CN109678771A - A kind of preparation method of lutein glycinate and its hydrochloride - Google Patents
A kind of preparation method of lutein glycinate and its hydrochloride Download PDFInfo
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- CN109678771A CN109678771A CN201811624808.1A CN201811624808A CN109678771A CN 109678771 A CN109678771 A CN 109678771A CN 201811624808 A CN201811624808 A CN 201811624808A CN 109678771 A CN109678771 A CN 109678771A
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- lutein
- glycinate
- preparation
- hydrochloride
- hydrochloric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides the preparation methods of a kind of lutein glycinate and its hydrochloride; the preparation method includes following technical characteristic: (1) using lutein and the acylated glycine of N- as raw material; acetone is reaction dissolvent; 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is condensing agent; I-hydroxybenzotriazole is catalyst, and esterification prepares lutein glycinate precursor；(2) lutein glycinate precursor obtains lutein glycinate by group deprotection reaction, and obtains its hydrochloride by hydrochloric acid alcoholic solution.Present invention process route is simple, and yield is higher, and product purity is high, is suitable for large-scale production.
Description
Technical field
The invention belongs to medicine, food and natural products molecular modification technical fields, and in particular to a kind of sweet ammonia of lutein
The preparation method of acid esters and its hydrochloride.
Background technique
Lutein (Lutein) is a kind of important carotenoid, has prevention macula retinae area lesion, enhancing
Immunity, the anti-oxidant functions such as anti-aging, is widely used in the fields such as medicine, food, cosmetics.
From the point of view of actual application, natural carotenol ester is mainly C12-18 aliphatic ester compound, although stable structure,
But since its digestibility is low, assimilation effect is poor.And free xanthophyll has longer conjugated carbon chain structure, on the one hand
Its intramolecular electronics is easy to be stimulated and migrate, and is easy to isomerization and degradation, influences its stability；On the other hand it is not dissolved in
Water is limited in terms of product formulation, and limited preparation formulation limits its scope of application.
The effect of property that how to improve lutein and stability are the more effective important topics for applying lutein, to lutein into
Row molecular modification is come to promote its both effectiveness and stability be a kind of thinking for being easier to reach.For the molecular structure of lutein
Feature can eaily protect unsaturated double-bond and functional hydroxy by esterification.Many researchs have confirmed, special
The lutein ester for determining structure can be converted into free xanthophyll in human body, play the physiological function of lutein.In addition to this, greatly
Part lutein ester also has the stability better than lutein, facilitates the stability of solution lutein in application process and asks
Topic.Many times, obtained lutein ester can also be further converted to salt, help to promote its water solubility, increase product
Preparation formulation.For this purpose, at ester being the hot spot studied at present by lutein molecular modification.
Chinese patent CN100338162C (esterification of lutein) provides lutein and the carboxylic acid with 5 to 12 carbon leads to
The method that over-churning reaction prepares lutein ester.The invention, as catalyst, is needed using inorganic acid, organic acid or metal chloride
Otherwise offset is except the water generated in reaction is to improve reaction yield, nonetheless, the catalyst effect used due to this method itself
Rate is not high, and in the prior art, this method difficulty is competitive.
Chinese patent CN103073471B (a kind of ultrasonic wave added synthetic method of lutein disuccinic acid ester) passes through leaf Huang
Element and succinic anhydride esterification prepare lutein disuccinic acid ester, and the receipts of esterification are improved under conditions of ultrasonic wave added
Rate, obtained ester obtain preferable effect in terms of water-soluble and stability.But succinic acid is improved as acidulant, PH
Agent, flavor substance and antibacterial agent easily cause the gastrointestinal reactions such as nausea,vomiting,diarrhea, loss of appetite, loose stools, a large amount of to absorb
There are certain potential risks for succinic acid, for this purpose, the substance for seeking more giving preferential treatment to the families of the armymen and martyrs property carries out molecular modification to lutein and just seems very
It is significant.
Significantly, since the sweetening agent that can preferably dissolve lutein is few, above technical scheme is in leaf Huang
The stronger methylene chloride of toxic, chloroform or N,N-dimethylformamide (DMF) etc. is mostly used to make in plain esterification greatly
For reaction dissolvent, it be easy to cause product dissolvent residual to be more toxic and is difficult to the problem of removing, it is necessary to according to lutein
Dissolution characteristics selection substitution solvent.
Summary of the invention
Amino acid biofacies content within the organization and nutritive value are got well than succinic acid, and lutein is synthesized with glycine
Lutein glycinate the stability and bioavailability of lutein not only can be improved, people can also be met simultaneously to leaf
The nutritional need of flavine and amino acid.
The purpose of the present invention is aiming at the problems existing in the prior art, utilize the molecular structure of lutein and glycine spy
Point gives full play to lutein and glycine to the nutritive value of human body, provides a kind of lutein glycinate and its hydrochloride
Preparation method, using lutein and the acylated glycine of N- as raw material, acetone is reaction dissolvent, 1- (3- dimethylamino-propyl) -3- second
Base carbodiimide hydrochloride is condensing agent, and I-hydroxybenzotriazole is catalyst, before esterification prepares lutein glycinate
Body, final group is deprotected to obtain lutein glycinate, and obtains its hydrochloride by hydrochloric acid alcoholic solution.Obtained leaf is yellow
Plain glycine ester hydrochloride obtains larger promotion in terms of water-soluble and stability.Present invention process route is simple, yield compared with
Height, product purity is high, is suitable for large-scale production.
The preparation method of lutein glycinate and its hydrochloride of the present invention includes following technical characteristic:
It (1) is raw material with lutein (I) and N- acylated glycine (II, wherein R is acyl group), acetone is reaction dissolvent, 1- (3- bis-
Methylaminopropyl) -3- ethyl-carbodiimide hydrochloride is condensing agent, I-hydroxybenzotriazole is catalyst, under nitrogen protection plus
Heat reflux, esterification prepare lutein glycinate precursor (III)；
(I)
(II)
(III)
(2) lutein glycinate precursor obtains lutein glycinate by group deprotection reaction, and molten by salt acid alcohol
Liquid obtains its hydrochloride (IV).
(IV)
The preparation method of above-mentioned lutein glycinate precursor, it is characterised in that: the N- acylated glycine, lutein, contracting
The dosage of mixture and catalyst is the acylated glycine of N-: lutein: condensing agent: catalyst=2.1-2.2: 1 in molar ratio:
2.2-2.4 : 0.01-0.05。
The preparation method of above-mentioned lutein glycinate precursor, it is characterised in that: the N- is acylated glycine and is preferably
N- acetoglycocoll or N- succinyl glycine.
The preparation method of above-mentioned lutein glycinate, it is characterised in that: group deprotection reaction is mixed in esters and alcohols
It is carried out in bonding solvent, and 20 % sodium hydroxide solution back flow reaction 6-12 h is added and complete.
The preparation method of above-mentioned lutein glycinate, esters solvent are preferably ethyl acetate, and alcohols solvent is preferably second
Alcohol or isopropanol.
The volume ratio of the preparation method of above-mentioned lutein glycinate, esters solvent and alcohols solvent is 1:3-4, and leaf is yellow
The solid-liquid ratio of plain glycinate precursor and the mixed solvent is 0.12-0.15 g/mL.
The preparation method of above-mentioned lutein glycine ester hydrochloride, it is characterised in that: lutein glycinate and salt acid alcohol
The solid-liquid ratio of solution is 0.1-0.15 g/mL, is completed by being stirred to react 1-2 h.
The preparation method of above-mentioned lutein glycine ester hydrochloride, it is characterised in that: the hydrochloric acid alcoholic solution is 20 %
(wt) methanol hydrochloride solution, 20 % (wt) ethanol solution hydrochloride or 20 % (wt) hydrochloric acid aqueous isopropanol.
The present invention have following technical characterstic and the utility model has the advantages that
Compared with prior art, the preferred substance that esterification occurs with lutein of the present invention, used glycine is in group
Biofacies content and nutritive value in knitting is high, free of a burden to the metabolic system of human body, have no adverse effects.
Compared with prior art, the preferred condensing agent and catalyst of esterification of the present invention, used condensing agent and
Catalyst can high efficiency and high-purity prepare lutein glycinate.
Compared with prior art, the preferred dicyandiamide solution of esterification of the present invention, used acetone solvent low boiling point,
Toxic is small, can high-purity prepare lutein glycinate, facilitate solve product problem of solvent residual.
Compared with prior art, prepared lutein glycinate and its hydrochloride can preferably improve the steady of lutein
It is qualitative, preferable promotion is also obtained in terms of product water solubility, provides reliable scheme for the more preferable application of lutein.
Detailed description of the invention
Fig. 1 is Technology Roadmap of the invention, and technology path mainly includes three steps, is respectively: esterification, group
Deprotection reaction and salt-forming reaction.It is described in detail in detail of the invention specific embodiment below.
Specific embodiment
Embodiment 1
The esterification of A.N- acetoglycocoll and lutein
The lutein of l0 g is added into 250 mL flasks, and the acetone ultrasound of 150 mL is added, dissolves lutein sufficiently.Again
It is added 2 g N- acetoglycocolls thereto, 10 g 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 0.05
G I-hydroxybenzotriazole, heating reflux reaction under nitrogen protection, TLC (thin-layer chromatography) observation is until raw material point disappears, esterification
Reaction is completed.Acetone solvent is recycled, l00 mL ethyl acetate is added, adds 100 mL deionized waters, is shaken to wash away wherein
Salt and impurity.Product and water are moved into separatory funnel, is extracted with ethyl acetate, water layer is separated, and use acetic acid
Ethyl ester extracts 3-4 times, discards water layer, merges organic layer, and recycling ethyl acetate obtains 8.78 g of concentrate of kermesinus, yield 67
%。
B. amino deprotection and salt-forming reaction
Concentrate is moved into the round-bottomed flask of 500 mL, 150 mL isopropanols are added, add the hydroxide of 60 mL, 20 %
Sodium solution, 8 h of back flow reaction, natural cooling are added hydrochloric acid/aqueous isopropanol (wt is 20 %) of 60 mL, stir under room temperature
1-2 h is reacted, is cooled to 0 DEG C, crystallization filters, and for several times with ethanol washing, 60 DEG C of vacuum drying obtain lutein glycine
7.03 g of ester hydrochloride, 78 % of yield, HPLC purity are 99 %.
Embodiment 2
The esterification of A.N- succinyl glycine and lutein
The lutein of l0 g is added into 250 mL flasks, and the acetone ultrasound of 150 mL is added, dissolves lutein sufficiently.Again
It is added 6.8 g N- succinyl glycine thereto, 10 g 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride,
0.05 g I-hydroxybenzotriazole, heating reflux reaction under nitrogen protection, TLC (thin-layer chromatography) observation until raw material point disappears,
Esterification is completed.Acetone solvent is recycled, l00 mL ethyl acetate is added, adds 100 mL deionized waters, is shaken to wash away
Salt and impurity therein.Product and water are moved into separatory funnel, is extracted with ethyl acetate, water layer is separated, be used in combination
Ethyl acetate extracts 3-4 times, discards water layer, merges organic layer, and recycling ethyl acetate obtains 8.41 g of concentrate of kermesinus, receives
54 % of rate.
B. amino deprotection and salt-forming reaction
Concentrate is moved into the round-bottomed flask of 500 mL, 150 mL ethyl alcohol are added, the sodium hydroxide for adding 60 mL 20% is molten
Liquid, 12 h of back flow reaction, natural cooling are added hydrochloric acid/ethanol solution (wt is 20 %) of 60 mL, are stirred to react 1- under room temperature
2 h are cooled to 0 DEG C, and crystallization filters, and for several times with ethanol washing, 60 DEG C of vacuum drying obtain lutein glycinate hydrochloric acid
5.9 g of salt, 76 % of yield, HPLC purity are 98 %.
Claims (8)
1. the preparation method of a kind of lutein glycinate and its hydrochloride, including following technical characteristic: (1) with lutein (I)
It is raw material with N- acylated glycine (II, wherein R is acyl group), acetone is reaction dissolvent, 1- (3- dimethylamino-propyl) -3- second
Base carbodiimide hydrochloride is condensing agent, and I-hydroxybenzotriazole is catalyst, is heated to reflux under nitrogen protection, esterification system
Standby lutein glycinate precursor (III)；
(I)
(II)
(III)
(IV)
(2) lutein glycinate precursor (III) obtains lutein glycinate by group deprotection reaction, and passes through hydrochloric acid
Alcoholic solution obtains its hydrochloride (IV).
2. preparation method according to claim 1, it is characterised in that: the N- is acylated glycine, lutein, condensing agent and urges
The dosage of agent is the acylated glycine of N-: lutein: condensing agent: catalyst=2.1-2.2: 1: 2.2-2.4 in molar ratio:
0.01-0.05。
3. preparation method according to claim 2, it is characterised in that: the acylated glycine of the N- is preferably N- acetoglycocoll
Or N- succinyl glycine.
4. preparation method according to claim 1, it is characterised in that: the group deprotection reaction is mixed in esters and alcohols
It is carried out in solvent, and 20 % sodium hydroxide solution back flow reaction 6-12 h is added and complete.
5. the preparation method according to claim 4, the esters solvent is preferably ethyl acetate, and alcohols solvent is preferably
Ethyl alcohol or isopropanol.
6. the volume ratio of preparation method according to claim 5, esters solvent and alcohols solvent is 1: 3-4, lutein
The solid-liquid ratio of glycinate precursor and the mixed solvent is 0.12-0.15 g/mL.
7. preparation method according to claim 1, it is characterised in that: lutein glycinate and the solid-liquid ratio of hydrochloric acid alcoholic solution are
0.1-0.15 g/mL is completed by being stirred to react 1-2 h.
8. preparation method according to claim 7, it is characterised in that: the hydrochloric acid alcoholic solution is that 20 % (wt) hydrochloric acid methanol is molten
Liquid, 20 % (wt) ethanol solution hydrochloride or 20 % (wt) hydrochloric acid aqueous isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811624808.1A CN109678771A (en) | 2018-12-28 | 2018-12-28 | A kind of preparation method of lutein glycinate and its hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811624808.1A CN109678771A (en) | 2018-12-28 | 2018-12-28 | A kind of preparation method of lutein glycinate and its hydrochloride |
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| CN109678771A true CN109678771A (en) | 2019-04-26 |
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ID=66190886
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| CN201811624808.1A Withdrawn CN109678771A (en) | 2018-12-28 | 2018-12-28 | A kind of preparation method of lutein glycinate and its hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111269162A (en) * | 2020-03-31 | 2020-06-12 | 江苏佰岁通源健康管理有限公司 | Compound modified by lutein and more stable and having double functions as well as preparation method and application thereof |
| CN113788867A (en) * | 2021-06-30 | 2021-12-14 | 东北林业大学 | Novel lutein water-soluble derivative and preparation process thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845009A (en) * | 2002-07-29 | 2010-09-29 | 卡达克斯药物公司 | Be used to suppress and improve the structural carotenoid analogs of disease |
-
2018
- 2018-12-28 CN CN201811624808.1A patent/CN109678771A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845009A (en) * | 2002-07-29 | 2010-09-29 | 卡达克斯药物公司 | Be used to suppress and improve the structural carotenoid analogs of disease |
Non-Patent Citations (2)
| Title |
|---|
| TING YANG ET AL.: "Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists", 《ACS MED. CHEM. LETT》 * |
| 田伟生等译: "《有机合成中的副反应-成功合成设计指南》", 31 March 2006, 华东理工大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111269162A (en) * | 2020-03-31 | 2020-06-12 | 江苏佰岁通源健康管理有限公司 | Compound modified by lutein and more stable and having double functions as well as preparation method and application thereof |
| CN113788867A (en) * | 2021-06-30 | 2021-12-14 | 东北林业大学 | Novel lutein water-soluble derivative and preparation process thereof |
| CN113788867B (en) * | 2021-06-30 | 2023-12-26 | 东北林业大学 | Lutein water-soluble derivative and preparation process thereof |
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Application publication date: 20190426 |