CN116621838A - Butterfly acid active ester and synthesis method thereof - Google Patents
Butterfly acid active ester and synthesis method thereof Download PDFInfo
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- CN116621838A CN116621838A CN202310417043.9A CN202310417043A CN116621838A CN 116621838 A CN116621838 A CN 116621838A CN 202310417043 A CN202310417043 A CN 202310417043A CN 116621838 A CN116621838 A CN 116621838A
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- active ester
- acid active
- pteroic acid
- compound
- synthesizing
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- 150000002148 esters Chemical class 0.000 title claims abstract description 41
- 239000002253 acid Substances 0.000 title claims description 4
- 238000001308 synthesis method Methods 0.000 title abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- JOAQINSXLLMRCV-UHFFFAOYSA-N 4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}benzoic acid Chemical compound C1=NC2=NC(N)=NC(O)=C2N=C1CNC1=CC=C(C(O)=O)C=C1 JOAQINSXLLMRCV-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229940126062 Compound A Drugs 0.000 claims abstract description 21
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001718 carbodiimides Chemical class 0.000 claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000000376 reactant Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 abstract description 18
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 abstract description 9
- 229960000304 folic acid Drugs 0.000 abstract description 9
- 235000019152 folic acid Nutrition 0.000 abstract description 9
- 239000011724 folic acid Substances 0.000 abstract description 9
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 3
- 238000006731 degradation reaction Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 230000007515 enzymatic degradation Effects 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- -1 e.g. Chemical compound 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a pteroic acid active ester and a synthesis method thereof, comprising the following steps: s1, dissolving a compound A in an organic solvent, and adding a carbodiimide condensing agent and N-hydroxysuccinimide for reaction; s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, crystallizing and filtering to obtain the pteroic acid active ester; compared with the conventional biosynthesis method for folic acid enzyme degradation, the synthesis method has the advantages of easy preparation of raw materials, mild conditions, good purification effect and high yield.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a pteroic acid active ester and a synthesis method thereof.
Background
Pteroic acid is a starting material useful in the preparation of folic acid derivatives, and can be combined with drugs to form conjugates in therapy; can be used as a target function conjugate in the field of medical treatment, and has good application prospect. The preparation method of the pteroic acid is various, folic acid is easy to decompose into the pteroic acid under the acidic condition, and in addition, the pteroic acid can be obtained through enzymatic degradation and biodegradation of the folic acid; however, the pteroic acid prepared by these methods is also easily contaminated with the same equivalent of folic acid, e.g., pteroic acid obtained by enzymatic degradation may contain 25% folic acid.
The pteroic acid active ester is also an important intermediate for synthesizing folic acid derivatives, and can be condensed with different amino acids. The publication CN101175757a discloses the synthesis and purification of pteroic acid and its conjugates by contacting a solution comprising pteroic acid, derivatives or combinations of pteroic acid with an anion exchange chromatography carrier, including but not limited to ion exchange resins, anion exchange resins, glycosyl resins and glycosyl anion exchange resins, however this process requires high water quality, poor thermal stability and easy dissolution of organics. At present, no report exists on the synthesis method of the pteroic acid active ester, so that a method for efficiently synthesizing the pteroic acid active ester is needed.
Disclosure of Invention
The application provides a pteroic acid active ester and a synthesis method thereof, which solve the technical problems of more impurities and low yield of the existing synthesis method.
The technical scheme of the application is realized as follows:
in one aspect, the application provides a pteroic acid active ester with a chemical structural formula of
In another aspect, the application provides a method for synthesizing the pteroic acid active ester, which comprises the following steps:
s1, dissolving a compound A in an organic solvent, and adding a carbodiimide condensing agent and N-hydroxysuccinimide for reaction;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, crystallizing and filtering to obtain the pteroic acid active ester.
On the basis of this technical scheme, it is preferable that the structural formula of the compound A in the step S1 is
Based on the technical scheme, the carbodiimide condensing agent in the step S1 is one of EDCI, DCC or DIC, preferably EDCI.
On the basis of this technical scheme, the organic solvent in step S1 is one of DMSO, DMF, THF or DCM, preferably DMSO.
On the basis of this technical solution, preferably, step S1 specifically includes the following steps:
s1, dissolving a compound A in an organic solvent, adding a carbodiimide condensing agent and N-hydroxysuccinimide, reacting for 0.5-1h at 25-40 ℃, and monitoring the reaction by HPLC;
on the basis of this technical solution, preferably, step S2 specifically includes the following steps:
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, continuously stirring for 0.5-1h, precipitating crystals, and filtering to obtain the pteroic acid active ester.
Based on this technical scheme, preferably, the molar ratio of the compound a, the carbodiimide condensing agent and the N-hydroxysuccinimide in step S1 is 1: (1-3): (1-1.2).
Based on the technical scheme, preferably, the mass ratio of methyl tertiary butyl ether, ethyl acetate and compound A in the step S2 is (7.4-8): (9.2-10): 1.
compared with the prior art, the synthesis method of the pteroic acid active ester has the following beneficial effects:
(1) At present, no method for synthesizing the pteroic acid active ester exists, but other pteroic acid and conjugate synthesis means are mostly biological means such as folic acid enzyme degradation, wherein most of the methods have poor yield, contain folic acid impurities, have poor purification effect and have harsh conditions; the application uses carboxylic acid and carbodiimide condensing agent to generate active amide, then condenses with N-hydroxysuccinimide to generate active ester containing OSu functional group, and then uses the similar compatible substance of methyl tertiary butyl ether and ethyl acetate to crystallize to obtain the product, the method is simple and convenient, and the purity and the yield are higher;
(2) The application avoids the defect of high folic acid impurity content caused by the degradation of folic acid enzyme by adopting a conventional method, can be prepared by a one-pot method, and is suitable for industrial mass production.
Drawings
In order to more clearly illustrate the embodiments of the application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the synthetic route of the pteroic acid active ester of the present application.
Detailed Description
The following description of the embodiments of the present application will clearly and fully describe the technical aspects of the embodiments of the present application, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present application without making any inventive effort, are intended to fall within the scope of the present application.
Example 1
A synthesis method of pteroic acid active ester comprises the following steps:
s1, dissolving 100g of a compound A in DCM, and adding a carbodiimide condensing agent and N-hydroxysuccinimide, wherein the molar ratio of the compound A to the carbodiimide condensing agent to the N-hydroxysuccinimide is 1:3:1.2, reaction at 40 ℃ for 0.5h, hplc monitoring reaction;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, wherein the mass ratio of the methyl tertiary butyl ether to the ethyl acetate to the compound A is 7.4:9.2:1, stirring for 0.5h, precipitating crystals, and filtering to obtain 110g of yellow solid, namely the pteroic acid active ester, with the purity of 95% and the yield of 84%.
The pteroic acid active ester 1 H NMR was (400 MHz, DMSO-d 6) δ11.68 (s, 1H), 8.65 (s, 1H), 7.14 (s, 2H), 6.59 (t, J=9.0 Hz, 1H), 4.53 (d, J=5.9 Hz, 2H), 2.82 (s, 4H).
Example 2
A synthesis method of pteroic acid active ester comprises the following steps:
s1, dissolving 100g of a compound A in THF, and adding a carbodiimide condensing agent and N-hydroxysuccinimide, wherein the molar ratio of the compound A to the carbodiimide condensing agent to the N-hydroxysuccinimide is 1:1:1, reacting at 25 ℃ for 1h, and monitoring the reaction by HPLC;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, wherein the mass ratio of the methyl tertiary butyl ether to the ethyl acetate to the compound A is 8:10:1, stirring for 1h, precipitating crystals, and filtering to obtain 105g of yellow solid, namely the pteroic acid active ester, with the purity of 94% and the yield of 82%.
Example 3
A synthesis method of pteroic acid active ester comprises the following steps:
s1, dissolving 100g of a compound A in DMF, and adding a carbodiimide condensing agent and N-hydroxysuccinimide, wherein the molar ratio of the compound A to the carbodiimide condensing agent to the N-hydroxysuccinimide is 1:3:1.05, at 30℃for 0.8h, monitored by HPLC;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, wherein the mass ratio of the methyl tertiary butyl ether to the ethyl acetate to the compound A is 7.8:9.6:1, stirring for 0.8h, precipitating crystals, and filtering to obtain 107g of yellow solid, namely the pteroic acid active ester, with the purity of 94% and the yield of 83%.
Example 4
A synthesis method of pteroic acid active ester comprises the following steps:
s1, dissolving 1000g of a compound A in DMSO, and adding a carbodiimide condensing agent and N-hydroxysuccinimide, wherein the molar ratio of the compound A to the carbodiimide condensing agent to the N-hydroxysuccinimide is 1:2:1.05, at 40 ℃ for 0.5h, HPLC monitoring reaction;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, wherein the mass ratio of the methyl tertiary butyl ether to the ethyl acetate to the compound A is 7.8:9.6:1, stirring for 0.5h, precipitating crystals, and filtering to obtain 1158g of yellow solid, namely the pteroic acid active ester, with the purity of 96% and the yield of 85%.
Comparative example 1
A synthesis method of pteroic acid active ester is different from example 1 in that the carbodiimide condensing agent is DCC, and the yield is 77%.
Comparative example 2
A synthesis method of pteroic acid active ester is different from example 2 in that the carbodiimide condensing agent is DIC, and the yield is 75%.
Comparative example 3
A synthesis method of pteroic acid active ester is different from that of example 3 in that petroleum ether and ethyl acetate are added in step S2, and target products are obtained without crystallization.
Comparative example 4
A synthesis method of pteroic acid active ester is different from example 4 in that methyl n-butyl ether and vinyl acetate are added in step S2, and the yield is 35%.
The foregoing description of the preferred embodiments of the application is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the application.
Claims (9)
1. A butterfly acid active ester is characterized in that the chemical structural formula of the butterfly acid active ester is
2. The method for synthesizing a pteroic acid active ester according to claim 1, comprising the steps of:
s1, dissolving a compound A in an organic solvent, and adding a carbodiimide condensing agent and N-hydroxysuccinimide for reaction;
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, crystallizing and filtering to obtain the pteroic acid active ester.
3. The method of synthesizing an active ester of pteroic acid according to claim 2, wherein the compound A of step S1 has the formula
4. The method of synthesizing a pteroic acid active ester according to claim 2, wherein the carbodiimide condensing agent in step S1 is one of EDCI, DCC, or DIC.
5. The method of claim 2, wherein the organic solvent in step S1 is one of DMSO, DMF, THF and DCM.
6. The method for synthesizing the pteroic acid active ester according to claim 2, wherein the step S1 specifically comprises the following steps:
s1, dissolving the compound A in an organic solvent, adding a carbodiimide condensing agent and N-hydroxysuccinimide, reacting for 0.5-1h at 25-40 ℃, and monitoring the reaction by HPLC.
7. The method for synthesizing the pteroic acid active ester according to claim 2, wherein the step S2 specifically comprises the following steps:
s2, adding methyl tertiary butyl ether and ethyl acetate into the reactant in the step S1, continuously stirring for 0.5-1h, precipitating crystals, and filtering to obtain the pteroic acid active ester.
8. The method of synthesizing a pteroic acid active ester according to claim 6, wherein the molar ratio of the compound A, the carbodiimide condensing agent and the N-hydroxysuccinimide in the step S1 is 1: (1-3): (1-1.2).
9. The method for synthesizing pteroic acid active ester according to claim 7, wherein the mass ratio of methyl tert-butyl ether, ethyl acetate to compound a in step S2 is (7.4-8): (9.2-10): 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310417043.9A CN116621838A (en) | 2023-04-17 | 2023-04-17 | Butterfly acid active ester and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310417043.9A CN116621838A (en) | 2023-04-17 | 2023-04-17 | Butterfly acid active ester and synthesis method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116621838A true CN116621838A (en) | 2023-08-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310417043.9A Pending CN116621838A (en) | 2023-04-17 | 2023-04-17 | Butterfly acid active ester and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116621838A (en) |
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2023
- 2023-04-17 CN CN202310417043.9A patent/CN116621838A/en active Pending
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