CN101880224B - Method for splitting 6,8-dichlorocaprylate - Google Patents
Method for splitting 6,8-dichlorocaprylate Download PDFInfo
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- CN101880224B CN101880224B CN 200910050877 CN200910050877A CN101880224B CN 101880224 B CN101880224 B CN 101880224B CN 200910050877 CN200910050877 CN 200910050877 CN 200910050877 A CN200910050877 A CN 200910050877A CN 101880224 B CN101880224 B CN 101880224B
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- dichloro
- octanoic acid
- dehydroabietylamine
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Abstract
The invention provides a method for optically splitting (+/-)-6,8-dichlorocaprylate. In the method, dehydroabietylamine with a structure expressed as the following figure is used as a splitting reagent, the dehydroabietylamine is reacted with racemized (+/-)-6,8-dichlorocaprylate to form a pair of diastereoisomer salts, and optical splitting is performed according to different solubility of the diastereoisomer salts to obtain (+)-6,8-dichlorocaprylate. Compared with the conventional splitting method, the splitting reagent is cheap and easily obtained, and the product is purified without repeated recrystallization.
Description
Technical field
The present invention relates to the important intermediate of preparation (R)-Thioctic Acid: the preparation method of (+)-6,8-dichloro-octanoic acid is specifically related to split the method that (±)-6,8-dichloro-octanoic acid obtains its single enantiomer (+)-6,8-dichloro-octanoic acid.
Background technology
The structural formula of (+)-6,8-dichloro-octanoic acid is as follows:
(+)-6,8-dichloro-octanoic acid is the important intermediate of synthetic (R)-Thioctic Acid.(R)-Thioctic Acid is a kind of multiduty natural product, belongs to vitamins, as the metabolism of coenzyme involved in sugar, has stronger oxidation-resistance.It is described as " omnipotent oxidation inhibitor " with (R)-Thioctic acid, dihydro-, can be applicable to diabetes and chronic complicating diseases of diabetes.It also can be used as additive and is used for healthcare products and cosmetics.Its structural formula is as follows:
D.S.Acker etc. have proposed take ephedrine as resolving agent, split the method (J.Am.Chem.Soc., 1957,79,6483.) of (±)-6,8-dichloro-octanoic acid.Although this method has obtained (+)-6,8-dichloro-octanoic acid for the synthesis of (R)-Thioctic Acid by fractionation, there is following defective in actual applications in this method:
1. the salt that (+)-6,8-dichloro-octanoic acid or (-)-6,8-dichloro-octanoic acid and ephedrine form need to just can obtain sterling through six recrystallizations, and complex operation, yield are very low;
2. the ephedrine price is relatively more expensive comparatively speaking, is not suitable for doing resolving agent.
Summary of the invention
Not high in order to overcome the existing method yield that splits (±)-6,8-dichloro-octanoic acid, defective and the deficiency such as resolving agent is rare have proposed the present invention.
The method according to this invention, the reagent that is used for splitting is carried out screening, described screening is extensive screening, and is at first sour to liking owing to what split, therefore selects the common alkaline resolving agent that is easy to get as screening target, such as cinchovatin, quinine, dehydroabietylamine, L-aminopropanol, cinchonine, the alkaline resolving agent such as phenylethylamine; Secondly respectively various resolving agents are mixed in solvent with (±)-6,8-dichloro-octanoic acid, during the conversion solvent, the solvent of selecting is ethyl acetate, hexanaphthene, acetone, toluene, the perhaps mixture of multiple above-mentioned solvent; Last observe phenomena if there is clarification or oily mater, shows that namely this resolving agent can not split (±)-6,8-dichloro-octanoic acid, shows then that if there is crystallization this resolving agent can split (±)-6,8-dichloro-octanoic acid.
By above-mentioned to the multiple cinchovatin that comprises, quinine, dehydroabietylamine, the L-aminopropanol, the screening of the resolving agents such as cinchonine, the present invention are selected to adopt dehydroabietylamine as resolving agent at last, be used for to split (±)-6,8-dichloro-octanoic acid.
With dehydroabietylamine as resolving agent and racemic (±)-6, the reaction of 8-dicloro caprylate, can form a pair of diastereomeric salt, can carry out optical resolution to described racemic (±)-6,8-dichloro-octanoic acid according to the different solubility of described diastereomeric salt.
According to the selection result of the present invention, dehydroabietylamine has more excellent fractionation efficient with respect to other resolving agent, generally speaking, dehydroabietylamine and (±)-6, the salt that the 8-dicloro caprylate forms, i.e. (+)-6,8-dichloro-octanoic acid dehydroabietylamine only need to be through 3 recrystallizations, (+)-6,8-dichloro-octanoic acid that can dissociate and obtain having high light purity.
Particularly, the method for splitting of (±) provided by the invention-6,8-dichloro-octanoic acid comprises the steps:
At first the resolving agent dehydroabietylamine is mixed in suitable solvent with (±)-6,8-dichloro-octanoic acid, form the solution of a pair of diastereomeric salt.
Then according to the difference of formed diastereomeric salt solubleness, separate different diastereomeric salts by the method for fractional crystallization.The salt solubility that (+)-6,8-dichloro-octanoic acid and dehydroabietylamine generate is little, preferentially separates out from solution.And the salt solubility that (-)-6,8-dichloro-octanoic acid and dehydroabietylamine generate is larger, stays in the solution.
The salt by (+)-6,8-dichloro-octanoic acid and dehydroabietylamine generation that collection is separated out after the again acidifying of alkalizing is free, can obtain (+)-6,8-dichloro-octanoic acid.
As non-dated especially, the fractional crystallization of diastereomeric salt of the present invention refers to: the diastereomer crystallization that solubleness is little in the solution of a pair of diastereomeric salt, behind recrystallizing and refining repeatedly, the each several part mother liquor of gained obtains respectively again second batch, the 3rd batch of crystallization through similar processing again.
In the above-mentioned split process, the resolving agent dehydroabietylamine is 0.5: 1 to 1: 1 with the molar ratio of (±)-6,8-dichloro-octanoic acid that is split, and is preferably 0.5: 1-0.8: 1.Such molar ratio can split the consumption of saving resolving agent under the essentially identical prerequisite of effect.
Solvent used during fractionation is selected from C
1-C
4The ester of straight or branched, hexanaphthene, pentamethylene, acetone, the mixture of butanone or above-mentioned solvent, preferred solvent is ethyl acetate.The selection of described solvent can take into account low price, and the problem such as polarity is moderate, if the polarity of solvent too greatly then solubleness is large, easily makes the solution of acquisition clarification occur, the too little then solubleness of polarity is little, easily makes in the solution of acquisition oily matter to occur.
The fractured operation temperature range is 0 ℃-60 ℃, is preferably 40 ℃.The crystallisation by cooling temperature range is 40 ℃ and slowly drops to-5 ℃.This temperature can adapt to the fusing point (44 ℃-45 ℃) of dehydroabietylamine.In addition, if temperature too Gao Zehui resolving agent is melted, be unfavorable for splitting, too low dehydroabietylamine and (±)-6,8-dichloro-octanoic acid of then being unfavorable for of temperature fully dissolves mixing.
The diastereomeric salt by dehydroabietylamine and the generation of (+)-6,8-dichloro-octanoic acid of separating out can add first one or more and be selected from NaOH, KOH, Ca (OH)
2, Ba (OH)
2Alkali, make dehydroabietylamine free, free dehydroabietylamine extracts recovery with the organic solvent that one or more are selected from methylene dichloride, ethyl acetate, toluene from solution.The material of staying in the alkaline solution adds the mineral acid that one or more are selected from hydrochloric acid, sulfuric acid, phosphoric acid, make (+)-6, the 8-dicloro caprylate is free, be selected from the organic solvent extraction of methylene dichloride, ethyl acetate, toluene with one or more, dry, concentrate, can obtain (+)-6,8-dichloro-octanoic acid of high-optical-purity.
As non-dated especially, described in the present invention one or more refer to the mixture of independent a kind of material or any many kinds of substance.For example, the organic solvent that one or more are selected from methylene dichloride, ethyl acetate, toluene means any described organic solvent, perhaps the mixture of two or more described organic solvent.
The invention has the advantages that: resolving agent cheaply is easy to get and can reclaims, and is conducive to reduce cost, environmental contamination reduction; The recrystallization number of times is few, can obviously improve resolution yield, and can reduce solvent consumption.
Embodiment
In order to understand better technique of the present invention, be described further below in conjunction with specific embodiments of the invention, but it does not limit the present invention.
Embodiment 1:
In 5 identical 50ml single port flasks, add respectively 5g (23.5mmol) (±)-6,8-dicloro caprylate and 20ml ethyl acetate, after fully shaking up, add respectively again the resolution reagent cinchovatin of 18.8mmol, quinine, dehydroabietylamine, the L-aminopropanol, cinchonine is in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, observe phenomena finds to only have crystallize out in the flask that adds the resolving agent dehydroabietylamine, be added with in the flask of other resolution reagents or clarification without phenomenon, perhaps separate out oily matter.
Embodiment 2:
In 50ml single port flask, add 2g (9.4mmol) (±)-6,8-dichloro-octanoic acid and 8ml ethyl acetate, after fully shaking up, add again 1.9g (6.6mmol) dehydroabietylamine, with the extremely clarification of 40 ℃ of stirred in water bath.Then slowly be cooled to 0 ℃, have crystal to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 1.1g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation.Survey optically-active, [α]
20 D:-11.2 ° (C=1, ethanol).
Embodiment 3:
In 100ml single port flask, add 8.8g (41.3mmol) (±)-6,8-dichloro-octanoic acid and 36ml ethyl acetate, after shaking up, add again 9.4g (33.1mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 5.2g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-12 ° (C=1, ethanol).First with the NaOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses dichloromethane extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 2.2g.Survey optically-active, [α]
20 D:+30.0 ° (c=2, toluene)
Embodiment 4:
In 250ml single port flask, add 20g (93.9mmol) (±)-6,8-dichloro-octanoic acid and 80ml ethyl acetate, after shaking up, add again 26.8g (93.9mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 12g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-11.5 ° (C=1, ethanol).First with the KOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses ethyl acetate extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 4.8g.Survey optically-active, [α]
20 D:+31.2 ° (c=2, toluene)
Embodiment 5:
In 250ml single port flask, add 20g (93.9mmol) (±)-6,8-dichloro-octanoic acid and 80ml ethyl acetate and hexanaphthene (volume ratio 1: 1) mixed solvent, after shaking up, add again 26.8g (93.9mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 12g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-11.5 ° (C=1, ethanol).First with the KOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses ethyl acetate extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 4.25g.Survey optically-active, [α]
20 D:+31.2 ° (c=2, toluene)
Embodiment 6:
In 100ml single port flask, add 10g (46.9mmol) (±)-6,8-dichloro-octanoic acid and 40ml butylacetate, after shaking up, add again 6.7g (23.5mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 4.82g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-11 ° (C=1, ethanol).First with the NaOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses dichloromethane extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 2.05g.Survey optically-active, [α]
20 D:+30.0 ° (c=2, toluene)
Embodiment 7:
In 100ml single port flask, add 8.8g (41.3mmol) (±)-6,8-dichloro-octanoic acid and 36ml acetone and hexanaphthene (volume ratio 1: 1) mixed solvent, after shaking up, add again 9.4g (33.1mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 3 times in ethyl acetate, vacuum-drying obtains white solid 4.72g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-12 ° (C=1, ethanol).First with the NaOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses dichloromethane extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 2.0g.Survey optically-active, [α]
20 D:+29.5 ° (c=2, toluene)
Comparative example 1:
In 250ml single port flask, 12.06g (0.073mol) racephedrine is joined in the ethyl acetate of the 100ml that is dissolved with 15.57g (0.073mol) (±)-6,8-dichloro-octanoic acid, fully after the dissolving, slowly be cooled to-18 ℃, crystallization.With the crystal collected recrystallization 6 times in ethyl acetate, obtain the 5.8g solid after the vacuum-drying, be (+)-6,8-dichloro-octanoic acid (-)-racephedrine, survey optically-active, [α]
24 D:-11.1 ° (C=1, ethanol).With solid with 5% cryosel acid acidifying after, with ether extraction 4 times, merge behind the organic layer with saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, the concentrated oily matter 3.1g that obtains.Survey optically-active, [α]
24 D:+30.5 ° (c=2, toluene)
| Resolution reagent | The recrystallization number of times | Product yield | |
| Embodiment 3 | Dehydroabietylamine | 3 times | 50％ |
| Comparative example 1 | Racephedrine | 6 times | 40％ |
The method of conclusion: embodiment is compared with the comparative example method, has the following advantages: the recrystallization number of times is few, the corresponding minimizing of solvent load, and resolution reagent cheaply is easy to get, and yield is higher.
Comparative example 2:
In 100ml single port flask, add 20g (93.9mmol) (±)-6,8-dichloro-octanoic acid and 80ml ethyl acetate, after shaking up, add again 26.8g (93.9mmol) dehydroabietylamine, in 40 ℃ of stirred in water bath to clarification.Then slowly be cooled to 0 ℃, have crystallization to generate.Suction filtration, with the crystal collected recrystallization 4 times in ethyl acetate, vacuum-drying obtains white solid 10.5g, is (+)-6,8-dichloro-octanoic acid and the salt of dehydroabietylamine formation, [α]
20 D:-11.0 ° (C=1, ethanol).First with the KOH alkalization, the alkaline solution of separation is used the dilute hydrochloric acid acidifying again with above-mentioned white solid, and then dissociate (+)-6,8-dichloro-octanoic acid uses dichloromethane extraction, and drying is concentrated, obtains oily matter (+)-6,8-dichloro-octanoic acid 4.4g.Survey optically-active, [α]
20 D:+29.5 ° (c=2, toluene)
| Resolving agent and racemic mixture mol ratio | The recrystallization number of times | Target product yield | |
| Embodiment 3 | 0.8∶1 | 3 times | 47.8％ |
| Comparative example 2 | 1∶1 | 4 times | 44％ |
Claims (11)
1. one kind 6, the method for splitting of 8-dicloro caprylate, it is characterized in that, use dehydroabietylamine as resolving agent, itself and racemic (±)-6,8-dichloro-octanoic acid are reacted, form a pair of diastereomeric salt, different solubility according to described diastereomeric salt carries out optical resolution, and wherein said resolving agent dehydroabietylamine is 0.5: 1 to 1: 1 with the molar ratio of (±)-6,8-dichloro-octanoic acid that is split.
2. method according to claim 1 is characterized in that, comprises the following steps:
(a) the resolving agent dehydroabietylamine is mixed in solvent with (±)-6,8-dichloro-octanoic acid, form the solution of a pair of diastereomeric salt;
(b) solution with described diastereomeric salt carries out fractional crystallization, and the salt that solubleness less (+)-6,8-dichloro-octanoic acid and dehydroabietylamine are generated is separated out from solution;
(c) collect the salt by (+)-6,8-dichloro-octanoic acid and dehydroabietylamine generation of separating out, after the again acidifying of alkalizing is free, obtain (+)-6,8-dichloro-octanoic acid.
3. method according to claim 1 is characterized in that, described resolving agent dehydroabietylamine is 0.5 with the molar ratio of (±)-6,8-dichloro-octanoic acid that is split: 1-0.8: 1.
4. method according to claim 2 is characterized in that, solvent is selected one or more following ingredients: C described in the step (a)
1-C
4The ester of straight or branched, hexanaphthene, pentamethylene, acetone, butanone, wherein C
1-C
4The ester of straight or branched does not comprise C
1Ester.
5. method according to claim 4 is characterized in that, solvent is ethyl acetate described in the step (a).
6. method according to claim 2 is characterized in that, the service temperature of step (a) is 0 ℃-60 ℃.
7. method according to claim 6 is characterized in that, the service temperature of step (a) is 40 ℃.
8. method according to claim 2 is characterized in that, fractional crystallization comprises the following steps: described in the step (b)
(b1) temperature with described solution slowly is reduced to-5 ℃.
9. method according to claim 2 is characterized in that, in the step (c),
The alkali that described alkalization is adopted is selected from one or more following material: NaOH, KOH, Ca (OH)
2, Ba (OH)
2
The acid that described acidifying is adopted is selected from one or more following materials: hydrochloric acid, sulfuric acid, phosphoric acid.
10. method according to claim 2 is characterized in that, after the described alkalization of step (c), also comprises the following steps:
(c1) from solution, extract the recovery dehydroabietylamine with one or more organic solvents that are selected from methylene dichloride, ethyl acetate, toluene.
11. method according to claim 2 is characterized in that, after the described acidifying of step (c), also comprises the following steps:
(c2) from solution, extract free (+)-6,8-dichloro-octanoic acid with one or more organic solvents that are selected from methylene dichloride, ethyl acetate, toluene, and it is carried out drying, concentrated.
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|---|---|---|---|
| CN 200910050877 CN101880224B (en) | 2009-05-08 | 2009-05-08 | Method for splitting 6,8-dichlorocaprylate |
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| CN101880224B true CN101880224B (en) | 2013-02-20 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731448A (en) * | 1995-09-13 | 1998-03-24 | Arzneimittelwerk Dresden Gmbh | (+) and (-)-8-chloro-6-sulfonyloxy-octanoic acid, its derivatives, and methods for making |
| CN101024641A (en) * | 2006-02-20 | 2007-08-29 | 南京莱尔生物化工有限公司 | R(1) lipoic acid and its salt preparation |
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| IT1319196B1 (en) * | 2000-10-10 | 2003-09-26 | Laboratorio Chimico Int Spa | SUMMARY OF R (+) ALPHA-LIPOIC ACID. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731448A (en) * | 1995-09-13 | 1998-03-24 | Arzneimittelwerk Dresden Gmbh | (+) and (-)-8-chloro-6-sulfonyloxy-octanoic acid, its derivatives, and methods for making |
| CN101024641A (en) * | 2006-02-20 | 2007-08-29 | 南京莱尔生物化工有限公司 | R(1) lipoic acid and its salt preparation |
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