CN104725259B - Preparation method for levodopa intermediate derivative - Google Patents
Preparation method for levodopa intermediate derivative Download PDFInfo
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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 is and in particular 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 is a kind of weight
Want medicine intermediate, can be used for preparing levodopa.
Levodopa is the active drug for the treatment of shaking plasy, is mainly used in Parkinsonism etc..Its structural formula is such as
Shown in following formula (2):
In prior art, domestic production levodopa bulk drug mainly extracts from lamb's-quarters seed, and price follows agricultural product valency
Lattice, fluctuation is larger, and the impurity of product is also more difficult to control effectively.
And biological fermentation process and chemical synthesis are prepared levodopa and be there is no industrialization report;The production of external levodopa
Levodopa is prepared using asymmetric catalytic hydrogenation method, because using the chiral ligand with intellectual property, technology barriers are higher,
Chiral ligand and heavy metal catalyst ruthenium, rhodium etc. simultaneously, costly, prior art cannot reclaim although usage amount is for price
Catalytic amount, but cost is not still low, and also final products may lead to heavy-metal residual.
In addition, the method for the fractionation having been reported prepares levodopa, and step is relatively complicated, and resolution reagent is more expensive,
So that relatively costly, be not suitable for industrialized production.
Content of the invention
Problem solved by the invention is, the step in order to overcome existing fractionation levodopa intermediate is relatively complicated,
Relatively costly, be not suitable for the defects such as industrialized production, the invention provides a kind of preparation side of levodopa midbody derivant
Method.The preparation method step of the present invention is simple, cost relatively low it is adaptable to industrialized production.
The invention provides a kind of preparation method of levodopa midbody derivant, it comprises the steps: in solvent
In, by 3, the 4- dimethoxy phenylalanine ester as shown in formula i with as shown in formula ii (+)-tartaric acid derivatives react, obtain
[(-) -3,4- dimethoxy phenylalanine ester]2The salt of (+)-tartaric acid derivatives;
Wherein, r is c1~c6Straight or branched alkane;R ' is to methyl benzoyl, o-methyl-benzene formoxyl, a first
Base benzoyl, benzoyl or acetyl group;Described solvent includes alcohols solvent and esters solvent.
The preparation method of described levodopa midbody derivant, it preferably includes following steps: by 3,4- dimethoxy
The solution of phenylalanine ester with (+) the solution hybrid reaction of-tartaric acid derivatives, separate out [(-) -3,4- dimethoxy phenylpropyl alcohol ammonia
Acid esters]2The salt of (+)-tartaric acid derivatives.
In described r, described c1~c6The preferred methyl of straight or branched alkane or ethyl.
Described 3,4- dimethoxy phenylalanine ester refers to the mixture that its enantiomter is formed, and it includes following several
Situation: 1, racemic (±) -3,4- dimethoxy phenylalanine ester;2nd, (+) -3,4- dimethoxy phenylalanine ester;3rd, contain
Have (-) -3,4- dimethoxy phenylalanine ester (+) -3,4- dimethoxy phenylalanine ester;4th, (-) -3,4- dimethoxy benzene
Alanine ester.
Described solvent may also include ketones solvent.Described ketones solvent is preferably used in mixed way with esters solvent.Described alcohol
Class solvent, ketones solvent and esters solvent all can contain water.The mixture of the preferred esters solvent of described solvent and ketones solvent, ketone
The mixture of the mixture, alcohols solvent and esters solvent of class solvent and aqueous alcohols solvent, or esters solvent with aqueous
Alcohols solvent mixture.The preferred c of described alcohols solvent1~c5Monohydric alcohol.The preferred c of described ketones solvent1~c6Ketone.
The preferred c of described esters solvent1~c5Monoacid and c1~c5Monohydric alcohol formed ester, i.e. (c1~c4)coo(c1~c5).
Described alcohols solvent is preferably (0.1~10) with the volume ratio of esters solvent: 1, more preferably for (0.2~2): 1.
When described solvent is in addition to alcohols solvent and esters solvent, when also including ketones solvent, its volume ratio is preferably ketone
Class solvent: esters solvent=(0.1~10): 1.
The ratio of the volume of described solvent and 3,4- dimethoxy phenylalanine ester quality is preferably 1.0~25.0ml/
1.0g.
Described (+)-tartaric acid derivatives can contain the crystallization water, its preferably include (+)-two pairs of toluoyltartaric,
- two pairs of toluoyltartaric monohydrates of (+), (+)-two methyl benzoyl tartaric acid, (+)-two toluyls
Base tartaric acid monohydrate, (+)-two o-methyl-benzene formoxyl tartaric acid, (+)-two o-methyl-benzene formoxyl tartaric acid one are hydrated
Thing, (+)-dibenzoyl tartaric acid, (+)-dibenzoyl tartaric acid monohydrate, (+)-acetyl tartaric acid and (+)-
One or more of acetyl tartaric acid monohydrate
Described (+) mol ratio of-tartaric acid derivatives and described 3,4- dimethoxy phenylalanine ester preferably (0.4~
0.6): 1, more preferably (0.45~0.55): 1.
Preferably 0~90 DEG C of the temperature of described reaction, more preferably 20~50 DEG C.
Described reaction typically no longer to separate out the terminal as reaction during solid, generally requires 0.5~48 hour, and preferably 24
Hour.
After described reaction terminates, be also may pass through post-process, with obtain drying [(-) -3,4- dimethoxy phenylalanine
Ester]2The salt of (+)-tartaric acid derivatives, described post processing comprises the steps: to filter reaction system, with alcohol (preferably methyl alcohol
Or ethanol) and ethyl acetate (preferred volume ratio be 1:1~3:2) mixed solution washing filter cake, and dry.
After described reaction terminates, obtain [(-) -3,4- dimethoxy phenylalanine ester]2(+)-tartaric acid derivatives
Salt be also may pass through following method process and obtain (-) -3,4- dimethoxy phenylalanine ester, it comprises the steps: less than 5
Under conditions of DEG C, will [(-) -3,4- dimethoxy phenylalanine ester]2The salt of (+)-tartaric acid derivatives and alkali are reacted
?.The described carbonate of alkali preferred as alkali or bicarbonate, more preferably sodium carbonate or potassium carbonate.Described alkali is preferably with water
The form of solution participates in reaction.Prepare containing (-) reaction system of -3,4- dimethoxy phenylalanine ester, also can lead to
Peracetic acid ethyl ester extractive reaction system, after removing organic phase solvent, obtain (-) -3,4- dimethoxy phenylalanine ester.
After described reaction terminates, in last handling process, described filter after still have in the filtrate that obtains a certain amount of (+) -3,
3, the 4- dimethoxy phenylalanine ester of this configuration can be carried out racemization, cover under being used for by 4- dimethoxy phenylalanine ester
Batch of preparation.
The method of described racemization preferably includes following steps: in the presence of aldehydes or ketones class catalyst, by above-mentioned mistake
(preferably 2~5 is little within 0.5~24 hour in 0~90 DEG C (preferably 10~90 DEG C, more preferably 40~60 DEG C) reactions to filter the filtrate obtaining
When), you can.
Described aldehydes or ketones class catalyst includes the 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 P-methoxybenzal-dehyde of described aromatic aldehyde, benzaldehyde, paranitrobenzaldehyde,
4-chloro-benzaldehyde or 5- nitrosalicylaldehyde.The preferred acetophenone of described aromatic ketone.The preferred acetaldehyde of aldehyde of described alkanes, propionic aldehyde or different
Propionic aldehyde.The preferred acetone of ketone of described alkanes or butanone.
Described aldehydes or ketones class catalyst, with (+) mol ratio of -3,4- dimethoxy phenylalanine ester be preferably (0.01~
1): 1, more preferably (0.05~0.1): 1.
After the reaction of described racemization terminates, also can further include following steps: reaction system is removed after solvent
The aqueous solution hybrid reaction of the solid obtaining and alkali, controls ph value for 7~8 and temperature is less than 5 DEG C, is extracted with ethyl acetate
Take, you can obtain racemic 3,4- dimethoxy phenylalanine ester.The preferred sodium carbonate of described alkali.
Present invention also offers the system of a kind of racemic 3,4- dimethoxy phenylalanine ester as shown in formula i or its salt
Preparation Method, it comprises the steps: in solvent, in the presence of aldehydes or ketones class catalyst, by 3, the 4- dimethoxy as shown in formula i
Base phenylalanine ester or its salt react 0.5~24 hour (preferably 2 in 0~90 DEG C (preferably 10~90 DEG C, more preferably 40~60 DEG C)
~5 hours), you can;Described 3,4- dimethoxy phenylalanine ester be (+) -3,4- dimethoxy phenylalanine ester, (-) -3,4-
Dimethoxy phenylalanine ester, or (+) -3,4- dimethoxy phenylalanine ester with (-) -3,4- dimethoxy phenylalanine ester
Molar content is not the mixture of enantiomers of 1:1;Described solvent includes alcohols solvent and esters solvent;
R is c1~c6Straight or branched alkane.
In process of racemizing, in r, described c1~c6The preferred methyl of straight or branched alkane or ethyl.
In process of racemizing, the salt of described 3,4- dimethoxy phenylalanine ester can be formed with tartaric acid derivatives for it
Salt, preferably its with (+)-tartaric acid derivatives formed salt.Described tartaric acid derivatives structure is preferably as follows:
Wherein, r ' is to methyl benzoyl, o-methyl-benzene formoxyl, a toluyl, benzoyl or acetyl group.
Described solvent may also include ketones solvent.Described ketones solvent is preferably used in mixed way with esters solvent.Described alcohol
Class solvent, ketones solvent and esters solvent all can contain water.The mixture of the preferred alcohols solvent of described solvent and ketones solvent, ketone
The mixture of the mixture, alcohols solvent and esters solvent of class solvent and aqueous alcohols solvent, or esters solvent with aqueous
Alcohols solvent mixture.The preferred c of described alcohols solvent1~c5Monohydric alcohol.The preferred c of described ketones solvent1~c6Ketone.
The preferred c of described esters solvent1~c5Monoacid and c1~c5Monohydric alcohol formed ester, i.e. (c1~c4)coo(c1~c5).
Described alcohols solvent is preferably (0.1~10) with the volume ratio of esters solvent: 1, more preferably for (0.2~2): 1.
When described solvent is in addition to alcohols solvent and esters solvent, when also including ketones solvent, its volume ratio is preferably ketone
Class solvent: alcohols solvent=(0.1~10): 1.
The ratio of the volume of described solvent and 3,4- dimethoxy phenylalanine ester or its salt quality be preferably 1.0~
25.0ml/1.0g.
Described aldehydes or ketones class catalyst includes the 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 P-methoxybenzal-dehyde of described aromatic aldehyde, benzaldehyde, paranitrobenzaldehyde,
4-chloro-benzaldehyde or 5- nitrosalicylaldehyde.The preferred acetophenone of described aromatic ketone.The preferred acetaldehyde of aldehyde of described alkanes, propionic aldehyde or different
Propionic aldehyde.The preferred acetone of ketone of described alkanes or butanone.
Described aldehydes or ketones class catalyst, with (+) mol ratio of -3,4- dimethoxy phenylalanine ester or its salt is preferably
(0.01~1): 1, more preferably (0.05~0.1): 1.
After the reaction of racemization terminates, also can further include following steps: by obtain after reaction system removing solvent
The aqueous solution hybrid reaction of solid and alkali, controls ph value for 7~8 and temperature is less than 5 DEG C, is extracted with ethyl acetate, you can
Obtain the 3,4- dimethoxy phenylalanine ester of racemization.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 conventional method in this area, is related to
Respectively walk reaction condition and step all can refer to the conventional steps of the such reaction in this area and condition is selected, for example following second
Step reaction refers to document: jpn.kokai tokkyo koho, 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 be combined, and obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are all commercially available.
The positive effect of the present invention is: the preparation method step letter of the levodopa midbody derivant of the present invention
Single, prepared enantiomeric purity is high, cost relatively low it is adaptable to industrialized production.Additionally, the present invention only needs the aldehydes or ketones of catalytic amount,
Just can achieve the racemization of 3,4- dimethoxy phenylalanine ester, 3,4- dimethoxy phenylalanine ester is still deposited in a salt form simultaneously
, the form stable of specific ionization alkali, improve the rate of recovery of 3,4- dimethoxy phenylalanine ester, and easy and simple to handle, decrease
The loss of material, is more suitable for large-scale production.
Specific embodiment
Further illustrate the present invention below by the mode of embodiment, but therefore do not limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1
The method for splitting of (±) -3,4- dimethoxy phenylalanine ethyl ester
By 4.96g (±) -3,4- dimethoxy phenylalanine ethyl ester is dissolved in 30ml ethanol, stirring is lower to be added by 3.56g
(+)-dibenzoyl tartaric acid and the mixed solution of 20ml ethyl acetate composition, after room temperature places 24h, separate out a large amount of solids, mistake
Filter, and the mixed solvent washing with 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 detects optics content 97.2%.
By this salt be placed in aqueous sodium carbonate (consumption of sodium carbonate be 0.5e.q. [(-) -3,4- dimethoxy phenylalanine
Ethyl ester]2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction, ethyl acetate is evaporated off, can
(-) -3,4- dimethoxy phenylalanine ethyl ester.
Embodiment 2
The method for splitting of (±) -3,4- dimethoxy phenylalanine ethyl ester
By 4.96g (±) -3,4- dimethoxy phenylalanine ethyl ester is dissolved in 25ml ethanol, stirring is lower to be added by 3.76g
(+)-dibenzoyl tartaric acid monohydrate and the mixed solution of 25ml ethyl acetate composition, after room temperature places 24h, separate out a large amount of
Solid, filters, and the mixed solvent washing with the ethanol of a little 1:1 and ethyl acetate, dries, obtain 3.1g [(-) -3,4- bis-
Methoxyphenylalanine ethyl ester]2(+)-dibenzoyl tartaric acid.Split chemical yield 36.4%, hplc detects optics content
97.7%.
By this salt be placed in aqueous sodium carbonate (consumption of sodium carbonate be 0.5e.q. [(-) -3,4- dimethoxy phenylalanine
Ethyl ester]2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction, ethyl acetate is evaporated off, can
(-) -3,4- dimethoxy phenylalanine ethyl ester.
Embodiment 3
The method for splitting of (±) -3,4- dimethoxy phenyalanine methyl ester
By 4.96g (±) -3,4- dimethoxy phenyalanine methyl ester is dissolved in 30ml methyl alcohol, stirring is lower to be added by 3.56g
(+)-dibenzoyl tartaric acid and the mixed solution of 15ml ethyl acetate composition, after room temperature places 24h, separate out a large amount of solids, mistake
Filter, and the mixed solvent washing with the methyl alcohol of a little 2:1 and ethyl acetate, dry, obtain 3.38g [(-) -3,4- dimethoxy
Phenyalanine methyl ester]2(+)-dibenzoyl tartaric acid.Split chemical yield 39.7%, hplc detects optics content 97.4%.
By this salt be placed in aqueous sodium carbonate (consumption of sodium carbonate be 0.5e.q. [(-) -3,4- dimethoxy phenylalanine
Methyl esters]2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction, ethyl acetate is evaporated off, can
(-) -3,4- dimethoxy phenyalanine methyl ester.
Embodiment 4
The method for splitting of (±) -3,4- dimethoxy phenyalanine methyl ester
By 4.96g (±) -3,4- dimethoxy phenyalanine methyl ester is dissolved in 30ml methyl alcohol, stirring is lower to be added by 3.76g
(+)-dibenzoyl tartaric acid monohydrate and the mixed solution of 30ml ethyl acetate composition, after room temperature places 24h, separate out a large amount of
Solid, filters, and the mixed solvent washing with the methyl alcohol of a little 1:1 and ethyl acetate, dries, obtain 3.1g [(-) -3,4- bis-
Methoxyphenylalanine methyl esters]2(+)-dibenzoyl tartaric acid.Split chemical yield 36.4%, hplc detects optics content
98.1%.
By this salt be placed in aqueous sodium carbonate (consumption of sodium carbonate be 0.5e.q. [(-) -3,4- dimethoxy phenylalanine
Methyl esters]2(+)-dibenzoyl tartaric acid) in, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction, ethyl acetate is evaporated off, can
(-) -3,4- dimethoxy phenyalanine methyl ester.
Embodiment 5
The racemization of (+) -3,4- dimethoxy phenylalanine ethyl ester
5% 5- nitrosalicylaldehyde (mole percent) is added, at 60 DEG C in the mother liquor being filtrated to get in embodiment 1
Stirring 3h, less than 40 DEG C vacuum rotary steams remove solvent, obtain solid salt, this salt is placed in aqueous sodium carbonate, control ph value
In 7-8, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction racemization (±) -3,4- dimethoxy phenylalanine second
Ester, can cover the fractionation for next group.Yield 96.4%, hplc detects purity 98.3%.
Embodiment 6
The racemization of (+) -3,4- dimethoxy phenyalanine methyl ester
10% 5- nitrosalicylaldehyde (mole percent) is added, at 50 DEG C in the mother liquor being filtrated to get in embodiment 3
Stirring 3h, removes solvent, obtains solid salt, this salt is placed in the aqueous sodium carbonate that 10ml mass percent is 10%, controls
In 7-8, temperature control is less than 5 DEG C to ph value, reaction, with ethyl acetate extraction racemization (±) -3,4- dimethoxy phenylpropyl alcohol ammonia
Sour methyl esters, can cover the fractionation for next group.Yield 96.8%, hplc detects purity 98.1%.
Embodiment 7
The racemization of (+) -3,4- dimethoxy phenyalanine methyl ester
Add 10% benzaldehyde (mole percent) in the mother liquor being filtrated to get in embodiment 4, stir at 60 DEG C
5h, removes solvent, obtains solid salt, this salt is placed in the aqueous sodium carbonate that 10ml mass fraction is 10%, controls ph value to exist
7-8, temperature control is less than 5 DEG C, reaction, with ethyl acetate extraction racemization (±) -3,4- dimethoxy phenyalanine methyl ester,
The fractionation for next group can be covered.Yield 95.6%, hplc detects purity 97.3%.
Embodiment 8
By embodiment 3 prepare (-) -3,4- dimethoxy phenyalanine methyl ester 5g, be dissolved in the first of NaOH
In alcohol and water solution, stir under room temperature, until hydrolysis is completely, adjusts ph value to 5~6 with 8n hcl, have white solid to separate out, mistake
Filter, is dried, obtain (-) -3,4- dimethoxy phenylalanine 4.4g, yield 94%.
Embodiment 9
By embodiment 8 prepare (-) -3,4- dimethoxy phenylalanine 4.4g is dissolved in 30ml48% hydrobromic acid solution
In, it is heated to reflux 12h, concentration of reaction solution, and deionized water band dry hydrogen bromic acid, be subsequently adding 30ml deionized water, use epoxy
Propane adjusts ph value to 5~6, has a large amount of white solids to separate out, obtains levodopa 3.5g, yield 91%.
Claims (12)
1. a kind of preparation method of levodopa midbody derivant, it comprises the steps: in a solvent, will be as shown in formula i
3,4- dimethoxy phenylalanine ester with as shown in formula ii (+)-tartaric acid derivatives react, obtain [(-) -3,4- diformazan
Epoxide phenylalanine ester]2The salt of (+)-tartaric acid derivatives;
Wherein, r is methyl or ethyl;R ' is to methyl benzoyl, o-methyl-benzene formoxyl, a toluyl, benzoyl
Base or acetyl group;Described solvent is that alcoholic solvent is molten with the mixture of aqueous alcoholic solvent, alcohol with the mixture of ketone solvent, ketone solvent
Agent and the mixture of ester solvent, or the mixture of ester solvent and aqueous alcoholic solvent;Described alcoholic solvent is c1~c5Unitary
Alcohol;Described ester solvent is c1~c5Monoacid and c1~c5Monohydric alcohol formed ester;Described ketone solvent is c1~c6Ketone.
2. levodopa midbody derivant as claimed in claim 1 preparation method it is characterised in that: include following walking
Rapid: by the solution of 3,4- dimethoxy phenylalanine ester with (+) the solution hybrid reaction of-tartaric acid derivatives, separate out [(-) -3,
4- dimethoxy phenylalanine ester]2The salt of (+)-tartaric acid derivatives.
3. levodopa midbody derivant as claimed in claim 1 preparation method it is characterised in that: described 3,4- diformazan
Epoxide phenylalanine ester refers to the mixture that its enantiomter is formed, and it is following either case: 1, racemic (±) -3,
4- dimethoxy phenylalanine ester;2nd, (+) -3,4- dimethoxy phenylalanine ester;3rd, contain (-) -3,4- dimethoxy phenylpropyl alcohol
Propylhomoserin ester (+) -3,4- dimethoxy phenylalanine ester;4th, (-) -3,4- dimethoxy phenylalanine ester;
Described (+)-tartaric acid derivatives contain the crystallization water or do not contain the crystallization water, its be (+)-two pairs of toluoyltartaric,
- two pairs of toluoyltartaric monohydrates of (+), (+)-two methyl benzoyl tartaric acid, (+)-two toluyls
Base tartaric acid monohydrate, (+)-two o-methyl-benzene formoxyl tartaric acid, (+)-two o-methyl-benzene formoxyl tartaric acid one are hydrated
Thing, (+)-dibenzoyl tartaric acid, (+)-dibenzoyl tartaric acid monohydrate, (+)-acetyl tartaric acid and (+)-
One or more of acetyl tartaric acid monohydrate.
4. levodopa midbody derivant as claimed in claim 1 preparation method it is characterised in that: described alcoholic solvent with
The volume ratio of ester solvent is (0.1~10): 1;The volume of described solvent and the ratio of 3,4- dimethoxy phenylalanine ester quality
For 1.0~25.0ml/1.0g;Described (+)-tartaric acid derivatives with the mol ratio of described 3,4- dimethoxy phenylalanine ester are
(0.4~0.6): 1.
5. levodopa midbody derivant as claimed in claim 4 preparation method it is characterised in that: described alcoholic solvent with
The volume ratio of ester solvent is (0.2~2): 1;Described (+)-tartaric acid derivatives and described 3,4- dimethoxy phenylalanine ester
Mol ratio is (0.45~0.55): 1.
6. levodopa midbody derivant as claimed in claim 1 preparation method it is characterised in that: the temperature of described reaction
Spend for 0~90 DEG C;The time of described reaction is 0.5~48 hour.
7. levodopa midbody derivant as claimed in claim 6 preparation method it is characterised in that: the temperature of described reaction
Spend for 20~50 DEG C;The time of described reaction is 24 hours.
8. levodopa midbody derivant as claimed in claim 1 preparation method it is characterised in that: described reaction terminates
Afterwards, also through post processing, described post processing comprises the steps: to filter reaction system, washs filter cake, dries;
By in the described filtrate being filtrated to get (+) -3,4- dimethoxy phenylalanine ester carries out racemization;Described racemic
The method changed comprises the steps:, in the presence of aldehydes or ketones catalyst, the described filtrate being filtrated to get to be reacted in 0~90 DEG C
0.5~24 hour, you can.
9. levodopa midbody derivant as claimed in claim 8 preparation method it is characterised in that: described racemization
Method in, the temperature of reaction is 10~90 DEG C;The time of reaction is 2~5 hours.
10. levodopa midbody derivant as claimed in claim 9 preparation method it is characterised in that: described racemic
In the method changed, the temperature of reaction is 40~60 DEG C.
The preparation method of 11. levodopa midbody derivants as claimed in claim 8 it is characterised in that: described aldehydes or ketones
Catalyst is P-methoxybenzal-dehyde, benzaldehyde, paranitrobenzaldehyde, 4-chloro-benzaldehyde, 5- nitrosalicylaldehyde, acetophenone, second
Aldehyde, propionic aldehyde, isopropyl aldehyde, acetone or butanone;
Described aldehydes or ketones catalyst, with (+) mol ratio of -3,4- dimethoxy phenylalanine ester is (0.01~1): 1.
The preparation method of 12. levodopa midbody derivants as claimed in claim 11 it is characterised in that: described aldehydes or ketones
Catalyst, with (+) mol ratio of -3,4- dimethoxy phenylalanine ester is (0.05~0.1): 1.
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