CN107188786B - Preparation method of optically pure cyclopentenol as medical intermediate - Google Patents
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Abstract
The invention relates to a preparation method of a medical intermediate optical pure cyclopentenol, which takes 3-butenal and 3-position or 4-position derivatives thereof as raw materials, synthesizes an optical pure aldol condensation product in the presence of catalytic amount of (S) -proline, reduces aldehyde group into hydroxyl group, protects the hydroxyl group with benzyl bromide, and obtains (1) through high-efficiency double-bond translocation ring-closing reactionS,2R) The method provided by the invention has the advantages of mild reaction conditions, cheap and easily obtained raw materials and reagents, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic chemical industry, in particular to a preparation method of optically pure cyclopentenol as a medical intermediate.
Background
(1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol is an important pharmaceutical intermediate for the synthesis of carbocyclic nucleoside drugs (Abdallah Ezzitouni, Pamela Russ, and Victor E.Marquez.J.Org.Chem.1997,62, 4870-.
Regarding the synthesis of (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol, sodium cyclopentadienyl is mainly used as a raw material, and the synthetic route is as follows:
reacting sodium cyclopentadienide with benzyl chloromethyl ether to obtain 5-benzyloxymethyl cyclopentadiene, carrying out hydroboration reaction by using dipenanylborane, and oxidizing to obtain the target product (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol. Although the synthetic route has only two steps, the reagents used are expensive and the reaction conditions are demanding, so that it is always a challenge to find a more convenient synthetic method.
Disclosure of Invention
The invention mainly aims to provide a preparation method of pharmaceutical intermediate optically pure cyclopentenol.
The technical scheme of the invention is as follows:
a preparation method of a pharmaceutical intermediate optical pure cyclopentenol is (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol, and the chemical structural formula is as follows:
the synthesis route is as follows:
the R is1And R2Are respectively H, C1-C8Or an alkyl with an aromatic group;
the method specifically comprises the following steps:
1) taking 3-butenal as a raw material, and carrying out aldol condensation reaction to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde;
2) reducing (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-alcohol;
3) protecting the primary hydroxyl group of (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol with benzyl bromide to obtain (3R,4S) -3-benzyloxymethyl hept-1, 6-dien-4-ol;
4) the (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-ol is subjected to a high-efficiency double bond metathesis ring-closure reaction to obtain (1S,2R) -2-benzyloxymethyl cyclopent-3-en-1-ol;
to complete the preparation of (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol.
Preferably, in the step 1), the aldol condensation reaction is carried out in a tetrahydrofuran solution by using (S) -proline as a catalyst, and the reaction solution is concentrated and then is separated by a column chromatography with a mixed solution of petroleum ether and ethyl acetate to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde.
Further preferably, the dosage of the catalyst is 5-20% of the mass of 3-butenal, the temperature of the aldol condensation reaction is 10-40 ℃, and the time is 18-24 h.
Preferably, the specific method in step 2) is as follows: stirring and reacting (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde, calcium chloride and methanol at 10-40 ℃ for 10-60 minutes; dropwise adding a reducing agent solution, continuously stirring and reacting for 10-60 minutes at 10-40 ℃ after dropwise adding, and then adding a hydrochloric acid solution to decompose the generated solid; removing methanol under reduced pressure, cooling to room temperature, adding ice water, extracting with dichloromethane, mixing organic phases, drying, concentrating, and separating by column chromatography to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-ol.
Further preferably, the reducing agent in step 2) is sodium borohydride or potassium borohydride.
Further preferably, the reducing agent in step 2) is sodium borohydride, and the preparation method of the sodium borohydride solution is as follows: dissolving sodium borohydride in a solution prepared from 20 times of methanol and 20 times of 1% sodium hydroxide aqueous solution, and stirring at 0 ℃ to obtain the sodium borohydride solution.
Preferably, the specific method in step 3) is as follows: adding (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol into a Dimethylformamide (DMF) solution of sodium hydride cooled at 0 ℃, adding benzyl bromide under stirring, continuing stirring and reacting at 10-40 ℃ for 10-60 minutes, pouring the reaction solution into ice after detecting no raw material spots through thin-plate chromatography, extracting with dichloromethane, combining the extracting solutions, drying, concentrating, and purifying through column chromatography to obtain (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-ol.
Further preferably, the reaction temperature is 10-40 ℃.
Preferably, the specific method of the efficient double bond metathesis ring-closing reaction in the step 4) is as follows:
dissolving (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-alcohol in cyclohexane, adding an improved Grubb' S catalyst at 10-40 ℃, reacting for 2-3h, adding ethyl vinyl ether into the reaction solution, and directly performing column chromatography separation and purification to obtain (1S,2R) -2-benzyloxymethyl cyclopent-3-en-1-ol.
Further preferably, in the step 4), the high-efficiency double bond metathesis ring-closing reaction uses a second-generation Grubb's catalyst as an improved Grubb's catalyst SBA-15), and the reaction temperature is 10-40 ℃.
The invention has the following beneficial effects:
1. the method comprises the steps of taking 3-butenal as an initial raw material, carrying out aldol condensation in the presence of catalytic amount of (S) -proline to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde, reducing by sodium borohydride to obtain corresponding alcohol, protecting primary hydroxy by benzyl, and carrying out high-efficiency double bond translocation ring-closing reaction to obtain (1S,2R) -2-benzyloxy methyl cyclopentyl-3-ene-1-alcohol. Although the synthetic route needs four-step reaction, all the reactions are carried out at room temperature (10-40 ℃), and only the last two-step reaction needs inert gas protection, so that the reaction condition is mild, the operation is simple, the yield is moderate, and the method is suitable for industrial production.
2. The total yield of the (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol prepared by the method is more than 50%, the yield of the method is high, the product purity meets the requirement (the HPLC purity is more than 98.0%), and the preparation in kilogram scale can be easily realized.
3. 3-butenal or 3-hexenal, (S) -proline is used as a catalyst for asymmetric synthesis, so that the price is low, and the cost is greatly reduced;
4. the synthetic route avoids using expensive pinene as a chemical reagent for asymmetric synthesis, so that the synthetic route is economical and practical.
Detailed Description
The invention is further illustrated by the following examples, but the scope of the invention as claimed is not limited to the scope of the examples.
EXAMPLE 1 preparation of (2R,3S) -3-hydroxy-2-vinylcyclohex-5-en-1-al
(S) -proline (14.9 mg, 0.13 mmol) was added to a stirred solution of 3-butenal (150 mg) in 1 ml of tetrahydrofuran, stirred at 25 ℃ for 20h, the reaction solution was concentrated and subjected to column chromatography using a mixture of petroleum ether and ethyl acetate to obtain 100 mg of (2R,3S) -3-hydroxy-2-vinylhex-5-ene-1-al. The yield thereof was found to be 67%,1H NMR(DMSO-d6)δ:1.95(brs,1H),2.11(m,2H),3.11(m,1H),3.51(m,1H),4.97(d,1H),5.03(d,1H),5.17(d,1H),5.19(d,1H),5.70(dd,1H),5.97(dd,1H),9.72(s,1H)。
EXAMPLE 2 preparation of (2R,3S) -3-hydroxy-2-vinylcyclohex-5-en-1-ol
2 mmol (222 mg) of calcium chloride and 1 mmol (140 mg) of (2R,3S) -3-hydroxy-2-vinylcyclohex-5-en-1-al were put in a 50 ml single-neck flask, 5 ml of methanol was added, and the mixture was stirred at 25 ℃ for 30 minutes. 1.2 mmol (50 mg) of sodium borohydride is dissolved in a solution prepared from 1 ml of methanol and 1 ml of 1% sodium hydroxide, and the sodium borohydride solution is added dropwise under ice bath and stirring. After the addition was complete, the reaction was stirred at 25 ℃ for a further 30 minutes and then 1 ml of 4M hydrochloric acid solution was added to decompose the emerging solid. Most of the methanol was removed under reduced pressure, cooled to 25 ℃, added with ice water 10 ml, extracted three times with dichloromethane, the organic phases were combined, dried, concentrated and separated by column chromatography to obtain 120 mg of (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol. The yield is 85 percent,1H NMR(DMSO-d6)δ:2.00(brs,2H),2.11(m,2H),2.33(m,1H),3.28(m,1H),3.53(m,2H),4.98(m,2H),5.02(m,2H),5.70(m,2H)。
EXAMPLE 3 preparation of (3R,4S) -3-benzyloxymethylhepta-1, 6-dien-4-ol
142 mg of (2R,3S) -3-hydroxy-2-vinylcyclohex-5-en-1-ol (1.0 mmol) are added to 200 mg of sodium hydride in 2 ml of DMF at 0 ℃ with cooling, and 342 mg of benzyl bromide (2 mmol) are then added with stirring. Stirring at 25 deg.C for 30 min, detecting no spot by thin-plate chromatography, pouring the reaction solution into 50 g ice, extracting with dichloromethane for three times, mixing extractive solutions, drying, concentrating, and purifying by column chromatography to obtain (3R,4S) -3-benzyl205 mg of oxymethylhepta-1, 6-dien-4-ol, yield 88%,1H NMR(DMSO-d6)δ:2.00(brs,1H),2.11(m,2H),2.56(m,1H),3.28(m,1H),3.37(m,2H),4.63(m,2H),4.97(m,2H),5.02(m,2H),5.70(m,2H),7.19-7.40(m,5H)。
EXAMPLE 4 preparation of (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol
233 mg of (3R,4S) -3-benzyloxymethylheptyl-1, 6-dien-4-ol (1.0 mmol) was dissolved in 10 ml of cyclohexane, improved Grubb' S catalyst SBA-15(34 mg, 3.4 micromole ruthenium) was added at 25 ℃ and ethyl vinyl ether was added to the reaction mixture after three hours, followed by direct column chromatography for purification to give 168 mg of (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol, yield 82%, nuclear magnetic spectrum was in accordance with standard spectrum.
The above-described embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and features in the embodiments and examples in the present application may be arbitrarily combined with each other without conflict. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.
Claims (3)
1. A preparation method of optically pure cyclopentenol as a medical intermediate is characterized in that the cyclopentenol is (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol, and the chemical structural formula of the cyclopentenol is as follows:
the synthesis route is as follows:
the R is1And R2Are respectively H, C1-C8Straight or branched chain ofParaffins, or alkanes with aromatic groups;
the method specifically comprises the following steps:
1) taking 3-butenal as a raw material, and carrying out aldol condensation reaction to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde;
2) reducing (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-alcohol;
3) protecting the primary hydroxyl group of (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol with benzyl bromide to obtain (3R,4S) -3-benzyloxymethyl hept-1, 6-dien-4-ol;
4) the (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-ol is subjected to a high-efficiency double bond metathesis ring-closure reaction to obtain (1S,2R) -2-benzyloxymethyl cyclopent-3-en-1-ol;
completing the preparation of (1S,2R) -2-benzyloxymethylcyclopent-3-en-1-ol;
the step 1) of aldol condensation reaction is to take (S) -proline as a catalyst, the aldol condensation reaction is carried out in a tetrahydrofuran solution, a reaction solution is concentrated and then is subjected to column chromatography separation by using a mixed solution of petroleum ether and ethyl acetate to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde, the amount of the catalyst is 5% -20% of the mass of 3-butenal, the temperature of the aldol condensation reaction is 10-40 ℃, and the time is 18-24 hours;
the specific method in the step 2) comprises the following steps: stirring and reacting (2R,3S) -3-hydroxy-2-vinyl hex-5-ene-1-aldehyde, calcium chloride and methanol at 10-40 ℃ for 10-60 minutes; dropwise adding a reducing agent solution, continuously stirring and reacting for 10-60 minutes at 10-40 ℃ after dropwise adding, and then adding a hydrochloric acid solution to decompose the generated solid; removing methanol under reduced pressure, cooling to room temperature, adding ice water, extracting with dichloromethane, mixing organic phases, drying, concentrating, and separating by column chromatography to obtain (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol; the reducing agent in the step 2) is sodium borohydride or potassium borohydride; the reducing agent in the step 2) is sodium borohydride, and the preparation method of the sodium borohydride solution comprises the following steps: dissolving sodium borohydride in a solution prepared from 20 times of methanol and 20 times of 1% sodium hydroxide aqueous solution, and stirring at 0 ℃ to obtain a sodium borohydride solution;
the specific method in the step 3) comprises the following steps: adding (2R,3S) -3-hydroxy-2-vinyl hex-5-en-1-ol into a Dimethylformamide (DMF) solution of sodium hydride cooled at 0 ℃, adding benzyl bromide under stirring, continuing stirring and reacting at 10-40 ℃ for 10-60 minutes, pouring the reaction solution into ice after detecting no raw material spots through thin-plate chromatography, extracting with dichloromethane, combining the extracting solutions, drying, concentrating, and purifying through column chromatography to obtain (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-ol.
2. The method of claim 1, wherein: the specific method of the efficient double bond translocation ring-closing reaction in the step 4) comprises the following steps:
dissolving (3R,4S) -3-benzyloxymethyl hepta-1, 6-diene-4-alcohol in cyclohexane, adding an improved Grubb' S catalyst at 10-40 ℃, reacting for 2-3h, adding ethyl vinyl ether into the reaction solution, and directly performing column chromatography separation and purification to obtain (1S,2R) -2-benzyloxymethyl cyclopent-3-en-1-ol.
3. The method of claim 1, wherein:
in the step 4), a second-generation Grubb's catalyst is used as an improved Grubb's catalyst SBA-15 in the efficient double-bond translocation ring-closing reaction, and the reaction temperature is 10-40 ℃.
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| CN103304375A (en) * | 2012-03-12 | 2013-09-18 | 浙江奥翔药业有限公司 | Synthesis intermediate of Entecavir and preparation method thereof |
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| CN1100406A (en) * | 1993-06-03 | 1995-03-22 | 住友化学工业株式会社 | A process for the production of a cyclopentenol derivative |
| CN102491960A (en) * | 2011-11-16 | 2012-06-13 | 福建广生堂药业股份有限公司 | Intermediate compound for synthesis of entecavir, and preparation method and application of intermediate compound |
| CN103304375A (en) * | 2012-03-12 | 2013-09-18 | 浙江奥翔药业有限公司 | Synthesis intermediate of Entecavir and preparation method thereof |
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