CN112920203A - Ruidexiwei related substance and preparation method thereof - Google Patents
Ruidexiwei related substance and preparation method thereof Download PDFInfo
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Abstract
The invention provides a Rudexilevir related substance I and a preparation method thereof, wherein the method takes iodo-triazine and nucleoside as raw materials, and specifically comprises the following steps: adding iodotriazine into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation; cooling to-30-20 deg.C, adding phenylmagnesium chloride, stirring for 30-60 min; adding isopropyl magnesium chloride-lithium chloride, and stirring for 30-60min under heat preservation; adding organic solvent solution of nucleoside, stirring for 30-60 min; adding acid water, extracting with organic solvent, concentrating to obtain crude product of related substance I, and refining to obtain pure product of related substance I. The preparation method has the advantages of easily available raw materials, mild reaction conditions, high safety coefficient and high purity of the obtained related substance I. And the method has strong operability and is easy to operate in a laboratory.
Description
Technical Field
The invention belongs to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a Rudexilvir related substance I and a preparation method thereof.
Background
In the process of drug production, impurity research is an indispensable and very important part, and the residual impurities of drug intermediates can bring potential risks to the drug finished products in the later period. The presence of these impurities not only affects the efficacy of the drug, but also causes problems during production and storage, and some impurities may even cause toxic side effects. Therefore, the analysis and research on the medicine impurities can ensure the safety, effectiveness and stability of the medicine application and provide a basis for the quality assurance of the production and circulation processes. The impurity standard substance is a standard substance for identifying, checking and measuring the content of impurities. Therefore, it is very necessary to prepare and study impurity standards during the production and quality control processes.
Reidesciclovir belongs to the class of nucleoside analogs, is an RNA-dependent RNA polymerase (RdRp) inhibitor, and can be used to combat viruses by inhibiting viral nucleic acid synthesis. Current clinical studies on ebola virus infection have progressed to phase II. Mice infected with MERS performed much better with this combination therapy, reduced viral replication and improved lung function. Recent research shows that the Redexilvir has a certain activity effect on inhibiting the new coronavirus.
The Reidesciclovir synthesis method disclosed in patent CN105343098A by Gilidex corporation is characterized in that iodo-aminotriazine and nucleoside lactone are used as starting materials, iodo-triazine and nucleoside are in butt joint to form a key intermediate P3, and further cyano substitution and other series of conversions are carried out to generate Reidesciclovir.
In the detection of the bulk drug of the Reidesciclovir, the inventor finds that an unknown impurity exists, and the peak area ratio of the unknown impurity is generally 0.05-0.10%. The impurity is a Reidesciclovir related substance I, namely (2R,3R,4R) -1, 1-di (4-aminopyrrolo [2, 1-f) through high resolution mass spectrum and nuclear magnetic resonance characterization][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the following structure:
in the process of development of a Reidesciclovir analysis method and subsequent finished product inspection, the impurities in the Reidesciclovir are required to be positioned and quantitatively researched by using the standard products of the impurities, so that a large amount of standard products of the Reidesciclovir impurity I are required to be used. For the preparation of the ridciclovir-related substance I, a conventional impurity separation method can be adopted: target impurities are separated from a Redexiluwei bulk drug sample, but the content of the target impurities can only reach 0.11% at most through HPLC (high performance liquid chromatography) detection, and the sample also contains a plurality of similar impurities with similar contents, which can interfere separation, the separation period is long, a pure product can be obtained through multiple times of separation, and the total yield is generally about 0.03%.
Based on the above, the application provides a Reidesciclovir related substance I and a preparation method thereof.
Disclosure of Invention
The invention aims to provide a preparation method of a Rudexilvir related substance I, namely (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol, which is used for researching impurity standards.
In order to achieve the purpose, the invention adopts the following technical scheme:
the related substance I of the Reidesciclovir is (2R,3R,4R) -1, 1-di (4-aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the formula:
the preparation method of the Reidesciclovir related substance I comprises the following steps:
(1) adding iodotriazine (P1) into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation;
(2) cooling to-30-20 deg.C, adding phenylmagnesium chloride, stirring for 30-60 min;
(3) adding isopropyl magnesium chloride-lithium chloride, and stirring for 30-60min under heat preservation;
(4) adding organic solvent solution of nucleoside (P2), keeping temperature and stirring for 30-60 min;
(5) adding acid water, extracting with organic solvent, concentrating to obtain crude product of related substance I, and refining to obtain pure product of related substance I.
The structure of the iodotriazine (P1) in the invention is as follows:
the structure of the nucleoside (P2) is:
preferably, the organic solvent in step (1) and step (4) is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-ether, dimethylformamide, chloroform, isopropyl acetate; further preferred is tetrahydrofuran; the volume mass ratio of the organic solvent to the iodotriazine is 5-20: 1; further preferably 10-15: 1.
Preferably, the molar ratio of trimethylchlorosilane to iodotriazine in step (1) is 1.0-2.5:1, more preferably 2.0-2.2: 1. The reaction temperature is more preferably 0 to 5 ℃.
Preferably, the molar ratio of phenylmagnesium chloride to iodotriazine in step (2) is 1.5-2.5:1, more preferably 2.0-2.2: 1. The reaction temperature is preferably-5 to 0 ℃.
Preferably, the molar ratio of isopropyl magnesium chloride-lithium chloride to iodotriazine in step (3) is 0.5 to 1.2:1, and more preferably 0.9 to 1.0: 1. The reaction temperature is preferably-5 to 0 ℃.
Preferably, the molar ratio of nucleoside to iodotriazine in step (4) is 0.3-1.5:1, more preferably 0.4-0.6: 1. The reaction temperature is preferably-5 to 0 ℃.
Preferably, the acid in step (5) is selected from an organic acid, an inorganic acid, or a combination thereof; the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
Preferably, the organic solvent in step (5) is one or more selected from ethyl acetate, toluene, xylene, dichloromethane, methyl tert-ether, chloroform and isopropyl acetate; further preferred is ethyl acetate or dichloromethane.
The refining specifically comprises the following steps: adding solvent 4-10 times of the mass of the crude product of the related substance I, heating to 50-70 ℃, slowly cooling to 0-20 ℃, and filtering to obtain a pure product.
Preferably, the solvent used in the refining process in the step (5) is one or more selected from ethyl acetate, toluene, xylene, methyl tert-ether, isopropyl acetate, n-hexane, n-heptane, cyclohexane and petroleum ether; more preferred is methyl tertiary ether.
Compared with the prior art, the invention has the following beneficial effects:
1) the method provided by the application is adopted to prepare the Reidesciclovir related substance I, the yield of the Reidesciclovir related substance I can reach 60-80%, the yield is greatly improved, and the quality is good; compared with the traditional method, the yield can be improved by more than one thousand times.
2) According to the method provided by the application, the adopted solvent can be tetrahydrofuran, dichloromethane, ethyl acetate, methyl tertiary ether and other organic solvents, and an unusual or expensive organic solvent is not involved, so that the chiral center of the product is stable under an acidic condition, and isomerization cannot occur.
3) In the whole preparation process, the used reagents are safe and environment-friendly, the reaction conditions are mild, special equipment and raw materials are not needed, the preparation period is short, the treatment is simple, the operation is easy, and the cost is low.
4) The related substance I obtained by the invention can be used as an important index in quality control of the Reidesciclovir, the intermediate thereof or the preparation thereof, and has the advantages of simple preparation method and environmental friendliness.
Drawings
Figure 1 is a liquid phase detection diagram of a reidesavir bulk drug substance produced by the process of example 1;
figure 2 is a liquid quality inspection chart of a ridciclovir bulk drug produced by the process of example 1;
FIG. 3 is a liquid phase diagram of related substance I in a bulk drug substance of Reidesciclovir produced by the process of example 1;
FIG. 4 is a liquid mass spectrum of related substance I in a bulk drug substance of Reidesciclovir produced by the process of example 1;
FIG. 5 is nuclear magnetic hydrogen spectrum of substance I prepared by the present invention;
FIG. 6 is a carbon spectrum of related substance I prepared by the present invention;
FIG. 7 shows the heavy water exchange hydrogen spectrum of related substance I prepared by the present invention.
Detailed Description
The present invention will be further explained with reference to specific examples in order to make the technical means, the technical features, the technical objectives and the effects of the present invention easier to understand, but the following examples are only preferred embodiments of the present invention, and not all embodiments of the present invention. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.
The experimental methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified. Wherein iodotriazine (P1), nucleoside (P2), Tetrahydrofuran (THF), trimethylchlorosilane (TMSCl), phenylmagnesium chloride in tetrahydrofuran (PhMgCl), isopropylmagnesium chloride in lithium chloride in tetrahydrofuran (i-PrMgCl. LiCl) are available from Michelin reagent. The manufacturer of the instrument used in the examples described below was Taizhou Xinli instruments, and the manufacturer of the detection instrument was Agilent.
Example 1
In the detection of the bulk drug of the Reidesciclovir, the applicant finds that an unknown impurity exists.
The route diagram for producing the bulk drug of the Reidesciclovir is as follows:
the inclusion of Reidesciclovir in the product prepared by the above procedure is demonstrated by liquid phase detection (FIG. 1) and liquid quality detection (FIG. 2). A liquid phase spectrum (figure 3) and a liquid mass spectrum (figure 4) prove that an impurity peak corresponding to 15min in the preparation process is related to a substance I, and the peak area ratio is generally 0.05-0.10%. The impurity is identified as a Reidesciclovir related substance I, namely (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol, which has the following structure through high resolution mass spectrum and nuclear magnetic resonance characterization:
example 2
The preparation method of the Reidesciclovir related substance I comprises the following synthetic process:
the method specifically comprises the following steps:
(1)130g of substrate P1(0.5mol) are dissolved in 1300mL of THF and cooled to 5 ℃. 108g of TMSCl is slowly added, the temperature is kept and the stirring is carried out for 0.5h, and the temperature is reduced to 0 ℃.
(2) 525mL of PhMgCl (2M in THF) is slowly dropped into the reactor, the internal temperature is controlled to be-5-0 ℃, the temperature is kept and the stirring is carried out for 0.5h after the addition is finished, and the temperature is cooled to-5 ℃. (Note: PhMgCl in a molar amount of 0.525X 2. about.1.05 mol)
(3) 330mL of i-PrMgCl. LiCl (1.5M in THF) was added dropwise, the internal temperature was controlled at-5 to 0 ℃ and the temperature was kept for 40min after the addition.
(4) A solution of P2(105g) in THF (200mL) was added dropwise thereto, the internal temperature was controlled at-5-0 ℃ and the temperature was kept for 1 hour after the addition.
(5) Dropwise adding dilute hydrochloric acid for quenching, adjusting the pH to 5-6, adding 1000mL of ethyl acetate for extraction, and concentrating an organic phase to obtain a crude product; adding methyl tertiary ether solvent with the mass 6 times of that of the crude product into the crude product of the related substance I, heating to 60 ℃, keeping for 1-2h, slowly cooling to 10 ℃, keeping for 1-2h, and filtering to obtain 137g of a pure product, wherein the yield is 80%, and the purity is 99.2%.
Example 3: 1.2 molar ratio (0.6mol) of phenylmagnesium chloride
The only difference from example 1 is that: the amount of PhMgCl added in step (2) was 300mL, and the other steps and experimental parameters were the same as those in example 1. The product was purified to obtain 127g of pure product, 74% yield and 98.6% purity.
Example 4: 1.2 molar ratio (0.6mol) of trimethylchlorosilane
The only difference from example 1 is that: the amount of TMSCl added in step (1) was 129.6g, and the other steps and experimental parameters were the same as those in example 1. The product was purified to obtain 121g of a pure product with a yield of 71% and a purity of 97.8%.
Example 5: 1.0 molar ratio (0.5mol) of nucleosides
The only difference from example 1 is that: step (4) 209g of P2 in THF (200mL) was added dropwise, and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 111g of pure product with a yield of 65% and a purity of 98.4%.
Example 6
The only difference from example 1 is that: the temperature in step (2) was set to 10 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 113g of pure product, yield 66% and purity 95.8%.
Comparative example 1
The only difference from example 1 is that: the temperature in step (1) was set at-20 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to give 96g of a pure product, 56% yield and 93.5% purity.
Comparative example 2
The only difference from example 1 is that: the stirring time in step (1) was set to 5min, and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 79g of a pure product with a yield of 46% and a purity of 92.8%.
Comparative example 3
The only difference from example 1 is that: the temperature in step (2) was set to 30 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 84g of a pure product with a yield of 49% and a purity of 91.8%.
Comparative example 4
The only difference from example 1 is that: the stirring time in step (2) was set to 20min, and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 87g of a pure product with a yield of 51% and a purity of 93.6%.
Comparative example 5
The only difference from example 1 is that: the temperature in step (3) was set to 40 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 72g of pure product, yield 42% and purity 92.3%.
Test example
The structural representation of the liquid mass and the nuclear magnetic resonance structure of the prepared Reidesciclovir related substance I confirms that the structure of a synthetic product is correct, and the liquid mass (figure 4), the nuclear magnetic resonance hydrogen spectrum (figure 5) and the carbon spectrum (figure 6) are analyzed. The molecular formula of the related substance I is as follows: C38H38N8O5, the calculated molecular weight is 686.30, the anion peak is [ M-H ]:685.10 and the cation peak is [ M + H ]:687.41 in figure 4, which is in accordance with the theoretical calculation.
The compound number is shown below:
TABLE 3 NMR analysis of Reidesciclovir-related substance I
| Proton type | Chemical shift | Home H encoding | Number of protons |
| O-H | 3.4ppm,5.0ppm | H-9,5 | 2H |
| C-H | 3.5-5.0ppm,5.5ppm | H-6,7,8,10,11,12,13 | 11H |
| C-H | 6.5-7.5ppm | H-(Ph1,2,3),3,3’,4,4’ | 19H |
| C-H | 7.7ppm,7.8ppm | H-2,2’ | 2H |
| N-H | 7.7-8.0ppm | H-1,1’ | 4H |
Note: the O-H and N-H chemical shifts disappeared after heavy water exchange, as shown in FIG. 7.
TABLE 4 NMR analysis of Reidesciclovir-related substance I
| Proton type | Chemical shift | Home H encoding | Number of protons |
| C | 70-90ppm | C-7,8,10,11,12,13,14 | 7C |
| C | 100-120ppm | C-3,3’,4,4’,5,5’ | 6C |
| C | 130-160ppm | C-(Ph1,2,3),1,1’,2,2’,6,6’ | 24C |
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The Reidcciclovir related substance I is characterized in that the related substance I is (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the formula:
2. a process for the preparation of reidecivir related substance I as defined in claim 1, comprising the steps of:
(1) adding iodotriazine into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation;
(2) cooling to-30-20 deg.C, adding phenylmagnesium chloride, stirring for 30-60 min;
(3) adding isopropyl magnesium chloride-lithium chloride, and stirring for 30-60min under heat preservation;
(4) adding organic solvent solution of nucleoside, stirring for 30-60 min;
(5) adding acid water, extracting with organic solvent, concentrating to obtain crude product of related substance I, and refining to obtain pure product of related substance I.
3. A preparation method of ridciclovir related substance I according to claim 2, characterized in that the organic solvent in step (1) and step (4) is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-ether, dimethylformamide, chloroform, isopropyl acetate; the volume mass ratio of the organic solvent to the iodotriazine is 5-20: 1.
4. A process for preparing ridciclovir related substance I according to claim 2, wherein the molar ratio of trimethylchlorosilane to iodotriazine in step (1) is 1.0-2.5: 1.
5. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of phenylmagnesium chloride to iodotriazine in step (2) is 1.5-2.5: 1.
6. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of isopropyl magnesium chloride-lithium chloride to iodotriazine in step (3) is 0.5-1.2: 1.
7. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of nucleoside to iodotriazine in step (4) is 0.3-1.5: 1.
8. A process for the preparation of ridciclovir related substance I according to claim 2, wherein in step (5) the acid is selected from organic acid, inorganic acid or combination thereof; preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
9. A preparation method of ridciclovir related substance I according to claim 2, wherein the organic solvent in step (5) is one or more selected from ethyl acetate, toluene, xylene, dichloromethane, methyl tert-ether, chloroform and isopropyl acetate.
10. A process for the preparation of reidecivir related substance I according to claim 2, wherein the purification process in step (5) is specifically operated as follows: adding a solvent with the mass of 4-10 times of the crude product of the related substance I, heating to 50-70 ℃, slowly cooling to 0-20 ℃, and filtering to obtain a pure product; preferably, the solvent used in the refining process is one or more selected from ethyl acetate, toluene, xylene, methyl tertiary ether, isopropyl acetate, n-hexane, n-heptane, cyclohexane and petroleum ether.
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| WO2019018185A1 (en) * | 2017-07-15 | 2019-01-24 | Arisan Therapeutics Inc. | Enantiomerically pure adamantane derivatives for the treatment of filovirus infection |
| US20200017514A1 (en) * | 2018-07-12 | 2020-01-16 | Michael Plewe | Adamantane derivatives for the treatment of filovirus infection |
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| CN111233930B (en) * | 2020-03-04 | 2022-05-13 | 江苏阿尔法药业股份有限公司 | Preparation method of Reidesciclovir |
| CN111961079A (en) * | 2020-07-17 | 2020-11-20 | 南京正济医药研究有限公司 | Ruideciclovir related substance and preparation method and application thereof |
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| WO2019018185A1 (en) * | 2017-07-15 | 2019-01-24 | Arisan Therapeutics Inc. | Enantiomerically pure adamantane derivatives for the treatment of filovirus infection |
| US20200017514A1 (en) * | 2018-07-12 | 2020-01-16 | Michael Plewe | Adamantane derivatives for the treatment of filovirus infection |
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Application publication date: 20210608 |