CN1204130C - Process for preparing optical purity tetrahydrofuran-2-aminic acid - Google Patents
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Abstract
The present invention relates to a novel technology for preparing optical purity tetrahydrofuran-2-aminic acid. Configurational tartaric acid derivative O, O'-diarylformacyl tartaric acid is adopted to resolve tetrahydrofuran-2-aminic acid; a reaction product is crystallized and recrystallized, and configurational optical purity tetrahydrofuran-2-aminic acid is obtained; another isomer in mother liquor which takes part in the crystallization operation and non-chirality amine form salt; the salt is crystallized and recrystallized, and the optical purity is between 89 and 99%e. e.; the configurational isomer whose optical purity is less than 98%e. e. in the mother liquor which takes part in the crystallization operation is heated for racemization under the alkaline condition, and racemate is generated; the resolution and the steps are repeated until optical purity tetrahydrofuran-2-aminic acid which has two kinds of conformation is obtained. Therefore, the resolution yield of the isomer is improved by more than 50%. The present invention has the advantages that the technology is simple and convenient, raw material is easily obtained, the yield is high, resolution agents and the configurational tetrahydrofuran-2-aminic acid are recovered and utilized, the preparation cost is reduced, the environment is protected, the present invention is good for realizing the industrial mass preparation, and people's the requirements are satisfied.
Description
Technical field
The invention belongs to the organic synthesis field, specifically be to use a kind of resolving agent of configuration to obtain the optical purity tetrahydrofuran (THF)-2-formic acid of two kinds of configurations and the method for R-or S-tetrahydrofuran (THF)-2-formic acid employing chemical method racemization.
Background technology
Optical purity tetrahydrofuran (THF)-2-formic acid is a kind of important intermediate, being widely used in a plurality of fields such as medicine, chemical industry, all is as the synthetic intermediate for preparing with optical purity tetrahydrofuran (THF)-2-formic acid as multiple medicine such as anti-dextrorotation terazosin with hypertension effect and Chemicals.Because optical purity tetrahydrofuran (THF)-2-formic acid can be applied to a plurality of fields, its preparation method attracts much attention.The existing method that racemic modification is split mainly contains 1, mechanical process; 2, biochemical process; 3, chemical method.Adopting chemical method to aspect racemic modification tetrahydrofuran (THF)-2-formic acid racemization, P.C.Belanger etc. [Can.J.Chem.61,13836 (1983)] have at first carried out effective fractionation to this compound.But its uses very big, expensive vauqueline of toxicity (Brucine dihydrate) as resolving agent, and its e.e. value can reach 94%, but yield very low only be 20%, the rate of recovery of resolving agent is also low.Japanese Patent [JP 01,216,983 (1989)], European patent [EP382,506 (1990)] and United States Patent (USP) [US 4,985,575 (1991)] optically active amines that then uses Alpha-Methyl benzylamine type is as resolving agent, and the e.e. value can reach 99%, resolving agent toxicity is low, and can reclaim preferably, but weak point is the salt that amine and acid generate, needs through recrystallization repeatedly, can obtain the higher tetrahydrofuran (THF) of optical purity-2-formic acid, the highest yield only is 30%.Chinese patent [CN 1176963 (1998)] has been reported use D-(+)-2-N, N-dialkyl amido-1-(4-nitrophenyl)-1, ammediol is as resolving agent, used resolving agent can be from the by product of industrial production paraxin, the mould amine of optically active chlorine { D-(+)-2-N, N-dialkyl amido-1-(4-nitrophenyl)-1, ammediol } alkylation and getting.Just can obtain optically pure product by need not recrystallization behind patent report tetrahydrofuran (THF)-2-formic acid salify, yield is 35%-40%, can't obtain The above results but we repeatedly repeat this experiment, generally need can obtain optically pure product through three recrystallizations, yield only is 18%.A.Mravik etc. [Chem.Eur.J.4,1621 (1998)] then utilize D-or L-O, O '-dibenzoyl tartaric acid (DBTA) can split alcohols and carboxylic acid compound as resolving agent effectively in the presence of metal oxide.Through facts have proved that this also is effective ways that split tetrahydrofuran (THF)-2-formic acid.These resolving agents are easily derived and are got from tartrate, and the source is abundant, cheap, and resolution yield can reach 30%-35%.But above-mentioned all method for splitting resolving agent with a kind of configuration in actually operating only can obtain a kind of optically pure isomer of configuration, and causes the abandonment of another isomer, can not effectively utilize raw material, brings pollution to environment again.
Summary of the invention
The object of the present invention is to provide a kind of process for preparing optical purity tetrahydrofuran-2-aminic acid; it is a resolving agent with a kind of O, O '-two sweet-smelling formacyl tartrate of configuration; split tetrahydrofuran (THF)-2-formic acid; finally obtain two kinds of isomer of optically pure tetrahydrofuran (THF)-2-formic acid, and have higher efficient (in raw material tetrahydrofuran (THF)-2-formic acid).
The present invention is achieved like this: at first; split the tetrahydrofuran (THF)-2-formic acid of racemization with chiral separation agent D-or L-O, O '-two sweet-smelling formacyl tartrate, again resultant of reaction is carried out crystallization, recrystallization, obtains a kind of optical purity tetrahydrofuran (THF)-2-formic acid of configuration.Then, its mother liquor (tetrahydrofuran (THF)-2-formic acid of the another kind of configuration that behind extraction, distillation procedure, obtains) and non chiral amine compounds reaction salify.Through crystallization, recrystallization; Its optical purity reaches between the 89-99%e.e.; Tetrahydrofuran (THF)-2-the formic acid that again optical purity that obtains in the above-mentioned mother liquor is lower than another configuration of 98%e.e. heats under alkaline condition and carries out racemization, at last, product with the previous step racemization is a raw material again, repeat above-mentioned fractionation and subsequent step, so circulation is until the optical purity tetrahydrofuran (THF)-2-formic acid that obtains two kinds of configurations.
The mol ratio of (resolving agent is a main body) Subjective and Objective is 1 in the above-mentioned resolution reaction: 2-2: 1; Resolving agent is optical purity O, O '-two sweet-smelling formacyl tartrate.
The non chiral amine that said process uses is:
Alkylamine: R
1NHR
2
R
1And R
2Can be hydrogen, C
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl and alkyl-substituted phenyl (wherein alkyl is C
1-C
4); R wherein
1=R
2Or R
1≠ R
2(R
1, R
2Can be arbitrary combination)
Alkyl diamine: H
2NRNH
2(R=C wherein
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl and C
1-C
4Alkyl-substituted phenyl.)
Above-mentioned non chiral amine is quadrol, cyclo-hexylamine, dicyclohexylamine and benzylamine preferably.
Employed solvent is ester class (manthanoate, acetic ester, propionic ester and butyric ester etc.), alcohols (methyl alcohol, ethanol, propyl alcohol and Virahol etc.), ketone (acetone, butanone etc.), alkanes (normal hexane etc.), ethers (sherwood oil and ether etc.), chloride class (chloroform and methylene dichloride etc.), aromatics (benzene, toluene and dimethylbenzene etc.) etc. and the mixed solvent of two or more (comprising two kinds) wherein in non chiral amine salt-forming reaction and recrystallization.In the non chiral amine salt-forming reaction, amine is 1 with the mol ratio of acid: 2-2: 1.
After the present invention splits the tetrahydrofuran (THF)-2-formic acid that obtains a kind of optical isomer, can also carry out splitting after the racemization to its another kind of optical isomer, the resolution yield of required like this configuration can be greater than 50% (in racemization tetrahydrofuran (THF)-2-formic acid) again.
The present invention is with a kind of optical isomer of tetrahydrofuran (THF)-2-formic acid, and preferably 80-500 ℃ of stirring heating under alkaline condition, temperature are carried out racemization.The alkali that uses in this process is oxyhydroxide (comprising sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide etc.) or strong base-weak acid salt (comprising yellow soda ash, salt of wormwood etc.).The ratio of alkali and tetrahydrofuran (THF)-2-formic acid is 1: 1-35: 1.This process is perhaps carried out racemization in the mode of solid salt in aromatic hydrocarbon (comprising toluene, dimethylbenzene and oil of mirbane etc.), dioxane, alcohol (comprising propyl carbinol, glycol ether and glycerol etc.), whiteruss and water etc. and two kinds and two or more mixed solvent.
Resolving agent recycling step of the present invention is: make the filtrate that splits in post crystallization and the recrystallization operation (be preferably pH=1-3) under acidic conditions, resolving agent is separated out, filter, reclaim;
The present invention is that resolving agent has split tetrahydrofuran (THF)-2-formic acid effectively with optical purity O, O '-two sweet-smelling formacyl tartrate; O, O '-two sweet-smelling formacyl tartrate of promptly using a kind of configuration are 1 by the mol ratio of Subjective and Objective: 2-2: 1; can obtain two kinds of optical isomers of tetrahydrofuran (THF)-2-formic acid simultaneously, its e.e. value is all greater than 98%.We can also select naturally to be easy to get in two kinds of configuration resolving agents, cheap L-tartaric acid derivatives prepares the optically pure tetrahydrofuran (THF)-2-formic acid of any configuration, and wherein used resolving agent all can reclaim and recycle easily.
Usefulness of the present invention is: the resolving agent raw material of use is a tartrate cheap and easy to get.Resolving agent can well obtain reclaiming in the present invention, and another configuration tetrahydrofuran (THF)-2-formic acid after splitting can improve optical purity by the non chiral amine salify, can reach (in racemization tetrahydrofuran (THF)-2-formic acid) more than 50% by the resolution yield that racemization improves another configuration again.Tetrahydrofuran (THF)-2-formic acid processing method is easy, raw material is easy to get, yield is higher, resolving agent and another configuration tetrahydrofuran (THF)-2-formic acid are easy to be recycled for the preparation optical purity among the present invention; thereby the cost and the protection that has strengthened environment of reduction preparation optical purity tetrahydrofuran (THF)-2-formic acid; these all help the big production that this invention realizes modern industrialization, satisfy the demand of people to it.Therefore, we can say, the invention solves the difficult problem that prior art is not suitable for industrialized production.
Embodiment
Be embodiments of the invention below.Among the embodiment, the yield of product is that benchmark calculates with the tetrahydrofuran (THF)-2-formic acid as raw material among the embodiment all.
Embodiment one:
162 gram (0.431mol) D-DBTA and 24 gram (0.431mol) CaO are added in 200 ml methanol, add 50 gram (0.431mol) (±)-tetrahydrofuran (THF)-2-formic acid again, drip 300ml water lentamente, refluxed 1 hour, solid is separated out in cooling.Filter, drying solid obtains 120 gram white crystals.Mother liquor adds acid and transfers to pH=1, and resolving agent is separated out, and filters, and reclaims; Filtrate merges organic phase with 5 * 30ml ethyl acetate extraction, anhydrous sodium sulfate drying, and underpressure distillation obtains (S)-tetrahydrofuran (THF)-2-formic acid 18.4 grams, and optical purity is 87%e.e., and yield is 36.8%.
Above-mentioned white crystal is carried out recrystallization in 800 ml methanol and 200 ml waters, filter and obtain white crystal 101 grams.Slow dripping hydrochloric acid transfers to pH=1 in this crystalline flask is housed, and tells lower floor's solid resolving agent, reclaims.Water merges organic phase with 5 * 30ml ethyl acetate extraction, anhydrous sodium sulfate drying, and underpressure distillation gets colourless oil liquid (R)-tetrahydrofuran (THF)-2-formic acid 19 grams, and optical purity is 98%e.e., yield 38%.Resolving agent DBTA total yield is more than 90%.
Embodiment two:
With 87%e.e. (S)-tetrahydrofuran (THF)-2-formic acid 1.16 grams (0.01mol) and 0.3 gram (0.005mol) quadrol mixing salify that obtain in embodiment one mother liquor, add the 10ml dehydrated alcohol, reflux all after the dissolving, leaves standstill cooling and separates out solid, filters and obtain white solid 1.431 grams.Behind the recrystallization, solid is added in the 15ml 1M sodium hydroxide solution stirred 10 minutes, after the washing of 3 * 15ml ethyl acetate, aqueous phase adds 17ml 1M hydrochloric acid and stirs, and with 3 * 15ml ethyl acetate extraction, merges organic phase, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid 0.93 gram, and optical purity is 89%e.e., and yield is 80.17%.
Embodiment three:
87%e.e. (S)-tetrahydrofuran (THF)-2-formic acid 1.16 grams (0.01mol) that obtain in embodiment one mother liquor are mixed salify with 0.99 gram (0.01mol) cyclo-hexylamine, add 4ml methyl alcohol again, reflux, all dissolvings, cooling are separated out solid, filtration obtains white solid 0.795 gram.Behind the recrystallization, solid is added in the 15ml 1M sodium hydroxide solution stirred 10 minutes, after the washing of 3 * 15ml ethyl acetate, aqueous phase adds 17ml 1M hydrochloric acid and stirs, and with 3 * 15ml ethyl acetate extraction, merges organic phase, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid 0.35 gram, and optical purity is 90.1%e.e., and yield is 30.17%.
Embodiment four:
87%e.e. (S)-tetrahydrofuran (THF)-2-formic acid 1.16 grams (0.01mol) that obtain in embodiment one mother liquor are joined in the 50ml acetone, after being heated to backflow, add 1.81 gram (0.01mol) dicyclohexylamine, solid is separated out in cooling, filtration obtains white solid 1.82 grams.Behind the recrystallization, solid is added in the 15ml 1M sodium hydroxide solution stirred 10 minutes, after the washing of 3 * 15ml ethyl acetate, aqueous phase adds 17ml 1M hydrochloric acid and stirs, and with 3 * 15ml ethyl acetate extraction, merges organic phase, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid 0.684 gram, and optical purity is 99%e.e., and yield is 59%.
Embodiment five:
With 87%e.e. (S)-tetrahydrofuran (THF)-2-formic acid 1.16 grams (0.01mol) and 1.07 gram (0.01mol) benzylamine mixing salifies that obtain in embodiment one mother liquor, add the 3.5ml Virahol again, reflux, all dissolving, be cooled to-30 ℃, separate out solid, filter and to obtain white solid 1.16 grams.Solid is added in the 15ml 1M sodium hydroxide solution stirred 10 minutes, after the washing of 3 * 15ml ethyl acetate, aqueous phase adds 17ml 1M hydrochloric acid and stirs, with 3 * 15ml ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid 0.59 gram, optical purity is 89.7%e.e., and yield is 50.86%.
Embodiment six:
Operate to such an extent that (R)-tetrahydrofuran (THF)-2-formic acid 18.9 restrains with L-DBTA by embodiment one scheme, optical purity is 86%e.e., and yield is 37.8%; (S)-and tetrahydrofuran (THF)-2-formic acid 18 grams, optical purity is 98%e.e, yield is 36%.
Embodiment seven:
86%e.e. (R)-tetrahydrofuran (THF)-2-formic acid 1.16 grams (0.01mol) that obtain in embodiment six mother liquors are joined in the 50ml acetone, after being heated to backflow, add 1.81 gram (0.01mol) dicyclohexylamine, solid is separated out in cooling, filtration obtains white solid 1.85 grams.Behind the recrystallization, solid joins in the 15ml 1M sodium hydroxide solution and stirred 10 minutes, after the washing of 3 * 15ml ethyl acetate, aqueous phase adds 17ml 1M hydrochloric acid and stirs, and with 3 * 15ml ethyl acetate extraction, merges organic phase, anhydrous sodium sulfate drying, solvent evaporated obtains (R)-tetrahydrofuran (THF)-2-formic acid 0.69 gram, and optical purity is 98.5%e.e., and yield is 59.5%.
Embodiment eight:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 1.272 gram NaOH (0.0318mol) is added to the water, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 65%e.e., and yield is 97.8%.
Embodiment nine:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 1.272 gram NaOH (0.0318mol) joins in the glycerol, reflux 5 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 2.3%e.e., and yield is 95.4%.
Embodiment ten:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 1.272 gram NaOH (0.0318mol) joins in water and the glycerol, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 39%e.e., and yield is 92.8%.
Embodiment 11:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 1.272 gram NaOH (0.0318mol) joins in the glycol ether, reflux 6 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 1%e.e., and yield is 93.1%.
Embodiment 12:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 1.272 gram NaOH (0.0318mol) joins in water and the glycol ether, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 24%e.e., and yield is 92.5%.
Embodiment 13:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 22.26 gram NaOH (0.556mol) is added to the water, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 52%e.e., and yield is 96.9%.
Embodiment 14:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 22.26 gram NaOH (0.556mol) joins in the glycerol, reflux 2 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 3.6%e.e., and yield is 94.2%.
Embodiment 15:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 22.26 gram NaOH (0.556mol) joins in water and the glycerol, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 26%e.e., and yield is 92.6%.
Embodiment 16:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 22.26 gram NaOH (0.556mol) joins in the glycol ether, reflux 1 hour, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 2.9%e.e., and yield is 94.9%.
Embodiment 17:
(S)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 87%e.e. of gained among the embodiment one, 22.26 gram NaOH (0.556mol) joins in water and the glycol ether, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 21%e.e., and yield is 89.4%.
Embodiment 18:
(S)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 87%e.e. of gained among the embodiment one are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 100 ℃ with solid form stirring heating 24 hours, add 40ml 3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 68%e.e., and yield is 96%.
Embodiment 19:
(S)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 87%e.e. of gained among the embodiment one are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 160 ℃ with solid form stirring heating 10 hours, add 40ml 3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 3.5%e.e., and yield is 97.8%.
Embodiment 20:
(S)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 87%e.e. of gained among the embodiment one are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 180 ℃ with solid form stirring heating 8 hours, add 40ml 3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 4.3%e.e., and yield is 94.4%.
Embodiment 21:
(S)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 87%e.e. of gained among the embodiment one are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 100 ℃ with solid form stirring heating 24 hours, add 250ml3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 56%e.e., and yield is 93.7%.
Embodiment 22:
5.8 grams (0.05mol) of acid among (S)-tetrahydrofuran (THF)-2-of the 87%e.e. of gained among the embodiment one are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 160 ℃ with solid form stirring heating 12 hours, add 250ml3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 2.3%e.e., and yield is 90.4%.
Embodiment 23:
(S)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 87%e.e. of gained among the embodiment one are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 180 ℃ with solid form stirring heating 6 hours, add 250ml 3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 5.2%e.e., and yield is 91.1%.
Embodiment 24:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 1.272 gram NaOH (0.0318mol) is added to the water, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 63%e.e., and yield is 93.7%.
Embodiment 25:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 1.272 gram NaOH (0.0318mol) joins in the glycerol, reflux 5 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 3.1%e.e., and yield is 95.1%.
Embodiment 26:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 1.272 gram NaOH (0.0318mol) joins in water and the glycerol, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 34%e.e., and yield is 92.3%.
Embodiment 27:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 1.272 gram NaOH (0.0318mol) joins in the glycol ether, reflux 6 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 1%e.e., and yield is 89.8%.
Embodiment 28:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 1.272 gram NaOH (0.0318mol) joins in water and the glycol ether, reflux 24 hours, cooling adds 35ml 1M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 18.7%e.e., and yield is 91.2%.
Embodiment 29:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 22.26 gram NaOH (0.556mol) is added to the water, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 56.4%e.e., and yield is 95.8%.
Embodiment 30:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 22.26 gram NaOH (0.556mol) joins in the glycerol, reflux 1.5 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 4.2%e.e., and yield is 94.9%.
The embodiment hentriaconta-:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 22.26 gram NaOH (0.556mol) joins in water and the glycerol, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 21.2%e.e., and yield is 91.8%.
Embodiment 32:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 22.26 gram NaOH (0.556mol) joins in the glycol ether, reflux 1 hour, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 1.5%e.e., and yield is 90.7%.
Embodiment 33:
(R)-tetrahydrofuran (THF)-2-formic acid 1.84 grams (0.0159mol) with the 86%e.e. of gained among the embodiment six, 22.26 gram NaOH (0.556mol) joins in water and the glycol ether, reflux 12 hours, cooling adds 20ml 3M hydrochloric acid and stirs, with 3 * 20ml ethyl acetate extraction, merge organic solvent, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, its optical purity is 24.6%e.e., and yield is 85.6%.
Embodiment 34:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 100 ℃ with solid form stirring heating 24 hours, add 30ml 4M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 64.9%e.e., and yield is 95.6%.
Embodiment 35:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 160 ℃ with solid form stirring heating 10 hours, add 30ml 4M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 3.5%e.e., and yield is 96.4%.
Embodiment 36:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 20ml 5M sodium hydroxide solution, evaporate to dryness, under 180 ℃ with solid form stirring heating 8 hours, add 30ml 4M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 4.1%e.e., and yield is 93.2%.
Embodiment 37:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 100 ℃ with solid form stirring heating 24 hours, add 250ml3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 53.1%e.e., and yield is 94.6%.
Embodiment 38:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 160 ℃ with solid form stirring heating 12 hours, add 250ml3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 6.3%e.e., and yield is 87.8%.
Embodiment 39:
(R)-tetrahydrofuran (THF)-2-formic acid 5.8 grams (0.05mol) of the 86%e.e. of gained among the embodiment six are joined in the 140ml 5M sodium hydroxide solution, evaporate to dryness, under 180 ℃ with solid form stirring heating 6 hours, add 250ml 3M hydrochloric acid and stir,, merge organic solvent with 3 * 20ml ethyl acetate extraction, anhydrous sodium sulfate drying, solvent evaporated obtains (S)-tetrahydrofuran (THF)-2-formic acid, and its optical purity is 1.2%e.e., and yield is 89.3%.
Claims (12)
1, a kind of optical purity tetrahydrofuran (THF)-2-formic acid preparation technology; with racemic modification tetrahydrofuran (THF)-2-formic acid is raw material; adopt a kind of O, O '-two sweet-smelling formacyl tartrate of configuration to split tetrahydrofuran (THF)-2-formic acid as resolving agent; resultant of reaction is carried out crystallization, recrystallization processing; obtain a kind of optical purity tetrahydrofuran (THF)-2-formic acid of configuration; it is characterized in that, except that above-mentioned splitting step, also comprise the steps:
A. with the tetrahydrofuran (THF)-2-formic acid of the another kind of configuration in the mother liquor of above-mentioned crystallization operation and non chiral amine reaction salify, obtain the tetrahydrofuran (THF)-2-formic acid of another kind of configuration through crystallization, recrystallization, its optical purity is between 89-99%e.e.;
B. steps A is obtained tetrahydrofuran (THF)-2-formic acid that optical purity is lower than another configuration of 98%e.e., racemization is carried out in heating under alkaline condition;
C. be raw material with the product behind the resulting racemization of step B, repeat aforementioned splitting step and follow-up A, B step, so circulation is until the optical purity tetrahydrofuran (THF)-2-formic acid that obtains two kinds of configurations.
2, optical purity tetrahydrofuran (THF) as claimed in claim 1-2-formic acid preparation technology is characterized in that, also comprises the resolving agent recycling step:
D. make the filtrate that splits in the post crystallization operation under acidic conditions, resolving agent is separated out, filter, reclaim;
The filtrate that splits in the recrystallization operation of back is separated out under acidic conditions, filter, reclaim.
3, optical purity tetrahydrofuran (THF) as claimed in claim 2-2-formic acid preparation technology is characterized in that, acidic conditions is pH=1-3 in the D step.
4, optical purity tetrahydrofuran (THF) as claimed in claim 1 or 2-2-formic acid preparation technology is characterized in that, the mol ratio of Subjective and Objective is 1: 2 in the described resolution reaction---2: 1; Described resolving agent is optical purity-O, O '-dibenzoyl tartaric acid.
5, optical purity tetrahydrofuran (THF) as claimed in claim 1 or 2-2-formic acid preparation technology is characterized in that, described non chiral amine compounds is: alkylamine: R
1NHR
2
R
1And R
2Can be hydrogen, C
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl and C
1-C
4Alkyl-substituted phenyl, R wherein
1=R
2Or R
1≠ R
2Or R
1, R
2Arbitrary combination;
Alkyl diamine: H
2NRNH
2
R=C
1-C
15Alkyl, C
3-C
8Cycloalkyl, phenyl and C
1-C
4Alkyl-substituted phenyl.
6, optical purity tetrahydrofuran (THF) as claimed in claim 5-2-formic acid preparation technology is characterized in that, described non chiral amine compounds is quadrol, cyclo-hexylamine, dicyclohexylamine and benzylamine.
7, optical purity tetrahydrofuran (THF) as claimed in claim 6-2-formic acid preparation technology is characterized in that, in the non chiral amine salt-forming reaction of described A step, amine is 1: 2 with the mol ratio of acid---2: 1.
8, optical purity tetrahydrofuran (THF) as claimed in claim 7-2-formic acid preparation technology, it is characterized in that described non chiral amine salt-forming reaction is to carry out in benzene, toluene and the dimethylbenzene equal solvent of the chloroform of the sherwood oil of normal hexane of the acetone of methyl alcohol, ethanol, propyl alcohol and Virahol etc., ketone of manthanoate, acetic ester, propionic ester and butyric ester etc., alcohols in the ester class and butanone etc., alkanes etc., ethers and ether etc., chloride class and methylene dichloride etc., aromatics or wherein above-mentioned two or more the mixed solvent.
9, optical purity tetrahydrofuran (THF) as claimed in claim 1 or 2-2-formic acid preparation technology, it is characterized in that, the employed alkali of the racemization reaction of described B step is sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide etc., or yellow soda ash and salt of wormwood etc.
10, optical purity tetrahydrofuran (THF) as claimed in claim 9-2-formic acid preparation technology, it is characterized in that, the employed solvent of the racemization reaction of described B step is toluene, dimethylbenzene or the oil of mirbane etc. of arene, dioxane, the propyl carbinol of alcohols, glycol ether and glycerol etc., whiteruss, water, and two or more mixed solvent, perhaps carry out racemization in the mode of solid salt.
11, optical purity tetrahydrofuran (THF) as claimed in claim 10-2-formic acid preparation technology is characterized in that, the amount of the employed alkali of racemization reaction of described B step and tetrahydrofuran (THF)-2-formic acid ratio is 35: 1-1: 1.
12, optical purity tetrahydrofuran (THF) as claimed in claim 11-2-formic acid preparation technology is characterized in that the racemization reaction of described B step is carried out under 80-500 ℃.
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| CN 02134132 CN1204130C (en) | 2002-11-22 | 2002-11-22 | Process for preparing optical purity tetrahydrofuran-2-aminic acid |
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| CN101429180B (en) * | 2007-11-09 | 2011-08-17 | 苏州雅本化学股份有限公司 | Process for producing S-tetrahydrochysene furoic acid |
| JP2012036093A (en) * | 2008-12-15 | 2012-02-23 | Kaneka Corp | Method for manufacturing (s)-1-phenyl-1,2,3,4-tetrahydroisoquinoline |
| JP5704182B2 (en) * | 2013-03-06 | 2015-04-22 | 東レ・ファインケミカル株式会社 | Process for producing optically active tetrahydrofuran-2-carboxylic acid |
| CN105669609B (en) * | 2016-03-08 | 2018-01-09 | 中国科学院成都有机化学有限公司 | A kind of formic acid of tetrahydrofuran 2 industrializes Racemic of N |
| CN106279073B (en) * | 2016-08-02 | 2018-09-07 | 浙江大学 | The racemization method of chiral tetrahydrochysene furoic acid |
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