CN116332824A - Heterocyclic compound, and preparation method and application thereof - Google Patents
Heterocyclic compound, and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 24
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- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 14
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of organic synthesis, and discloses a heterocyclic compound, a preparation method and application thereof. The preparation method comprises the following steps: (1) Carrying out a first reaction on a compound shown in a formula (I-1) and an acidic reagent in the presence of an organic solvent to obtain a compound shown in a formula (I-2); (2) And (3) carrying out a second reaction on the compound shown in the formula (I-2) and the compound shown in the formula (I-3) to obtain the heterocyclic compound shown in the formula (I). The method provided by the invention has the advantages of mild reaction conditions, lower production cost, no need of separation of the intermediate obtained by the reaction, shorter reaction period, and higher reaction yield and purity.
R 1 -O-R formula (I-3)
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a heterocyclic compound, a preparation method and application thereof.
Background
Indocyanine green (Indocyanine Green, ICG) was a fluorescent tricarbocyanine dye developed by kodak laboratories in 1955. Because of good fluorescence property, strong penetrability and high binding rate with plasma protein, the choroid image can be clearly displayed, and the composition is used for diagnosing human diseases from 1956.
Indocyanine green is injected into human body through vein, then is combined with plasma protein, and is rapidly distributed in whole blood vessel along with blood circulation, is efficiently and selectively taken up by liver cells, is excreted into bile from liver cells in free form, enters intestine through biliary tract, and is discharged out of human body along with excrement.
ICG molecular fluorescence imaging techniques were applied early in the ophthalmic field, and later this technique began to be used for intra-operative navigation, to identify critical structures and guide excision of solid tumors, for vascular visualization in neurosurgery, cardiac surgery, vascular surgery, and sentinel lymph node labeling in breast cancer, gastric cancer, etc.
Impurities in a drug refer to all other chemicals than the target compound introduced or generated during the drug production, storage or use; impurities in the medicament directly affect the curative effect of the medicament and may cause other adverse toxic and side effects, and the impurities must be controlled.
At present, in the United States Pharmacopoeia (USP) and the pharmacopoeia of the people's republic of China (Chp), only the quality standard of the indole fine material and the indocyanine green for injection is carried, but no definite process impurity and degradation impurity are carried; in the related literature, no clear detection of impurities has been reported.
Disclosure of Invention
The invention aims to provide a heterocyclic compound generated in the process of preparing indocyanine green, and solves the problems that clear process impurities and degradation impurities are not carried in the quality standard of the existing indocyanine green.
In order to achieve the above object, a first aspect of the present invention provides a heterocyclic compound having a structure represented by formula (I),
wherein in formula (I), R 1 Selected from methyl, ethyl, n-propyl.
In a second aspect, the present invention provides a process for preparing the heterocyclic compound of the first aspect, which comprises:
(1) Carrying out a first reaction on a compound shown in a formula (I-1) and an acidic reagent in the presence of an organic solvent to obtain a compound shown in a formula (I-2); the conditions of the first reaction include: the temperature is 0-5 ℃, the time is 0.5-1h, and the pH value of the reaction system is 5-6;
(2) Carrying out a second reaction on the compound shown in the formula (I-2) and the compound shown in the formula (I-3) to obtain a heterocyclic compound shown in the formula (I); the conditions of the second reaction include: the temperature is 80-120 ℃ and the time is 5-10h; and the compound shown in the formula (I-3) is selected from any one of trimethyl orthoformate, triethyl orthoformate and tri-n-propyl formate;
preferably, in step (1), the organic solvent is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
Preferably, in step (1), the acidic reagent is selected from at least one of sulfuric acid and hydrochloric acid.
Preferably, in the step (1), the weight ratio of the compound represented by the formula (I-1) to the organic solvent is 1:4-6.
Preferably, in the step (2), the compound represented by the formula (I-3) is used in an amount of 10 to 13mol relative to 1mol of the compound represented by the formula (I-1).
Preferably, the operation of step (2) comprises: and (3) carrying out the second reaction on the compound shown in the formula (I-3) and the compound shown in the formula (I-2) in a dropwise adding mode.
Preferably, in the step (2), the dropping speed of the compound represented by the formula (I-3) is 1-2mL/min.
Preferably, in step (2), the method further comprises: and (3) contacting the material obtained after the second reaction with water to obtain a mixed material I, and performing post-treatment on the mixed material I to obtain the heterocyclic compound shown in the formula (I).
The third aspect of the invention provides an application of the heterocyclic compound of the first aspect as a standard reference substance in the field of medicines.
According to the method for preparing the heterocyclic compound shown in the formula (I), the compound shown in the formula (I-1) is reacted with the acidic reagent to generate the compound shown in the formula (I-2), and then the compound shown in the formula (III) is reacted with the compound.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the compound I obtained in preparation example 1.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
As described above, the first aspect of the present invention provides a heterocyclic compound having a structure represented by formula (I),
wherein in formula (I), R 1 Selected from methyl, ethyl, n-propyl.
Preferably, the heterocyclic compound represented by formula (I) is selected from the following compounds:
compound I:
compound II:
compound III:
the present invention is not particularly limited to the specific method for preparing the heterocyclic compound of the first aspect, and a person skilled in the art can determine a suitable synthetic route according to the structural formula in combination with synthetic methods known in the art. However, in order to increase the yield and purity of the heterocyclic compound, the present invention provides a method for producing the heterocyclic compound described in the first aspect according to the second aspect.
As previously mentioned, the second aspect of the present invention provides a process for preparing the heterocyclic compound of the first aspect, which comprises:
(1) Carrying out a first reaction on a compound shown in a formula (I-1) and an acidic reagent in the presence of an organic solvent to obtain a compound shown in a formula (I-2); the conditions of the first reaction include: the temperature is 0-5 ℃, the time is 0.5-1h, and the pH value of the reaction system is 5-6;
(2) Carrying out a second reaction on the compound shown in the formula (I-2) and the compound shown in the formula (I-3) to obtain a heterocyclic compound shown in the formula (I); the conditions of the second reaction include: the temperature is 80-120 ℃ and the time is 5-10h; and the compound shown in the formula (I-3) is selected from any one of trimethyl orthoformate, triethyl orthoformate and tri-n-propyl formate;
preferably, in step (1), the organic solvent is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
Preferably, in step (1), the acidic reagent is selected from at least one of sulfuric acid and hydrochloric acid.
Preferably, in the step (1), the weight ratio of the compound shown in the formula (I-1) to the organic solvent is 1:4-6. More preferably, in the step (1), the weight ratio of the compound represented by the formula (I-1) to the organic solvent is 1:4.2-5. Such as a range of 1:4.2,1:4.3,1:4.4, 1:4.6, 1:4.8, 1:5, and any combination thereof. The inventors have found that under this preferred embodiment, the heterocyclic compound obtained in the present invention has a higher purity.
According to a particularly preferred embodiment, in step (1), the method further comprises: and carrying out the first reaction on the acidic reagent and the compound shown in the formula (I-1) in a dropwise adding mode, wherein the dropping speed of the acidic reagent is 1-2mL/min. Illustratively, the acidic reagent has a drop rate in the range of 1mL/min, 1.2mL/min, 1.5mL/min, 1.8mL/min, 2mL/min, and any combination thereof.
Preferably, the method of the present invention comprises directly using the obtained compound represented by the formula (I-2) in the second reaction without refining treatment.
In another preferred embodiment, the compound of formula (I-2) obtained is purified to obtain a purified compound of formula (I-2), and the purified compound of formula (I-2) is used in the second reaction.
In the present invention, there is no particular requirement on the apparatus and process used to perform the refining treatment, and those skilled in the art can use the refining treatment techniques known in the art for the present invention, and the present invention is not described herein in detail, and those skilled in the art should not understand the limitation of the present invention.
Preferably, in step (2), the compound of formula (I-3) is used in an amount ranging from 10 to 13 moles, for example, 10 moles, 11 moles, 12 moles, 13 moles, and any combination thereof, relative to 1 mole of the compound of formula (I-1).
More preferably, in step (2), the compound of formula (I-3) is used in an amount ranging from 10 to 10.5 moles, for example, 10 moles, 10.2 moles, 10.5 moles, and any combination thereof, relative to 1 mole of the compound of formula (I-1). The inventors have found that under this preferred embodiment, the heterocyclic compound obtained in the present invention has a higher purity.
Preferably, the operation of step (2) comprises: and (3) carrying out the second reaction on the compound shown in the formula (I-3) and the compound shown in the formula (I-2) in a dropwise adding mode.
Preferably, in the step (2), the dropping speed of the compound represented by the formula (I-3) is 1-2mL/min. Illustratively, the acidic reagent has a drop rate of 1mL/min, 1.2mL/min, 1.5mL/min, 1.8mL/min, or 2mL/min. The inventors have found that in this preferred embodiment, the yield of the heterocyclic compound obtained in the present invention is higher.
According to a particularly preferred embodiment, in step (2), the method further comprises: before the second reaction is carried out, the dropping speed of the compound shown in the formula (I-3) is controlled so that the temperature of the reaction system is kept at 0-5 ℃ after the completion of the dropping of the compound shown in the formula (I-3).
Preferably, in the step (2), the compound represented by the formula (I-3) is at least one selected from trimethyl orthoformate, triethyl orthoformate and tripropyl orthoformate.
Preferably, in step (2), the method further comprises: and (3) contacting the material obtained after the second reaction with water to obtain a mixed material I, and performing post-treatment on the mixed material I to obtain the heterocyclic compound shown in the formula (I).
Preferably, the weight ratio of the material obtained after the second reaction to the water is 1:50-100.
More preferably, the material obtained after the second reaction is contacted with water and subjected to a stirring treatment under conditions including: the stirring time is 10-20min, and the stirring speed is 200-400rpm.
According to a particularly preferred embodiment, in step (2), the post-treatment operation comprises: the present invention is not particularly limited as long as the heterocyclic compound of the structure represented by the aforementioned formula (I) of the present invention can be obtained by extraction, washing, rotary evaporation, column chromatography, recrystallization, etc.
The invention will be described in detail below by way of examples and is not thereby limited. In the following examples, all materials used are commercially available unless otherwise specified.
Unless otherwise specified, room temperature or normal temperature is 25.+ -. 1 ℃ in the examples below.
Unless otherwise specified, the mass fraction of sulfuric acid in the following examples was 98%.
The compound represented by the following formula (I-1) was used in an amount of 0.029mol, unless otherwise specified.
The purity of the compound I prepared was determined by High Performance Liquid Chromatography (HPLC).
The structure of the prepared compound I is determined by nuclear magnetic resonance hydrogen spectroscopy (HNMR).
The compound shown in the formula (I-1) is a CAS of 63149-24-6, purchased from Shanghai Haohong biological medicine technology Co., ltd, and has a purity of 95%, and the dosage of the compound is calculated as a pure substance;
the compound of the formula (I-3) in the present invention, i.e., trimethyl orthoformate, is purchased from Shanghai Haohong biomedical technology Co., ltd. With a purity of 97%, and hereinafter the amount of the compound is calculated as a pure substance.
The yield of the heterocyclic compound prepared in the present invention was calculated based on the amount of the compound represented by the formula (I-1), and the specific data are shown in Table 1.
The synthetic route of the invention is as follows:
preparation example 1
The present preparation provides a method for producing a heterocyclic compound represented by the formula (I), which comprises:
(1) Adding 0.029mol of a compound shown in a formula (I-1) and 50mL of N, N-dimethylacetamide into a 200mL three-necked flask, cooling to 5 ℃ after dissolution, and dropwise adding 1.6mL of sulfuric acid into a reaction system to perform a first reaction to obtain the compound shown in the formula (I-2);
wherein the conditions of the first reaction are: the temperature is 5 ℃, the time is 0.5h, the pH value of the reaction system is 5, and the dropping speed of sulfuric acid is 1mL/min;
(2) Dropwise adding 0.30mol of trimethyl orthoformate into the reaction system, and carrying out a second reaction with the compound shown in the formula (I-2) obtained in the step (1);
wherein the conditions of the second reaction are: the temperature is 90 ℃ and the time is 10 hours;
the compound shown in the formula (I-2) is directly used in the second reaction without refining treatment, namely, the material obtained after the first reaction is directly used in the second reaction;
before the second reaction is carried out, controlling the dropping speed of the trimethyl orthoformate to be 1mL/min, so that the temperature of a reaction system is 5 ℃ after the trimethyl orthoformate is added;
(3) After completion of TLC detection, the reaction system was cooled to room temperature and poured into 500mL of water and stirred at 400rpm for 10min, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and column-chromatographed after removal of the solvent under reduced pressure to give Compound I.
The nuclear magnetic pattern of compound I is shown in FIG. 1. 1 H NMR(400MHz,DMSO-d 6 )δ7.98-7.91(m 1H),7.89-7.82(m,1H),7.78-7.69(m,2H),7.36-7.31(m,1H),6.97-6.92(m,1H),3.39-3.30(m,4H),2.99-2.97(m,1H),2.80(s,3H),1.72-1.46(m,4H),1.27(s,6H),1.14(s,3H)。
Preparation example 2
This preparation was conducted in a similar manner to preparation 1 except that trimethyl orthoformate was used in an amount of 0.35mol in this preparation.
The remainder was the same as in preparation example 1 to obtain compound I.
Preparation example 3
This preparation was conducted in a similar manner to preparation 1 except that N, N-dimethylacetamide was used in an amount of 64mL in this preparation.
The remainder was the same as in preparation example 1 to obtain compound I.
Preparation example 4
This preparation was carried out in a similar manner to preparation 1, except that the second reaction time in this preparation was 6 hours.
The remainder was the same as in preparation example 1 to obtain compound I.
TABLE 1
| Numbering device | Yield/%of Compound I | Purity/%of Compound I | Properties of Compound I |
| Preparation example 1 | 93.0 | 96.6 | Dark green solid |
| Preparation example 2 | 92.8 | 95.3 | Dark green solid |
| Preparation example 3 | 91.5 | 95.0 | Dark green solid |
| Preparation example 4 | 92.3 | 94.5 | Dark green solid |
The result shows that the method provided by the invention can be used for preparing the heterocyclic compound with high purity and high yield. Through further purification analysis, the compound can be used as a standard reference substance in the field of medicine.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (10)
1. A heterocyclic compound is characterized in that the heterocyclic compound has a structure shown in a formula (I),
wherein in formula (I), R 1 Selected from methyl, ethyl, n-propyl.
2. A process for preparing the heterocyclic compound of claim 1, comprising:
(1) Carrying out a first reaction on a compound shown in a formula (I-1) and an acidic reagent in the presence of an organic solvent to obtain a compound shown in a formula (I-2); the conditions of the first reaction include: the temperature is 0-5 ℃, the time is 0.5-1h, and the pH value of the reaction system is 5-6;
(2) Carrying out a second reaction on the compound shown in the formula (I-2) and the compound shown in the formula (I-3) to obtain a heterocyclic compound shown in the formula (I); the conditions of the second reaction include: the temperature is 80-120 ℃ and the time is 5-10h; and the compound shown in the formula (I-3) is selected from any one of trimethyl orthoformate, triethyl orthoformate and tri-n-propyl formate;
3. the method according to claim 2, wherein in step (1), the organic solvent is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
4. The method according to claim 2, wherein in step (1), the acidic reagent is selected from at least one of sulfuric acid and hydrochloric acid.
5. The method according to any one of claims 2 to 4, wherein in step (1), the weight ratio of the compound represented by the formula (I-1) to the organic solvent is 1:4 to 6.
6. The method according to any one of claims 2 to 4, wherein the compound of formula (I-3) is used in an amount of 10 to 13mol relative to 1mol of the compound of formula (I-1) in step (2).
7. The method of any one of claims 2-4, wherein the operation of step (2) comprises: and (3) carrying out the second reaction on the compound shown in the formula (I-3) and the compound shown in the formula (I-2) in a dropwise adding mode.
8. The method according to claim 7, wherein in the step (2), the dropping speed of the compound represented by the formula (I-3) is 1 to 2mL/min.
9. The method according to any one of claims 2-4, wherein in step (2), the method further comprises: and (3) contacting the material obtained after the second reaction with water to obtain a mixed material I, and performing post-treatment on the mixed material I to obtain the heterocyclic compound shown in the formula (I).
10. The use of the heterocyclic compound of claim 1 as a standard reference substance in the medical field.
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