comparative examples of the present invention were commercially available unless otherwise specified.
Example 1
Synthesis of compounds of formula (II):
adding 1.1 kg TBDPSCl and 239 g imidazole into 2L DMF, cooling to 0-5 ℃, dropwise adding 200 g compound shown in formula (I), controlling the temperature not higher than 10 ℃, heating to 25 ℃ after the dropwise adding is finished, and reacting for 2 hours. TLC monitoring the completion of the reaction, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, column chromatography gave 506 g% of the compound of formula (II), yield 60%.
Synthesis of compounds of formula (III):
93 g CuI is added into anhydrous 2.5L THF, the temperature is reduced to minus 15 ℃, 4.8L vinyl magnesium bromide is added dropwise, after the dropwise addition is finished, the temperature is controlled between minus 10 ℃ and minus 20 ℃, 506 g THF solution of the compound shown in the formula (II) (the compound shown in the formula (II) is dissolved in 2.5L THF) is added dropwise into the reaction system, and the reaction is carried out overnight after the dropwise addition is finished, the temperature is naturally raised to room temperature. TLC was used to monitor the completion of the reaction, water was added to quench the reaction, extraction was performed with ethyl acetate, washing was performed with saturated brine, concentration was performed under reduced pressure, and column chromatography was performed to obtain 430 g of the compound represented by the formula (III), and the yield was 78%.
Synthesis of compounds of formula (IV):
430 g of the compound represented by formula (III) was added to 2.1L of anhydrous THF, a THF solution of TBAF was added dropwise under ice bath (0 ℃) and after the completion of the dropwise addition, the temperature was raised to room temperature, TLC was monitored to be complete, and the reaction was concentrated under reduced pressure to give the compound represented by formula (IV) 116 g by column chromatography in 90% yield.
Synthesis of Compound of formula (V) and Compound of formula (VI):
After the compound shown in the formula (IV) of 116 g is dissolved in 1.3L THF and stirred for 20 minutes under ice bath, 301 g of Na2CO3 is added in batches, the temperature is raised to room temperature and stirred for 30 minutes, the temperature is reduced to 0 ℃ again, 577 g solid iodine is added in batches, the system is naturally heated to room temperature after the addition, TLC monitors the reaction completion, sodium sulfite solid is added to neutralize redundant iodine until the reaction solution is clear and transparent, ethyl acetate is used for extraction, saturated saline solution is used for washing, decompression concentration and column chromatography are carried out, and a mixture of the compound shown in the formula (VI) and the compound shown in the formula (VII) of 205 g is obtained, and the yield is 79%.
Synthesis of a Compound of formula (VII) and a Compound of formula (VIII):
A mixture of 205 g of the compound of formula (VI) and the compound of formula (VII) was dissolved in 1L DMF, and 101 g of 18-crown-6 and 315 g of p-nitrobenzoic acid were added thereto and reacted at 90℃overnight. TLC was used to monitor completion of the reaction, ice-water was added thereto and stirred for 15 minutes, followed by extraction with ethyl acetate, washing with an aqueous sodium thiosulfate solution, washing with a saturated saline solution, concentrating under reduced pressure, and column chromatography to give 164 g of a mixture of the compound represented by the formula (XI) and the compound represented by the formula (XII) in 80% yield.
Synthesis of Compound of formula (IX) and Compound of formula (X):
A mixture of a compound shown in a formula (XI) and a compound shown in a formula (XII) in 164 g is dissolved in 820 mL ACN, 354 g sodium tert-butoxide is added in portions and reacted for 3-4 hours at room temperature under the protection of nitrogen, TLC monitors that the reaction is complete, the reaction liquid is filtered, and the filtrate is concentrated to obtain a mixture of the compound shown in the formula (XI) and the compound shown in the formula (XII), and the compound shown in a formula (IX) in 41 g and the compound shown in a formula (X) in 10 g are obtained after column chromatography separation, and the yield is 70%.
The prepared 1HNMR spectra of formula (IX) and 1HNMR spectra of formula (X) are shown in FIGS. 1 and 2.
Example 2
Synthesis of compounds of formula (XII):
Adding imidazole of 1.67 kg TBDPSCl and 358 g into 2L DMF, cooling to 0-5 ℃, dripping a compound shown in a formula (XI) of 300-g, controlling the temperature to be not higher than 10 ℃, heating to 25 ℃ after dripping, and reacting for 2 hours. TLC was used to monitor the completion of the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column-chromatographed to give 759 g of the compound of formula (XII) in 60% yield.
Synthesis of compounds of formula (XIII):
139 g CuI is added into anhydrous 3.8L THF, the temperature is reduced to minus 15 ℃, 7.3L vinyl magnesium bromide is added dropwise, after the dropwise addition, the temperature is controlled between minus 10 ℃ and minus 20 ℃, 759 g THF solution of the compound shown in formula (XII) (the compound shown in formula (XII) is dissolved in 2.5L THF) is added dropwise into the reaction system, and the reaction is carried out overnight after the dropwise addition, the temperature is naturally raised to room temperature. TLC was used to monitor the completion of the reaction, water was added to quench the reaction, extraction was performed with ethyl acetate, washing was performed with saturated brine, concentration was performed under reduced pressure, and column chromatography was performed to obtain 645 g compound of formula (XIII), yield 78%.
Synthesis of compounds of formula (XIV):
The compound represented by formula (XII) of 645 g was added to 3.2L of anhydrous THF, a THF solution of TBAF was added dropwise under ice bath (0 ℃ C.), after the completion of the dropwise addition, the temperature was raised to room temperature, TLC was monitored to be complete, and the reaction was concentrated under reduced pressure to give 174: 174 g (XIV) in 90% yield.
Synthesis of Compound of formula (XV) and Compound of formula (XVI):
After the compound represented by the formula (XIV) 174 g was dissolved in 1.3L THF and stirred for 20 minutes in an ice bath, 430 g of Na2CO3 was added in portions, the temperature was raised to room temperature and stirred for 30 minutes, the temperature was lowered again to 0 ℃, 866 g solid iodine was added in portions, the system was naturally warmed to room temperature after the addition, TLC was monitored to complete the reaction, sodium sulfite solid was added to neutralize the surplus iodine until the reaction solution was clear and transparent, extraction was performed with ethyl acetate, washing with saturated brine, concentration under reduced pressure and column chromatography were performed to obtain 307g of a mixture of the compound represented by the formula (XV) and the compound represented by the formula (XVI) in a yield of 79%.
Synthesis of Compound of formula (XVII) and Compound of formula (XVII):
307g of a mixture of the compound represented by formula (XV) and the compound represented by formula (XVI) was dissolved in 1L DMF, and 152 g of 18-crown-6 and 472 g p-nitrobenzoic acid were added thereto and reacted at 90℃overnight. TLC was used to monitor completion of the reaction, ice-water was added thereto and stirred for 15 minutes, followed by extraction with ethyl acetate, washing with an aqueous sodium thiosulfate solution, washing with a saturated saline solution, concentration under reduced pressure and column chromatography, whereby a mixture of the compound represented by the formula (XVII) and the compound represented by the formula (XVII) was obtained in 246 g% yield.
Synthesis of Compound of formula (XIX) and Compound of formula (XX):
A mixture of the compound shown in the formula (XVII) of 246 g and the compound shown in the formula (XVII) is dissolved in 1.2 mL ACN, 530 g sodium tert-butoxide is added in portions, the reaction is carried out for 3 to 4 hours at room temperature under the protection of nitrogen, TLC monitors that the reaction is complete, the reaction liquid is filtered, the filtrate is concentrated to obtain a mixture of the compound shown in the formula (XI) and the compound shown in the formula (XIX), and the compound shown in the formula (XI) of 61 g and the compound shown in the formula (XIX) of 15 g can be obtained by column chromatography separation, and the yield is 70%.
Example 3
Synthesis of compounds of formula (XXII):
3.7L vinyl magnesium bromide was added to a 1.2L THF solution of 107. 107 g CuBr at-50-60℃and then 230g of the compound of formula (XXI) was slowly added dropwise to the above system, after which the reaction was carried out overnight at-30 ℃. TLC was used to monitor completion of the reaction, the reaction solution was added to saturated ammonium chloride, extracted with ethyl acetate, concentrated under reduced pressure, and column-chromatographed to give 285, 285 g of the compound of formula (XXII), in 95% yield.
Synthesis of compounds of formula (XXIII):
to 285 g of the compound of formula (XXII), 501 g of Na2CO3 solid was added, and the reaction was carried out at 90℃overnight. TLC monitored completion of the reaction, extracted with ethyl acetate, concentrated under reduced pressure, and column chromatography gave 161 g of formula (XXIII) in 81% yield.
Synthesis of compounds of formula (XXIV):
161 g of the compound of formula (XXIII) was added to 805: 805 mL of water, the temperature was raised to 90℃and the reaction was carried out overnight. TLC monitored completion of the reaction, extracted with ethyl acetate, concentrated under reduced pressure, and column chromatography gave the compound of formula (XXIV) 111 g in 57% yield.
Synthesis of Compound of formula (XXV) and Compound of formula (XXVI):
Or 111 g formula (XXIV) is dissolved in 1.3L THF, stirred for 20 minutes in an ice bath, 275 g Na2CO3 is added in portions, the temperature is raised to room temperature and stirred for 30 minutes, then the temperature is reduced to 0 ℃ again, 554 g solid iodine is added in portions, the system is naturally heated to room temperature after the addition, TLC monitors the reaction completion, sodium sulfite solid is added to neutralize redundant iodine until the reaction solution is clear and transparent, ethyl acetate is used for extraction, saturated saline solution is used for washing, decompression concentration and column chromatography are carried out, thus obtaining a mixture of 189 g formula (XXV) and formula (XXVI), and the yield is 76%.
Synthesis of a Compound of formula (XXVII) and a Compound of formula (XXVIII):
a mixture of 189 g of the compound of formula (XXV) and of the compound of formula (XXVI) was dissolved in 1L DMF, and 93 g of 18-crown-6 and 290 g of p-nitrobenzoic acid were added and reacted at 90℃overnight. TLC monitored completion of the reaction, and after stirring for 15 minutes with ice water, extraction with ethyl acetate, washing with aqueous sodium thiosulfate, washing with saturated saline, concentrating under reduced pressure, and column chromatography gave 151 g of the compound represented by formula (XXVII) and a mixture of the compound represented by formula (XXVIII) in 80% yield.
Synthesis of a Compound of formula (XXIX) and a Compound of formula (XXX):
A mixture of a compound shown in a formula (XXIX) and a compound shown in a formula (XXVIII) in 151 g is dissolved in 820 mL ACN, 326 sodium tert-butoxide of g is added in portions and reacted for 3 to 4 hours at room temperature under the protection of nitrogen, TLC monitors that the reaction is complete, the reaction liquid is filtered, and the filtrate is concentrated to obtain a mixture of the compound shown in the formula (XXIX) and the compound shown in a formula (XXX), and the compound shown in a formula (XXIX) in 37 g and the compound shown in a formula 9 g (XXX) are separated by column chromatography, so that the yield is 69%.
It should be noted that the foregoing description is only a preferred embodiment of the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood that modifications, equivalents, improvements and modifications to the technical solution described in the foregoing embodiments may occur to those skilled in the art, and all modifications, equivalents, and improvements are intended to be included within the spirit and principle of the present invention.