CN114380783B - Preparation method of olopatadine deuterium labeled metabolite - Google Patents
Preparation method of olopatadine deuterium labeled metabolite Download PDFInfo
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- CN114380783B CN114380783B CN202210055475.5A CN202210055475A CN114380783B CN 114380783 B CN114380783 B CN 114380783B CN 202210055475 A CN202210055475 A CN 202210055475A CN 114380783 B CN114380783 B CN 114380783B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
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- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of an olopatadine deuterium labeled metabolite, which takes (Z) -2- (11- (3-hydroxypropyl) -6,11-dihydrodibenzo [ b, e ] oxcarbazepine-2-yl) methyl acetate as a raw material to synthesize the olopatadine deuterium labeled metabolite through five steps of reaction. The preparation method provided by the invention has the advantages of reasonable process design, strong operability, mild reaction conditions and high yield. The olopatadine deuterium labeled metabolite prepared by the invention can provide important basis for scientific evaluation of quality, safety and efficiency of olopatadine and provide a standard reference substance for further research of the drug. The isotope labeled drug can be used for tracking the metabolic process of the drug in the organism, and has great application and research values in clinical pharmacokinetic research.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of an olopatadine deuterium labeled metabolite.
Technical Field
Olopatadine (Olopatadine), a selective dibenzoxepin-2-acetic acid histamine H1 receptor antagonist and mast cell stabilizer, inhibits the release of tachykinins and other chemical transmitters, such as histamine, arachidonic acid, thromboxane, leukotriene, and the like. It is used for treating allergic rhinitis, allergic conjunctivitis, urticaria, skin diseases (eczema, erythema multiforme exudativum, etc.) complicated with pruritus, and asthma. It can be used for treating allergic rhinitis, urticaria, and dermatoses accompanied by pruritus (eczema, erythema multiforme and exudation). The 1% eye drop can be used for treating allergic conjunctivitis. 0.6% nasal spray is used for relieving seasonal allergic rhinitis symptoms of patients of 6 years old or older.
With the progress of the times and the improvement of the technological level, people have more sufficient understanding on the importance of scientific evaluation of the quality, safety, efficacy and the like of the medicine before the medicine is marketed, wherein the control of deuterium labeled metabolites contained in the medicine is closely related to the quality of the medicine. Deuterium labeled metabolites are often associated with drug safety and in rare cases also efficacy. Therefore, controlling the level of deuterium-labeled metabolites is becoming more and more appreciated by medical workers in the process of drug development and research.
The synthetic method of the olopatadine deuterium labeled metabolite provided by the invention is not reported, the research on the olopatadine deuterium labeled metabolite on relevant pharmacology, pharmacokinetics and the like is carried out, and the deuterium labeled drug can be used for tracking the metabolic process of the drug in a living body, so that the synthetic method has great application and research values in clinical pharmacokinetic research.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the defects of the prior art and provides a method for synthesizing a novel drug molecule olopatadine deuterium labeled metabolite with reasonable process design, high yield and convenient and controllable operation process.
The technical scheme is as follows: in order to achieve the above purpose, the invention adopts the technical scheme that:
a preparation method of olopatadine deuterium labeled metabolite is characterized by comprising the following steps:
(1) Reacting the compound II under the action of a brominating reagent to obtain a compound III;
(2) Taking a compound III and a marked compound IV to react in an aprotic solvent under the action of alkali by heating and stirring, and finishing the reaction
Purifying by column chromatography to obtain a compound V;
(3) Dissolving a compound V in an organic solvent, adding chloroformate, and reacting to obtain a compound VI;
(4) Dissolving a compound VI in a protic solvent, and obtaining a compound VII after the reaction is finished;
(5) Dissolving the compound VII in an organic solvent, adding inorganic base under the ice bath condition, carrying out hydrolysis reaction, adjusting acid to separate out solid after the reaction is finished, and drying to obtain a compound I, namely the olopatadine deuterium labeled metabolite
The chemical name of the olopatadine deuterium labeled metabolite prepared by the invention is (Z) -2- (11- (3- ((methyl-d 3) amino) propylene) -6,11-dihydrodibenzo [ b, e]Oxcarbazepine-2-yl) acetate having a molecular weight of 362.87 and a molecular formula of C 20 H 19 D 3 ClNO 3 。
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the bromination reagent in the step (1) is phosphorus tribromide, triphenylphosphine/carbon tetrabromide, hydrobromic acid and the like;
preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the molar ratio of the compound II in the step (1) to the bromination reagent is 1:1-1:3, and preferably 1.5.
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the base in the step (2) is sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, or the like.
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the aprotic solvent in the step (2) is dimethyl sulfoxide, N-dimethylformamide, acetonitrile, tetrahydrofuran, or the like.
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the molar ratio of the substrate (compound iii and labeled compound iv) to the base in the step (2) is 1:1-1:3, and preferably 1. Wherein the molar ratio of the compound III to the labeled compound IV is 1:1-1.7.
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the organic solvent in the step (3) is dichloromethane, 1,2-dichloroethane, toluene, n-hexane, or the like.
Preferably, in the above method for preparing the olopatadine deuterium labeled metabolite, the chloroformate in the step (3) is ethyl chloroformate, 1-chloroethyl chloroformate, trichloroethyl chloroformate, methyl chloroformate, or the like.
Preferably, in the preparation method of the olopatadine deuterium labeled metabolite, the protic solvent in the step (4) is methanol, ethanol, isopropanol, or the like.
Preferably, in the above preparation method of the olopatadine deuterium-labeled metabolite, the organic solvent in the step (5) is methanol, ethanol, tetrahydrofuran, dioxane, or the like, and the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like.
Has the advantages that: the preparation method of the olopatadine deuterium labeled metabolite provided by the invention has the following advantages:
1. the synthesis method of the novel drug molecule olopatadine deuterium labeled metabolite provided by the invention has the advantages of reasonable process design, simple operation method, easily obtained raw materials, high synthesis efficiency, high purity, controllable reaction process and good environmental protection effect.
2. The olopatadine deuterium labeled metabolite prepared by the invention can provide important basis for scientific evaluation of quality, safety and efficiency of olopatadine, and has important application value.
Drawings
Fig. 1 is a flow chart of a preparation process of olopatadine deuterium-labeled metabolite provided by the invention.
FIG. 2 shows compounds I according to the invention 1 H-NMR chart (DMSO-d 6).
FIG. 3 shows the preparation of compound I of the present invention 1 H-NMR chart (DMSO-D6 + D2O).
FIG. 4 is a drawing of Compound III of the present invention 1 H-NMR chart (DMSO-d 6).
Detailed Description
The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention.
Example 1
As shown in fig. 1: the preparation method of the olopatadine deuterium labeled metabolite specifically comprises the following steps:
(1) Preparation of Compound III Compound II (12g, 37mmol) was dissolved in 100ml hydrobromic acid and reacted overnight at 50 ℃ to give Compound III (13 g) in 90.8% correct nuclear magnetic resonance (FIG. 4): DMSO-d6: δ 2.93 (m, 2H), 3.60 (s, 5H), 3.67 (t, 2H), 5.24 (br, 2H), 5.66 (t, 1H), 6.77 (d, 1H), 7.05-7.11 (m, 2H), 7.28-7.30 (m, 1H), 7.31-7.43 (m, 3H).
(2) Preparation of Compound V Compound III (13g, 33mmol) and Compound IV (4.6g, 37mmol) were dissolved in tetrahydrofuran (650 mL), 7g of potassium carbonate was added, and after refluxing for 20h, after suction filtration and concentration, purification by column chromatography (developing solvent: dichloromethane-methanol: 100) gave Compound V (13.0 g), correct for MS: m/z,431.2 with a yield of 90.06%.
(3) Preparation of Compound VI Compound V (13g, 30mmol) was dissolved in toluene (130 mL), 1-chloroethyl chloroformate (8.63g, 60mmol) was added, and after 2h reaction at 60 ℃ direct concentration and drying gave 13.4g of yellow oil VI, correct mass spectrum, MS: m/z,447.2, 99% yield.
(4) Preparation of compound VII, compound VI (13.4g, 30mmol) is taken to be dissolved in ethanol (250 mL), after reflux reaction overnight, the raw material is reacted completely, after the reaction is finished and concentrated, 8.0g of light yellow oily substance VII is obtained by column chromatography separation (developing agent: dichloromethane-methanol: 20: m/z,341.2, yield 78.48%.
(5) Preparation of compound i: dissolving the compound VII (8.0 g, 23mmol) in tetrahydrofuran (100 mL), adding 2M sodium hydroxide solution (8 mL) at room temperature, reacting at room temperature for 2 hours, concentrating, dissolving in water, adjusting to acidity with dilute hydrochloric acid, filtering, and vacuum drying to obtain 5.30g of off-white solid compound I with the yield of 62.30%. Process for preparing compounds I 1 The H NMR spectrum is shown in FIG. 2 and FIG. 3: DMSO-D6+ D2O: δ 2.73 (m, 2H), 3.10 (t, 2H), 3.53 (s, 2H), 4.80-5.60 (br, 2H), 5.66 (t, 1H), 6.81 (d, 1H), 7.03-7.04 (s, 1H), 7.11-7.13 (d, 1H), 7.30-7.45 (m, 4H).
Example 2
The process flow diagram is shown in figure 1: the preparation method of the olopatadine deuterium labeled metabolite specifically comprises the following steps:
(1) Preparation of Compound III (5.6 g) was obtained by dissolving Compound II (5 g, 15mmol) in 50ml of hydrobromic acid and reacting overnight at 100 ℃ in the same manner as in example 1 with an H-NMR yield of 93.9%.
(2) Compound V is prepared by dissolving compound III (13g, 33mmol) and compound IV (4.6g, 37mmol) in tetrahydrofuran (650 mL), adding 2g sodium hydroxide, refluxing for 20h, vacuum filtering for concentration, and purifying by column chromatography (as in example 1) to obtain compound V (13.5 g), with MS data as in example 1, at a yield of 93.53%.
(3) Compound VI is prepared by dissolving compound V (13g, 30mmol) in 1,2 dichloroethane (130 mL), adding ethyl chloroformate (6.55g, 60mmol), reacting at 60 deg.C for 3h, directly concentrating and drying to obtain 13.0g yellow oil VI, the MS data is the same as example 1, the yield is 96.3%.
(4) The preparation of the compound VII comprises the steps of dissolving a compound VI (13.4g, 30mmol) in isopropanol (250 mL), completely reacting after refluxing and reacting overnight, concentrating after the reaction, and separating by column chromatography (the same chromatographic conditions as in example 1) to obtain 7.5g of light yellow oily substance VII, wherein the MS data is the same as in example 1, and the yield is 73.6%.
(5) The compound I is prepared by dissolving compound VII (8.0 g, 23mmol) in methanol (100 mL), adding 2M sodium hydroxide solution 8mL at room temperature, reacting for 2 hours at room temperature, concentrating, dissolving in water, adjusting to acidity with dilute hydrochloric acid, filtering, and vacuum drying to obtain 5.5g off-white solid compound I with a yield of 64.66%. Process for preparing compounds I 1 The H NMR spectrum is shown in FIGS. 2 and 3.H-NMR data were as in example 1.
Example 3
The process flow diagram is shown in figure 1, and the preparation method of the olopatadine deuterium labeled metabolite specifically comprises the following steps:
(1) Compound III was prepared by dissolving compound II (5 g, 15mmol) in 50ml of tetrahydrofuran, adding triphenylphosphine (4.85g, 18mmol) and carbon tetrabromide (7.67g, 23mmol), reacting overnight at room temperature, concentrating, and purifying by column chromatography to give compound III (5.7 g), H-NMR data similar to example 1, yield 95.6%.
(2) Compound V was prepared by dissolving compound III (13g, 33mmol) and compound IV (6.3g, 50mmol) in tetrahydrofuran (650 mL), adding 2g sodium hydroxide, refluxing for 20h, concentrating by suction filtration, and purifying by column chromatography (as in example 1) to give compound V (14.0 g), MS data as in example 1, 97.0% yield.
(3) Compound VI is prepared by dissolving compound V (13g, 30mmol) in toluene (130 mL), adding trichloroethylchloroformate (12.79g, 60mmol), reacting at 20 deg.C for 2h, directly concentrating and drying to obtain 13.5g yellow oil VI, the MS data is the same as example 1, the yield is 99.9%.
(4) The preparation of the compound VII comprises the steps of dissolving a compound VI (13.4g, 30mmol) in ethanol (130 mL), completely reacting the raw materials after refluxing and reacting overnight, concentrating the reaction product, and separating by using column chromatography (the chromatographic conditions are the same as in example 1) to obtain 8.2g of light yellow oily substance VII, wherein the MS data are the same as in example 1, and the yield is 80.4%.
(5) The compound I is prepared by dissolving compound VII (8.0 g, 23mmol) in tetrahydrofuran (100 mL), adding 2M sodium hydroxide solution at room temperature for 8mL, reacting at 40 deg.C for 1 hr, concentrating, dissolving in water, adjusting to acidity with dilute hydrochloric acid, suction filtering, and vacuum drying to obtain 6.0g of off-white solid compound I with a yield of 70.5%. Process for preparing compounds I 1 The H NMR is shown in FIGS. 2 and 3.H-NMR data were as in example 1.
It can be seen from the comparison analysis of example 1, example 2 and example 3 that the yields of the synthesized products are different from each other due to the different reaction raw materials, the different amount ratios of the reaction raw materials and the different reaction conditions, wherein the yields of the steps of example 3 are higher than those of example 1 and example 2, which indicates that the reaction conditions according to example 3 are the best. And a better technical progress is achieved.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of olopatadine deuterium labeled metabolite is characterized by comprising the following steps:
(1) Reacting the compound II under the action of a brominating reagent to obtain a compound III;
(2) Taking a compound III and a marked compound IV to react in an aprotic solvent under the action of alkali by heating and stirring, and after the reaction is finished, purifying by using column chromatography to obtain a compound V;
(3) Dissolving a compound V in an organic solvent, adding chloroformate, and reacting to obtain a compound VI; the chloroformate is ethyl chloroformate, 1-chloroethyl chloroformate or trichloroethyl chloroformate;
(4) Dissolving a compound VI in a protic solvent, and obtaining a compound VII after the reaction is finished;
(5) Dissolving the compound VII in an organic solvent, adding inorganic base under the ice bath condition, carrying out hydrolysis reaction, adjusting acid to separate out solid, drying to obtain a compound I, namely the olopatadine deuterium labeled metabolite,
2. the process for the preparation of olopatadine deuterium labeled metabolites of claim 1 wherein the brominating agent of step (1) is phosphorous tribromide, triphenylphosphine/carbon tetrabromide or hydrobromic acid.
3. The method for preparing olopatadine deuterium labeled metabolite according to claim 1, wherein the molar use ratio of the compound II to the brominating reagent in the step (1) is 1:1-1:3.
4. The method for preparing olopatadine deuterium labeled metabolite according to claim 1, wherein the base of step (2) is sodium hydroxide, potassium carbonate, sodium carbonate, or triethylamine.
5. The method for preparing olopatadine deuterium labeled metabolite of claim 1, wherein the aprotic solvent of step (2) is dimethyl sulfoxide, N-dimethylformamide, acetonitrile or tetrahydrofuran.
6. The method for preparing a metabolite labeled with olopatadine deuterium according to claim 1, wherein the molar ratio of the compound III to the labeled compound IV to the base in step (2) is 1:1-1:3.
7. The method for preparing olopatadine deuterium labeled metabolite of claim 1, wherein the organic solvent of step (3) is dichloromethane, 1,2-dichloroethane, toluene, or n-hexane.
8. The method for preparing olopatadine deuterium labeled metabolite of claim 1, wherein the protic solvent of step (4) is methanol, ethanol or isopropanol.
9. The method for preparing a metabolite labeled with olopatadine deuterium according to claim 1, wherein the organic solvent in step (5) is methanol, ethanol, tetrahydrofuran or dioxane; the inorganic alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116863A (en) * | 1986-03-03 | 1992-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof |
| WO2014147647A1 (en) * | 2013-03-19 | 2014-09-25 | Council Of Scientific & Industrial Research | A process for the synthesis of olopatadine |
| WO2017178510A1 (en) * | 2016-04-12 | 2017-10-19 | Laboratorios Del Dr. Esteve, S.A. | Arylamide derivatives having multimodal activity against pain |
| CN108467385A (en) * | 2017-06-27 | 2018-08-31 | 浙江同源康医药股份有限公司 | Deuterated difficult to understand this of one kind replacing Buddhist nun's derivative and its application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5116863A (en) * | 1986-03-03 | 1992-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof |
| WO2014147647A1 (en) * | 2013-03-19 | 2014-09-25 | Council Of Scientific & Industrial Research | A process for the synthesis of olopatadine |
| WO2017178510A1 (en) * | 2016-04-12 | 2017-10-19 | Laboratorios Del Dr. Esteve, S.A. | Arylamide derivatives having multimodal activity against pain |
| CN108467385A (en) * | 2017-06-27 | 2018-08-31 | 浙江同源康医药股份有限公司 | Deuterated difficult to understand this of one kind replacing Buddhist nun's derivative and its application |
Non-Patent Citations (1)
| Title |
|---|
| 《Russian Journal of Organic Chemistry》;S. Endoori 等;《Novel and Efficient Synthesis of Deuterium-Labeled Olopatadine-d6》;20191022;第55卷;第1387–1393页 * |
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