CN104725259A - Preparation method for levodopa intermediate derivative - Google Patents
Preparation method for levodopa intermediate derivative Download PDFInfo
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- CN104725259A CN104725259A CN201310705178.1A CN201310705178A CN104725259A CN 104725259 A CN104725259 A CN 104725259A CN 201310705178 A CN201310705178 A CN 201310705178A CN 104725259 A CN104725259 A CN 104725259A
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Abstract
The invention relates to a preparation method for a levodopa intermediate derivative. The preparation method comprises: in a solvent, reacting 3, 4-dimethoxybenzene phenylalanine shown as formula I with (+)-tartaric acid derivative to obtain the salt of a [(-)-3, 4-dimethoxybenzene phenylalanine]2.(+)- tartaric acid derivative. The solvent includes an alcohol solvent and an ester solvent. The racemization method includes: in the solvent, under the action of an aldehyde or ketone catalyst, reacting the 3, 4-dimethoxybenzene phenylalanine shown as formula I at 0-90DEG C for 0.5-24 h. The preparation method for the levodopa intermediate derivative provided by the invention has simple steps, and the prepared enantiomer has high purity and is low in cost, thus being applicable to industrial production. (reaction formula).
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to a kind of preparation method of levodopa midbody derivant.
Background technology
L-(-)-3,4-dimethoxy phenylalanine ester or L-(-)-3,4-dimethoxy phenylalanine ester salt are a kind of important medicine intermediates, can be used for preparing levodopa.
Levodopa is the active drug for the treatment of Parkinsonism, is mainly used in Parkinsonism etc.Its structural formula is as shown in the formula shown in (2):
In prior art, domestic production levodopa bulk drug mainly extracts from lamb's-quarters seed, and price follows agricultural product price, and fluctuation is comparatively large, and the impurity of product is also more difficult to control effectively.
And biological fermentation process and chemical synthesis prepare levodopa there is no industrialization report; The production of external levodopa adopts asymmetric catalytic hydrogenation legal system for levodopa, owing to using the chiral ligand with intellecture property, technology barriers are higher, chiral ligand and heavy metal catalyst ruthenium, rhodium etc. simultaneously, costly, prior art cannot reclaim price, although usage quantity is catalytic amount, but cost is still not low, and the finished product may cause heavy-metal residual.
In addition, the method for the fractionation had been reported prepares levodopa, and step is comparatively loaded down with trivial details, and resolution reagent is more expensive, so that cost is higher, is not suitable for suitability for industrialized production.
Summary of the invention
Problem solved by the invention is, in order to the step overcoming existing fractionation levodopa intermediate is comparatively loaded down with trivial details, cost is higher, is not suitable for the defects such as suitability for industrialized production, the invention provides a kind of preparation method of levodopa midbody derivant.Preparation method's step of the present invention is simple, and cost is lower, is applicable to suitability for industrialized production.
The invention provides a kind of preparation method of levodopa midbody derivant, it comprises the steps: in a solvent, by such as formula 3 shown in I, 4-dimethoxy phenylalanine ester with react such as formula (+) shown in II-tartaric acid derivatives, obtain [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives;
Wherein, R is C
1~ C
6straight or branched alkane; R ' is to methyl benzoyl, o-methyl-benzene formyl radical, a toluyl, benzoyl or ethanoyl; Described solvent comprises alcoholic solvent and esters solvent.
The preparation method of described levodopa midbody derivant, it preferably includes following steps: by 3, the solution of 4-dimethoxy phenylalanine ester and the solution hybrid reaction of (+)-tartaric acid derivatives, separate out [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives.
In described R, described C
1~ C
6straight or branched alkane preferable methyl or ethyl.
Described 3,4-dimethoxy phenylalanine esters refer to the mixture that its enantiomer is formed, and it comprises following several situation: 1, racemic (±)-3,4-dimethoxy phenylalanine ester; 2, (+)-3,4-dimethoxy phenylalanine ester; 3, containing (-)-3,4-(+)-3,4-dimethoxy phenylalanine ester of dimethoxy phenylalanine ester; 4, (-)-3,4-dimethoxy phenylalanine ester.
Described solvent also can comprise ketones solvent.Described ketones solvent is preferably used in combination with esters solvent.Described alcoholic solvent, ketones solvent and esters solvent all can contain water.The mixture of the mixture of the mixture of the preferred esters solvent of described solvent and ketones solvent, ketones solvent and moisture alcoholic solvent, alcoholic solvent and esters solvent, or the mixture of esters solvent and moisture alcoholic solvent.The preferred C of described alcoholic solvent
1~ C
5monohydroxy-alcohol.The preferred C of described ketones solvent
1~ C
6ketone.The preferred C of described esters solvent
1~ C
5monoprotic acid and C
1~ C
5monohydroxy-alcohol formed ester, i.e. (C
1~ C
4) COO (C
1~ C
5).
The volume ratio of described alcoholic solvent and esters solvent is preferably (0.1 ~ 10): 1, is more preferably (0.2 ~ 2): 1.
When described solvent is except alcoholic solvent and esters solvent, when also comprising ketones solvent, its volume ratio is preferably ketones solvent: esters solvent=(0.1 ~ 10): 1.
The volume of described solvent and the ratio of 3,4-dimethoxy phenylalanine ester quality are preferably 1.0 ~ 25.0mL/1.0g.
Described (+)-tartaric acid derivatives can contain crystal water, it preferably includes (+)-two pairs of toluoyltartaric, (+)-two pairs of toluoyltartaric monohydrates, (+)-two methyl benzoyl tartrate, (+)-two methyl benzoyl tartrate monohydrates, (+)-two o-methyl-benzene formyl radical tartrate, (+)-two o-methyl-benzene formyl radical tartrate monohydrate, (+)-dibenzoyl tartaric acid, (+)-dibenzoyl tartaric acid monohydrate, one or more in (+)-acetyl tartaric acid and (+)-acetyl tartaric acid monohydrate
The mol ratio preferred (0.4 ~ 0.6) of described (+)-tartaric acid derivatives and described 3,4-dimethoxy phenylalanine esters: 1, more preferably (0.45 ~ 0.55): 1.
The temperature of described reaction preferably 0 ~ 90 DEG C, more preferably 20 ~ 50 DEG C.
As the terminal of reaction when described reaction is generally no longer to separate out solid, generally need 0.5 ~ 48 hour, preferably 24 hours.
After described reaction terminates, also can be passed through aftertreatment, to obtain dry [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives, described aftertreatment comprises the steps: to filter reaction system, with the mixing solutions washing leaching cake of alcohol (particular methanol or ethanol) and ethyl acetate (preferred volume ratio is 1:1 ~ 3:2), and dries.
After described reaction terminates, [(-)-3,4-dimethoxy phenylalanine ester] that obtain
2the salt of (+)-tartaric acid derivatives also can be passed through following method process and obtains (-)-3,4-dimethoxy phenylalanine ester, it comprises the steps: be less than under the condition of 5 DEG C, will [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives and alkali carry out reacting.The carbonate of described alkali preferred as alkali or supercarbonate, more preferably sodium carbonate or salt of wormwood.Described alkali preferably participates in reaction in form of an aqueous solutions.Prepare containing (-)-3,4-reaction system of dimethoxy phenylalanine ester, also by extraction into ethyl acetate reaction system, after removing organic phase solvent, obtain (-)-3,4-dimethoxy phenylalanine ester.
After described reaction terminates, in last handling process, in the filtrate obtained after described filtration, still there is a certain amount of (+)-3,4-dimethoxy phenylalanine ester, 3,4-dimethoxy phenylalanine esters of this configuration can be carried out racemization, cover is used for the preparation of next batch.
The method of described racemization preferably includes following steps: under the effect of aldehydes or ketones class catalyzer, and the filtrate above-mentioned filtration obtained reacts 0.5 ~ 24 hour (preferably 2 ~ 5 hours) in 0 ~ 90 DEG C (preferably 10 ~ 90 DEG C, more preferably 40 ~ 60 DEG C).
Described aldehydes or ketones class catalyzer comprises aromatic aldehyde containing electron-withdrawing substituent or electron donating group or aromatic ketone, and the aldehyde of alkanes or the ketone of alkanes.The preferred aubepine of described aromatic aldehyde, phenyl aldehyde, paranitrobenzaldehyde, 4-chloro-benzaldehyde or 5-nitrosalicylaldehyde.The preferred methyl phenyl ketone of described aromatic ketone.The preferred acetaldehyde of aldehyde of described alkanes, propionic aldehyde or isopropyl aldehyde.The preferred acetone of ketone of described alkanes or butanone.
Described aldehydes or ketones class catalyzer, with (+)-3,4-dimethoxy phenylalanine ester mol ratio be preferably (0.01 ~ 1): 1, more preferably (0.05 ~ 0.1): 1.
After the reaction of described racemization terminates, the aqueous solution of reaction system except the solid obtained after desolventizing and alkali also can be comprised the steps: further to react, control ph is 7 ~ 8 and temperature is less than 5 DEG C, extract by ethyl acetate, racemic 3,4-dimethoxy phenylalanine esters can be obtained.The preferred sodium carbonate of described alkali.
Present invention also offers a kind of racemic such as formula 3 shown in I, the preparation method of 4-dimethoxy phenylalanine ester or its salt, it comprises the steps: in solvent, under the effect of aldehydes or ketones class catalyzer, by such as formula 3 shown in I, 4-dimethoxy phenylalanine ester or its salt react 0.5 ~ 24 hour (preferably 2 ~ 5 hours) in 0 ~ 90 DEG C (preferably 10 ~ 90 DEG C, more preferably 40 ~ 60 DEG C); Described 3,4-dimethoxy phenylalanine ester is (+)-3,4-dimethoxy phenylalanine ester, (-)-3,4-dimethoxy phenylalanine ester, or (+)-3,4-dimethoxy phenylalanine ester and (-)-3,4-the molar content of dimethoxy phenylalanine ester be not the mixture of enantiomers of 1:1; Described solvent comprises alcoholic solvent and esters solvent;
R is C
1~ C
6straight or branched alkane.
In process of racemizing, in R, described C
1~ C
6straight or branched alkane preferable methyl or ethyl.
In process of racemizing, the salt of described 3,4-dimethoxy phenylalanine esters can be the salt that itself and tartaric acid derivatives are formed, preferably the salt that formed of itself and (+)-tartaric acid derivatives.Described tartaric acid derivatives structure optimization is as follows:
Wherein, R ' is to methyl benzoyl, o-methyl-benzene formyl radical, a toluyl, benzoyl or ethanoyl.
Described solvent also can comprise ketones solvent.Described ketones solvent is preferably used in combination with esters solvent.Described alcoholic solvent, ketones solvent and esters solvent all can contain water.The mixture of the mixture of the mixture of described solvent preferred alcohols kind solvent and ketones solvent, ketones solvent and moisture alcoholic solvent, alcoholic solvent and esters solvent, or the mixture of esters solvent and moisture alcoholic solvent.The preferred C of described alcoholic solvent
1~ C
5monohydroxy-alcohol.The preferred C of described ketones solvent
1~ C
6ketone.The preferred C of described esters solvent
1~ C
5monoprotic acid and C
1~ C
5monohydroxy-alcohol formed ester, i.e. (C
1~ C
4) COO (C
1~ C
5).
The volume ratio of described alcoholic solvent and esters solvent is preferably (0.1 ~ 10): 1, is more preferably (0.2 ~ 2): 1.
When described solvent is except alcoholic solvent and esters solvent, when also comprising ketones solvent, its volume ratio is preferably ketones solvent: alcoholic solvent=(0.1 ~ 10): 1.
The volume of described solvent and the ratio of 3,4-dimethoxy phenylalanine ester or its salt quality are preferably 1.0 ~ 25.0mL/1.0g.
Described aldehydes or ketones class catalyzer comprises aromatic aldehyde containing electron-withdrawing substituent or electron donating group or aromatic ketone, and the aldehyde of alkanes or the ketone of alkanes.The preferred aubepine of described aromatic aldehyde, phenyl aldehyde, paranitrobenzaldehyde, 4-chloro-benzaldehyde or 5-nitrosalicylaldehyde.The preferred methyl phenyl ketone of described aromatic ketone.The preferred acetaldehyde of aldehyde of described alkanes, propionic aldehyde or isopropyl aldehyde.The preferred acetone of ketone of described alkanes or butanone.
Described aldehydes or ketones class catalyzer, with (+)-3,4-the mol ratio of dimethoxy phenylalanine ester or its salt be preferably (0.01 ~ 1): 1, more preferably (0.05 ~ 0.1): 1.
After the reaction of racemization terminates, the aqueous solution of reaction system except the solid obtained after desolventizing and alkali also can be comprised the steps: further to react, and control ph is 7 ~ 8 and temperature is less than 5 DEG C, extracts by ethyl acetate, 3,4-dimethoxy phenylalanine esters of racemization can be obtained.The preferred sodium carbonate of described alkali.
According to the present invention, by (-)-3,4-dimethoxy phenylalanine ester according to following reactions steps, through hydrolysis, deprotection can prepare levodopa further.The described method preparing levodopa is the method for this area routine, the each step reaction conditions related to and step all can refer to this type of conventional steps reacted of this area and condition is selected, such as following second step reaction can reference: Jpn.Kokai TokkyoKoho, 56043261,21Apr1981.
In the present invention, room temperature refers to 10 DEG C ~ 30 DEG C, preferably 25 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method's step of levodopa midbody derivant of the present invention is simple, and obtained enantiomeric purity is high, and cost is lower, is applicable to suitability for industrialized production.In addition, the present invention only needs the aldehydes or ketones of catalytic amount, just can realize the racemization of 3,4-dimethoxy phenylalanine ester, simultaneously 3,4-dimethoxy phenylalanine ester still exists in a salt form, and the form stable of specific ionization alkali, improves 3, the rate of recovery of 4-dimethoxy phenylalanine ester, and easy and simple to handle, decrease the loss of material, be more suitable for scale production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1
(±)-3,4-method for splitting of dimethoxy phenylalanine ethyl ester
By 4.96g (±)-3,4-dimethoxy phenylalanine ethyl ester is dissolved in 30mL ethanol, the mixing solutions be made up of 3.56g (+)-dibenzoyl tartaric acid and 20mL ethyl acetate is added under stirring, room temperature separates out a large amount of solid after placing 24h, filters, and wash with the mixed solvent of the ethanol of a little 3:2 and ethyl acetate, dry, obtain 3.24g [(-)-3,4-dimethoxy phenylalanine ethyl ester]
2(+)-dibenzoyl tartaric acid.Split chemical yield 38.0%, HPLC detecting optical content 97.2%.
(consumption of sodium carbonate is 0.5e.q. [(-)-3,4-dimethoxy phenylalanine ethyl ester] this salt to be placed in aqueous sodium carbonate
2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with extraction into ethyl acetate, steams except ethyl acetate, can obtain (-)-3,4-dimethoxy phenylalanine ethyl ester.
Embodiment 2
(±)-3,4-method for splitting of dimethoxy phenylalanine ethyl ester
By 4.96g (±)-3,4-dimethoxy phenylalanine ethyl ester is dissolved in 25mL ethanol, the mixing solutions be made up of 3.76g (+)-dibenzoyl tartaric acid monohydrate and 25mL ethyl acetate is added under stirring, room temperature separates out a large amount of solid after placing 24h, filters, and wash with the mixed solvent of the ethanol of a little 1:1 and ethyl acetate, dry, obtain 3.1g [(-)-3,4-dimethoxy phenylalanine ethyl ester]
2(+)-dibenzoyl tartaric acid.Split chemical yield 36.4%, HPLC detecting optical content 97.7%.
(consumption of sodium carbonate is 0.5e.q. [(-)-3,4-dimethoxy phenylalanine ethyl ester] this salt to be placed in aqueous sodium carbonate
2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with extraction into ethyl acetate, steams except ethyl acetate, can obtain (-)-3,4-dimethoxy phenylalanine ethyl ester.
Embodiment 3
(±)-3,4-method for splitting of dimethoxy phenylalanine methyl ester
By 4.96g (±)-3,4-dimethoxy phenylalanine methyl ester is dissolved in 30mL methyl alcohol, the mixing solutions be made up of 3.56g (+)-dibenzoyl tartaric acid and 15mL ethyl acetate is added under stirring, room temperature separates out a large amount of solid after placing 24h, filters, and wash with the mixed solvent of the methyl alcohol of a little 2:1 and ethyl acetate, dry, obtain 3.38g [(-)-3,4-dimethoxy phenylalanine methyl ester]
2(+)-dibenzoyl tartaric acid.Split chemical yield 39.7%, HPLC detecting optical content 97.4%.
(consumption of sodium carbonate is 0.5e.q. [(-)-3,4-dimethoxy phenylalanine methyl ester] this salt to be placed in aqueous sodium carbonate
2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with extraction into ethyl acetate, steams except ethyl acetate, can obtain (-)-3,4-dimethoxy phenylalanine methyl ester.
Embodiment 4
(±)-3,4-method for splitting of dimethoxy phenylalanine methyl ester
By 4.96g (±)-3,4-dimethoxy phenylalanine methyl ester is dissolved in 30mL methyl alcohol, the mixing solutions be made up of 3.76g (+)-dibenzoyl tartaric acid monohydrate and 30mL ethyl acetate is added under stirring, room temperature separates out a large amount of solid after placing 24h, filters, and wash with the mixed solvent of the methyl alcohol of a little 1:1 and ethyl acetate, dry, obtain 3.1g [(-)-3,4-dimethoxy phenylalanine methyl ester]
2(+)-dibenzoyl tartaric acid.Split chemical yield 36.4%, HPLC detecting optical content 98.1%.
(consumption of sodium carbonate is 0.5e.q. [(-)-3,4-dimethoxy phenylalanine methyl ester] this salt to be placed in aqueous sodium carbonate
2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with extraction into ethyl acetate, steams except ethyl acetate, can obtain (-)-3,4-dimethoxy phenylalanine methyl ester.
Embodiment 5
(+)-3,4-racemization of dimethoxy phenylalanine ethyl ester
The 5-nitrosalicylaldehyde (molecular fraction) adding 5% will be filtered in the mother liquor that obtains in embodiment 1,3h is stirred at 60 DEG C, less than 40 DEG C vacuum rotary steams, except desolventizing, obtain solid salt, this salt are placed in aqueous sodium carbonate, control ph is at about 7-8, temperature control is less than 5 DEG C, and reaction, with (±)-3 of extraction into ethyl acetate racemization, 4-dimethoxy phenylalanine ethyl ester, can overlap the fractionation for next batch.Yield 96.4%, HPLC detects purity 98.3%.
Embodiment 6
(+)-3,4-racemization of dimethoxy phenylalanine methyl ester
The 5-nitrosalicylaldehyde (molecular fraction) adding 10% will be filtered in the mother liquor that obtains in embodiment 3,3h is stirred at 50 DEG C, except desolventizing, obtain solid salt, this salt is placed in the aqueous sodium carbonate that 10ml mass percent is 10%, control ph is at about 7-8, temperature control is less than 5 DEG C, and reaction, with (±)-3 of extraction into ethyl acetate racemization, 4-dimethoxy phenylalanine methyl ester, can overlap the fractionation for next batch.Yield 96.8%, HPLC detects purity 98.1%.
Embodiment 7
(+)-3,4-racemization of dimethoxy phenylalanine methyl ester
The phenyl aldehyde (molecular fraction) adding 10% will be filtered in the mother liquor that obtains in embodiment 4,5h is stirred at 60 DEG C, except desolventizing, obtain solid salt, this salt is placed in the aqueous sodium carbonate that 10ml massfraction is 10%, control ph is at about 7-8, temperature control is less than 5 DEG C, and reaction, with (±)-3 of extraction into ethyl acetate racemization, 4-dimethoxy phenylalanine methyl ester, can overlap the fractionation for next batch.Yield 95.6%, HPLC detects purity 97.3%.
Embodiment 8
By (-)-3 that embodiment 3 prepares, 4-dimethoxy phenylalanine methyl ester 5g, in the methyl alcohol being dissolved in sodium hydroxide and the aqueous solution, stirred at ambient temperature, until hydrolysis completely, with 8N HCl adjust ph to 5 ~ 6, adularescent solid is separated out, and filters, dry, obtain (-)-3,4-dimethoxy phenylalanine 4.4g, yield 94%.
Embodiment 9
By (-)-3 that embodiment 8 prepares, 4-dimethoxy phenylalanine 4.4g is dissolved in 30mL48% hydrobromic acid solution, reflux 12h, concentration of reaction solution, and with deionized water band dry hydrogen bromic acid, then add 30ml deionized water, with propylene oxide adjust ph to 5 ~ 6, there is a large amount of white solid to separate out, obtain levodopa 3.5g, yield 91%.
Claims (17)
1. the preparation method of a levodopa midbody derivant, it comprises the steps: in a solvent, by such as formula 3 shown in I, 4-dimethoxy phenylalanine ester with react such as formula (+) shown in II-tartaric acid derivatives, obtain [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives;
Wherein, R is C
1~ C
6straight or branched alkane, described C
1~ C
6straight or branched alkane preferable methyl or ethyl; R ' is to methyl benzoyl, o-methyl-benzene formyl radical, a toluyl, benzoyl or ethanoyl; Described solvent comprises alcoholic solvent and esters solvent.
2. the preparation method of levodopa midbody derivant as claimed in claim 1, it is characterized in that: comprise the steps: 3, the solution of 4-dimethoxy phenylalanine ester and the solution hybrid reaction of (+)-tartaric acid derivatives, separate out [(-)-3,4-dimethoxy phenylalanine ester]
2the salt of (+)-tartaric acid derivatives.
3. the preparation method of levodopa midbody derivant as claimed in claim 1 or 2, it is characterized in that: described 3,4-dimethoxy phenylalanine ester refers to the mixture that its enantiomer is formed, it comprises following several situation: 1, racemic (±)-3,4-dimethoxy phenylalanine ester; 2, (+)-3,4-dimethoxy phenylalanine ester; 3, containing (-)-3,4-(+)-3,4-dimethoxy phenylalanine ester of dimethoxy phenylalanine ester; 4, (-)-3,4-dimethoxy phenylalanine ester;
Described (+)-tartaric acid derivatives contains crystal water or does not contain crystal water, it comprises (+)-two pairs of toluoyltartaric, (+)-two pairs of toluoyltartaric monohydrates, (+)-two methyl benzoyl tartrate, (+)-two methyl benzoyl tartrate monohydrates, (+)-two o-methyl-benzene formyl radical tartrate, (+)-two o-methyl-benzene formyl radical tartrate monohydrate, (+)-dibenzoyl tartaric acid, (+)-dibenzoyl tartaric acid monohydrate, one or more in (+)-acetyl tartaric acid and (+)-acetyl tartaric acid monohydrate.
4. the preparation method of levodopa midbody derivant as claimed in claim 1 or 2, is characterized in that: described solvent also comprises ketones solvent; Described alcoholic solvent, ketones solvent and esters solvent are all moisture or not moisture; Described solvent is the mixture of the mixture of the mixture of alcoholic solvent and ketones solvent, ketones solvent and moisture alcoholic solvent, alcoholic solvent and esters solvent, or the mixture of esters solvent and moisture alcoholic solvent; Described alcoholic solvent is C
1~ C
5monohydroxy-alcohol; Described ketones solvent is C
1~ C
6ketone; Described esters solvent is C
1~ C
5monoprotic acid and C
1~ C
5monohydroxy-alcohol formed ester.
5. the preparation method of the levodopa midbody derivant as described in claim 1 or 4, is characterized in that: the volume ratio of described alcoholic solvent and esters solvent is (0.1 ~ 10): 1; When described solvent also comprises ketones solvent, its volume ratio is ketones solvent: esters solvent=(0.1 ~ 10): 1; The volume of described solvent and the ratio of 3,4-dimethoxy phenylalanine ester quality are 1.0 ~ 25.0mL/1.0g; The mol ratio of described (+)-tartaric acid derivatives and described 3,4-dimethoxy phenylalanine esters is (0.4 ~ 0.6): 1.
6. the preparation method of levodopa midbody derivant as claimed in claim 5, is characterized in that: the volume ratio of described alcoholic solvent and esters solvent is (0.2 ~ 2): 1; The mol ratio of described (+)-tartaric acid derivatives and described 3,4-dimethoxy phenylalanine esters is (0.45 ~ 0.55): 1.
7. the preparation method of levodopa midbody derivant as claimed in claim 1 or 2, is characterized in that: in described R, described C
1~ C
6straight or branched alkane be methyl or ethyl; The temperature of described reaction is 0 ~ 90 DEG C; The time of described reaction is 0.5 ~ 48 hour.
8. the preparation method of levodopa midbody derivant as claimed in claim 7, is characterized in that: the temperature of described reaction is 20 ~ 50 DEG C; The time of described reaction is 24 hours.
9. the preparation method of levodopa midbody derivant as claimed in claim 1, is characterized in that: after described reaction terminates, also through aftertreatment, and described aftertreatment comprises the steps: to filter reaction system, washing leaching cake, dries;
(+) in the filtrate that described filtration is obtained-3,4-dimethoxy phenylalanine ester carry out racemization; The method of described racemization comprises the steps: under the effect of aldehydes or ketones class catalyzer, and the filtrate described filtration obtained is reacted 0.5 ~ 24 hour in 0 ~ 90 DEG C.
10. the preparation method of levodopa midbody derivant as claimed in claim 9, it is characterized in that: in the method for described racemization, the temperature of reaction is 10 ~ 90 DEG C; The time of reaction is 2 ~ 5 hours.
The preparation method of 11. levodopa midbody derivants as claimed in claim 10, is characterized in that: in the method for described racemization, the temperature of reaction is 40 ~ 60 DEG C.
The preparation method of 12. levodopa midbody derivants as claimed in claim 9, it is characterized in that: described aldehydes or ketones class catalyzer comprises aromatic aldehyde containing electron-withdrawing substituent or electron donating group or aromatic ketone, and the aldehyde of alkanes or the ketone of alkanes; Described aromatic aldehyde is aubepine, phenyl aldehyde, paranitrobenzaldehyde, 4-chloro-benzaldehyde or 5-nitrosalicylaldehyde; Described aromatic ketone is methyl phenyl ketone; The aldehyde of described alkanes is acetaldehyde, propionic aldehyde or isopropyl aldehyde; The ketone of described alkanes is acetone or butanone;
Described aldehydes or ketones class catalyzer, with (+)-3,4-the mol ratio of dimethoxy phenylalanine ester be (0.01 ~ 1): 1.
The preparation method of 13. levodopa midbody derivants as claimed in claim 12, is characterized in that: described aldehydes or ketones class catalyzer, with (+)-3,4-the mol ratio of dimethoxy phenylalanine ester be (0.05 ~ 0.1): 1.
14. 1 kinds of racemic preparation methods such as formula 3,4-dimethoxy phenylalanine esters shown in I or its salt, it comprises the steps: in solvent, under the effect of aldehydes or ketones class catalyzer, react such as formula 3,4-dimethoxy phenylalanine esters shown in I 0.5 ~ 24 hour in 0 ~ 90 DEG C; Described 3,4-dimethoxy phenylalanine ester is (+)-3,4-dimethoxy phenylalanine ester, (-)-3,4-dimethoxy phenylalanine ester, or (+)-3,4-dimethoxy phenylalanine ester and (-)-3,4-the molar content of dimethoxy phenylalanine ester be not the mixture of enantiomers of 1:1; Described solvent comprises alcoholic solvent and esters solvent;
R is C
1~ C
6straight or branched alkane.
15. racemic preparation methods such as formula 3,4-dimethoxy phenylalanine esters shown in I or its salt as claimed in claim 14, is characterized in that: in described process of racemizing, in R, described C
1~ C
6straight or branched alkane be methyl or ethyl;
In process of racemizing, the salt of described 3,4-dimethoxy phenylalanine esters is the salt that it is formed with (+)-tartaric acid derivatives; Described (+)-tartaric acid derivatives structure is as follows:
Wherein, R ' is to methyl benzoyl, o-methyl-benzene formyl radical, a toluyl, benzoyl or ethanoyl;
Described solvent also comprises ketones solvent;
Described alcoholic solvent, ketones solvent and esters solvent are all containing water or not moisture; Described solvent is the mixture of the mixture of the mixture of alcoholic solvent and ketones solvent, ketones solvent and moisture alcoholic solvent, alcoholic solvent and esters solvent, or the mixture of esters solvent and moisture alcoholic solvent; Described alcoholic solvent is C
1~ C
5monohydroxy-alcohol; Described ketones solvent is C
1~ C
6ketone; Described esters solvent is C
1~ C
5monoprotic acid and C
1~ C
5monohydroxy-alcohol formed ester;
The volume of described solvent and the ratio of 3,4-dimethoxy phenylalanine ester quality are 1.0 ~ 25.0mL/1.0g.
16. racemic preparation methods such as formula 3,4-dimethoxy phenylalanine esters shown in I or its salt as claimed in claim 15, is characterized in that: the volume ratio of described alcoholic solvent and esters solvent is (0.2 ~ 2): 1; The volume ratio of described alcoholic solvent and esters solvent is (0.1 ~ 10): 1; The volume ratio of described ketones solvent and alcoholic solvent is (0.1 ~ 10): 1.
17. is racemic such as formula 3 shown in I as claimed in claim 14, the preparation method of 4-dimethoxy phenylalanine ester or its salt, it is characterized in that: described aldehydes or ketones class catalyzer comprises aromatic aldehyde containing electron-withdrawing substituent or electron donating group or aromatic ketone, and the aldehyde of alkanes or the ketone of alkanes; Described aromatic aldehyde is aubepine, phenyl aldehyde, paranitrobenzaldehyde, 4-chloro-benzaldehyde or 5-nitrosalicylaldehyde; Described aromatic ketone is methyl phenyl ketone; The aldehyde of described alkanes is acetaldehyde, propionic aldehyde or isopropyl aldehyde; The ketone of described alkanes is acetone or butanone;
Described aldehydes or ketones class catalyzer, with (+)-3,4-the mol ratio of dimethoxy phenylalanine ester or its salt be (0.01 ~ 1): 1.
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| CN107012179A (en) * | 2017-05-15 | 2017-08-04 | 南京医科大学 | The enzymatic conversion preparation method of 3,4 dimethoxy L phenylalanines |
| CN107382755A (en) * | 2017-06-09 | 2017-11-24 | 浙江工业大学 | A kind of preparation method of levodopa |
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| CN1583714A (en) * | 2004-06-02 | 2005-02-23 | 上海医药工业研究院 | Preparation of [(S)-(-)-alpha-methylamino phenylketone]2.(2R,3R)-tartaric acid derivative |
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| CN1583714A (en) * | 2004-06-02 | 2005-02-23 | 上海医药工业研究院 | Preparation of [(S)-(-)-alpha-methylamino phenylketone]2.(2R,3R)-tartaric acid derivative |
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| AMERICAN CHEMICAL SOCIETY: "FIL REG", 《STN ON THE WEB》, 16 November 1984 (1984-11-16), pages 1 - 11 * |
| HEE JIN KIM ET AL.: "Enantiomeric Resolution of α-Amino Acid Derivatives on Two Diastereomeric Chiral Stationary Phases Based on Chiral Crown Ethers Incorporating Two Different Chiral Units", 《BULL. KOREAN CHEM. SOC.》, vol. 31, no. 6, 31 December 2010 (2010-12-31), pages 1 - 17 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107012179A (en) * | 2017-05-15 | 2017-08-04 | 南京医科大学 | The enzymatic conversion preparation method of 3,4 dimethoxy L phenylalanines |
| CN107012179B (en) * | 2017-05-15 | 2020-05-29 | 南京医科大学 | Enzymatic conversion preparation method of 3, 4-dimethoxy-L-phenylalanine |
| CN107382755A (en) * | 2017-06-09 | 2017-11-24 | 浙江工业大学 | A kind of preparation method of levodopa |
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