CN1181054C - Process for preparing D-proline - Google Patents
Process for preparing D-proline Download PDFInfo
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- CN1181054C CN1181054C CNB021126976A CN02112697A CN1181054C CN 1181054 C CN1181054 C CN 1181054C CN B021126976 A CNB021126976 A CN B021126976A CN 02112697 A CN02112697 A CN 02112697A CN 1181054 C CN1181054 C CN 1181054C
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- proline
- pro
- tartaric acid
- salt
- tartrate
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Abstract
The present invention relates to a method for preparing D-proline, which has the advantages of low cost and easy post-treatment and is suitable for mass production. The method comprises the following steps: a, mixing and dissolving L-proline and D-tartaric acid in organic acid; adding 10 to 30% of aldehyde catalyst and stirring the organic acid and the aldehyde catalyst at a temperature of 70 to 90 DEG C for 4 to 8 hours; c, cooling the organic acid and the aldehyde catalyst by ice water bath, filtering the organic acid and the aldehyde catalyst, and washing and drying the organic acid and the aldehyde catalyst by anhydrous alcohol; d, recrystallizing coarse salt in the alcohol to obtain refined salt of D-tartaric acid. D-proline; e, dissolving the refined salt of D-tartaric acid. D-proline in methanol; f, at the temperature of 20 to 65 DEG C, stirring and adding aminating agent to the refined salt of D-tartaric acid. D-proline until the solution is alkalescent; g, after stirring the refined salt of D-tartaric acid. D-proline at room temperature, cooling the refined salt of D-tartaric acid. D-proline to 5 to 10 DEG C, and filtering D-tartaric acid aminium salt; and h, recrystallizing mother liquor after steaming the methanol to obtain the D-proline. The mixing ratio of the L-proline and the D-tartaric acid is 1: 1.
Description
One, technical field:
The present invention is a kind of method for preparing chiral organic compound, especially a kind of method for preparing the D-proline(Pro).
Two, background technology:
D-amino acid is important chiral reagent of a class and chiral intermediate.The amino acid whose production of D-at present, majority is to prepare racemic modification with synthetic method, splits then to obtain optically active isomer.Therefore, the fractionation of DL-Amino Acid is an important step during D-amino acid is produced.
One of method for splitting that DL-Amino Acid is the most frequently used is a chemical resolution method, even DL-Amino Acid and chiral reagent effect generate diastereomer, utilizes the difference of diastereomer physics, chemical property and they are separated.Amino acid had both contained acidic-group, contained basic group again, was amphoteric substance, therefore the method for most convenient is to make itself and asymmetric acid or alkali effect, generate the salt of two kinds of diastereomers, utilize the difference of the solubleness of salt in solvent, they are separated by the method for recrystallization, diastereomer separately, with acid commonly used or alkali neutralization, just can obtain optically-active amino acid, simultaneously, dissociate the acid or the alkali of chirality recycle.
Yet, can only obtain 50%D-type optically active amino acids at most by the general chemistry Split Method, other 50% is L-type isomer.In order to improve resolution yield, the method for L-type amino acid by racemization need be transformed into racemic modification and recycle then.This method has following shortcoming: total recovery is lower; In splitting step, have carrying secretly of diastereomer and separate out, cause polarimetry purity to reduce; Increase a racemization step, operation increases, and the consumption of each side increases.
Another kind of method for splitting is asymmetric conversion, is improved chemical resolution method.Asymmetric conversion process is as the advanced person's of optically active compound method for splitting, be that crystallization and enantiomer racemization with diastereomer in the satiety system combines, make crystallization, fractionation and racemization (one-pot), raceme mixture is converted into a kind of optical isomer, this method has been saved the step of the racemization in the classical fractionation, avoided the loss of another kind of enantiomorph, fractionation efficient is improved greatly; Also avoided separating out phenomenon because of enantiomorph concentration increases carrying secretly of causing in the classical chemistry fractionation, optical purity is guaranteed.
D-proline(Pro) (proline) is the important intermediate of synthetic various optically active compounds, pyrrolidin derivatives, also is one of important chiral reagent.Preparation D-proline(Pro) method generally is earlier synthetic racemize proline(Pro), splits with chemical process then.Because therefore its synthetic difficulty of racemize proline(Pro) splits gained D-proline(Pro) and costs an arm and a leg.The L-proline(Pro) can be from natural protein separation and Extraction, cheap and easy to get, the D-proline(Pro) differs bigger with the price ratio of L-proline(Pro), therefore, prepares the D-proline(Pro) by asymmetric conversion by the L-proline(Pro) and has very important significance.Japanese SHIRAIWA etc. once reported asymmetric conversion processes D-proline(Pro) technology, but raw material and solvent consumption are many, are not easy to obtain pure product, do not have practical significance on industrial production.
Three, summary of the invention:
(1) goal of the invention
The method that the purpose of this invention is to provide a kind of D-of preparation proline(Pro) that a kind of production cost is low, aftertreatment easy, be suitable for producing in enormous quantities.
(2) technical scheme
The present invention is a kind of method of the D-of preparation proline(Pro), its method is: a, the L-proline(Pro) is mixed with D-tartrate and be dissolved in the organic acid, b, the aldehydes catalyzer of adding 10～30%, under 80 ± 10 ℃ condition, stirred 4～8 hours, c, cool off with ice-water bath, filter, use absolute ethanol washing, dry, d, crude salt obtains D-tartrate D proline(Pro) refined salt, e with recrystallization in the ethanol, D-tartrate D-proline(Pro) refined salt is dissolved in the methyl alcohol, f, under 20～65 ℃ condition, stir and add ammonia (ammoniation agent) and be weakly alkaline to solution, g, after at room temperature stirring, be cooled to 5～10 ℃, filter out D-tartrate ammonium salt, h, after mother liquor boiled off methyl alcohol, recrystallization obtained the D-proline(Pro).
The tartaric recovery of D-: use in the vitriol oil tartrate ammonium salt and dissolving.Add acetone or dehydrated alcohol and be settled out ammonium sulfate.Mother liquor concentrates postcooling and promptly gets D-tartrate crystal, can be used for the fractionation of next batch, has reduced the consumption of resolving agent.
(3) technique effect
The present invention solves and prepares three subject matters in the asymmetric conversion process of D-proline(Pro) by L-type proline(Pro).Comprise:
1, solvent consumption problem:
(1) uses by splitting Recycling Mother Solution, reduced the usage quantity of more valuable organic acid solvent, reduced cost;
(2) during the crude salt aftertreatment, replace volatile, difficult, difficult recovered solvent ether with cheap ethanol, cost is reduced, it is easier to operate; Recrystallization in crude salt 95% ethanol replaces stirring under the room temperature of mixture of original dehydrated alcohol and water, the consumption of solvent reduces, low price, recovery easily, mother liquor reclaims 95% ethanol and can be recycled.
(3) in the ammonification step, ammoniation agent makes the consumption of methyl alcohol in the ammonification step reduce to original 1/3-1/4 after improving, and solvent is saved greatly.Because ammonium tartrate is soluble in water, and be insoluble in organic solvent such as methyl alcohol,, must add relatively large methyl alcohol, ammonium tartrate is precipitated fully, separate, be beneficial to purifying products with the D-proline(Pro) if water is arranged in the system;
2, aftertreatment problem
(1) D-proline(Pro)-D tartrate solid replaces the ether washing with dehydrated alcohol, and washing effect is better, and solvent is handled easily.Recrystallization in crude salt 95% ethanol replaces the mixture of original dehydrated alcohol and water, and the consumption of solvent reduces, low price, recovery are easy.
When (2) preparing the D-proline(Pro), in the ammonification step, after this improvement, can in reaction system, not introduce moisture, make easy suction and more easily separated, the purifying of D-proline(Pro) of solubleness is greatly arranged in water.
3, the recovery problem of resolving agent
The use of resolving agent is to consume morely in the optically active isomer split process, and bigger one of proportion in cost the invention solves recovery, the regeneration problem of resolving agent.
In sum, the invention solves by L-type proline(Pro) and prepare problems such as cost height, aftertreatment trouble in the asymmetric conversion process of D-proline(Pro), therefore, make to prepare the asymmetric conversion process of D-proline(Pro) by L-type proline(Pro) and can be used for industrial production in enormous quantities.
Four, embodiment
The preparation of the first step D-tartrate D-proline salt
11.5g L-proline(Pro), the tartaric mixture of 15.0g D-are dissolved in the 150.00mL organic acid, add the alkanoic of 10-30%, stirred 4 hours down, be chilled to after the room temperature, filter and then with ice-water bath cooling 0.5 hour at 80 ± 5 ℃.The solid absolute ethanol washing, drying obtains the white crystal 23.1g of D-proline(Pro) D-tartrate, yield 87.2%, [α]
D 2022.0 °.
With crude salt 95% ethyl alcohol recrystallization, get 19.0g refined salt, yield 82.3%, [α]
D 2024.0 °.
The preparation of the second step D-proline(Pro)
Above recrystallization gained D-tartrate D-proline(Pro) refined salt 26.5g is dissolved in the methyl alcohol, in 20-65 ℃ and stir and slowly to add ammonia down and make solution become weakly alkaline, at room temperature stir 1h postcooling to 5～10 ℃, filter and with an amount of methanol wash solid 1～2 time, get D-tartrate ammonium salt 17.8g, yield 97.0%.Mother liquor pressure reducing and steaming methyl alcohol, and use the mixed solvent recrystallization, obtaining D-proline(Pro) crystal 11.0g, yield is 95.6%.[α]
D 20＝+84°。
The tartaric recovery of the 3rd step D-
18.4g (0.1mol) tartrate ammonium salt is moistening with suitable quantity of water.Under agitation adding the vitriol oil to solid dissolves fully.Stir 1h after adding acetone.Filter, mother liquor concentrates postcooling, gets D-tartrate crystal 12.0g, yield 80%.[α]
D 20＝-12.0°。
Claims (3)
1, a kind of method for preparing the D-proline(Pro) is characterized in that the method for preparing is:
A, the L-proline(Pro) mixed with D-tartrate and be dissolved in the organic acid,
The aldehydes catalyzer of b, adding 10～30% stirred under 80 ± 10 ℃ condition 4～8 hours,
C, with ice-water bath cooling, filter, with absolute ethanol washing, drying,
D, crude salt obtain D-tartrate D proline(Pro) refined salt with recrystallization in the ethanol,
E, D-tartrate D-proline(Pro) refined salt is dissolved in the methyl alcohol,
F, under 20～65 ℃ condition, stir and add ammonia to solution and be weakly alkaline,
After g, the stirring at room temperature, be cooled to 5～10 ℃, filter out D-tartrate ammonium salt,
After h, mother liquor boiled off methyl alcohol, recrystallization obtained the D-proline(Pro).
2, a kind of method for preparing the D-proline(Pro) according to claim 1 is characterized in that the tartaric blending ratio of L-proline(Pro) and D-is 1: 1.
3, a kind of method for preparing the D-proline(Pro) according to claim 1 and 2 is characterized in that the aldehydes catalyzer is an alkanoic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021126976A CN1181054C (en) | 2002-02-26 | 2002-02-26 | Process for preparing D-proline |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021126976A CN1181054C (en) | 2002-02-26 | 2002-02-26 | Process for preparing D-proline |
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| CN1373125A CN1373125A (en) | 2002-10-09 |
| CN1181054C true CN1181054C (en) | 2004-12-22 |
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| CNB021126976A Expired - Fee Related CN1181054C (en) | 2002-02-26 | 2002-02-26 | Process for preparing D-proline |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105152911B (en) * | 2015-08-17 | 2017-05-31 | 浙江邦成化工有限公司 | A kind of recovery method of tartaric acid |
| CN106008316B (en) * | 2016-06-17 | 2018-04-27 | 成都百事兴科技实业有限公司 | A kind of method of synthesis Lei Dipawei chiral intermediates |
| CN107827802B (en) * | 2017-10-17 | 2021-06-11 | 南京红杉生物科技有限公司 | Synthesis method of D-proline |
| CN112851560B (en) * | 2021-01-26 | 2022-04-29 | 南京红杉生物科技有限公司 | Preparation method of cis-D-hydroxyproline |
| CN113880802A (en) * | 2021-11-09 | 2022-01-04 | 深圳萨特瓦生物科技有限公司 | Tartaric acid-nicotine salt, preparation method and application thereof, and preparation method of anhydrous tartaric acid crystal |
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