CN110878039A - Preparation method of Sacubitril valsartan sodium impurity - Google Patents
Preparation method of Sacubitril valsartan sodium impurity Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a Sacubitril valsartan sodium impurity. The method adopts PyBOP as a condensing agent, can synthesize an impurity compound II, further limits the reaction temperature, can obviously improve the yield and purity of the impurity compound II, is simple to operate, has mild conditions, is suitable for large-scale industrial production of the impurity compound II of the valsartan sodium Sacubitril, is used for detecting and monitoring the impurity in the production of the raw material medicine of the valsartan sodium Sacubitril, and thus controls the quality of the raw material medicine of the valsartan sodium Sacubitril.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a Sacubitril valsartan sodium impurity.
Background
The valsartan sodium Sacubitril is a compound of an enkephalinase inhibitor Sacubitril and an angiotensin II receptor blocker valsartan, is suitable for patients with chronic heart failure (NYHA classes II-IV), has the advantages of reducing the probability of cardiovascular death and hospitalization of the heart failure, is the first and only drug with the curative effect remarkably superior to that of standard therapeutic drug enalapril (enalapril) in clinical tests, shows higher safety and has wide market prospect.
The conventional method for synthesizing the sabotara valsartan sodium is basically prepared by co-crystallizing sabotara, valsartan and an aqueous solution of sodium hydroxide, for example, WO2008/083967 discloses a preparation method for preparing the sabotara valsartan sodium, and the reaction route is as follows:
in the process of preparing the intermediate 1, the intermediate 1 can undergo aminolysis and cyclization to form an impurity compound II, the impurity compound II exists in a final product and affects the purity of the valsartan sodium drug substance, and the impurity needs to be detected and monitored in the process of synthesizing the valsartan sodium drug substance, so that the quality of the valsartan sodium drug substance is controlled.
However, at present, the synthesis of impurity compound II is less studied, and only a few literature references are mentioned. WO2009/90251 discloses a method for preparing a racemate of an impurity compound II, in which a raw material compound III is reduced with hydrogen to obtain the impurity compound II and its corresponding isomer, but hydrogen leakage or improper handling in the reaction is liable to cause explosion, which has a certain safety hazard.
For example, WO2008/83967 also discloses a method for preparing a racemate of an impurity compound II, in which a raw material compound IV is subjected to a carbanion alkylation reaction to prepare the impurity compound II and its corresponding isomer, but in the process of forming carbanions, n-butyllithium, which is harmful to the environment and human body, needs to be added, and the reaction needs to be carried out at-78 ℃, and the conditions are harsh.
Therefore, the prepared impurity compound II is a racemic mixture, chirality is not distinguished, a large amount of impurity compound II with high purity is difficult to separate, a corresponding reference substance is lacked, the preparation method is not easy to control, the method is not suitable for large-scale industrial production, and detection and monitoring of the impurity in the process of synthesizing the sargasbara valsartan sodium are greatly influenced. Therefore, a preparation method of the impurity compound II of the valsartan sodium sabotartan, which is simple to operate, is urgently needed.
Disclosure of Invention
The invention aims to solve the technical problems that the synthesis method in the prior art is harsh in conditions and difficult to control, the synthesized impurity compound II is not chiral and is difficult to separate to obtain the impurity compound II with high purity, and provides the preparation method of the impurity compound II of the Sacubitril valsartan sodium, which is simple to operate, and the yield and the purity of the impurity compound II are improved by further limiting the reaction conditions.
The above purpose of the invention is realized by the following technical scheme:
a preparation method of a Sacubitril valsartan sodium impurity comprises the following reaction route:
the method specifically comprises the following steps:
dissolving a compound I in an aprotic organic solvent, adding a condensing agent and alkali for reaction, filtering after the reaction is completed, and performing post-treatment and drying on the filtrate to obtain the compound I;
wherein the condensing agent is benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
In practice, it is found that in the process of synthesizing the impurity compound II by using the compound I under an alkaline condition, intermolecular amide condensation occurs at the same time to generate the byproduct compound V, which greatly affects the purity of the target product impurity compound II, and even the byproduct becomes a main reaction product, and the target product impurity compound II cannot be obtained:
the inventors have found in practice that the above problems can be solved by using the specific condensing agent benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), which can promote the reaction toward the formation of the impurity compound II: under the alkaline condition, carboxyl negative ions attack a condensation reagent to generate acyloxyphosphorus positive ions, then the active intermediate is attacked by benzotriazole oxyl negative ions to generate acyl halide, and then the acyl halide reacts with intramolecular amino to form a stable lactam ring, so that an impurity compound II is generated.
Further, the temperature of the dropwise adding alkali reaction is-10-25 ℃.
Preferably, the temperature of the dropwise alkali reaction is-10 to 0 ℃. In practice, the yield and the purity of the impurity compound II of the target product can be obviously improved under the reaction temperature condition of-10-0 ℃.
Further, the base is selected from one of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), and sodium bicarbonate.
Preferably, the base is triethylamine or N, N-diisopropylethylamine.
More preferably, the base is N, N-diisopropylethylamine. In practice, it has been found that the impurity compounds prepared under these conditions are obtained in high yield and purity.
Furthermore, the mass ratio of the compound I to the condensing agent is 1 (1-2).
Furthermore, the mass ratio of the compound I and the alkali is 1 (1-5).
Further, the aprotic organic solvent is selected from one of Dichloromethane (DCM), N-Dimethylformamide (DMF), acetonitrile (MeCN).
Preferably, the aprotic organic solvent is acetonitrile. In practice, the impurity compound II prepared under the condition has higher yield and purity.
Furthermore, the weight-volume ratio of the compound I to the aprotic organic solvent is 1 (5-15) g/mL.
The invention has the following beneficial effects:
according to the preparation method of the impurity compound II of the Sacubitril valsartan sodium, disclosed by the invention, the impurity compound II can be synthesized by adopting PyBOP as a condensing agent, the reaction temperature is further limited, the yield and the purity of the impurity compound II can be obviously improved, the method is simple to operate and mild in conditions, and the preparation method is suitable for large-scale industrial production of the impurity compound II of the Sacubitril valsartan sodium and is used for detecting and monitoring the impurity in the production of the raw material medicine of the Sacubitril valsartan sodium, so that the quality of the raw material medicine of the Sacubitril valsartan sodium is controlled.
Drawings
Fig. 1 is a synthesis route diagram of the preparation method of the impurity compound II of sarkubaroptically valsartan sodium.
Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of the impurity compound II of sabotartan sodium prepared in example 9 of the present invention.
Fig. 3 is a high performance liquid chromatogram of the impurity compound II of sabotara valsartan sodium prepared in example 9 of the present invention.
Fig. 4 is a chromatogram peak table of a high performance liquid chromatogram of the Sacubitril valsartan sodium impurity compound II prepared in example 9 of the invention.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The synthetic route of the preparation method of the impurity compound II of the Sacubitril and valsartan is as follows:
wherein, the yield of the invention is as follows: amount of compound II actually obtained/amount of compound II theoretically obtained × 100%.
EXAMPLE 1 preparation of Sacubitril sodium valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of dichloromethane, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 6.3g of alkali TEA at the speed of 1mL/min at the temperature of 25 ℃, monitoring the complete reaction by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, carrying out vacuum concentration on the filtrate until the filtrate is dried, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 3.87g of impurity compound II, wherein the yield is 46.6%, and the purity is 65.72%.
Example 2 preparation of Sacubitril sodium valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of dichloromethane, adding 19.5g of condensing agent PyBOP, adding 7.6g of alkali DMAP three times at the temperature of 25 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, performing suction filtration, and drying the obtained solid to obtain 3.76g of impurity compound II, wherein the yield is 45.3%, and the purity is 65.82%.
Example 3 preparation of Sacubitril sodium impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of dichloromethane, adding 19.5g of condensing agent PyBOP, adding 5.3g of sodium bicarbonate three times at the temperature of 25 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 3.73g of impurity compound II, wherein the yield is 45.0%, and the purity is 55.37%.
Example 4 preparation of Sacubitril sodium impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of dichloromethane, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 8.1g of alkali DIPEA at the speed of 1mL/min at the temperature of 25 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 3.94g of impurity compound II, wherein the yield is 47.5%, and the purity is 75.84%.
EXAMPLE 5 preparation of Sacubitril sodium valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of dichloromethane, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 8.1g of alkali DIPEA at the speed of 1mL/min at the temperature of 0 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 7.08g of impurity compound II, wherein the yield is 85.3%, and the purity is 88.95%.
EXAMPLE 6 preparation of Sacubitril sodium Valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of N, N-dimethylformamide, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 8.1g of alkali DIPEA at the speed of 1mL/min at the temperature of 0 ℃, monitoring the reaction by TLC to be complete, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of N-hexane, cooling to 0 ℃, performing suction filtration, and drying the obtained solid to obtain 6.50g of impurity compound II, wherein the yield is 78.3%, and the purity is 89.80%.
Example 7 preparation of Sacubitril sodium impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of acetonitrile, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 8.1g of alkali DIPEA at the speed of 1mL/min under the temperature condition of minus 10 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, carrying out reduced pressure concentration on the filtrate until the filtrate is dry, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 6.65g of impurity compound II, wherein the yield is 80.2%, and the purity is 92.52%.
EXAMPLE 8 preparation of Sacubitril sodium Valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 10.0g of compound I in 80mL of acetonitrile, adding 19.5g of condensing agent PyBOP, slowly dropwise adding 8.1g of alkali DIPEA at the speed of 1mL/min at the temperature of-5 ℃, monitoring the reaction completion by TLC, filtering, adding 100mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, concentrating the filtrate under reduced pressure to dryness, pulping for 2h at the temperature of 40 ℃ by using 20mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, and drying the obtained solid to obtain 6.81g of impurity compound II, wherein the yield is 82.1%, and the purity is 91.79%.
EXAMPLE 9 preparation of Sacubitril sodium valsartan impurity Compound II
The impurity compound II of the valsartan sodium of the Sacubitril is prepared and separated by the following method:
dissolving 100g of compound I in 800mL of acetonitrile, adding 195.3g of condensing agent PyBOP, slowly dropwise adding 80.8g of alkali DIPEA at the speed of 1mL/min under the condition of 0 ℃, monitoring the complete reaction by TLC, filtering, adding 1000mL of saturated ammonium chloride solution into filtrate, stirring, collecting an organic layer after layering, adding anhydrous ammonium sulfate, drying for 1h, carrying out suction filtration, carrying out reduced pressure concentration on the filtrate until the filtrate is dry, pulping for 2h under the condition of 40 ℃ by 200mL of n-hexane, cooling to 0 ℃, carrying out suction filtration, drying the obtained solid to obtain 71.77g of impurity compound II, wherein the yield is 86.5%, and the purity is 97.80%.
The nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatogram of the impurity compound II of the Sacubitril valsartan in example 9 are determined, and the results are shown in figures 2-4.
Wherein, when the high performance liquid phase is detected, the sample solution: 10mg of the impurity compound II prepared in example 9 was weighed out precisely, placed in a 10mL volumetric flask, dissolved and diluted with an aqueous acetonitrile solution (acetonitrile: water: 33:67), and shaken up to obtain a sample solution.
The conditions of the high performance liquid chromatography are as follows: a chromatographic column using octadecylsilane chemically bonded silica as a filler is adopted, the detection wavelength is set to be 254nm, the flow rate is 1.0mL/min, the sample injection amount is 10 mu L, 0.1% trifluoroacetic acid water solution is used as a mobile phase A, 0.1% trifluoroacetic acid acetonitrile solution is used as a mobile phase B, gradient elution is carried out according to the conditions in the table 1, and a chromatogram is recorded.
TABLE 1 high Performance liquid chromatography gradient elution conditions
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 67 | 33 |
| 26 | 67 | 33 |
| 38 | 20 | 80 |
| 50 | 20 | 80 |
| 51 | 67 | 33 |
| 60 | 67 | 33 |
As can be seen from the graphs in FIGS. 3 to 4, the peak-off time of the impurity compound II of the valsartan sodium sabotara is about 26.7 min.
Comparative examples 1-3 preparation of Sacubitril valsartan sodium impurity compound II
Reference example 1 preparation of impurity compound II of valsartan sodium sabotartan with the difference that different condensing agents (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N-Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide/1-hydroxybenzotriazole (EDCI/HOBT), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU)), bases (triethylamine (TEA), N-Diisopropylethylamine (DIPEA)), reaction temperature, aprotic organic solvents were used to prepare impurity compound II, and the remaining parameters or operations were referenced to example 1. And recording the reaction condition, and calculating and detecting the yield and purity of the obtained compound II. Specific condensing agents, alkalis, reaction temperatures, aprotic organic solvents and experimental results are shown in tables 2 to 3.
TABLE 2 Effect of different condensing Agents on the reaction conditions
As can be seen from Table 1, when the condensing agent used was CDI, EDCI/HOBT or HATU, no target product was produced, and only when the condensing agent used was PyBOP, the yield of the target product was 46.6%.
TABLE 3 influence of different bases, reaction temperatures, aprotic organic solvents on yield and purity
As can be seen from table 3, the yield and purity of the target product impurity compound II prepared by the reaction at-10 to 0 ℃ are both high, and when the reaction temperature is increased to 25 ℃, the yield and purity are significantly reduced; when other conditions are the same, acetonitrile is used as the aprotic organic solvent, so that the yield and the purity are higher.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. A preparation method of a Sacubitril valsartan sodium impurity is characterized in that the reaction route is as follows:
the method specifically comprises the following steps:
dissolving a compound I in an aprotic organic solvent, adding a condensing agent and alkali for reaction, filtering after the reaction is completed, and performing post-treatment and drying on the filtrate to obtain the compound I;
wherein the condensing agent is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; the alkali is selected from one of triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine and sodium bicarbonate.
2. The preparation method according to claim 1, wherein the temperature of the dropwise addition reaction of the alkali is-10 to 25 ℃.
3. The preparation method according to claim 2, wherein the temperature of the dropwise addition reaction of the alkali is-10 to 0 ℃.
4. The method according to claim 1, wherein the base is triethylamine or N, N-diisopropylethylamine.
5. The method according to claim 4, wherein the base is N, N-diisopropylethylamine.
6. The preparation method according to claim 1, wherein the mass ratio of the compound I to the condensing agent is 1 (1-2).
7. The preparation method according to claim 1, wherein the mass ratio of the compound I and the base is 1 (1-5).
8. The method according to claim 1, wherein the aprotic organic solvent is one selected from dichloromethane, N-dimethylformamide, and acetonitrile.
9. The preparation method according to claim 1, wherein the weight-to-volume ratio of the compound I and the aprotic organic solvent is 1: 5-15 g/mL.
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| CN110845349A (en) * | 2019-11-26 | 2020-02-28 | 株洲千金药业股份有限公司 | Purification method of Sacubitril valsartan sodium intermediate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112730721A (en) * | 2020-12-29 | 2021-04-30 | 重庆三圣实业股份有限公司 | Method for separating and measuring Shakubatroxa calcium salt and isomer thereof |
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