CN105566141B - A kind of preparation method of L-aminobutanedioic acid condensation product - Google Patents
A kind of preparation method of L-aminobutanedioic acid condensation product Download PDFInfo
- Publication number
- CN105566141B CN105566141B CN201510965114.4A CN201510965114A CN105566141B CN 105566141 B CN105566141 B CN 105566141B CN 201510965114 A CN201510965114 A CN 201510965114A CN 105566141 B CN105566141 B CN 105566141B
- Authority
- CN
- China
- Prior art keywords
- condensation product
- aminobutanedioic acid
- preparation
- aminobutanedioic
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to technical field of organic synthesis, more particularly to a kind of preparation method of L-aminobutanedioic acid condensation product, the preparation method to comprise the following steps：(1) with alcohol esterification occurs for L-aminobutanedioic acid, obtains L-aminobutanedioic acid diester；(2) benzyl ester of Boc L aspartic acids 1 is reacted with L-aminobutanedioic acid diester, obtains condensation product；(3) condensation product is hydrolyzed, produces the L-aminobutanedioic acid condensation product.The present invention is using L-aminobutanedioic acid and the benzyl ester of Boc L aspartic acids 1 as raw material, through being esterified, being condensed, hydrolyzing, isolating and purifying to obtain the L-aminobutanedioic acid condensation product of high-purity.The preparation method is adapted to more large batch of preparation in laboratory, good impurity removing effect in purge process.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of preparation method of L-aminobutanedioic acid condensation product.
Background technology
Aspartic acid ornithine is mainly used in treatment because of acute and chronic hepatopathy (such as various hepatitis, hepatic sclerosis, fatty liver, hepatitis
Syndrome afterwards) trigger blood ammonia rise and hepatic encephalopathy.L-aminobutanedioic acid condensation product is aspartic acid ornithine bulk drug and preparation
In major impurity, and mention in aspartic acid ornithine exposure draft and to need to study the impurity with control.Door winter ammonia
The chemical name of sour condensation product：2- [(3- amino -3- pyruvic alcohols base) amino] succinic acid), structural formula is as follows：
The impurity market price is high and is difficult to ensure card product purity, is unfavorable for daily production detection and uses.For accurate detection
The content of L-aminobutanedioic acid condensation product impurity in aspartic acid ornithine bulk drug and preparation, need the L-aminobutanedioic acid condensation product of high-purity
As reference substance.Present invention process can stablize the L-aminobutanedioic acid condensation product of output high-purity steady quality, for L-aminobutanedioic acid
The control of the production process and quality of ornithine bulk drug and preparation has very high application value.
According to the synthetic method that the impurity is not yet found in the document retrieved at present.
The content of the invention
The purpose of the present invention is for shortcomings and deficiencies present in prior art, there is provided a kind of L-aminobutanedioic acid condensation product
Preparation method, the preparation method comprise the following steps：
(1) with alcohol esterification occurs for L-aminobutanedioic acid, obtains L-aminobutanedioic acid diester；
(2) Boc-L- aspartic acids -1- benzyl esters are reacted with L-aminobutanedioic acid diester, obtain condensation product；
(3) condensation product is hydrolyzed, produces the L-aminobutanedioic acid condensation product.
Wherein, the concrete operations of step (1) are：Absolute alcohol is added into L-aminobutanedioic acid, under the conditions of -20 DEG C~-10 DEG C,
Thionyl chloride is added dropwise, after completion of dropwise addition, reacts at room temperature, concentration of reaction solution after reacting completely, obtains containing the L-aminobutanedioic acid two
The grease of ester.
The alcohol is the one or more in methanol, ethanol, preferably methanol.
The volume mass of the absolute alcohol and L-aminobutanedioic acid is than being preferably (15-25)：1, more preferably 20:1(mL：
g)。
The mol ratio of the L-aminobutanedioic acid and thionyl chloride is preferably 1：(3.5~5).
Wherein, the concrete operations of step (2) are：Add solvent and dissolve the Boc-L- aspartic acids -1- benzyl esters, and to its
Interior to add 1,1 '-carbonyl dimidazoles and the grease of the L-aminobutanedioic acid diester or the diester containing L-aminobutanedioic acid react in 45-55 DEG C,
Concentration of reaction solution after reaction completely, produces the oily solid mixture containing the condensation product.
The solvent is the one or more in anhydrous tetrahydro furan, 2- methyltetrahydrofurans, preferably tetrahydrofuran.
Boc-L- aspartic acids -1- the benzyl esters and the mol ratio of 1,1 '-carbonyl dimidazoles are preferably 1：(1-2), enters one
Step is preferably 1:1.
Boc-L- aspartic acids -1- the benzyl esters and the mol ratio of the L-aminobutanedioic acid diester are preferably 1：(1~3), enters
One step is preferably 1：(2~3).
Wherein, the concrete operations of step (3) are：To the condensation product or in the oily solid mixture containing the condensation product
Acid solution and organic solvent are added, reaction is hydrolyzed under room temperature condition, after reaction completely, the pH value for adjusting reaction solution is 7~8,
Divide and remove organic solvent layer, concentration water layer produces the L-aminobutanedioic acid condensation product.
The organic solvent is the one or more in ethyl acetate, butyl acetate, preferably ethyl acetate；
The acid solution is hydrochloric acid solution.
The invention provides a kind of preparation method of preferable L-aminobutanedioic acid condensation product, its reaction mechanism mechanism of reaction is：
(1) esterification
(2) condensation reaction
(3) hydrolysis
Specifically operation is for it：
(1) absolute methanol is added into L-aminobutanedioic acid, under the conditions of -20 DEG C~-10 DEG C, thionyl chloride is added dropwise, knot is added dropwise
Shu Hou, react at room temperature, concentration of reaction solution after reacting completely, obtain the grease of the dimethyl ester containing L-aminobutanedioic acid；
(2) tetrahydrofuran dissolving Boc-L- aspartic acid -1- benzyl esters are added, and 1 is added into it, 1 '-carbonyl dimidazoles
Grease with the diester containing L-aminobutanedioic acid concentration of reaction solution after reacting completely, produces the oil containing condensation product in 45-55 DEG C of reaction
Solid mixture；
(3) hydrochloric acid and ethyl acetate are added into the oily solid mixture containing condensation product, is hydrolyzed under room temperature condition anti-
Should, after reaction completely, the pH value for adjusting reaction solution is 7~8, divides and removes ethyl acetate layer, and concentration water layer produces L-aminobutanedioic acid condensation
Thing.
Invention also provides the method purified using column chromatography to the L-aminobutanedioic acid condensation product, the purification
Concrete operations be：Using silica gel as stationary phase, using methanol and dichloromethane mixed liquor as eluent, collecting makes what ninhydrin developed the color
Efflux, concentration, concentrate is added in petroleum ether, it is the L-aminobutanedioic acid condensation product to separate out solid.
The volume ratio of methanol and dichloromethane is preferably 1 in the eluent:1.
The present invention using L-aminobutanedioic acid and Boc-L- aspartic acid -1- benzyl esters as raw material, through be esterified, be condensed, hydrolyze, separate it is pure
Change obtains the L-aminobutanedioic acid condensation product of high-purity.The preparation method is adapted to more large batch of preparation in laboratory, in purge process
Good impurity removing effect.
Brief description of the drawings
Fig. 1 is the HPLC spectrograms for the L-aminobutanedioic acid condensation product that embodiment 1 is prepared.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.Unless otherwise specified, embodiment
In the conventional meanses that are well known to those skilled in the art of used technological means, raw materials used is commercial goods.
The synthesis of the L-aminobutanedioic acid dimethyl ester of embodiment 1
L-aminobutanedioic acid 20g is taken to add absolute methanol 400ml as raw material, stir, at outer -20 DEG C of the temperature of ice bath, chlorination is added dropwise
Sulfoxide 80g, 30min are added dropwise, and solid gradually dissolves during dropwise addition, insulation reaction 1h, then heat to room temperature, continue anti-
Answer 12h.60 DEG C are concentrated in vacuo reaction solutions to dry, add the dissolving of 200ml methanol, then 60 DEG C are concentrated in vacuo to dry, obtain the ammonia of winter containing door
The grease 25g of dimethyl phthalate.
The synthesis of the L-aminobutanedioic acid dimethyl ester of embodiment 2
L-aminobutanedioic acid 20g is taken to add absolute methanol 300ml as raw material, stir, at outer -20 DEG C of the temperature of ice bath, chlorination is added dropwise
Sulfoxide 70g, 25min are added dropwise, and solid gradually dissolves during dropwise addition, insulation reaction 1h, then heat to room temperature, continue anti-
Answer 12h.60 DEG C are concentrated in vacuo reaction solutions to dry, add the dissolving of 200ml methanol, then 60 DEG C are concentrated in vacuo to dry, obtain the ammonia of winter containing door
The grease 24.2g of dimethyl phthalate.
The synthesis of the condensation product of embodiment 3
Boc-L- aspartic acid -1- benzyl ester 10g are weighed, anhydrous tetrahydro furan 100ml is added and dissolving is stirred at room temperature, add
CDI 5g (1,1 '-carbonyl dimidazoles), 55 DEG C of reaction 1h, the gained grease 12.8g of embodiment 1 is added, 50 DEG C are continued to react 2h,
50 DEG C of reaction solutions that are concentrated under reduced pressure have solid precipitation, obtain the oily solid mixture containing condensation product to doing.
The synthesis of the condensation product of embodiment 4
Boc-L- aspartic acid -1- benzyl ester 10g are weighed, anhydrous tetrahydro furan 100ml is added and dissolving is stirred at room temperature, add
CDI 5g (1,1 '-carbonyl dimidazoles), 50 DEG C of reaction 1h, the gained grease 12.8g of embodiment 1 is added, 50 DEG C are continued to react 2h,
50 DEG C of reaction solutions that are concentrated under reduced pressure have solid precipitation, obtain the oily solid mixture containing condensation product to doing.
The synthesis of the L-aminobutanedioic acid condensation product of embodiment 5
The oily solid mixture of gained in embodiment 3 is added in 250ml three-necked flasks, adds the salt of 200ml mixed solvents 10%
Acid and ethyl acetate (v：V=1:2) 40min, is stirred at room temperature.Reaction finishes, and adds 10% ammoniacal liquor regulation pH to 7~8, point
Liquid, divide and remove organic ethyl acetate layer, 50 DEG C of water layer is concentrated under reduced pressure into 30ml, produces L-aminobutanedioic acid condensation product crude product.
The purification of the L-aminobutanedioic acid condensation product crude product of embodiment 6
Post is filled using 200 mesh silica gel, using methanol：Dichloromethane 1:1 is used as eluent, and hydrolysate upper prop uses
Ninhydrin developer (ninhydrin 1g to 50ml acetone solns), collects color product, and gained collection liquid is concentrated under reduced pressure into 50 DEG C
20ml, take out, be slowly added dropwise at room temperature in 50ml petroleum ethers, there is white solid generation, stirring 30min is added dropwise, filters,
Gained solid 40 DEG C of 8h that are concentrated under reduced pressure in vacuum drying chamber, obtain sticky crystalline solid 5.2g.HPLC contents 98.89%.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (4)
1. a kind of preparation method of L-aminobutanedioic acid condensation product, the chemical name of the L-aminobutanedioic acid condensation product：2- [(3- amino -3- carboxylics
Benzylacetone base) amino] succinic acid, it is characterised in that the preparation method comprises the following steps：
1) absolute methanol is added into L-aminobutanedioic acid, under the conditions of -20 DEG C~-10 DEG C, thionyl chloride is added dropwise, after completion of dropwise addition,
React at room temperature, concentration of reaction solution after reacting completely, obtain the grease of the dimethyl ester containing L-aminobutanedioic acid；
2) tetrahydrofuran dissolving Boc-L- aspartic acid -1- benzyl esters are added, and to its interior addition 1,1 '-carbonyl dimidazoles and containing door
The grease of winter propylhomoserin dimethyl ester concentration of reaction solution after reacting completely, produces the oil containing condensation product and mixed admittedly in 45-55 DEG C of reaction
Compound；
3) hydrochloric acid and ethyl acetate are added into the oily solid mixture containing condensation product, reaction is hydrolyzed under room temperature condition, instead
After answering completely, the pH value for adjusting reaction solution is 7~8, divides and removes ethyl acetate layer, and concentration water layer produces L-aminobutanedioic acid condensation product；
The L-aminobutanedioic acid condensation product is purified using column chromatography, the concrete operations of the purification are：Using silica gel as fixation
Phase, using methanol and dichloromethane mixed liquor as eluent, the efflux for making ninhydrin develop the color is collected, concentration, concentrate is added
In petroleum ether, it is the L-aminobutanedioic acid condensation product to separate out solid.
2. preparation method according to claim 1, it is characterised in that：The volume mass of the absolute methanol and L-aminobutanedioic acid
Than for 20：1；
And/or the mol ratio of the L-aminobutanedioic acid and thionyl chloride is 1：(3.5~5).
3. preparation method according to claim 2, it is characterised in that：
Boc-L- aspartic acids -1- the benzyl esters and the mol ratio of 1,1 '-carbonyl dimidazoles are 1：(1-2)；
And/or the Boc-L- aspartic acids -1- benzyl esters and the mol ratio of the L-aminobutanedioic acid dimethyl ester are 1：(1~3).
4. preparation method according to claim 1, it is characterised in that：The volume ratio of the methanol and dichloromethane is 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510965114.4A CN105566141B (en) | 2015-12-17 | 2015-12-17 | A kind of preparation method of L-aminobutanedioic acid condensation product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510965114.4A CN105566141B (en) | 2015-12-17 | 2015-12-17 | A kind of preparation method of L-aminobutanedioic acid condensation product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105566141A CN105566141A (en) | 2016-05-11 |
| CN105566141B true CN105566141B (en) | 2018-01-26 |
Family
ID=55876848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510965114.4A Active CN105566141B (en) | 2015-12-17 | 2015-12-17 | A kind of preparation method of L-aminobutanedioic acid condensation product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566141B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108264538B (en) * | 2017-01-04 | 2023-08-29 | 辽宁药联制药有限公司 | Solid Phase Synthesis Method of Aspartic Acid Condensate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7544833B2 (en) * | 2006-09-07 | 2009-06-09 | Hoffmann-La Roche Inc. | Methods for producing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid |
| JP2010275229A (en) * | 2009-05-28 | 2010-12-09 | Ikutoku Gakuen | Hydantoin derivative |
| CN103570601B (en) * | 2012-07-20 | 2016-03-30 | 重庆博腾制药科技股份有限公司 | A kind of preparation method of optical active medicine intermediate |
| CN104211756B (en) * | 2013-06-05 | 2017-03-01 | 首都医科大学 | 2 amino 1,3 propanediol derivative, its preparation, nanostructured, Plumbum removing activity and application |
-
2015
- 2015-12-17 CN CN201510965114.4A patent/CN105566141B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses;Mizuho Hasegawa等;《JOURNAL OF BIOLOGICAL CHEMISTRY》;20070420;第282卷(第16期);第11757-11764页 * |
| Enantioselective synthesis of α-alkenyl α-amino acids via N–H insertion reactions;Jun-Xia Guo等;《Chem.Sci.》;20151028;第7卷;第1104-1108页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105566141A (en) | 2016-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10322996B2 (en) | Method for producing N-retinoylcysteic acid alkyl ester | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN106256825A (en) | The synthetic method of his Wei of Dacca | |
| CN112010770A (en) | Novel production method of glycine ethyl ester hydrochloride | |
| CN105566141B (en) | A kind of preparation method of L-aminobutanedioic acid condensation product | |
| CN106748843A (en) | A kind of preparation method of levocarnitine | |
| RU2708243C1 (en) | Method of producing a phenylalanine compound | |
| CN111943862A (en) | Preparation method of heart failure resistant drug Entresto key component Shakuba koji | |
| CN110041300A (en) | A kind of pharmaceutical intermediate compound and its synthetic method | |
| CN102010345A (en) | Method for preparing D-phenylalanine through dynamic kinetic resolution | |
| CN105294428B (en) | 2-adamantanecarboxylic acid and 1-adamantane methanol separation and purification method | |
| CN109096098B (en) | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid | |
| CN105906583B (en) | A kind of preparation technology of repaglinide intermediate | |
| CN106397239A (en) | Amino acid ester cationic chiral ionic liquid and preparation method thereof | |
| CN108383754B (en) | Preparation method and application of aryl oxime ester compound | |
| CN111333529A (en) | Preparation method of pregabalin | |
| CN111393426A (en) | Rivaroxaban thiophene carboxylate impurity reference substance and preparation method thereof | |
| CN110256492A (en) | One kind compound containing phosphine carboxylic acid and preparation method thereof | |
| CN109438243A (en) | A kind of preparation method of electronic grade gallic acid monooctyl ester | |
| CN115385789B (en) | Synthesis method of methyl 4-oxo-butyrate | |
| CN103709092B (en) | The preparation method of Mitiglinide Calcium | |
| CN114133421B (en) | Preparation method of beta-mouse cholic acid | |
| JP4255296B2 (en) | Method for producing cyclic fluorinated alcohol | |
| JP2006104172A (en) | Novel 1-alkylcyclohexyl (meth)acrylate compounds | |
| CN110305083B (en) | Process for preparing 5-chloromethyl furfural from fructose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |