CN106977413B - A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine - Google Patents
A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine Download PDFInfo
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- CN106977413B CN106977413B CN201710239961.1A CN201710239961A CN106977413B CN 106977413 B CN106977413 B CN 106977413B CN 201710239961 A CN201710239961 A CN 201710239961A CN 106977413 B CN106977413 B CN 106977413B
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- Prior art keywords
- preparation
- acid
- ornithine
- aminobutanedioic
- racemization
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- AHLPHDHHMVZTML-UHFFFAOYSA-N Ornithine Chemical compound NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 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 20
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 19
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 19
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims abstract description 17
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 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 10
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000007792 addition Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 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
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 abstract 2
- 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
- 238000001514 detection method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000013558 reference 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
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- 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 methods for preparing raceme aspartic acid ornithine.The preparation method comprises the following steps: (1) using acetic acid aqueous solution as solvent, racemization occurs under the action of catalyst for L-ASPARTIC ACID L-Orn salt, obtains racemization liquid；(2) be added anti-solvent into racemization liquid, crystallization, filtering, drying to get.Preparation method raw material provided by the invention is easy to get, easy to operate, and easily controllable, preparation process is reliable and stable, is suitble to large-scale production raceme aspartic acid ornithine sample.
Description
Technical field
The present invention relates to a kind of preparation methods of DL- L-aminobutanedioic acid DL- ornithine, belong to technology of pharmaceutical engineering field.
Background technique
DL- L-aminobutanedioic acid DL- ornithine is chirality that may be present in L-ASPARTIC ACID L-Orn bulk pharmaceutical chemicals and preparation
Impurity.Its structural formula is as follows:
Although used in L-ASPARTIC ACID L-Orn quality standard the method for specific rotation to problem chiral in compound into
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 pharmaceutical chemicals and preparation, so that it is guaranteed that L-
The quality of L-aminobutanedioic acid L-Orn needs the DL- L-aminobutanedioic acid DL- ornithine of high-purity as the working reference substance of detection.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine, gained DL- L-aminobutanedioic acids
Detection of the DL- ornithine for chiral isomer content in L-ASPARTIC ACID L-Orn bulk pharmaceutical chemicals and preparation.The present invention provides
Preparation method raw material be easy to get, easy to operate, easily controllable, gained raceme DL- L-aminobutanedioic acid DL- ornithine purity is high produces
Rate is higher, is suitble to large-scale production preparation.
To achieve the goals above, described the present invention provides a kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine
Method the following steps are included:
(1) using acetic acid aqueous solution as solvent, racemization occurs under the action of catalyst for L-ASPARTIC ACID L-Orn salt,
Obtain racemization liquid；
(2) be added anti-solvent into racemization liquid, crystallization, filtering, drying to get.
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
Amount is 4~7 times, preferably 5~6 times of L-ASPARTIC ACID L-Orn salt quality.
In the step (1), the catalyst is selected from salicylide or benzaldehyde；The dosage of the catalyst is L- winter ammonia
The 5~10% of sour L-Orn salt quality, preferably 8~10%, to guarantee to obtain preferable racemization effect.
In the step (1), the temperature of the racemization is controlled between 60~80 DEG C, preferably between 70~80 DEG C
And 3~4h of stirring.
In the step (2), the anti-solvent is selected from one of methanol, ethyl alcohol, isopropanol or a variety of.The anti-solvent
Mass ratio with acetic acid aqueous solution is (0.8~1): 1, preferably (0.9~1): 1, further preferably 1:1；Selection is suitable anti-
Solvent and dosage can not only guarantee that gained crystalline particle is dimensioned for, and be easy to filter, and can guarantee product yield.
In the step (2), the anti-solvent need to be added in racemization liquid in a manner of dropwise addition, and time for adding should be controlled 1
~4h, preferably 2~3h, and ensure be added dropwise during temperature control at 45~65 DEG C, preferably 50~60 DEG C；So be conducive to crystalline substance
It the growth of body and is slowly precipitated, to obtain that purity is higher and larger-size crystal, is conducive to subsequent filter processing.
In the step (2), after the crystallization, system is cooled to 20~40 DEG C, preferably 30~35 DEG C, with simultaneous
Care for production efficiency and product quality.
In the step (2), the drying uses vacuum drying mode, and temperature controls between 40~60 DEG C, and preferably 45
~50 DEG C, drying time is 4~8h, and preferably 6h, vacuum degree is -0.08~-0.1MPa.
As a preferred embodiment of the present invention, the preparation method of the DL- L-aminobutanedioic acid DL- ornithine includes following step
It is rapid:
(1) L-ASPARTIC ACID L-Orn salt is added in acetic acid aqueous solution and is dissolved completely, catalyst is added, heating exists
Racemization is carried out between 60~80 DEG C, obtains racemization liquid；
(2) under heat-retaining condition, anti-solvent is added dropwise into racemization liquid, temperature control is at 45~65 DEG C during dropwise addition, simultaneously
A large amount of crystal are precipitated, rear 2~4h of insulated and stirred is added dropwise, are cooled to 20~40 DEG C of crystallizations, the solid was filtered, in 40~60 DEG C
Carry out vacuum drying to get.
Preparation method raw material provided by the invention is easy to get, easy to operate, easily controllable, gained raceme DL- L-aminobutanedioic acid
DL- ornithine purity is high, yield is higher, is suitble to large-scale production preparation.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Unless otherwise specified, embodiment
Used in the conventional means that are well known to those skilled in the art of technological means, raw materials used is commercial goods.
The preparation of embodiment 1:DL- L-aminobutanedioic acid DL- ornithine
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 500g acetic acid aqueous solution (50% concentration), is stirred
Dissolution completely, is added salicylide 10g, is heated to 70 DEG C of stirring 3.5h in Xiang Shangshu solution；
2) step 1) acquired solution is kept the temperature 50~60 DEG C, methanol 500g, time for adding 2.5h, during dropwise addition is added dropwise
It gradually precipitates crystal, insulated and stirred 4h growing the grain is added dropwise, is cooled to 30 DEG C, the solid was filtered, and 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 in every 1ml containing 80mg 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,.
The preparation of embodiment 2:DL- L-aminobutanedioic acid DL- ornithine
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 600g acetic acid aqueous solution (40% concentration), is stirred
Dissolution completely, is added salicylide 8g, is heated to 70 DEG C of stirring 4h in Xiang Shangshu solution；
2) step 1) acquired solution is kept the temperature into 50 DEG C of dropwise additions methanol 500g, time for adding 2h, is gradually analysed during being added dropwise
Crystal out is added dropwise insulated and stirred 3h growing the grain, is cooled to 35 DEG C, and the solid was filtered, and 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 in every 1ml containing 80mg 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,.
The preparation of embodiment 3:DL- L-aminobutanedioic acid DL- ornithine
1) L-ASPARTIC ACID L-Orn salt solid 100g is added in 500g acetic acid aqueous solution (50% concentration), is stirred
Dissolution completely, is added salicylide 10g, is heated to 65 DEG C of stirring 3.5h in Xiang Shangshu solution；
2) step 1) acquired solution is kept the temperature into 50~60 DEG C of dropwise additions ethyl alcohol 400g, time for adding 2.5h, during dropwise addition
It gradually precipitates crystal, insulated and stirred 4h growing the grain is added dropwise, is cooled to 30 DEG C, the solid was filtered, and 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 in every 1ml containing 80mg 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, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (12)
1. a kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine, which comprises the following steps:
(1) using acetic acid aqueous solution as solvent, L-ASPARTIC ACID L-Orn salt disappears in 60~80 DEG C under the action of catalyst
Rotation reaction, obtains racemization liquid；
The catalyst is selected from salicylide or benzaldehyde；
(2) anti-solvent is added into racemization liquid, the anti-solvent need to be added in racemization liquid in a manner of dropwise addition, and during dropwise addition
Temperature control is at 45~65 DEG C, crystallization, filtering, drying to get；
The anti-solvent is selected from one of methanol, ethyl alcohol, isopropanol or a variety of.
2. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 1, which is characterized in that in step (1),
The mass concentration of the acetic acid aqueous solution is 40~60%；The additional amount of the acetic acid aqueous solution is L-ASPARTIC ACID L-Orn
4~7 times of salt quality.
3. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 2, which is characterized in that the acetic acid water
The additional amount of solution is 5~6 times of L-ASPARTIC ACID L-Orn salt quality.
4. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 1, which is characterized in that in step (1),
The dosage of the catalyst is the 5~10% of L-ASPARTIC ACID L-Orn salt quality.
5. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 4, which is characterized in that in step (1),
The dosage of the catalyst is the 8~10% of L-ASPARTIC ACID L-Orn salt quality.
6. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 1, which is characterized in that in step (1),
The temperature of the racemization controls between 70~80 DEG C.
7. the preparation method of -6 any DL- L-aminobutanedioic acid DL- ornithines according to claim 1, which is characterized in that step
(2) in, temperature control is at 50~60 DEG C during the dropwise addition.
8. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 7, which is characterized in that in step (2),
After the crystallization, system is cooled to 20~40 DEG C of crystallizations.
9. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 8, which is characterized in that in step (2),
After the crystallization, system is cooled to 30~35 DEG C.
10. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 9, which is characterized in that step (2)
In, the drying uses vacuum drying mode, and temperature controls between 40~60 DEG C, and vacuum degree is -0.08~-0.1MPa.
11. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 10, which is characterized in that step (2)
In, the drying uses vacuum drying mode, and temperature controls between 45~50 DEG C.
12. the preparation method of DL- L-aminobutanedioic acid DL- ornithine according to claim 1, which is characterized in that including as follows
Step:
(1) L-ASPARTIC ACID L-Orn salt is added in acetic acid aqueous solution and is dissolved completely, be added catalyst, heating 60~
Racemization is carried out between 80 DEG C, obtains racemization liquid；
(2) under heat-retaining condition, anti-solvent is added dropwise into racemization liquid, temperature control is precipitated simultaneously at 45~65 DEG C during dropwise addition
Rear 2~4h of insulated and stirred is added dropwise in a large amount of crystal, is cooled to 20~40 DEG C of crystallizations, and the solid was filtered, carries out in 40~60 DEG C
Vacuum drying to get.
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| CN201710239961.1A CN106977413B (en) | 2017-04-13 | 2017-04-13 | A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine |
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| CN201710239961.1A CN106977413B (en) | 2017-04-13 | 2017-04-13 | A kind of preparation method of DL- L-aminobutanedioic acid DL- ornithine |
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| 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 |
|---|
| "化学酶法制备D-鸟氨酸盐酸盐";刘莉等;《安徽农业科学》;20091231;第37卷(第20期);9317-9319 |
| "药用氨基酸复合盐的合成研究";郑岚等;《化学试剂》;20090930;第31卷(第9期);740-742 |
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