Process for preparing high purity azilsartan

Abstract

The application belongs to the field of medicine synthesis, and particularly relates to a preparation process of high-purity azilsartan. Compound I and compound II are added into a solvent, a base and a catalyst are added, compound III is obtained after reaction; compound III and compound IV are added into a solvent, a catalyst and a base are added, compound V is obtained after reaction; compound V is subjected to an oximation reaction with hydroxylamine hydrochloride to obtain VI; VI is subjected to ring closure under the action of CDI, and azilsartan is finally obtained; a reaction equation is as follows: the application can shorten a synthesis route, simplify process steps, select cheap and green and environmental protection raw materials, avoid the use of toxic raw materials, is convenient to operate, has less impurities generated in a synthesis process, improves the purity and yield of product azilsartan, and is convenient for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation process of high-purity azilsartan medoxomil. BACKGROUND

[0002] Azilsartan medoxomil is a prodrug which can be rapidly converted into the active ingredient azilsartan after oral absorption. Azilsartan blocks the action of angiotensin II in various tissues by selectively blocking the binding of angiotensin II to AT1 receptors. Angiotensin II is the main pressor substance of the RAAS, and has the effects of vasoconstriction, stimulation of aldosterone synthesis and release, cardiac excitation, and sodium reabsorption in the kidney. Azilsartan medoxomil blocks the vasoconstrictor effect and aldosterone secretion effect of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors in many tissues such as vascular smooth muscle and adrenal glands. Therefore, its action is independent of the angiotensin II synthesis pathway. The affinity of azilsartan medoxomil for AT1 receptors is more than 10,000 times higher than that for AT2 receptors. Azilsartan medoxomil was first approved for marketing by the FDA in 2011.

[0003] The chemical structural formula of azilsartan medoxomil is as follows:

[0004]

[0005] From the reported synthesis routes of azilsartan medoxomil, there are two types in general. One type is esterification first, and then formation of an oxadiazole ring, and the other type is formation of an oxadiazole ring first, and then esterification, i.e. azilsartan is used as a raw material to form an ester with a side chain 4-hydroxymethyl-5-methyl-1,3-dioxol-2-ketone. The first type is esterification first and then ring formation, and the disadvantage is that the ester group is unstable and will decompose in the ring formation process, affecting the product quality and yield. The second type is ring formation first and then esterification, and compared with the first type, the product quality is easier to control, and the yield is relatively high, but ester exchange impurities are easily introduced.

[0006] The currently reported synthesis methods mainly include the following:

[0007] Patent WO2013156005A1 reports the following route:

[0008]

[0009] The preparation route of the side chain is as follows:

[0010]

[0011] This route is currently used by most manufacturers, using azilsartan as raw material and esterifying with side chain 4-hydroxymethyl-5-methyl-1,3-dioxol-2-ketone. The advantage is higher yield, but the preparation route of azilsartan ester is long, and methanol is easily introduced into the side chain, increasing the methyl ester impurity, which is difficult to remove in the product.

[0012] Patent US20140113942A1 reports the following route:

[0013]

[0014] This synthetic route uses azilsartan as raw material and reacts directly with 4-chloromethyl-5-methyl-1,3-dioxol-2-ketone under the action of base to obtain azilsartan ester. Although this synthetic route uses cheaper 4-chloromethyl-5-methyl-1,3-dioxol-2-ketone instead of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-ketone as the esterification raw material, it is easy to produce double-substituted impurities, which seriously affects the product quality and yield, and the product also needs to be purified by column chromatography, with a yield of only 22%.

[0015] WO2013114305A1 reports the following route:

[0016]

[0017] The difference between this synthetic route and the synthetic route of the original research patent is that the synthetic route is esterification first and then ring formation, and uses cheaper 4-chloromethyl-5-methyl-1,3-dioxol-2-ketone instead of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-ketone as the esterification raw material, which is a novel route design. However, the third step of this synthetic route is prone to impurities due to the presence of multiple active groups in the reactants, and the obtained intermediate is not very stable due to the ester group, which is prone to decomposition in subsequent reaction steps, thereby affecting the product quality and yield. In addition, this synthetic route uses the highly toxic ethyl chloroformate in the ring formation process, which is not conducive to industrial operation. In summary, this route is not suitable for industrialization.

[0018] CN103588765A improves the above process by using carbonyl diimidazole to close the ring in the fourth step, making the subsequent reaction more mild, and the yield of this step reaches more than 90%. However, the starting material used in this technology is expensive and has high cost.

[0019] CN105399738A reports the following route:

[0020]

[0021] The route respectively ring-closes segment 1 and esterifies segment 2, and then condenses to obtain the product, the route has short steps, but in the preparation process of segment 2, due to the non-obvious selectivity of the carboxyl and the amino, a large amount of impurities are generated, resulting in low yield and high impurities in the step, and in the last step of condensation, excessive alkalinity can cause product decomposition, and the overall yield is not high. SUMMARY

[0022] In order to overcome the shortcomings of the prior art, the purpose of the present application is to provide a preparation process of high-purity azilsartan medoxomil, shorten the synthesis route, simplify the process steps, select cheap and green environmental protection raw materials, avoid the use of toxic raw materials, convenient operation, less impurities generated in the synthesis process, improve the purity and yield of the product azilsartan medoxomil, and facilitate industrialized production.

[0023] The present application provides a preparation process of high-purity azilsartan medoxomil, comprising the following steps:

[0024] Step S1: Compound I and compound II are added to a solvent, a base and a catalyst are added, and compound III is obtained after reaction;

[0025] Step S2: Compound III and compound IV are added to a solvent, a catalyst and a base are added, and compound V is obtained after reaction;

[0026] Step S3: Compound V is subjected to oximation reaction with hydroxylamine hydrochloride to obtain VI;

[0027] Step S4: Compound VI is subjected to ring closure under the action of CDI (carbonyl diimidazole) to finally obtain azilsartan medoxomil.

[0028] The reaction equation is as follows:

[0029]

[0030] Preferably, the solvent in step S1 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, dichloroethane, methanol, ethanol; the base in step S1 is one or more of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropyl ethylamine, DBU.

[0031] More preferably, the solvent in step S1 is acetonitrile and N,N-dimethylacetamide in a volume ratio of 10-20:1. It is found in the experiment of the present application that if the solvent is only acetonitrile, the reaction product has high purity, but the reaction speed is slow, and if the solvent is only N,N-dimethylacetamide, the reaction speed is fast, but the bromine loss impurity of compound II is obviously high. We find that by adding a small amount of N,N-dimethylacetamide to acetonitrile, using acetonitrile and N,N-dimethylacetamide in a volume ratio of 10-20:1 as the solvent, the reaction speed is fast, and the impurities are less, and the product has high purity.

[0032] More preferably, the base in step S1 is potassium carbonate and triethylamine in a mass ratio of 100-110:10. It is found in the research of the present application that in the reaction process, the reaction speed using potassium carbonate is obviously faster than that using triethylamine, but the bromine loss impurity of compound II is obviously high. We find that by adding part of triethylamine to potassium carbonate, using potassium carbonate and triethylamine in a mass ratio of 100-110:10, the impurities are obviously reduced, the high yield is maintained, and the fast reaction speed is maintained.

[0033] Preferably, the reaction temperature in step S1 is 20-120°C, preferably 60-80°C.

[0034] Preferably, the molar ratio of compound I, compound II, and base in step S1 is 1:0.85-1.1:1.5-3.0. Preferably, the amount of compound I in step S1 is 1.0 eq; the amount of compound II is 0.85-1.1 eq, preferably 0.95 eq; and the amount of base is 1.5-3.0 eq, preferably 2.0 eq.

[0035] Preferably, the solvent in step S2 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, toluene, xylene, acetonitrile, acetone, dichloromethane, ethyl acetate, and 1,4 dioxane; preferably toluene or acetonitrile.

[0036] Preferably, the reaction temperature in step S2 is 20-80°C.

[0037] Preferably, the catalyst in step S2 is catalyst 1 and catalyst 2 in a molar ratio of 1-3:1-3.

[0038] Catalyst 1 is one or more of palladium acetate, dichloro[1,2-bis(diphenylphosphino)ethane]palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium acetate, bis(diphenylphosphino) palladium, and dichlorobistriphenylphosphine palladium; preferably dichlorobistriphenylphosphine palladium and bis(triphenylphosphine)palladium acetate.

[0039] The catalyst S2 is one or more of bidentate phosphine ligands or biaryl phosphine ligands.

[0040] Preferably, the catalyst 2 in step S2 is biaryl phosphine ligand and bidentate phosphine ligand in a molar ratio of 0.01±0.001:0.01.

[0041] The bidentate phosphine ligand is one or more of CyPF-t-Bu, JosiPhos, Binap, XantPhos or DPPF.

[0042] The biaryl phosphine ligand is one or more of BrettPhos, RuPhos, XPhos, SPhos, BippyPhos.

[0043] More preferably, the catalyst 2 is RuPhos and DPPF in a molar ratio of 0.01±0.001:0.01. By using RuPhos and DPPF in combination, the present application not only has a faster reaction speed than single catalyst, but also produces less impurities and greatly improves the yield.

[0044] Preferably, the base in step S2 is one or more of triethylamine, DBU, sodium methoxide, sodium ethoxide or sodium tert-butoxide. More preferably, DBU and triethylamine in a mass ratio of 30-35:5, a small amount of triethylamine is added to DBU as a base, which can inhibit the generation of impurities of azithromycin and azithromycin methyl ester, improve the purity of the product, and at the same time obtain a higher yield.

[0045] Preferably, the molar ratio of compound III, compound IV, catalyst 1, catalyst 2 and base in step S2 is 1:1.2-2.0:0.01-0.03:0.01-0.03:1.5-3.0. Preferably, the amount of compound III in step S2 is 1.0 eq; the amount of compound IV is 1.5 eq; the amount of catalyst 1 is 0.01 eq; the amount of catalyst 2 is 0.02 eq; and the amount of base is 1.5 eq. If the amount of compound IV is too small, the reaction is incomplete and the impurities are too high; if the amount of catalyst 1 and catalyst 2 is too small, the reaction is slow, and if it is too much, the cost is high; if the amount of base is too much, the impurities are too much, and if it is too small, the reaction is slow.

[0046] Preferably, step S3 is: adding hydroxylamine hydrochloride in NMP, adding sodium bicarbonate in batches, controlling the temperature below 40℃, stirring after adding, then heating to 60±5℃, adding compound V, incubating, after the reaction is completed, cooling to 30-40℃, adding purified water, adjusting the pH to neutral with hydrochloric acid, and precipitating a large amount of white solid, filtering, adding isopropyl alcohol to the wet sample, beating at 30-40℃, then filtering, and drying at 40-50℃ under reduced pressure to obtain compound VI.

[0047] Preferably, step S4 is: adding compound VI, triethylamine, carbonyldiimidazole in dichloromethane, heating to reflux to react, after the reaction is completed, adding purified water to quench, and separating into organic phase and aqueous phase, collecting the organic phase, concentrating under reduced pressure, adding acetonitrile, hot beating at 40-50 DEG C, then cooling to 0-5 DEG C to crystallize, filtering, and drying to obtain compound azilsartan ester.

[0048] Compared with the prior art, the present application has the following beneficial effects:

[0049] The present application designs a brand new reaction route, shortens the synthesis route, simplifies the process steps, selects cheap and green raw materials, avoids the use of toxic raw materials, is easy to operate, has fast reaction speed, generates less impurities in the synthesis process, has high purity and high yield of the product azilsartan ester, and is convenient for industrial production of the route, thereby providing a direction for process improvement of azilsartan ester. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 : Liquid phase purity chart of azilsartan ester prepared in Example 1;

[0051] Figure 2 : Mass spectrum chart of azilsartan ester prepared in Example 1;

[0052] Figure 3 : Hydrogen spectrum chart of azilsartan ester prepared in Example 1. DETAILED DESCRIPTION

[0053] The present application is further described below through specific examples, and the examples described in the present application are only used to illustrate the present application and do not limit the scope of the present application.

[0054] Example 1

[0055] A preparation process of high-purity azilsartan ester includes the following steps:

[0056] (1) Preparation of compound III

[0057]

[0058] Into a reaction bottle, 800 ml of acetonitrile and 50 ml of N,N-dimethylacetamide are added, 100 g of compound I is added, 112.9 g of compound II is added, 110 g of potassium carbonate and 10 g of triethylamine are added, stirring is performed, and the temperature is raised to reflux to react for 8 h, after the reaction is completed, the temperature is lowered to 20-30 DEG C, filtering is performed, the filtrate is collected, 1200 ml of purified water is slowly added at 20-30 DEG C, a large amount of white solid is precipitated, stirring is performed for 30 min, filtering is performed, the filter cake is eluted with 50% acetonitrile aqueous solution, and drying is performed under reduced pressure at 40-50 DEG C to obtain 165.7 g of compound III, with a yield of 92.4% and a purity of 98.5%.

[0059] (2) Preparation of compound V

[0060]

[0061] Into the reaction bottle, 800 ml of acetonitrile was added, 100 g of compound III was added, 55 g of compound IV was added, 0.16 g of dichlorobis-triphenylphosphine palladium was added, 0.11 g of RuPhos (Shanghai Macklin Biochemical Technology Co., Ltd.) and 0.14 g of DPPF (Arlaudin Biochemical Technology Co., Ltd.) were added, 8 g of triethylamine and 53 g of DBU were added, and the reaction was stirred and heated to 60°C under inert gas protection. After 5 h of reaction, the temperature was lowered to 20-30°C, and diatomite was used for filtration. The filtrate was collected, 1000 ml of purified water was slowly added at 20-30°C, a large amount of light yellow solid was precipitated, and the stirring was continued for 30 min. The wet sample was filtered to obtain a wet sample. The wet sample was added to 500 ml of methyl tert-butyl ether, and the slurry was prepared at 20-30°C for 1 h. The filter cake was dried under reduced pressure at 40-50°C to obtain 96.6 g of compound V with a yield of 82.06% and a purity of 97.8%.

[0062] (3) Preparation of compound VI

[0063]

[0064] Into the reaction bottle, 1000 ml of NMP was added, 95 g of hydroxylamine hydrochloride was added, 140 g of sodium bicarbonate was added in batches, and the temperature was controlled below 40°C. After the addition was completed, the reaction was stirred for 1 h, and then the temperature was raised to 60°C. 100 g of compound V was added and reacted for 12 h. After the reaction was completed, the temperature was lowered to 30-40°C, 1000 ml of purified water was slowly added, the pH was adjusted to neutral with 2M hydrochloric acid, and a large amount of white solid was precipitated. The filter cake was filtered to obtain a wet sample. The wet sample was added to 800 ml of isopropyl alcohol, and the slurry was prepared at 30-40°C for 1 h. Then the filter cake was filtered and dried under reduced pressure at 40-50°C to obtain 84.5 g of compound VI with a yield of 79.36% and a purity of 99.0%.

[0065] (4) Preparation of azilsartan medoxomil

[0066]

[0067] Into a reaction flask, 1000 ml of dichloromethane was added, 100 g of compound VI was added, 22.5 g of triethylamine was added, 42 g of carbonyldiimidazole was added, the temperature was raised to reflux and reacted for 6 h, after the reaction was completed, 500 ml of purified water was slowly added to quench and separate, the organic phase was collected, then 500 ml of purified water was added and washed once, the organic phase was collected, concentrated to dryness under reduced pressure, 500 ml of acetonitrile was added, and the slurry was heated at 40-50°C for 1 h, then cooled to 0-5°C for 2 h, filtered, and dried under reduced pressure at 40-50°C to obtain 92.60 g of compound azilsartan ester. The liquid chromatography purity chart of the prepared azilsartan ester is shown in Figure 1 , the mass spectrum chart is shown in Figure 2 , and the hydrogen spectrum chart is shown in Figure 3 , the yield was 88.37%, and the purity was 99.9%.

[0068] Comparative Example 1

[0069] Step (1) Preparation of compound III:

[0070] Comparative Example 1 is basically the same as Example 1, the only difference being that in step (1): triethylamine is replaced by potassium carbonate.

[0071] Result: the reaction was incomplete, there were many impurities, 110.5 g of compound III was obtained, the yield was 56.05%, the purity was 83.5%, and it contained 11% of compound I and 4% of compound II.

[0072] Comparative Example 2

[0073] Step (1) Preparation of compound III:

[0074] Comparative Example 1 is basically the same as Example 1, the only difference being that in step (1): triethylamine is replaced by sodium hydroxide.

[0075] Result: the reaction was complete after 1 h, a large amount of bromine loss impurity of compound II was produced in the reaction solution, 110.6 g of compound III was obtained, the yield was 61.7%, the purity was 81%, and it contained 14% of bromine loss impurity of compound II.

[0076] Comparative Example 3

[0077] Step (1) Preparation of compound III:

[0078] Comparative Example 1 is basically the same as Example 1, the only difference being that in step (1): N,N-dimethylacetamide is replaced by acetone.

[0079] Result: after 48 h of monitoring, the remaining raw material in the reaction solution was 52%, the product accounted for 36%, and the bromine loss impurity of compound II accounted for 9%, and the reaction solution was not subjected to post-treatment.

[0080] Comparative Example 4

[0081] Step (1) Preparation of compound III:

[0082] Comparative Example 1 is substantially identical to Example 1, except in Step (1): N,N-dimethylacetamide is replaced by acetonitrile.

[0083] Result: The monitoring found that the reaction was completed only after 40 h, and 166.2 g of compound III was obtained, with a yield of 92.7% and a purity of 99.1%.

[0084] Comparative Example 5

[0085] Step (2) Preparation of compound V:

[0086] Comparative Example 2 is substantially identical to Example 1, except that:

[0087] In Step (2), DPPF is replaced by an equimolar amount of RuPhos, i.e., 0.11 g of RuPhos and 0.14 g of DPPF are replaced by 0.22 g of RuPhos.

[0088] Result: The reaction was completed only after 30 h, and 73.17 g of compound V was obtained, with a yield of 62.2% and a purity of 92.4%, containing 8.5% of hydrolysis impurities.

[0089] Comparative Example 6

[0090] Step (2) Preparation of compound V:

[0091] Comparative Example 2 is substantially identical to Example 1, except that:

[0092] In Step (2), RuPhos is replaced by an equimolar amount of DPPF, i.e., 0.11 g of RuPhos and 0.14 g of DPPF are replaced by 0.28 g of DPPF.

[0093] Result: The reaction was completed only after 42 h, and 75.9 g of compound V was obtained, with a yield of 64.5% and a purity of 80.51%, containing 18% of hydrolysis impurities, i.e., azithromycin.

[0094] Comparative Example 7

[0095] Step (2) Preparation of compound V:

[0096] Comparative Example 2 is substantially identical to Example 1, except that:

[0097] In Step (2), triethylamine is replaced by sodium methoxide.

[0098] Results: The reaction was completed in 4h, and 80.5g of compound V was obtained with a yield of 68.5%, a purity of 54%, 23% of hydrolysis impurity of azithromycin, and 8% of azithromycin methyl esterization impurity.

[0099] Comparative Example 8

[0100] Step (2) Preparation of compound V:

[0101] Comparative Example 2 was basically the same as Example 1, with the only difference being that:

[0102] In Step (2), DBU was replaced by triethylamine.

[0103] Results: The reaction was completed in 6h, and 87.8g of compound V was obtained with a yield of 74.6%, a purity of 86%, and 11% of hydrolysis impurity of azithromycin.

Claims

1. A preparation process for high-purity azilsartan medoxomil, characterized in that: Includes the following steps: Step S1: Compound I and Compound II are added to a solvent, a base is added, and after the reaction, Compound III is obtained; Step S2: Compound III and compound IV are added to a solvent, along with a catalyst and a base. After the reaction, compound V is obtained. Step S3: Compound V is oximated with hydroxylamine hydrochloride to obtain VI; Step S4: Compound VI is cyclized under the action of CDI to finally obtain azilsartan ester; The reaction equation is as follows: 。 2. The preparation process of high-purity azilsartan medoxomil according to claim 1, characterized in that: The solvent in step S1 is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, dichloroethane, methanol, and ethanol; the base in step S1 is one or more of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, and DBU.

3. The preparation process of high-purity azilsartan medoxomil according to claim 2, characterized in that: In step S1, the solvent is acetonitrile and N,N-dimethylacetamide in a volume ratio of 10~20:1; the base in step S1 is potassium carbonate and triethylamine in a mass ratio of 100~110:

10.

4. The preparation process of high-purity azilsartan medoxomil according to claim 1, characterized in that: In step S2, the base is DBU and triethylamine in a mass ratio of 30~35:

5.

5. The preparation process of high-purity azilsartan medoxomil according to claim 1, characterized in that: In step S2, the catalysts are catalyst 1 and catalyst 2 in a molar ratio of 1~3:1~3; Catalyst 1 is one or more of palladium acetate, dichloro[1,2-bis(diphenylphosphine)ethane]palladium, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, tetra(triphenylphosphine)palladium, di(triphenylphosphine)palladium acetate, bis(diphenylacetone)palladium, and bis(triphenylphosphine)palladium dichloride; Catalyst 2 is one or more of bidentate phosphine ligands or biarylphosphine ligands.

6. The preparation process of high-purity azilsartan medoxomil according to claim 5, characterized in that: Catalyst 2 is a combination of biarylphosphine ligands and bidentate phosphine ligands in a molar ratio of 0.01 ± 0.001: 0.01; The bidentate phosphine ligand is one or more of CyPF-t-Bu, JosiPhos, Binap, XantPhos, or DPPF; The biarylphosphine ligands are one or more of BrettPhos, RuPhos, XPhos, SPhos, and BippyPhos.

7. The preparation process of high-purity azilsartan medoxomil according to claim 6, characterized in that: Catalyst 2 is RuPhos and DPPF in a molar ratio of 0.01±0.001:0.

01.

8. The preparation process of high-purity azilsartan medoxomil according to claim 5, characterized in that: The reaction temperature in step S1 is 20~120℃; the molar ratio of compound I, compound II, and base in step S1 is 1:0.85~1.1:1.5~3.0; In step S2, the molar ratio of compound III, compound IV, catalyst 1, catalyst 2 and base is 1:1.2~2.0:0.01~0.03:0.01~0.03:1.5~3.

0.

9. The preparation process of high-purity azilsartan medoxomil according to claim 1, characterized in that: Step S3 is as follows: Add hydroxylamine hydrochloride to NMP, add sodium bicarbonate in batches, control the temperature below 40℃, stir the reaction after the addition is complete, then raise the temperature to 60±5℃, add compound V, keep the reaction at this temperature, after the reaction is complete, cool down to 30~40℃, add purified water, adjust the pH to neutral with hydrochloric acid, and a large amount of white solid precipitates. Filter to obtain a wet sample, add isopropanol to the wet sample, slurry at 30~40℃, then filter, and dry under reduced pressure at 40~50℃ to obtain compound VI.

10. The preparation process of high-purity azilsartan medoxomil according to claim 1, characterized in that: Step S4 is as follows: Compound VI, triethylamine, and carbonyl diimidazole are added to dichloromethane, and the mixture is heated to reflux. After the reaction is complete, purified water is added to quench the reaction, and the mixture is separated into liquid and liquid phases. The organic phase is collected, concentrated under reduced pressure, acetonitrile is added, and the mixture is hot-beaten at 40-50°C. Then the mixture is cooled to 0-5°C to crystallize, filtered, and dried to obtain the compound azisartan ester.

Images