CN104478833A - Synthetic method of (S)-(+)-3-hydroxytetrahydrofuran - Google Patents
Synthetic method of (S)-(+)-3-hydroxytetrahydrofuran Download PDFInfo
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- CN104478833A CN104478833A CN201410682644.3A CN201410682644A CN104478833A CN 104478833 A CN104478833 A CN 104478833A CN 201410682644 A CN201410682644 A CN 201410682644A CN 104478833 A CN104478833 A CN 104478833A
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- hydroxyl tetrahydrofuran
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
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Abstract
The invention provides a synthetic method of (S)-(+)-3-hydroxytetrahydrofuran. The synthetic method comprises the following steps: (1) with L-malic acid as a raw material, carrying out esterification on two carboxyls of the L-malic acid to obtain a product with a formula shown in the specification; (2) reducing a product in the first step by virtue of sodium borohydride to obtain a product with a formula shown in the specification; and (3) carrying out cyclization on a product obtained in the second step to obtain the (S)-(+)-3-hydroxytetrahydrofuran. According to the synthetic method provided by the invention, the synthetic route is short in step, the used raw materials are cheap and easy to acquire, no racemization phenomenon occurs in the reaction process, a by-product in the third step is easy to remove, the total yield is high, and the (S)-(+)-3-hydroxytetrahydrofuran is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran, belong to pharmaceutical intermediate synthesis field.
Background technology
Amprenavir (Amprenavir), systematic naming method is (3S)-3-tetrahydrofuran oxygen base N-[(1S, 2R)-3-(N-isobutyl-N-4-aminobenzene sulfonamide base)-1-phenyl-2-hydroxypropyl] carbamate, the 5th generation of being developed by Glaxo-Smith company of Britain degeneration-resistantly turn hiv protease inhibitor, in May, 1999 in the U.S. and Japan's listing.It has stronger antiviral activity and good resistance, therefore has good clinical value.The synthetic route of existing industrial prospect is with the derivative (2R of L-Phe; 3S)-2-epoxy group(ing)-4-phenyl-3-butyl carbamic acid the tert-butyl ester is raw material; intermediate (I) is obtained by reacting through carrying out amino-alkylation with isobutylamine; sulfonylation is carried out again with 4-nitrobenzene sulfonyl chloride; deprotection; carry out condensation reaction with (S)-(+)-3-tetrahydrofuran oxygen base-succinimidyl carbonate and obtain intermediate (II), last hydrogenation obtains bulk drug amprenavir.
Need to use important intermediate (S)-(+)-3-hydroxyl tetrahydrofuran in existing synthetic route, (S)-(+)-3-hydroxyl tetrahydrofuran need through synthesis such as the enzyme Split Methods of 3-hydroxyl tetrahydrofuran raceme, and in how many situations, the optical purity of product is inadequate.Employ expensive and inflammable and explosive lithium aluminum hydride in other synthetic methods to reduce malic acid diester, and need protection secondary hydroxyl to prevent racemization.The product that aforesaid method obtains or be difficult to reach purity requirement, or be not easy to suitability for industrialized production, be therefore necessary to adopt new synthetic method to obtain qualified (S)-(+)-3-hydroxyl tetrahydrofuran of purity.
Summary of the invention
The object of the invention is the shortcoming existed for the problems referred to above, provide a kind of reaction conditions gentle, raw material route cheap and easy to get is to synthesize (S)-(+)-3-hydroxyl tetrahydrofuran.
A kind of synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran, synthetic route is as follows:
Comprise the following steps:
(1) take L MALIC ACID as raw material, by two of L MALIC ACID carboxyl esterifications, obtain:
(2) product in step (1) is obtained through sodium borohydride reduction:
(3) step (2) product cyclisation is obtained (S)-(+)-3-hydroxyl tetrahydrofuran.
Preferably, in step (1), R is the one in methyl, ethyl, propyl group, sec.-propyl.
Preferably, enzymatic synthesis condition is that L MALIC ACID first forms acyl chlorides, then reacts with alcohol.
Preferably, enzymatic synthesis condition is that L MALIC ACID and alcohol react, and sulfuric acid is catalyzer.
Preferably, when step (3) is cyclized by treatment, catalyzer is tosic acid.
Compared with prior art, beneficial effect of the present invention at least comprises: synthetic route step is short, and use cheaper starting materials to be easy to get, reaction process occurs without racemization phenomenon, and the 3rd step by product easily removes, and total recovery is high, is suitable for suitability for industrialized production.
Embodiment
Below will describe the present invention.But these embodiments do not limit the present invention, the conversion in the method that those of ordinary skill in the art makes according to these embodiments is all included in protection scope of the present invention.
Embodiment 1
(1) in there-necked flask, add 100g L MALIC ACID, 650ml methyl alcohol, under stirring, add vitriol oil 1ml, be warming up to 60 ~ 70 DEG C of back flow reaction 10h.Cool, drip saturated sodium bicarbonate aqueous solution to pH value to 7 ~ 8, concentrated, add water, extraction into ethyl acetate, organic phase is washed, dry, concentrates and obtains colourless liquid 103.0g, yield 85.2%, purity 98.9%; HNMR (CDCl
3, 300MHz) and δ: 4.47 (d, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.19 (br, 1H), 2.71 ~ 2.88 (m, 2H).
(2) in there-necked flask, add ethanol 500ml ethanol, 103g sodium borohydride, stirring lower control temperature is 0 ~ 10 DEG C, drip ethanol (250ml) solution of step 1 product of 103.0g, drip in 90min and finish, at 20 ~ 25 DEG C, react 12h, be warming up to 70 ~ 80 DEG C of backflow 8h.Cooling, is concentrated into solvent-free, adds 2h methyl alcohol in residuum, drip 10% methanol hydrochloride solution, suction filtration, mother liquor concentrations, obtain the crude product of step (2), is directly used in next step reaction.
(3) in the crude product of step (2), 10g p-TsOHH is added
2o, heating for dissolving is also warming up to 200 DEG C, vacuum fractionation (45 ~ 88 DEG C/20mmHg), adds gained cut in the 1M NaOH solution of 50ml, stirs and react 3h under room temperature, add 10% salt acid for adjusting pH value to 7 ~ 8, underpressure distillation, collects the cut of 60 ~ 62 DEG C/20mmHg, obtains colourless transparent liquid (S)-(+)-3-hydroxyl tetrahydrofuran 36.1g, yield 55%, purity 99.4%; HNMR (CDCl
3, 300MHz) and δ: 4.42 ~ 4.44 (m, 1H), 3.90 ~ 3.93 (m, 3H), 3.67 ~ 3.78 (m, 3H), 3.02 (s, 1H), 1.99 ~ 2.04 (m, 1H), 1.81 ~ 1.87 (m, 1H).
Embodiment 2
(1) in there-necked flask, add 100g L MALIC ACID, 300ml methyl alcohol, be cooled to-10 DEG C ~ 0 DEG C, stir lower dropping 120ml thionyl chloride, 2h drips complete, stirred at ambient temperature 4h, be warming up to 60 DEG C ~ 70 DEG C reaction 1h again, cooling, concentrated, saturated sodium bicarbonate aqueous solution is dripped to pH value to 7 ~ 8 in resistates, concentrated, add water, extraction into ethyl acetate, organic phase is washed, dry, concentrate and obtain colourless liquid 106.9g, yield 88.4%, purity 97.9%; HNMR (CDCl
3, 300MHz) and δ: 4.47 (d, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.19 (br, 1H), 2.71 ~ 2.88 (m, 2H).
(2) in there-necked flask, add ethanol 500ml ethanol, 103g sodium borohydride, stirring lower control temperature is 0 ~ 10 DEG C, drip ethanol (250ml) solution of step 1 product of 106.9g, drip in 90min and finish, at 20 ~ 25 DEG C, react 12h, be warming up to 70 ~ 80 DEG C of backflow 8h.Cooling, is concentrated into solvent-free, adds 2h methyl alcohol in residuum, drip 10% methanol hydrochloride solution, suction filtration, mother liquor concentrations, obtain the crude product of step (2), is directly used in next step reaction.
(3) in the crude product of step (2), 10g p-TsOHH is added
2o, heating for dissolving is also warming up to 200 DEG C, vacuum fractionation (45 ~ 88 DEG C/20mmHg), adds gained cut in the 1M NaOH solution of 50ml, stirs and react 3h under room temperature, add 10% salt acid for adjusting pH value to 7 ~ 8, underpressure distillation, collects the cut of 60 ~ 62 DEG C/20mmHg, obtains colourless transparent liquid (S)-(+)-3-hydroxyl tetrahydrofuran 37.4g, yield 57%, purity 99.1%; HNMR (CDCl
3, 300MHz) and δ: 4.42 ~ 4.44 (m, 1H), 3.90 ~ 3.93 (m, 3H), 3.67 ~ 3.78 (m, 3H), 3.02 (s, 1H), 1.99 ~ 2.04 (m, 1H), 1.81 ~ 1.87 (m, 1H).
Embodiment 3
(1) in there-necked flask, add 100g L MALIC ACID, 700ml Virahol, under stirring, add vitriol oil 1ml, be warming up to 60 ~ 70 DEG C of back flow reaction 10h.Cool, drip saturated sodium bicarbonate aqueous solution to pH value to 7 ~ 8, concentrated, add water, extraction into ethyl acetate, organic phase is washed, dry, concentrates and obtains colourless liquid 133.2g, yield 81.9%, purity 98.7%; HNMR (CDCl
3, 300MHz) and δ: 4.47 (d, 1H), 3.57 (m, 1H), 3.19 (br, 1H), 2.71 ~ 2.88 (m, 2H), 1.16 (d, 6H).
(2) in there-necked flask, add ethanol 500ml ethanol, 103g sodium borohydride, stirring lower control temperature is 0 ~ 10 DEG C, drip ethanol (250ml) solution of step 1 product of 133.2g, drip in 90min and finish, at 20 ~ 25 DEG C, react 12h, be warming up to 70 ~ 80 DEG C of backflow 8h.Cooling, is concentrated into solvent-free, adds 2h methyl alcohol in residuum, drip 10% methanol hydrochloride solution, suction filtration, mother liquor concentrations, obtain the crude product of step (2), is directly used in next step reaction.
(3) in the crude product of step (2), 10g p-TsOHH is added
2o, heating for dissolving is also warming up to 200 DEG C, vacuum fractionation (45 ~ 88 DEG C/20mmHg), adds gained cut in the 1M NaOH solution of 50ml, stirs and react 3h under room temperature, add 10% salt acid for adjusting pH value to 7 ~ 8, underpressure distillation, collects the cut of 60 ~ 62 DEG C/20mmHg, obtains colourless transparent liquid (S)-(+)-3-hydroxyl tetrahydrofuran 34.8g, yield 53%, purity 98.8%; HNMR (CDCl
3, 300MHz) and δ: 4.42 ~ 4.44 (m, 1H), 3.90 ~ 3.93 (m, 3H), 3.67 ~ 3.78 (m, 3H), 3.02 (s, 1H), 1.99 ~ 2.04 (m, 1H), 1.81 ~ 1.87 (m, 1H).
Embodiment 4
(1) in there-necked flask, add 100g L MALIC ACID, 320ml ethanol, be cooled to-10 DEG C ~ 0 DEG C, stir lower dropping 120ml thionyl chloride, 2h drips complete, stirred at ambient temperature 4h, be warming up to 70 DEG C ~ 80 DEG C reaction 1h again, cooling, concentrated, saturated sodium bicarbonate aqueous solution is dripped to pH value to 7 ~ 8 in resistates, concentrated, add water, extraction into ethyl acetate, organic phase is washed, dry, concentrate and obtain colourless liquid 119.2g, yield 84.1%, purity 99.0%; HNMR (CDCl
3, 300MHz) and δ: 4.47 (d, 1H), 3.68 (m, 2H), 3.19 (br, 1H), 2.71 ~ 2.88 (m, 2H), 1.26 (t, 3H).
(2) in there-necked flask, add ethanol 500ml ethanol, 103g sodium borohydride, stirring lower control temperature is 0 ~ 10 DEG C, drip ethanol (250ml) solution of step 1 product of 119.2g, drip in 90min and finish, at 20 ~ 25 DEG C, react 12h, be warming up to 70 ~ 80 DEG C of backflow 8h.Cooling, is concentrated into solvent-free, adds 2h methyl alcohol in residuum, drip 10% methanol hydrochloride solution, suction filtration, mother liquor concentrations, obtain the crude product of step (2), is directly used in next step reaction.
(3) in the crude product of step (2), 10g p-TsOHH is added
2o, heating for dissolving is also warming up to 200 DEG C, vacuum fractionation (45 ~ 88 DEG C/20mmHg), adds gained cut in the 1M NaOH solution of 50ml, stirs and react 3h under room temperature, add 10% salt acid for adjusting pH value to 7 ~ 8, underpressure distillation, collects the cut of 60 ~ 62 DEG C/20mmHg, obtains colourless transparent liquid (S)-(+)-3-hydroxyl tetrahydrofuran 35.5g, yield 54%, purity 99.1%; HNMR (CDCl
3, 300MHz) and δ: 4.42 ~ 4.44 (m, 1H), 3.90 ~ 3.93 (m, 3H), 3.67 ~ 3.78 (m, 3H), 3.02 (s, 1H), 1.99 ~ 2.04 (m, 1H), 1.81 ~ 1.87 (m, 1H).
Although above-described embodiment is only given out for the reaction process of methyl, ethyl and sec.-propyl, those skilled in the art can easily expect using propyl alcohol to carry out above-mentioned reaction.
Be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
Claims (5)
1. a synthetic method for (S)-(+)-3-hydroxyl tetrahydrofuran, is characterized in that, comprise the following steps:
(1) take L MALIC ACID as raw material, by two of L MALIC ACID carboxyl esterifications, obtain:
(2) product in step (1) is obtained through sodium borohydride reduction:
(3) step (2) product cyclisation is obtained (S)-(+)-3-hydroxyl tetrahydrofuran.
2. the synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran according to claim 1, is characterized in that, in step (1), R is the one in methyl, ethyl, propyl group, sec.-propyl.
3. the synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran according to claim 2, is characterized in that, enzymatic synthesis condition is that L MALIC ACID first forms acyl chlorides, then reacts with alcohol.
4. the synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran according to claim 2, is characterized in that, enzymatic synthesis condition is that L MALIC ACID and alcohol react, and sulfuric acid is catalyzer.
5. the synthetic method of (S)-(+)-3-hydroxyl tetrahydrofuran according to claim 1, is characterized in that, when step (3) is cyclized by treatment, catalyzer is tosic acid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961711A (en) * | 2015-07-23 | 2015-10-07 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran |
| CN107235937A (en) * | 2017-07-12 | 2017-10-10 | 海门华祥医药科技有限公司 | A kind of synthetic method of (S) 3 hydroxyl tetrahydrofuran |
| CN111377889A (en) * | 2018-12-27 | 2020-07-07 | 江苏联昇化学有限公司 | Production process of 3-hydroxytetrahydrofuran by combining pipeline reaction |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961711A (en) * | 2015-07-23 | 2015-10-07 | 沧州那瑞化学科技有限公司 | Preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran |
| CN104961711B (en) * | 2015-07-23 | 2017-03-08 | 沧州那瑞化学科技有限公司 | （S）3 hydroxyl tetrahydrofurans and（R）The preparation method of 3 hydroxyl tetrahydrofurans |
| CN107235937A (en) * | 2017-07-12 | 2017-10-10 | 海门华祥医药科技有限公司 | A kind of synthetic method of (S) 3 hydroxyl tetrahydrofuran |
| CN111377889A (en) * | 2018-12-27 | 2020-07-07 | 江苏联昇化学有限公司 | Production process of 3-hydroxytetrahydrofuran by combining pipeline reaction |
| CN111377889B (en) * | 2018-12-27 | 2023-07-18 | 江苏联昇化学有限公司 | Production process of 3-hydroxytetrahydrofuran combined with pipeline reaction |
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Application publication date: 20150401 |