CN113527124A - Preparation method of chiral azide intermediate compound of Idoxaban - Google Patents
Preparation method of chiral azide intermediate compound of Idoxaban Download PDFInfo
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- CN113527124A CN113527124A CN202011518719.6A CN202011518719A CN113527124A CN 113527124 A CN113527124 A CN 113527124A CN 202011518719 A CN202011518719 A CN 202011518719A CN 113527124 A CN113527124 A CN 113527124A
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Abstract
The invention provides a preparation method of chiral azide intermediate compounds of Eicosa-Saxaban, which comprises the following steps of taking a hydroxyl compound shown as a formula (II) as a substrate, and carrying out substitution reaction with organic azide compounds in an organic solvent in the presence of amidine structural compounds to obtain the chiral azide intermediate compounds shown as a formula (I); the method directly optimizes two-step synthesis reaction into one-step synthesis reaction, takes organic azide compounds such as diphenylphosphorylazide, p-toluenesulfonylazide and trimethylsilyl azide as the source of azide groups, and generates substitution reaction in a proper solvent with the help of amidine structural compounds such as formamidine, DBN, DBU, triazamidine and the like to obtain a target compound chiral azide intermediate; not only successfully avoids the use of hypertoxic products such as methanesulfonyl chloride and explosive sodium azide, but also reduces the process difficulty and the production cost.
Description
(I) technical field
The invention relates to a preparation method of an Edison chiral azide intermediate compound.
(II) background of the invention
Edoxaban is a small molecule oral anticoagulant of the first three co-company corporation of japan. Approval was obtained in 2011 at month 4 and marketed in 2011 in japan at month 7. In the coagulation process, activated coagulation factor x (FXa) activates prothrombin (FII) to thrombin (FIIa), causing fibrin formation, thereby forming thrombus, and FXa has become the main eight major of the next generation of anticoagulant drugs. The doxifaban can achieve the aim of inhibiting thrombosis through selectively and reversibly inhibiting FXa. Clinical studies verify the good safety, oral absorbability and anticoagulant activity of the composition. The chemical structure of edoxaban is shown in figure 1.
Currently, edoxaban is mainly prepared by synthesizing three fragments A, B, C through constructing an amido bond, wherein the fragment a is a key intermediate in a synthetic route and has 3 chiral centers, and the preparation route is shown in fig. 2.
In this route, the conversion from intermediate 04 to intermediate 06 uses NaN in the prior art documents (WO2014081047, EP1925611, EP2407450, EP2407457, EP2589590, US20150353577, JP5801011 and org. process res.dev.2019, 23(4), 524-3This highly explosive hazard limits the industrial preparation of the compounds.
The above prior art also has the following disadvantages: (1) in the preparation of the intermediate 04 (i.e. the compound (II)) to the intermediate 05, methanesulfonyl chloride is used for protecting hydroxyl, and the methanesulfonyl chloride is used as a highly toxic substance and has inconvenience in various aspects such as purchase, storage, use and the like; (2) in the preparation of intermediate 05 to intermediate 06 (i.e. compound (I)), NaN was used3The mesyl is substituted, and the patent US2012053349A1 describes that the reaction eliminates more by-products, the chiral selectivity of the product is poor, the generated chiral isomer is difficult to separate, and the chiral purity of the target compound is low; (3) sodium azide in large excess, containing NaN3The organic solvent and the waste water are not easy to treat, and are not beneficial to environmental protection.
Disclosure of the invention
The invention aims to provide a preparation method of an Edosasant chiral azide intermediate compound, which is low in safety risk, suitable for industrial production and high in efficiency.
The technical scheme adopted by the invention is as follows:
a preparation method of chiral azide intermediate compounds of Eicosa-Spain is characterized in that a hydroxyl compound shown as a formula (II) is used as a substrate, and is subjected to substitution reaction with organic azide compounds in an organic solvent in the presence of amidine structural compounds to obtain the chiral azide intermediate compounds shown as a formula (I);
specifically, the organic azide compound is one of the following compounds: diphenyl phosphorazidate, p-toluenesulfonylazide, trimethylsilyl azide.
The organic azide is used as the source of the azide group, and NaN is avoided3The highly explosive dangerous goods are safer. Moreover, the yield of the method can reach more than 85 percent, which is much higher than that of the prior art by 23.9-68.1 percent (from patents EP2407450, WO2007032498 and the like). The method can also well control the chirality and obtain a target compound with completely reversed configuration, the crude product obtained by the compound after palladium-carbon hydrogenation reduction is recrystallized, and the chiral purity of the obtained diamine compound can reach almost 100%.
Preferably, the amidine structural compound is one of the following compounds: formamidine, DBN, DBU, triazamidine.
Preferably, the organic solvent is one of the following or a mixture of two or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, dichloromethane, methyl isobutyl ketone.
Preferably, the amount ratio of the hydroxyl compound, the organic azide compound and the amidine structural compound is 1: 1-2.
Preferably, the substitution reaction is carried out at-20 ℃ to 50 ℃.
Preferably, the reaction is carried out under nitrogen protection.
Specifically, the method comprises the following steps: under the protection of nitrogen, sequentially adding a hydroxyl compound shown in the formula (II), an organic azide compound and an organic solvent into a reaction container, cooling to 0 +/-5 ℃, adding an amidine structural compound, reacting at 0 +/-5 ℃ for 1-2 hours, then recovering to room temperature, continuing to react for 12-18 hours, after the reaction is finished, sequentially washing a reaction system with water and a 3-5% hydrochloric acid solution, then carrying out reduced pressure concentration, and carrying out column purification to obtain a chiral azide intermediate compound shown in the formula (I).
The invention has the following beneficial effects: the method directly optimizes two-step synthesis reaction into one-step synthesis reaction, takes organic azide compounds such as diphenylphosphorylazide, p-toluenesulfonylazide and trimethylsilyl azide as the source of azide groups, and generates substitution reaction in a proper solvent with the help of amidine structural compounds such as formamidine, DBN, DBU, triazamidine and the like to obtain a target compound chiral azide intermediate; not only successfully avoids the use of hypertoxic products such as methanesulfonyl chloride and explosive sodium azide, but also reduces the process difficulty and the production cost.
(IV) description of the drawings
FIG. 1 is a chemical structure diagram of edoxaban;
FIG. 2 is a preparation roadmap for edoxaban;
FIG. 3 is a HPLC chart showing the purity of the chiral azide intermediate compound of formula (I) obtained in example 1;
FIG. 4 is a chiral purity analytical HPLC chart of the chiral azide intermediate compound of formula (I) obtained in example 1.
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1:
a50 ml reaction flask was charged with the hydroxy compound represented by the formula (II) (3.0g, 10.5mmol), diphenyl azidophosphate (CAS:26386-88-9) (3.5g, 12.7mmol) and toluene (18ml) in this order under nitrogen protection. Cooled to 0 ℃. Formamidine (0.56g, 12.7mmol) was added. The reaction was allowed to react at 0 ℃ for 2 hours and then returned to room temperature for further 16 hours. The content of the liquid phase tracking intermediate 04 is lower than 0.2 percent. The system was washed with 10ml of water 2 and 10ml of 5% (w/w) hydrochloric acid in sequence, then concentrated under reduced pressure, and Column purified Agela Flash Column Silica-CS (40g) to obtain 2.89g (yield 88.5%) of the chiral azide intermediate compound of formula (I) (purity 98.5%), which was shown in FIG. 3 for HPLC chart of purity and in FIG. 4 for HPLC chart of chiral purity.
Nuclear magnetic data: 1H-NMR (CDCl 3). delta.1.45 (9H, s), 1.58-1.66(1H, m), 1.67-1.76(1H, m), 1.84-1.96(2H, m), 2.04-2.15(1H, m), 2.17-2.26(1H, m), 2.75-2.81(1H, m), 2.94(3H, s), 3.04(3H, s), 3.07(3H, s), 4.00-4.08(1H, m), 4.69-4.82(2H, m).
Palladium-carbon hydrogenation reduction: taking 1g of chiral azide intermediate compound shown as formula (I) (with the purity of 98.5%), adding 10mL of methanol, stirring to dissolve, adding 0.05g of 10% palladium carbon (with the water content of 50%), heating to 40 ℃, introducing hydrogen for 1 hour, cooling, carrying out suction filtration and concentration, and recrystallizing the obtained concentrate with twice as much acetonitrile to obtain 0.8g of diamine compound (with the chiral purity of 99.99%).
Example 2:
a50 ml reaction flask was charged with the hydroxy compound represented by the formula (II) (3.0g, 10.5mmol), diphenyl phosphorazidate (3.5g, 12.7mmol) and toluene (18ml) in this order under nitrogen protection. Cooled to 0 ℃. DBU (1.93g, 12.7mmol) was added. The reaction was allowed to react at 0 ℃ for 2 hours and then returned to room temperature for further 16 hours. The content of the liquid phase tracking intermediate 04 is lower than 0.2 percent. The reaction system was washed with 10ml of water and 10ml of 5% hydrochloric acid in this order, and then concentrated under reduced pressure and column-purified to obtain 2.97g (yield 91%) of the chiral azide intermediate compound represented by the formula (I) (purity 98.9%).
Example 3:
a50 ml reaction flask was charged with a hydroxy compound represented by the formula (II) of intermediate 04 (3.0g, 10.5mmol), diphenyl phosphorazidate (3.5g, 12.7mmol), and anhydrous tetrahydrofuran (18ml) in this order under nitrogen protection. Cooled to 0 ℃. DBU (1.93g, 12.7mmol) is added, the reaction is carried out at 0 ℃ for 2 hours, then the reaction is continued for 16 hours after the temperature is returned to room temperature, the content of the intermediate 04 is tracked to be lower than 0.2 percent in the liquid phase, 20ml of water and 20ml of toluene are added, the mixture is stirred for 15 minutes and then stands for layering, the organic phase system is washed by 10ml of water and 2 ml of 5 percent hydrochloric acid in sequence, and then is purified by a reduced pressure concentration column to obtain 2.90g (yield is 89 percent) of the chiral azide intermediate compound shown in the formula (I) (purity is 98.7 percent).
Example 4:
a50 ml reaction flask was charged with the hydroxy compound represented by the formula (II) (3.0g, 10.5mmol), diphenyl phosphorazidate (3.5g, 12.7mmol) and methyl tert-butyl ether (18ml) in this order under nitrogen protection. Cooled to 0 ℃. DBU (1.93g, 12.7mmol) is added to react at 0 ℃ for 2 hours, then the reaction is continued at room temperature for 16 hours, the content of the intermediate 04 is tracked to be lower than 0.2% in the liquid phase, and the system is washed by 10ml of 2 and 10ml of 5% hydrochloric acid in sequence, and then purified by a reduced pressure concentration column to obtain 2.90g (yield is 89%) of the chiral azide intermediate compound shown in the formula (I) (purity is 98.4%).
Example 5:
a50 ml reaction flask was charged with the hydroxy compound represented by the formula (II) (3.0g, 10.5mmol), diphenyl phosphorazidate (3.5g, 12.7mmol) and methyl tert-butyl ether (18ml) in this order under nitrogen protection. Cooled to 0 ℃. DBN (1.58g, 12.7mmol) is added, the reaction is carried out at 0 ℃ for 2 hours, then the reaction is continued for 16 hours after the temperature is returned to room temperature, the content of the intermediate 04 is tracked to be lower than 0.2%, and the system is washed by 10ml of 2 and 10ml of 5% hydrochloric acid in sequence and then purified by a reduced pressure concentration column to obtain 2.80g (yield 86%) of the chiral azide intermediate compound shown in the formula (I) (purity is 98.2%).
Example 6:
a250 ml reaction flask was charged with a hydroxy compound represented by the formula (II) (30g, 0.105mol), diphenyl phosphorazidate (35g, 0.127mmol) and toluene (180ml) in this order under nitrogen protection. Cooled to 0 ℃. DBU (19.3g, 0.127 mol) is added to react at 0 ℃ for 2 hours, then the reaction is continued for 16 hours after the temperature is returned to room temperature, the content of the intermediate 04 is tracked to be lower than 0.2 percent in the liquid phase, and the system is washed by 100ml of 2 and 100ml of 5 percent hydrochloric acid in sequence and then purified by a reduced pressure concentration column to obtain 29.4g (yield is 90 percent) of the chiral azide intermediate compound shown in the formula (I) (purity is 98.8 percent).
Claims (8)
1. A preparation method of chiral azide intermediate compounds of Eicosa-Spain is characterized in that a hydroxyl compound shown as a formula (II) is used as a substrate, and is subjected to substitution reaction with organic azide compounds in an organic solvent in the presence of amidine structural compounds to obtain the chiral azide intermediate compounds shown as a formula (I);
2. the method of claim 1, wherein the organic azide compound is one of: diphenyl phosphorazidate, p-toluenesulfonylazide, trimethylsilyl azide.
3. The method according to claim 1, characterized in that the amidine structural compound is one of the following: formamidine, DBN, DBU, triazamidine.
4. The method according to claim 1, wherein the organic solvent is one of the following or a mixture of two or more thereof: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, dichloromethane, methyl isobutyl ketone.
5. The method according to claim 1, wherein the amount of the hydroxy compound, the organic azide compound and the amidine structure compound is 1: 1-2.
6. The method of claim 1, wherein the substitution reaction is carried out at a temperature of from-20 ℃ to 50 ℃.
7. The method of claim 1, wherein the reaction is conducted under nitrogen protection.
8. The method of claim 1, wherein the method is as follows: under the protection of nitrogen, sequentially adding a hydroxyl compound shown in the formula (II), an organic azide compound and an organic solvent into a reaction container, cooling to 0 +/-5 ℃, adding an amidine structural compound, reacting at 0 +/-5 ℃ for 1-2 hours, then recovering to room temperature, continuing to react for 12-18 hours, after the reaction is finished, sequentially washing a reaction system with water and a 3-5% hydrochloric acid solution, then carrying out reduced pressure concentration, and carrying out column purification to obtain a chiral azide intermediate compound shown in the formula (I).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116102465A (en) * | 2023-02-17 | 2023-05-12 | 珠海市海瑞德生物科技有限公司 | Process for producing optically active diamine compound |
| WO2024053350A1 (en) * | 2022-09-09 | 2024-03-14 | 株式会社カネカ | Method for producing aminoazide compound, diamine compound, and edoxaban |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111606827A (en) * | 2020-06-23 | 2020-09-01 | 内蒙古京东药业有限公司 | Method for preparing chiral amine intermediate of edoxaban |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111606827A (en) * | 2020-06-23 | 2020-09-01 | 内蒙古京东药业有限公司 | Method for preparing chiral amine intermediate of edoxaban |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024053350A1 (en) * | 2022-09-09 | 2024-03-14 | 株式会社カネカ | Method for producing aminoazide compound, diamine compound, and edoxaban |
| CN116102465A (en) * | 2023-02-17 | 2023-05-12 | 珠海市海瑞德生物科技有限公司 | Process for producing optically active diamine compound |
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