CN110467539A - The method for splitting of one kind 2,6- dimethyltyrosine ester and its application - Google Patents
The method for splitting of one kind 2,6- dimethyltyrosine ester and its application Download PDFInfo
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- CN110467539A CN110467539A CN201910816367.3A CN201910816367A CN110467539A CN 110467539 A CN110467539 A CN 110467539A CN 201910816367 A CN201910816367 A CN 201910816367A CN 110467539 A CN110467539 A CN 110467539A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/36—Racemisation of optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses one kind 2; 6- dimethyl-l-tyrosine preparation method; this method comprises the following steps: by the 2 of racemization; 6- dimethyl-tyrosine ester; then 2 are obtained by Dynamic Kinetic Resolution; 6- dimethyl-l-tyrosine ester double salt, then target product 2,6- dimethyl-l-tyrosine are obtained by deprotection.The features such as present invention is easy to get with raw material, easy to operate, high income has good industrial application and economic value.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, it is related to preparing 2,6- dimethyl-L- with racemization by splitting
The preparation method of tyrosine ester.
Background technique
2,6- dimethyl-l-tyrosine is as a kind of important unnatural amino acid, as people are to polypeptide drug
Further research is widely used in many new polypeptide compounds.
There is the synthesis of 2,6- of different document reports dimethyl-l-tyrosine.Dygos etc. in Synthesis.1992,
741 and Praquin etc. is urged in Org.Process.Res.Dev.2011,1124 etc. different documents using different noble metals
Change and 2,6- dimethyl-l-tyrosine is prepared by asymmetric hydrogenation, these synthetic routes have used expensive noble metal to urge
Agent and relevant ligand, the production cost is very high；In addition, some documents such as Balducci etc. is in Tetrahedron:
Asymmetry.2009,1398 using chiral coordination compound induction building chiral centre, and condition is harsh difficult, so, develop one kind
It is necessary that industrialization, which is easily achieved, simple effective method obtains 2,6- dimethyl-l-tyrosine.
Summary of the invention
The present invention provides the method for splitting of one kind 2,6- dimethyltyrosine ester and its applications, are made using the method for splitting
2,6- dimethyl-l-tyrosine can be obtained with higher yield for committed step, while avoid expensive catalyst and matching
The use of body.
The method for splitting of one kind 2,6- dimethyltyrosine ester, comprising:
In the presence of inorganic acid, resolving agent and racemization agent, Dynamic Kinetic hand is carried out to 2,6- dimethyl-tyrosine ester
Property split, obtain 2,6- dimethyl-l-tyrosine ester double salt；
2,6- dimethyl-tyrosine ester structural formula is as follows:
Wherein, R is selected from C1~C5Alkyl.
In the Dynamic Kinetic chiral resolution process, L isomers 2 in 2,6- dimethyl-tyrosine ester, 6- diformazan
Base-l-tyrosine ester is first precipitated from reaction solution in the form of double salt, 2,6- dimethyl-D- junket ammonia under the action of resolving agent
Acid esters is enriched in mother liquor；Then under the action of racemization agent, racemization occurs for 2,6- dimethyl-D-Tyrosine ester, and part turns
2,6- dimethyl-l-tyrosine ester is turned to, which continues to be precipitated under the action of resolving agent again,
So that total recovery can be more than 50%, the reaction yield of single fractionation is significantly improved.
Preferably, the resolving agent is selected from D- camphorsulfonic acid, L- dibenzoyl tartaric acid, substituted L- aryl formyl
Tartaric acid；
The racemization agent is selected from benzaldehyde or salicylide；
The inorganic acid is hydrochloric acid or sulfuric acid.
Resolving agent and the type of racemization agent can generate large effect to resolution yield, as a further preference, described
Resolving agent be L- dibenzoyl tartaric acid；
The racemization agent is salicylide；
The inorganic acid is sulfuric acid, at this point, single can be made to split yield with higher, meanwhile, obtained product
Purity is high.
Preferably, the Dynamic Kinetic chiral resolution carries out in alcoholic solvent；
The alcoholic solvent is ethyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, one of isobutanol and isooctanol or more
Kind.
Preferably, the alcoholic solvent is isopropanol.
Preferably, the temperature of Dynamic Kinetic chiral resolution is 30-80 degree.
Preferably, the molar ratio of 2,6- dimethyl-tyrosine ester and resolving agent is 1.0:1.0-3.0.As further
It is preferred, in step (2), the molar ratio of 2,6- dimethyl-tyrosine ester and resolving agent is 1.0:1.5.
In the present invention, the inorganic acid and racemization agent and 2,6- dimethyl-tyrosine ester molar ratio are as follows: 0.036:
0.14:1.
The present invention also provides 2,6- of one kind dimethyl-l-tyrosine preparation methods, comprising the following steps:
(1) 2, the 6- dimethyl-tyrosine Yu alcohol of racemization carry out esterification and form 2,6- dimethyl-tyrosine ester；
(2) 2,6- dimethyl-l-tyrosine ester double salt is obtained according to the method；
(3) 2,6- dimethyl-l-tyrosine ester double salt is hydrolyzed, then obtains described 2,6- after post treatment
Dimethyl-l-tyrosine.
The process of the preparation method is as follows:
In step (1), alcohol used is C1~C5Alkylol, further preferably ethyl alcohol.
In step (1), the condition of esterification can be carried out according to the state of the art.
In step (2), the double salt is directly precipitated from reaction system, or a small amount of ammonium hydroxide is added and is precipitated again.
In step (3), the hydrolysis carries out in acid condition.
Compared with the existing technology, the beneficial effects of the present invention are embodied in:
The present invention is by carrying out 2,6- dimethyl-l-tyrosine ester using resolving agent and racemization agent in same system
Dynamic Kinetic chiral resolution, improves resolution yield；Material used by simultaneously is common and cheap, easy to operate, is convenient for work
Industry metaplasia produces.
Specific embodiment
The present invention is further detailed below by specific embodiment, but protection scope of the present invention and is not only limited
In this.
2,6- dimethyltyrosine or its ester in the present invention be not as marked configuration, all referring to 2, the 6- dimethyl junket of racemization
Propylhomoserin or its ester.
Embodiment 1
2,6- dimethyl-tyrosine of 245g racemization is dissolved in 1L ethyl alcohol, 179g thionyl chloride is instilled under low temperature, is added
Heat reflux 2 hours, is concentrated to dryness after reaction.Water is added and methylene chloride is extracted, it is water-soluble with 10% sodium hydroxide
Liquid adjusts pH to 9-10, layering, and water phase extracts once again, washes after merging organic phase, organic phase is concentrated to dryness, and is obtained about
225g2,6- dimethyl-tyrosine ethyl ester.
Embodiment 2
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, is cooled to 30 degree, keep the temperature 1 hour, filter, the isopropanol of solid room temperature washs.The racemization of mother liquor progress next step
Operation, filter cake forced air drying under 50 degree are dried, and 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid salt is obtained
Product, yield 38%, ee value are 96%.
Embodiment 3
By mother liquor obtained in the previous step, methylene chloride and water is added, adjusts pH to 9- with 10% sodium hydrate aqueous solution
10, layering, water phase extracts once again, washes after merging organic phase, and organic phase is concentrated to dryness, and the 1g concentrated sulfuric acid and 5g bigcatkin willow is added
Aldehyde, 300g isopropanol flow back 4 hours.It is concentrated to dryness, retrieves 2,6- dimethyl-tyrosine ethyl ester of racemization.Recycling is received
Rate is 70%.Meanwhile water phase also recycles L- dibenzoyl tartaric acid.
Embodiment 4
2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid salt is added in methylene chloride and water, is used
10% NaOH dissociates layering, and water phase extracts once again, washes after merging organic phase, and organic phase is concentrated to dryness, and 6N hydrochloric acid is added,
Temperature rising reflux hydrolyzes about 5 hours, is concentrated to dryness, obtains 2,6- dimethyl-l-tyrosine hydrochloride, yield 95%.
Embodiment 5
Solvent in embodiment 2 is changed to n-butanol, isobutanol and isooctanol, yield respectively 32%, 34% and 35%,
Ee value is respectively 97%, 96% and 96%.
Embodiment 6
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 7g salicylide is added, continue to stir 20 hours under 50 degree, 2.6g ammonium hydroxide, cooling are added later
To 30 degree, 1 hour is kept the temperature, is filtered, the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, and filter cake exists
50 degree of lower forced air drying drying, obtain 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield is
65%, ee value are 94%.
Embodiment 7
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 7g salicylide is added, continue to stir 20 hours under 50 degree, be cooled to 30 degree, keep the temperature 1 hour,
It filters, the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, and filter cake forced air drying under 50 degree is dried
It is dry, 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield 45% are obtained, ee value is 98%.
Embodiment 8
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 7g salicylide is added, continue to stir 20 hours under 70 degree, 2.6g ammonium hydroxide, cooling are added later
To 30 degree, 1 hour is kept the temperature, is filtered, the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, and filter cake exists
50 degree of lower forced air drying drying, obtain 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield is
42%, ee value are 95%.
Embodiment 9
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 7g salicylide is added, continue to stir 20 hours under 40 degree, 2.6g ammonium hydroxide, cooling are added later
To 30 degree, 1 hour is kept the temperature, is filtered, the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, and filter cake exists
50 degree of lower forced air drying drying, obtain 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield is
41%, ee value are 94%.
Embodiment 10
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 14g salicylide is added, continue to stir 20 hours under 40 degree, 2.6g ammonium hydroxide, drop are added later
Temperature keeps the temperature 1 hour to 30 degree, filters, and the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, filter cake
Forced air drying is dried under 50 degree, obtains 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield
It is 94% for 63%, ee value, but product colour band is red.
Embodiment 11
The L- dibenzoyl tartaric acid of 238g is dissolved in 800g isopropanol, 70 degree is heated to, is slowly dropped into 100g2,
6- dimethyl-tyrosine ethyl ester 300g aqueous isopropanol, is added a small amount of crystal seed, has and is precipitated compared with polycrystal, continues to stir at 70 degree
It mixes 2 hours, 1.5g sulfuric acid and 7g benzaldehyde is added, continue to stir 20 hours under 50 degree, 2.6g ammonium hydroxide, cooling are added later
To 30 degree, 1 hour is kept the temperature, is filtered, the isopropanol of solid room temperature washs.Mother liquor carries out further racemization operation, and filter cake exists
50 degree of lower forced air drying drying, obtain 2,6- dimethyl-l-tyrosine ethyl ester L- dibenzoyl tartaric acid product salt, yield is
40%, ee value are 95%.
Embodiment 12
The L- dibenzoyl tartaric acid in embodiment 2 is replaced with the L-TARTARIC ACID of same molar, other conditions are constant, nothing
Method goes on smoothly crystallization.
Embodiment 13
The L- dibenzoyl tartaric acid in embodiment 2 is replaced with the L- camphorsulfonic acid of same molar, other conditions are constant,
It can not be successfully and carry out crystallization.
Embodiment 14
The L- dibenzoyl tartaric acid in embodiment 2 is replaced with the L MALIC ACID of same molar, other conditions are constant, nothing
Method goes on smoothly crystallization.
Embodiment 15
The L- dibenzoyl tartaric acid in embodiment 2 is replaced with the L- vinylbenzene sulfonic acid of same molar, other conditions are not
Become, can not be successfully carry out crystallization.
Claims (9)
1. one kind 2, the method for splitting of 6- dimethyltyrosine ester characterized by comprising
In the presence of inorganic acid, resolving agent and racemization agent, Dynamic Kinetic chirality is carried out to 2,6- dimethyltyrosine ester and is torn open
Point, obtain 2,6- dimethyl-l-tyrosine ester double salt；
The structural formula of 2, the 6- dimethyltyrosine ester is as follows:
Wherein, R is selected from C1~C5Alkyl.
2. the method for splitting of 2,6- dimethyltyrosine ester according to claim 1, which is characterized in that the resolving agent
Selected from D- camphorsulfonic acid, L- dibenzoyl tartaric acid or substituted L- aryl formyl tartaric acid；
The racemization agent is selected from benzaldehyde or salicylide；
The inorganic acid is hydrochloric acid or sulfuric acid.
3. the method for splitting of 2,6- dimethyltyrosine ester according to claim 2, which is characterized in that the resolving agent
For L- dibenzoyl tartaric acid；
The racemization agent is salicylide；
The inorganic acid is sulfuric acid.
4. the method for splitting of 2,6- dimethyltyrosine ester according to claim 1, which is characterized in that the dynamic is dynamic
Mechanics chiral resolution carries out in alcoholic solvent；
The alcoholic solvent is one or more of ethyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, isobutanol and isooctanol.
5. the method for splitting of 2,6- dimethyltyrosine ester according to claim 4, which is characterized in that the alcoholic solvent
For isopropanol.
6. the method for splitting of 2,6- dimethyltyrosine ester according to claim 1, which is characterized in that Dynamic Kinetic hand
Property split temperature be 30-80 degree.
7. the method for splitting of 2,6- dimethyltyrosine ester according to claim 1, which is characterized in that 2,6- dimethyl junket
The molar ratio of propylhomoserin ester and resolving agent is 1.0:1.0-3.0.
8. the method for splitting of 2,6- dimethyltyrosine ester according to claim 7, which is characterized in that 2,6- dimethyl junket
The molar ratio of propylhomoserin ester and resolving agent is 1.0:1.5.
9. one kind 2,6- dimethyl-l-tyrosine preparation method, which comprises the following steps:
(1) 2,6- dimethyltyrosine react to form 2,6- dimethyltyrosine ester with alcohol；
(2) method according to any one of claims 1 to 8 splits 2,6- dimethyltyrosine ester, obtains 2,6-
Dimethyl-l-tyrosine ester double salt；
(3) 2,6- dimethyl-l-tyrosine ester double salt is hydrolyzed, then obtains 2, the 6- diformazan after post treatment
Base-l-tyrosine.
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