CN112898211A - Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine - Google Patents
Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine Download PDFInfo
- Publication number
- CN112898211A CN112898211A CN202110103708.XA CN202110103708A CN112898211A CN 112898211 A CN112898211 A CN 112898211A CN 202110103708 A CN202110103708 A CN 202110103708A CN 112898211 A CN112898211 A CN 112898211A
- Authority
- CN
- China
- Prior art keywords
- carboxymethyl
- oxo
- piperazine
- pentanoyl
- aza
- 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.)
- Pending
Links
- -1 3-carboxymethyl-3-aza-pentanoyl Chemical group 0.000 title claims abstract description 38
- 150000004885 piperazines Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 29
- 239000012043 crude product Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- RNNLFWDSPUNOAP-UHFFFAOYSA-N CCN(CC(N(CCN1CC(O)=O)CC1=O)=O)CC(O)=O Chemical compound CCN(CC(N(CCN1CC(O)=O)CC1=O)=O)CC(O)=O RNNLFWDSPUNOAP-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 238000001179 sorption measurement Methods 0.000 claims description 7
- 230000015556 catabolic process Effects 0.000 claims description 6
- 238000006731 degradation reaction Methods 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- 238000001953 recrystallisation Methods 0.000 claims 1
- OCDAWJYGVOLXGZ-VPVMAENOSA-K gadobenate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)C(C([O-])=O)COCC1=CC=CC=C1 OCDAWJYGVOLXGZ-VPVMAENOSA-K 0.000 abstract description 8
- 229940096814 gadobenate dimeglumine Drugs 0.000 abstract description 8
- 238000002347 injection Methods 0.000 abstract description 8
- 239000007924 injection Substances 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000013558 reference substance Substances 0.000 abstract description 2
- FXHYAXBIUKRLLT-UHFFFAOYSA-N 2-(decylazaniumyl)acetate Chemical compound CCCCCCCCCCNCC(O)=O FXHYAXBIUKRLLT-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of preparation of gadobenate dimeglumine injection-related impurities, and particularly relates to a preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine, wherein the reaction formula is as follows:
the invention provides a preparation method of gadobenate dimeglumine injection-related impurity 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine for the first time; the prepared target compound has the purity of 97.6 percent and the content of 96.1 percent, and can be used as a reference substance of impurities related to the gadobenate dimeglumine injection after calibration.
Description
Technical Field
The invention belongs to the technical field of preparation of gadobenate dimeglumine injection-related impurities, and particularly relates to a preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine.
Background
The gadobenate dimeglumine injection is a novel paramagnetic gadolinium chelator, has high strengthening degree, liver tissue specificity, wider imaging time window and high safety, can further improve the diagnosis and differential diagnosis capability of MRI on diseases, and is a novel gadolinium contrast agent with wide application prospect.
No report is found on the current preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine hydride (gadobenate dimeglumine injection-related impurities).
Disclosure of Invention
The invention aims to provide a preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine comprises the following steps:
s1, taking 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with a structural formula shown as a compound (I) as a starting material, and performing heating degradation and cyclization reaction in the presence of purified water to obtain a crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydrogenated piperazine with a structural formula shown as a compound (II);
s2, taking the obtained 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine crude product, recrystallizing and drying to obtain a target product finished product;
the reaction formulae of the above steps S1 and S2 are shown below:
preferably, the step S1, after the thermal degradation and cyclization reaction, obtaining the crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine with the structural formula shown as the compound (II), comprises the following steps: cooling the reaction solution to room temperature, and purifying by using adsorption resin;
concentrating the collected liquid containing the compound shown in the structural formula (II) after being purified by the adsorption resin under reduced pressure at 50-60 ℃, slowly dropwise adding the concentrated liquid into a mixed solvent, stirring the solution while dropwise adding, loosely separating out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II), crystallizing for 15-30 min, filtering, and washing a filter cake by absolute ethyl alcohol to obtain a crude product of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II).
Preferably, the volume ratio of the concentrated solution to the mixed solvent is 1: 40-50.
Preferably, step s1. conditions of the thermal degradation and cyclization reaction: heating and refluxing the mixture in an oil bath at 105-115 ℃, and reacting for 12-20 h.
Preferably, the mass ratio of the 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with the structural formula shown as the compound (I) to the purified water is 1: 10-12.
Specifically, step s2. the step of recrystallizing comprises: heating and dissolving a crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine with a structural formula shown as a compound (II) in a ratio of 1g to 6-7 mL of purified water at 50-60 ℃ to obtain a clear solution;
slowly dropwise adding the dissolved crude product solution into a mixed solvent, stirring the solution while dropwise adding, loosely separating out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II), crystallizing for 15-30 min, filtering, and washing a filter cake with absolute ethyl alcohol;
the feed-liquid ratio of the crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine with the structural formula shown as the compound (II) to the mixed solvent is 1g: 93-94 mL.
Preferably, in the step S2, the filter cake is controlled to be dried for 16-20 hours in vacuum at 50-60 ℃ to obtain a target product finished product.
Preferably, the mixed solvent consists of absolute ethyl alcohol and isopropyl ether according to a volume ratio of 5: 2.
Compared with the prior art, the invention provides a preparation method of gadobenate dimeglumine injection-related impurity 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine for the first time; the prepared compound has the purity of 97.8-98.3% and the content of 96.2-97.0%, and can be used as a reference substance of related impurities of the gadobenate dimeglumine injection after calibration.
Drawings
FIG. 1 is a high performance liquid chromatogram of a finished target product prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of a finished target product prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic carbon spectrum of a finished target product prepared in example 1 of the present invention.
Detailed Description
The following is a detailed description of specific embodiments of the invention.
Example 1
A preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine comprises the following steps:
s1, taking 30g of 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with the structural formula shown as a compound (I), adding 300g of purified water, heating and refluxing in an oil bath at 110 ℃, reacting for 16h, cooling to room temperature, passing through LX-18 adsorption resin, eluting with the purified water, tracking by HPLC, collecting the part with higher intermediate content, concentrating at 55 ℃ under reduced pressure to about 30ml, slowly dropwise adding the concentrated solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dropwise adding to loosely separate out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine with the structural formula shown as a compound (II), crystallizing for 25min, and filtering; washing the filter cake with absolute ethyl alcohol to obtain a crude product of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine hydride.
S2, taking 15g of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine crude product, adding 100ml of purified water, and heating to dissolve at 55 ℃ to be clear; slowly dropwise adding the clear solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dropwise adding the clear solution to ensure that 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine is separated out loosely, and crystallizing for 25 min; filtering, washing a filter cake by absolute ethyl alcohol; the filter cake was vacuum dried at 55 ℃ for 18 hours to give 13.5g of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine solid in a yield of 72.8% with a purity of 98.1% and a content of 96.7% calculated as 30g of 4-carboxy-5, 8, 11-tris (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-oic acid.
Example 2
A preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine comprises the following steps:
s1, taking 30g of 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with the structural formula shown as a compound (I), adding 360g of purified water, heating and refluxing in an oil bath at 115 ℃, reacting for 12h, cooling to room temperature, passing through LX-18 adsorption resin, eluting with the purified water, tracking by HPLC, collecting the part with higher intermediate content, concentrating at 60 ℃ under reduced pressure to about 30ml, slowly dropwise adding the concentrated solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dropwise adding to loosely separate out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine with the structural formula shown as a compound (II), crystallizing for 30min, and filtering; washing the filter cake with absolute ethyl alcohol to obtain a crude product of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine hydride.
S2, taking 15g of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine crude product, adding 100ml of purified water, and heating to dissolve at 60 ℃ to be clear; slowly dripping the clear solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dripping the clear solution to ensure that 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine is separated out loosely and crystallized for 20 min; filtering, washing a filter cake by absolute ethyl alcohol; the filter cake was vacuum dried at 60 ℃ for 16 hours to give 13.4g of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine solid in a yield of 72.3% with a purity of 98.3% and a content of 97.0% calculated as 30g of 4-carboxy-5, 8, 11-tris (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-oic acid.
Example 3
A preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine comprises the following steps:
s1, taking 30g of 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with the structural formula shown as a compound (I), adding 330g of purified water, heating and refluxing in an oil bath at 105 ℃, reacting for 20h, cooling to room temperature, passing through LX-18 adsorption resin, eluting with the purified water, tracking by HPLC, collecting the part with higher intermediate content, concentrating at 50 ℃ under reduced pressure to about 30ml, slowly dropwise adding the concentrated solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dropwise adding to loosely separate out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine with the structural formula shown as a compound (II), crystallizing for 15min, and filtering; washing the filter cake with absolute ethyl alcohol to obtain a crude product of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine hydride.
S2, taking 15g of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine crude product, adding 100ml of purified water, and heating to dissolve the crude product at 50 ℃ to obtain a clear solution; slowly dripping the clear solution into a mixed solvent of 1000ml of absolute ethyl alcohol and 400ml of isopropyl ether, stirring the solution while dripping the clear solution to ensure that 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine is separated out loosely, and crystallizing for 30 min; filtering, washing a filter cake by absolute ethyl alcohol; the filter cake was vacuum-dried at 50 ℃ for 20 hours to give 13.2g of a solid of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydropiperazine in a yield of 71.2% in purity of 97.8% and 96.2% in a yield of 30g of 4-carboxy-5, 8, 11-tris (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-oic acid.
The above embodiments are merely preferred embodiments of the present invention, and any simple modification, modification and substitution changes made to the above embodiments according to the technical spirit of the present invention are within the scope of the technical solution of the present invention.
Claims (8)
1. A preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine is characterized by comprising the following steps:
s1, taking 4-carboxyl-5, 8, 11-tri (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid with a structural formula shown as a compound (I) as a starting material, and performing heating degradation and cyclization reaction in the presence of purified water to obtain a crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) hydrogenated piperazine with a structural formula shown as a compound (II);
s2, taking the obtained 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine crude product, recrystallizing and drying to obtain a target product finished product;
the reaction formulae of the above steps S1 and S2 are shown below:
2. the method for preparing 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine according to claim 1, wherein step S1. the step of obtaining the crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine with the structural formula shown as compound (II) through thermal degradation and cyclization comprises: cooling the reaction solution to room temperature, and purifying by using adsorption resin;
concentrating the collected liquid containing the compound shown in the structural formula (II) after being purified by the adsorption resin under reduced pressure at 50-60 ℃, slowly dropwise adding the concentrated liquid into a mixed solvent, stirring the solution while dropwise adding, loosely separating out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II), crystallizing for 15-30 min, filtering, and washing a filter cake by absolute ethyl alcohol to obtain a crude product of the 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II).
3. The method for preparing 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine according to claim 2, wherein the volume ratio of the concentrated solution to the mixed solvent is 1: 40-50.
4. The method for preparing 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine according to claim 1, wherein the degradation and cyclization reaction conditions are as follows: heating and refluxing the mixture in an oil bath at 105-115 ℃, and reacting for 12-20 h.
5. The preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-azapentanoyl) piperazine according to claim 1, wherein the mass ratio of 4-carboxy-5, 8, 11-tris (carboxymethyl) -1-phenyl-2-oxa-5, 8, 11-azatridecane-13-acid shown in the structural formula (I) to purified water is 1: 10-12.
6. The method for preparing 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine according to claim 2, wherein the step S2. recrystallization comprises: heating and dissolving a crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine with a structural formula shown as a compound (II) in a ratio of 1g to 6-7 mL of purified water at 50-60 ℃ to obtain a clear solution;
slowly dropwise adding the dissolved crude product solution into a mixed solvent, stirring the solution while dropwise adding, loosely separating out the compound 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine shown in the structural formula (II), crystallizing for 15-30 min, filtering, and washing a filter cake with absolute ethyl alcohol;
the feed-liquid ratio of the crude product of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine with the structural formula shown as the compound (II) to the mixed solvent is 1g: 93-94 mL.
7. The preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) piperazine according to claim 6, wherein in step S2, the filter cake is vacuum dried at 50-60 ℃ for 16-20 h to obtain a target product.
8. The process according to claim 2, 3 or 6, wherein the mixed solvent comprises absolute ethanol and isopropyl ether at a volume ratio of 5: 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110103708.XA CN112898211A (en) | 2021-01-26 | 2021-01-26 | Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110103708.XA CN112898211A (en) | 2021-01-26 | 2021-01-26 | Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112898211A true CN112898211A (en) | 2021-06-04 |
Family
ID=76120088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110103708.XA Pending CN112898211A (en) | 2021-01-26 | 2021-01-26 | Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112898211A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017020010A1 (en) * | 2015-07-29 | 2017-02-02 | Neuropore Therapies, Inc. | Bis-heteroaryl derivatives as modulators of protein aggregation |
-
2021
- 2021-01-26 CN CN202110103708.XA patent/CN112898211A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017020010A1 (en) * | 2015-07-29 | 2017-02-02 | Neuropore Therapies, Inc. | Bis-heteroaryl derivatives as modulators of protein aggregation |
Non-Patent Citations (2)
| Title |
|---|
| Y. GÖCKE ET AL.: ""BIODEGRADATION OF DIETHYLENETRIAMINEPENTAACETIC ACID (DTPA)"", 《PROCEEDINGS OF THE THIRD INTERNATIONAL CONFERENCE ON REMEDIATION OF CHLORINATED AND RECALCITRANT COMPOUNDS》, pages 2295 - 2302 * |
| 翟国庆等: ""碳氮键断裂的研究进展"", 《化学通报》, vol. 81, pages 579 - 586 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0390054A (en) | Preparation of cyclic amino acid and its interme- diate | |
| CN101942001B (en) | Purification method of loteprednol etabonate | |
| CN115093386B (en) | Production method of colorless, tasteless and borate-free vitreous chromogen | |
| CN115073312A (en) | Novel synthesis method of noradrenaline bitartrate | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| CN102180820B (en) | Purification method for preparing high-purity Fudosteine | |
| CN112898211A (en) | Preparation method of 1-carboxymethyl-2-oxo-4- (3-carboxymethyl-3-aza-pentanoyl) hydrogenated piperazine | |
| CN113651706A (en) | Preparation process of high-purity esmolol hydrochloride | |
| CN115322194B (en) | Method for resolving carboxylic acid of non-neridone intermediate | |
| CN111825703B (en) | Preparation method of gadobenate dimeglumine injection impurity | |
| CN114605332B (en) | Preparation process of metronidazole | |
| CN113603610B (en) | Naphthalene hydrazide organic gel factor and preparation method and application thereof | |
| CN107382898B (en) | Energetic material based on ANPZ energetic parent structure and synthetic method thereof | |
| CN108911999B (en) | Synthesis method of 1-aminoanthraquinone | |
| CN113185423A (en) | Method for refining chloroprocaine hydrochloride | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN111848561A (en) | Method for purifying mycophenolic acid | |
| CN110790723A (en) | Synthesis method of tianeptine sodium | |
| CN101570564B (en) | Method for refining tanshinone II A acrylic acid | |
| CN111303218B (en) | Synthetic method and application of verbena glycoside | |
| CN115536558B (en) | Refining process of bumetanide crude product | |
| CN109438243B (en) | Preparation method of electronic grade octyl gallate | |
| CN113443995B (en) | Preparation method of key intermediate of Gerastib | |
| CN116375583A (en) | Preparation method of 1,3, 5-trialkoxy-2, 4, 6-trinitrobenzene | |
| CN116903608A (en) | Preparation method of penehyclidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |