CN106831760B - Preparation method of riociguat - Google Patents
Preparation method of riociguat Download PDFInfo
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- CN106831760B CN106831760B CN201510884059.6A CN201510884059A CN106831760B CN 106831760 B CN106831760 B CN 106831760B CN 201510884059 A CN201510884059 A CN 201510884059A CN 106831760 B CN106831760 B CN 106831760B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of Riociguat (Riociguat), which takes a compound shown in a formula 2 as a raw material and reacts in a solvent in the presence of a methylating reagent Me-X and alkali to obtain the Riociguat. The method avoids using NaH or LiHMDS and other alkalis which are expensive and difficult to store and use, and the reaction result shows that the yield is obviously improved, the impurity content of the product is obviously reduced, and the method is suitable for industrial use.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of Riociguat (Riociguat).
Background
Riociguat is produced by Bayer (Bayer)AG) was approved by FDA in 2013 at 10 months for the treatment of persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH) under the trade name AdempasTM. The chemical name of riociguat is 4, 6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b]Pyridin-3-yl]-5-pyrimidinyl-N-methylcarbamic acid methyl ester, CAS number 625115-55-1, having the structure shown below:
WO2003095451 discloses a process for preparing riociguat from a compound of formula 2 as a starting material, which is reacted with a methylating agent Me-X in the presence of a base to produce a compound of formula 1:
in the method, the base is selected from NaH or LiHMDS. This method has the following problems: the yield is low, when the base is selected from NaH, the reported yield is 29%, when the base is selected from LiHMDS, the reported yield is 72%; NaH and LiHMDS are expensive, have high activity, are easy to lose alkaline activity, are difficult to store and use, and are not suitable for industrial use.
Disclosure of Invention
The invention provides a preparation method of riociguat, which comprises the following steps of reacting a compound shown in a formula 2 in a solvent in the presence of a methylating agent Me-X and a base:
in the above step, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide, preferably from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, more preferably from potassium carbonate.
In some embodiments of the present invention, the molar ratio of the compound of formula 2 to the base is 1.0: 1.0-10.0, preferably 1.0: 1.0-8.0, more preferably 1.0: 1.0-8.0, even more preferably 1.0: 2.0-6.0, and particularly preferably 1.0: 4.0.
In some embodiments of the invention, the methylating agent Me-X is chosen from methyl iodide, dimethyl sulfate or methyl tosylate, preferably from methyl iodide.
In some embodiments of the present invention, the molar ratio of the compound of formula 2 to the methylating agent Me-X is 1.0: 1.0-3.0, preferably 1.0: 1.1-2.0, more preferably 1.0: 1.3-2.0, and further preferably 1.0: 1.5-2.0.
In some embodiments of the invention, the solvent used for the reaction is selected from the group consisting of methanol, ethanol, propanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, acetone, acetonitrile, toluene, dichloromethane, dichloroethane, N-methylpyrrolidone or hexamethylphosphoramide or a mixed solvent of any two or more of the above solvents is preferably selected from methanol, ethanol, propanol, isopropanol, N-butanol, t-butanol, tetrahydrofuran, dimethyltetrahydrofuran, dimethylsulfoxide, N-dimethylformamide or N-methylpyrrolidone or a mixed solvent of any two or more of the above solvents, more preferably from N, N-dimethylformamide, N-methylpyrrolidone or a mixed solvent of methanol and N-methylpyrrolidone.
Compared with the prior art, the method for preparing riociguat avoids using NaH or LiHMDS and other alkalis which are expensive and difficult to store and use, and the reaction result shows that the yield is obviously improved, the impurity content of the product is obviously reduced, and the method is suitable for industrial use.
The invention employs the following abbreviations: NaH represents sodium hydride; LiHMDS represents lithium bis (trimethylsilyl) amide; DMSO represents dimethyl sulfoxide; DMF stands for N, N-dimethylformamide.
All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out in an anhydrous solvent under inert nitrogen. The compound is made by hand or
The software names, and the commercial compounds are under the supplier catalog name.
The HPLC detection method of the present invention may employ the following conditions: a chromatographic column: waters SunFire C18(5 μm, 4.6 × 250 mm); flow rate: 1.0 mL/min; column temperature: 40 ℃; detection wavelength: 237nm, mobile phase acetonitrile/water, with 0.1% formic acid in water. One skilled in the art can also run the HPLC using other conditions depending on the technical situation.
Detailed Description
The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention.
Example 1
Mixing 50g (0.122mol) of the compound shown in the formula 2 with 375mL of a mixed solvent of N-methylpyrrolidone and anhydrous methanol, namely 2:1, and stirring uniformly; adding 67.5g (0.488mol) of anhydrous potassium carbonate, stirring and cooling to 0-10 ℃ under the protection of nitrogen, adding 11.44mL (0.184mol) of methyl iodide, controlling the temperature to 0-10 ℃ for reaction, reacting for 24h, and monitoring by TLC (thin layer chromatography) until the reaction is basically complete; dropwise adding the reaction solution into 2500mL of purified water, stirring for 10min, carrying out suction filtration, washing with 100mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 40.5g (0.096mol) of an off-white solid are obtained in 78.3% yield and 93.45% purity by HPLC.
MS(ESI+):m/z＝423.17[M+H]+。
Example 2
Mixing 50g (0.122mol) of the compound shown in the formula 2 with 375mL of a mixed solvent of N-methylpyrrolidone and anhydrous methanol, namely 2:1, and stirring uniformly; adding 67.5g (0.488mol) of anhydrous potassium carbonate, stirring and cooling to 0-10 ℃ under the protection of nitrogen, adding 15.25mL (0.245mol) of methyl iodide, controlling the temperature to 0-10 ℃ for reaction, reacting for 24h, monitoring by TLC, and reacting completely; dropwise adding the reaction solution into 2500mL of purified water, stirring for 10min, carrying out suction filtration, washing with 100mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 42g (0.099mol) of an off-white solid were obtained in 81.2% yield and 94.83% HPLC purity.
Example 3
2g (4.90mmol) of the compound of formula 2 are mixed with 15mL of N-methylpyrrolidone: anhydrous methanol 2:1, mixing the mixed solvents, and uniformly stirring; adding 2.7g (19.6mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, respectively adding 0.31mL (4.98mmol) of methyl iodide, controlling the temperature to be 0-10 ℃ for reaction, reacting for 24h, monitoring by TLC, and displaying the purity of the reaction liquid to be 84.69% by HPLC; dropwise adding the reaction solution into 100mL of purified water, stirring for 10min, carrying out suction filtration, washing with 4mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 1.75g (4.14mmol) of an off-white solid were obtained in 84.5% yield.
Example 4
2g (4.90mmol) of the compound of formula 2 are mixed with 15mL of N-methylpyrrolidone: anhydrous methanol 2:1, mixing the mixed solvents, and uniformly stirring; adding 2.7g (19.6mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, adding 0.34mL (54.6mmol) of iodomethane (1.1-fold molar ratio), controlling the temperature to be 0-10 ℃ for reaction, monitoring by TLC after 24 hours of reaction, and displaying that the purity of the reaction solution is 87.43% by HPLC; dropwise adding the reaction solution into 100mL of purified water, stirring for 10min, carrying out suction filtration, washing with 4mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 1.70g of an off-white solid was obtained with a yield of 84.1%.
Example 5
1g (2.45mmol) of the compound of formula 2 was mixed with 7.5mL of N-methylpyrrolidone: anhydrous methanol 2:1, mixing the mixed solvents, and uniformly stirring; adding 0.675g (4.89mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, adding 0.23mL (3.69mmol) of iodomethane, controlling the temperature to be 0-10 ℃ for reaction, and monitoring by TLC after 24 hours of reaction to complete the reaction; and dropwise adding the reaction solution into 50mL of purified water, stirring for 10min, carrying out suction filtration, washing with 2mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 0.82g of an off-white solid was obtained in 79.6% yield and 92.13% HPLC purity.
Example 6
1g (2.45mmol) of the compound of formula 2 was mixed with 7.5mL of N-methylpyrrolidone: anhydrous methanol 2:1, mixing the mixed solvents, and uniformly stirring; stirring 2.03g (14.7mmol) of anhydrous potassium carbonate under the protection of nitrogen, adding 0.23mL (3.69mmol) of methyl iodide, controlling the temperature to be 0-10 ℃ for reaction, and monitoring by TLC after 24 hours of reaction to complete the reaction; and dropwise adding the reaction solution into 50mL of purified water, stirring for 10min, carrying out suction filtration, washing with 2mL of purified water, and carrying out vacuum drying at 50-60 ℃ for 24 h. 0.83g of an off-white solid was obtained in 80.6% yield and 94.89% HPLC purity.
Example 7
Mixing 2g (4.90mmol) of the compound shown as the formula 2 with 20mL of N-methylpyrrolidone, and uniformly stirring; adding 2.7g (19.6mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, adding 0.46mL (7.35mmol) of iodomethane, controlling the temperature to be 0-10 ℃ for reaction, reacting for 24h, and monitoring by TLC; HPLC analysis of the reaction solution showed that 88.23% of the compound of formula 1 was produced.
Example 7
2g (4.90mmol) of the compound of formula 2 are mixed with 30mL of N-methylpyrrolidone: anhydrous methanol 2:1, mixing and stirring uniformly; adding 2.7g (19.6mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, adding 0.46mL (7.35mmol) of methyl iodide, controlling the temperature to be 0-10 ℃ for reaction, after 24h of reaction, monitoring by TLC, and detecting a reaction liquid by HPLC to generate 98.28% of a compound of the formula 1.
Example 8
Mixing 2g (4.90mmol) of the compound of formula 2 with 20mL of DMF and 50mL of anhydrous methanol, and stirring uniformly; adding 2.7g (19.6mmol) of anhydrous potassium carbonate, stirring under the protection of nitrogen, adding 0.46mL (7.35mmol) of methyl iodide, controlling the temperature to be 0-10 ℃ for reaction, and monitoring by TLC after the reaction is carried out for 24 hours to generate a compound 93.52 of the formula 1.
Example 9
Mixing 2g (4.90mmol) of the compound shown as the formula 2 with 10mL of N-methylpyrrolidone, and uniformly stirring; stirring and cooling to-20 to-10 ℃ under the protection of nitrogen, adding 7.4mL of 1mol/L THF solution of LiHMDS, and stirring for 10 min; controlling the temperature to be minus 20 ℃ to minus 10 ℃, and adding 0.46mL (7.13mmol) of methyl iodide; controlling the temperature to be 0-10 ℃ after the addition, reacting for 12h, and then monitoring by TLC (thin layer chromatography), wherein the reaction is not complete and more impurities are generated; HPLC showed that the compound of formula 1 was 42.24% and the compound of formula 2 was 18.65% at this time, with an impurity level of 19.58%.
Claims (6)
1. A process for the preparation of riociguat which comprises reacting a compound of formula 2 in a solvent in the presence of a methylating agent Me-X and a base:
the base is selected from potassium carbonate;
the molar ratio of the compound of the formula 2 to the alkali is 1.0: 2.0-6.0;
the molar ratio of the compound shown in the formula 2 to the methylating agent Me-X is 1.0: 1.0-3.0;
the methylating agent Me-X is selected from methyl iodide;
the solvent used for the reaction is selected from methanol, N-dimethylformamide or N-methylpyrrolidone or a mixed solvent of any two or more of the solvents.
2. The method of claim 1, wherein the molar ratio of the compound of formula 2 to the base is 1.0: 4.0.
3. The method for preparing riociguat according to claim 1, wherein the molar ratio of the compound of formula 2 to the methylating agent Me-X is 1.0: 1.1-2.0.
4. The method for preparing riociguat according to claim 1, wherein the molar ratio of the compound of formula 2 to the methylating agent Me-X is 1.0: 1.3-2.0.
5. The method for preparing riociguat according to claim 1, wherein the molar ratio of the compound of formula 2 to the methylating agent Me-X is 1.0: 1.5-2.0.
6. The process according to claim 1, wherein the solvent used in the reaction is selected from the group consisting of N, N-dimethylformamide, N-methylpyrrolidone, and a mixture of methanol and N-methylpyrrolidone.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070225299A1 (en) * | 2003-11-06 | 2007-09-27 | Bayer Healthcare Ag | Novel Combination Containing a Stimulator of Soluble Guanylate Cyclase and a Lipid-Lowering Substance |
| US20140148433A1 (en) * | 2010-09-03 | 2014-05-29 | Bayer Intellectual Property Gmbh | Bicyclic aza heterocycles, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070225299A1 (en) * | 2003-11-06 | 2007-09-27 | Bayer Healthcare Ag | Novel Combination Containing a Stimulator of Soluble Guanylate Cyclase and a Lipid-Lowering Substance |
| US20140148433A1 (en) * | 2010-09-03 | 2014-05-29 | Bayer Intellectual Property Gmbh | Bicyclic aza heterocycles, and use thereof |
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