CN106977413A - A kind of preparation method of DL L-aminobutanedioic acids DL ornithines - Google Patents
A kind of preparation method of DL L-aminobutanedioic acids DL ornithines Download PDFInfo
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- CN106977413A CN106977413A CN201710239961.1A CN201710239961A CN106977413A CN 106977413 A CN106977413 A CN 106977413A CN 201710239961 A CN201710239961 A CN 201710239961A CN 106977413 A CN106977413 A CN 106977413A
- Authority
- CN
- China
- Prior art keywords
- preparation
- ornithines
- aminobutanedioic
- racemization
- solvent
- 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.)
- Granted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000002253 acid Substances 0.000 title claims description 12
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical class N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 title abstract 4
- 150000007513 acids Chemical class 0.000 title 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 39
- 230000006340 racemization Effects 0.000 claims abstract description 21
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims abstract description 18
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 16
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000012296 anti-solvent Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 3
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 14
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 14
- 229960005261 aspartic acid Drugs 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- -1 acids DL- ornithines Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 abstract 2
- 235000003704 aspartic acid Nutrition 0.000 abstract 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 abstract 2
- 229960003104 ornithine Drugs 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of method for preparing raceme aspartic acid ornithine.The preparation method comprises the following steps：(1) using acetic acid aqueous solution as solvent, under catalyst action racemization occurs for L L-aminobutanedioic acid L ornithine salts, obtains racemization liquid；(2) anti-solvent is added into racemization liquid, crystallization is filtered, and drying is produced.The preparation method raw material that the present invention is provided is easy to get, and easy to operate, it is easy to control, preparation process is reliable and stable, is adapted to large-scale production raceme aspartic acid ornithine sample.
Description
Technical field
The present invention relates to a kind of preparation method of DL- L-aminobutanedioic acids DL- ornithines, belong to technology of pharmaceutical engineering field.
Background technology
DL- L-aminobutanedioic acid DL- ornithines are chiralitys that may be present in L-ASPARTIC ACID L-Orn bulk drug and preparation
Impurity.Its structural formula is as follows：
Although being entered with the method for specific rotation to chiral problem in compound in L-ASPARTIC ACID L-Orn quality standard
Go certain control, but the content of the wherein chiral isomer of the proof without standard measure.
In order to accurately detect the content of chiral photo-isomerisation in L-ASPARTIC ACID L-Orn bulk drug and preparation, so that it is guaranteed that L-
The quality of L-aminobutanedioic acid L-Orn, it is necessary to high-purity DL- L-aminobutanedioic acid DL- ornithines as detection working reference substance.
The content of the invention
It is an object of the invention to provide a kind of preparation method of DL- L-aminobutanedioic acids DL- ornithines, gained DL- L-aminobutanedioic acids
DL- ornithines are used for the detection of chiral isomer content in L-ASPARTIC ACID L-Orn bulk drug and preparation.The present invention is provided
Preparation method raw material be easy to get, easy to operate, it is easy to control, gained raceme DL- L-aminobutanedioic acid DL- ornithines purity is high, production
Rate is higher, is adapted to large-scale production and prepares.
To achieve these goals, it is described the invention provides a kind of preparation method of DL- L-aminobutanedioic acids DL- ornithines
Method comprises the following steps：
(1) using acetic acid aqueous solution as solvent, under catalyst action racemization occurs for L-ASPARTIC ACID L-Orn salt,
Obtain racemization liquid；
(2) anti-solvent is added into racemization liquid, crystallization is filtered, and drying is produced.
The reaction mechanism mechanism of reaction of the racemization is as follows：
In the step (1), the mass concentration of the acetic acid aqueous solution is 40~60%；The addition of the acetic acid aqueous solution
Measure as 4~7 times of L-ASPARTIC ACID L-Orn salt quality, preferably 5~6 times.
In the step (1), the catalyst is selected from salicylide or benzaldehyde；The consumption of the catalyst is L- winter ammonia
The 5~10% of sour L-Orn salt quality, preferably 8~10%, to ensure to obtain preferable racemization effect.
In the step (1), the temperature control of the racemization is between 60~80 DEG C, preferably between 70~80 DEG C
And 3~4h of stirring.
In the step (2), one or more of the anti-solvent in methanol, ethanol, isopropanol.The anti-solvent
Mass ratio with acetic acid aqueous solution is (0.8~1):1, preferably (0.9~1)：1, more preferably 1:1；Selection is suitable anti-
Solvent and consumption can not only ensure that gained crystalline particle is dimensioned for, it is easy to filter, and ensure that product yield.
In the step (2), the anti-solvent need to be added in racemization liquid in dropwise addition mode, and time for adding should be controlled 1
~4h, preferably 2~3h, and ensure that temperature control is at 45~65 DEG C during being added dropwise, preferably 50~60 DEG C；So be conducive to crystalline substance
The growth of body and slow precipitation, so as to obtain that purity is higher and larger-size crystal, are conducive to subsequent filter to handle.
In the step (2), after the crystallization terminates, system is cooled to 20~40 DEG C, preferably 30~35 DEG C, with simultaneous
Turn round and look at production efficiency and product quality.
In the step (2), the drying uses vacuum drying mode, and temperature control is between 40~60 DEG C, and preferably 45
~50 DEG C, drying time is 4~8h, and preferably 6h, vacuum is -0.08~-0.1MPa.
As the preferred embodiment of the present invention, the preparation method of the DL- L-aminobutanedioic acids DL- ornithines includes following step
Suddenly：
(1) L-ASPARTIC ACID L-Orn salt is added in acetic acid aqueous solution and dissolves complete, add catalyst, heating exists
Racemization is carried out between 60~80 DEG C, racemization liquid is obtained；
(2) under heat-retaining condition, temperature control is at 45~65 DEG C during anti-solvent, dropwise addition are added dropwise into racemization liquid, simultaneously
2~4h of insulated and stirred after a large amount of crystal, completion of dropping is separated out, 20~40 DEG C of crystallizations is cooled to, solid is filtered to obtain, in 40~60 DEG C
Vacuum drying is carried out, is produced.
The preparation method raw material that the present invention is provided is easy to get, easy to operate, it is easy to control, gained raceme DL- L-aminobutanedioic acids
DL- ornithines purity is high, and yield is higher, is adapted to large-scale production and prepares.
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.
Embodiment 1：The preparation of DL- L-aminobutanedioic acid DL- ornithines
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 500g acetic acid aqueous solutions (50% concentration), stirred
Dissolving is complete, and salicylide 10g is added into above-mentioned solution, is heated to 70 DEG C of stirring 3.5h；
2) by step 1) 50~60 DEG C of resulting solution insulation, methanol 500g is added dropwise, time for adding is 2.5h, during dropwise addition
Crystal is gradually separated out, completion of dropping insulated and stirred 4h growing the grains are cooled to 30 DEG C, filter to obtain solid, 45 DEG C of drying 6h of vacuum must consolidate
Body 86.7g.Yield 86.7%, purity 99.7%.
This product is taken, it is accurately weighed, the solution containing 80mg in every 1ml is made, the temperature of test liquid should be 20 DEG C ± 0.5 DEG C,
It is 0 ° that detection, which calculates specific rotatory power,.
Embodiment 2：The preparation of DL- L-aminobutanedioic acid DL- ornithines
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 600g acetic acid aqueous solutions (40% concentration), stirred
Dissolving is complete, and salicylide 8g is added into above-mentioned solution, is heated to 70 DEG C of stirring 4h；
2) by step 1) 50 DEG C of dropwise addition methanol 500g of resulting solution insulation, time for adding is 2h, is gradually analysed during dropwise addition
Go out crystal, completion of dropping insulated and stirred 3h growing the grains are cooled to 35 DEG C, filter to obtain solid, 50 DEG C of drying 6h of vacuum obtain solid
82.4g.Yield 82.4%, purity 99.6%.
This product is taken, it is accurately weighed, the solution containing 80mg in every 1ml is made, the temperature of test liquid should be 20 DEG C ± 0.5 DEG C,
It is 0 ° that detection, which calculates specific rotatory power,.
Embodiment 3：The preparation of DL- L-aminobutanedioic acid DL- ornithines
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 500g acetic acid aqueous solutions (50% concentration), stirred
Dissolving is complete, and salicylide 10g is added into above-mentioned solution, is heated to 65 DEG C of stirring 3.5h；
2) by step 1) 50~60 DEG C of dropwise addition ethanol 400g of resulting solution insulation, time for adding is 2.5h, during dropwise addition
Crystal is gradually separated out, completion of dropping insulated and stirred 4h growing the grains are cooled to 30 DEG C, filter to obtain solid, 45 DEG C of drying 6h of vacuum must consolidate
Body 84.7g.Yield 84.7%, purity 99.6%.
This product is taken, it is accurately weighed, the solution containing 80mg in every 1ml is made, the temperature of test liquid should be 20 DEG C ± 0.5 DEG C,
It is 0 ° that detection, which calculates specific rotatory power,.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of preparation method of DL- L-aminobutanedioic acids DL- ornithines, it is characterised in that comprise the following steps：
(1) using acetic acid aqueous solution as solvent, under catalyst action racemization occurs for L-ASPARTIC ACID L-Orn salt, obtains
Racemization liquid；
(2) anti-solvent is added into racemization liquid, crystallization is filtered, and drying is produced.
2. the preparation method of DL- L-aminobutanedioic acids DL- ornithines according to claim 1, it is characterised in that in step (1),
The mass concentration of the acetic acid aqueous solution is 40~60%；The addition of the acetic acid aqueous solution is L-ASPARTIC ACID L-Orn
4~7 times of salt quality, preferably 5~6 times.
3. the preparation method of DL- L-aminobutanedioic acids DL- ornithines according to claim 1 or 2, it is characterised in that step (1)
In, the catalyst is selected from salicylide or benzaldehyde.
4. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-3, it is characterised in that step
(1) in, the consumption of the catalyst is 5~10%, preferably the 8~10% of L-ASPARTIC ACID L-Orn salt quality.
5. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-4, it is characterised in that step
(1) in, the temperature control of the racemization is between 60~80 DEG C, preferably between 70~80 DEG C.
6. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-5, it is characterised in that step
(2) in, one or more of the anti-solvent in methanol, ethanol, isopropanol.
7. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-6, it is characterised in that step
(2) in, the anti-solvent need to be added in racemization liquid in dropwise addition mode, and be added dropwise during temperature control at 45~65 DEG C,
It is preferred that 50~60 DEG C.
8. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-7, it is characterised in that step
(2) in, after the crystallization terminates, system is cooled to 20~40 DEG C of crystallizations, preferably 30~35 DEG C.
9. according to the preparation method of any described DL- L-aminobutanedioic acid DL- ornithines of claim 1-8, it is characterised in that step
(2) in, it is described drying use vacuum drying mode, temperature control is between 40~60 DEG C, preferably 45~50 DEG C, vacuum for-
0.08~-0.1MPa.
10. the preparation method of DL- L-aminobutanedioic acids DL- ornithines according to claim 1, it is characterised in that including as follows
Step：
(1) L-ASPARTIC ACID L-Orn salt is added in acetic acid aqueous solution and dissolves complete, add catalyst, heating 60~
Racemization is carried out between 80 DEG C, racemization liquid is obtained；
(2) under heat-retaining condition, temperature control is separated out simultaneously at 45~65 DEG C during anti-solvent, dropwise addition are added dropwise into racemization liquid
2~4h of insulated and stirred after a large amount of crystal, completion of dropping, is cooled to 20~40 DEG C of crystallizations, filters to obtain solid, in 40~60 DEG C of progress
Vacuum drying, is produced.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710239961.1A CN106977413B (en) | 2017-04-13 | 2017-04-13 | A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710239961.1A CN106977413B (en) | 2017-04-13 | 2017-04-13 | A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106977413A true CN106977413A (en) | 2017-07-25 |
| CN106977413B CN106977413B (en) | 2019-03-05 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2851482A (en) * | 1957-05-20 | 1958-09-09 | Gen Mills Inc | L-arginine-l-glutamate |
| CN101284796A (en) * | 2008-05-30 | 2008-10-15 | 何关昌 | Process for preparing DL-phenylalanine and DL-asparaginic acid by mother liquor reclamation |
-
2017
- 2017-04-13 CN CN201710239961.1A patent/CN106977413B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2851482A (en) * | 1957-05-20 | 1958-09-09 | Gen Mills Inc | L-arginine-l-glutamate |
| CN101284796A (en) * | 2008-05-30 | 2008-10-15 | 何关昌 | Process for preparing DL-phenylalanine and DL-asparaginic acid by mother liquor reclamation |
Non-Patent Citations (2)
| Title |
|---|
| 刘莉等: ""化学酶法制备D-鸟氨酸盐酸盐"", 《安徽农业科学》 * |
| 郑岚等: ""药用氨基酸复合盐的合成研究"", 《化学试剂》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
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| Publication number | Publication date |
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| CN106977413B (en) | 2019-03-05 |
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