Preparation process of high-purity azilsartan medoxomil

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation process of high-purity azilsartan medoxomil. Adding the compound I and the compound II into a solvent, adding alkali and a catalyst, and reacting to obtain a compound III; adding the compound III and the compound IV into a solvent, adding a catalyst and alkali, and reacting to obtain a compound V; performing oximation reaction on the compound V by using hydroxylamine hydrochloride to obtain VI; the compound VI is subjected to ring closing under the action of CDI, and finally azilsartan medoxomil is obtained. According to the present invention, with the method, the synthesis route can be shortened, the process steps can be simplified, the cheap and environmentally-friendly raw materials can be selected, the use of the toxic raw materials can be avoided, the operation is convenient, the impurities produced during the synthesis process are less, the purity and the yield of the product azilsartan medoxomil can be improved, and the industrial production can be conveniently achieved.

Description

Technical Field

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

[0002] Azilsartan medoxomil is a prodrug that can be rapidly converted into the active ingredient azilsartan after oral absorption. The latter can block the effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors in various tissues. Angiotensin II is the main pressor substance of RAAS, which has the effects of constricting blood vessels, stimulating the synthesis and release of aldosterone, exciting the heart, and reabsorb sodium by the kidneys. Azilsartan medoxomil blocks the vasoconstriction and aldosterone secretion 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 effects are unrelated to 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 by the FDA for marketing in 2011.

[0003] The chemical structure of Azilsartan medoxomil is shown below:

[0004]

[0005] From the currently reported synthesis routes of azilsartan medoxomil, it can be roughly divided into two categories. One is esterification first and then forming an oxadiazole ring, and the other is forming an oxadiazole ring first and then esterification, that is, using azilsartan as the raw material and forming an ester with the side chain 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one. The first type is esterification first and then cyclization. The disadvantage is that the ester group is unstable and will decompose during the cyclization process, affecting the product quality and yield. The second type is cyclization first and then esterification. Compared with the first type, the product quality is easier to control and the yield is relatively high, but it is easy to introduce ester exchange impurities.

[0006] The main synthetic methods reported so far are as follows:

[0007] Patent WO2013156005A1 reports the following route:

[0008]

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

[0010]

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

[0012] Patent US20140113942A1 reports the following route:

[0013]

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

[0015] WO2013114305A1 reports the following route:

[0016]

[0017] The difference between this synthetic route and the original patented synthetic route is that this synthetic route is esterification before cyclization, and uses cheaper 4-chloromethyl-5-methyl-1,3-dioxole-2-one instead of 4-hydroxymethyl-5-methyl-1,3-dioxole-2-one as the esterification raw material. The route design is relatively novel, but the third step reaction of this synthetic route is prone to produce impurities due to the large number of active groups in the reactants, and the obtained intermediate is prone to decompose in subsequent reaction steps due to the unstable ester group, producing impurities, thereby affecting the product quality and yield. In addition, this synthetic route uses highly toxic ethyl chloroformate in the cyclization process, which is not conducive to industrial operation. Based on the above analysis, this route is not very 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 milder and the yield of this step more than 90%. However, the starting materials used in this technology are expensive and the cost is high.

[0019] CN105399738A reports the following route:

[0020]

[0021] This route involves ring-closing fragment 1 and esterifying fragment 2, followed by condensation to obtain the product. This route has a short number of steps, but during the preparation of fragment 2, a large amount of impurities are generated due to the lack of selectivity for carboxyl and amino groups, resulting in a low yield and high impurities in this step. In addition, in the last condensation step, the alkalinity is too strong, which can cause decomposition of the product, resulting in a low overall yield. Summary of the invention

[0022] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide a preparation process of high-purity azilsartan medoxomil, shorten the synthesis route, simplify the process steps, select cheap, green and environmentally friendly raw materials, avoid the use of toxic raw materials, facilitate operation, generate fewer impurities during the synthesis process, improve the purity and yield of the product azilsartan medoxomil, and facilitate industrial production.

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

[0024] Step S1: adding compound I and compound II into a solvent, adding a base and a catalyst, and obtaining compound III after reaction;

[0025] Step S2: adding compound III and compound IV into a solvent, adding a catalyst and a base, and obtaining compound V after reaction;

[0026] Step S3: subjecting compound V to oximation reaction with hydroxylamine hydrochloride to obtain VI;

[0027] Step S4: Compound VI is subjected to ring closure under the action of CDI (carbonyldiimidazole) 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, 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.

[0031] More preferably, the solvent in step S1 is acetonitrile and N, N-dimethylacetamide in a volume ratio of 10 to 20: 1. The present invention found in the experimental process that if only acetonitrile is used as the solvent, the reaction product has high purity, but the reaction speed is slow. If only N, N-dimethylacetamide is used as the solvent, the reaction speed is fast, but the bromine impurities of compound II are significantly high. We found that by adding a small amount of N, N-dimethylacetamide to acetonitrile and using acetonitrile and N, N-dimethylacetamide in a volume ratio of 10 to 20: 1 as the solvent, not only the reaction speed is fast, but also the impurities are few and the product purity is high.

[0032] More preferably, the base in step S1 is potassium carbonate and triethylamine in a mass ratio of 100 to 110:10. The present invention has found that in the reaction process, the reaction speed of potassium carbonate is significantly faster than that of triethylamine, but the bromine impurity of compound II is significantly higher. We found that by adding part of triethylamine to potassium carbonate and using potassium carbonate and triethylamine in a mass ratio of 100 to 110:10, impurities are significantly reduced, and a high yield is maintained while maintaining a faster reaction speed.

[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; 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, 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(diphenylphosphine)ethane]palladium, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium acetate, bis(dibenzylideneacetone)dipalladium, and bistriphenylphosphinepalladium dichloride; preferably bistriphenylphosphinepalladium dichloride and bis(triphenylphosphine)palladium acetate;

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

[0040] Preferably, in step S2, catalyst 2 is a biaryl phosphine ligand and a 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 biarylphosphine ligand is one or more of BrettPhos, RuPhos, XPhos, SPhos and BippyPhos.

[0043] More preferably, the catalyst 2 is RuPhos and DPPF in a molar ratio of 0.01±0.001:0.01. The present invention uses RuPhos and DPPF in combination, which not only has a faster reaction speed than a 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, the mass ratio of DBU to triethylamine is 30 to 35:5. Adding a small amount of triethylamine as a base to DBU can inhibit the generation of impurities of Azilsartan and impurities of methyl ester of Azilsartan, improve the purity of the product, and 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 1.0eq; the amount of compound IV is 1.5eq; the amount of catalyst 1 is 0.01 equivalent; the amount of catalyst 2 is 0.02 equivalent; the amount of base is 1.5eq. If compound IV is too little, the reaction is incomplete and the impurities are too high; if catalyst 1 and catalyst 2 are too little, the reaction will be slow, if too much, the cost will be high; if the base is too much, there will be many impurities, too little, and the reaction will be slow.

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

[0047] Preferably, step S4 is: adding compound VI, triethylamine, and carbonyldiimidazole to dichloromethane, heating to reflux reaction, adding purified water to quench after the reaction is complete, and separating the liquids, collecting the organic phase, concentrating under reduced pressure, adding acetonitrile, hot slurrying at 40-50° C., then cooling to 0-5° C. for crystallization, filtering, and drying to obtain the compound azilsartan medoxomil.

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

[0049] The invention designs a completely new reaction route, shortens the synthesis route, simplifies the process steps, selects cheap, green and environmentally friendly raw materials, avoids the use of toxic raw materials, is easy to operate, has a fast reaction speed, generates fewer impurities during the synthesis process, and the product azilsartan medoxomil has high purity and high yield, is convenient for industrial production of the route, and provides a direction for process improvement of azilsartan medoxomil. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 : The liquid phase purity diagram of Azilsartan Medoxomil prepared in Example 1;

[0051] Figure 2 : The mass spectrum of Azilsartan medoxomil prepared in Example 1;

[0052] Figure 3 : Hydrogen spectrum of Azilsartan medoxomil prepared in Example 1. DETAILED DESCRIPTION

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

[0054] Example 1

[0055] A preparation process of high-purity azilsartan medoxomil comprises the following steps:

[0056] (1) Preparation of Compound III

[0057]

[0058] Add 800 ml of acetonitrile and 50 ml of N, N-dimethylacetamide to the reaction bottle, add 100 g of compound I, add 112.9 g of compound II, add 110 g of potassium carbonate and 10 g of triethylamine, stir and heat to reflux for 8 hours. After the reaction is completed, cool to 20-30 ° C, filter, collect the filtrate, slowly add 1200 ml of purified water at 20-30 ° C, a large amount of white solid precipitated, stir for 30 minutes, filter, rinse the filter cake with 50% acetonitrile aqueous solution, and dry under reduced pressure at 40-50 ° 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] Add 800 ml of acetonitrile to the reaction bottle, add 100 g of compound III, add 55 g of compound IV, add 0.16 g of bistriphenylphosphine palladium dichloride, add 0.11 g of RuPhos (Shanghai MacLean Biochemical Technology Co., Ltd.) and 0.14 g of DPPF (Aladdin Biochemical Technology Co., Ltd.), add 8 g of triethylamine and 53 g of DBU, protect with inert gas, stir and heat to 60°C, react for 5 hours, after the reaction is completed, cool to 20-30°C, filter with diatomaceous earth, collect the filtrate, slowly add 1000 ml of purified water at 20-30°C, precipitate a large amount of light yellow solid, stir for 30 minutes, filter, and obtain a wet sample; add 500 ml of methyl tert-butyl ether to the wet sample, pulp at 20-30°C for 1 hour, filter, and dry 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] Add 1000 ml of NMP to the reaction bottle, add 95 g of hydroxylamine hydrochloride, add 140 g of sodium bicarbonate in batches, control the temperature below 40 ° C, stir and react for 1 hour after the addition, then raise the temperature to 60 ° C, add 100 g of compound V, keep the temperature for 12 hours, after the reaction is completed, cool to 30-40 ° C, slowly add 1000 ml of purified water, adjust the pH to neutral with 2M hydrochloric acid, and precipitate a large amount of white solid, filter to obtain a wet sample, add 800 ml of isopropanol to the wet sample, pulp at 30-40 ° C for 1 hour, then filter, and dry 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] Add 1000 ml of dichloromethane to the reaction bottle, add 100 g of compound VI, add 22.5 g of triethylamine, add 42 g of carbonyldiimidazole, heat to reflux reaction for 6 hours, after the reaction is complete, slowly add 500 ml of purified water to quench, separate the liquid, collect the organic phase, and then wash it once with 500 ml of purified water. Collect the organic phase, concentrate it to dryness under reduced pressure, add 500 ml of acetonitrile, heat beat at 40-50 ° C for 1 hour, then cool to 0-5 ° C for crystallization for 2 hours, filter, and dry under reduced pressure at 40-50 ° C to obtain 92.60 g of compound azilsartan medoxomil. The liquid phase purity of the prepared azilsartan medoxomil is shown in the figure. Figure 1 , mass spectrum see Figure 2 , hydrogen spectrum see Figure 3 , yield 88.37%, purity 99.9%.

[0068] Comparative Example 1

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

[0070] Comparative Example 1 is substantially the same as Example 1, except that in step (1), triethylamine is replaced by potassium carbonate.

[0071] Results: The reaction was not complete and there were many impurities. 110.5 g of compound III was obtained with a yield of 56.05% and a purity of 83.5%, containing 11% compound I and 4% compound II.

[0072] Comparative Example 2

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

[0074] Comparative Example 1 is substantially the same as Example 1, except that in step (1), triethylamine is replaced by sodium hydroxide.

[0075] Results: The reaction was complete after 1 hour, and a large amount of debrominated impurities of compound II were produced in the reaction solution. 110.6 g of compound III was obtained with a yield of 61.7%, a purity of 81%, and containing 14% debrominated impurities of compound II.

[0076] Comparative Example 3

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

[0078] Comparative Example 1 is substantially the same as Example 1, except that in step (1), N,N-dimethylacetamide is replaced by acetone.

[0079] Results: After 48 hours of reaction, the reaction solution contained 52% raw material, 36% product, and 9% debrominated impurities of compound II. No post-treatment was performed on the reaction solution.

[0080] Comparative Example 4

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

[0082] Comparative Example 1 is substantially the same as Example 1, except that in step (1), N,N-dimethylacetamide is replaced by acetonitrile.

[0083] Results: Monitoring revealed that the reaction was completed after 40 hours, yielding 166.2 g of compound III 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 basically the same as Example 1, except that:

[0087] In step (2), DPPF is replaced with an equimolar amount of RuPhos, that is, 0.11 g of RuPhos and 0.14 g of DPPF are replaced with 0.22 g of RuPhos.

[0088] Results: The reaction was completed after 30 hours, and 73.17 g of compound V was obtained with a yield of 62.2%, a purity of 92.4%, and a hydrolyzed impurity content of 8.5%.

[0089] Comparative Example 6

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

[0091] Comparative Example 2 is basically the same as Example 1, except that:

[0092] In step (2), RuPhos is replaced with an equal molar equivalent of DPPF, that is, 0.11 g of RuPhos and 0.14 g of DPPF are replaced with 0.28 g of DPPF.

[0093] Results: The reaction was completed after 42 hours, and 75.9 g of compound V was obtained with a yield of 64.5% and a purity of 80.51%. The hydrolyzed impurity Azilsartan contained 18%.

[0094] Comparative Example 7

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

[0096] Comparative Example 2 is basically the same as Example 1, except that:

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

[0098] Results: The reaction was completed in 4 hours to obtain 80.5 g of compound V with a yield of 68.5% and a purity of 54%. The hydrolyzed impurity Azilsartan was 23% and the methyl ester impurity Azilsartan was 8%.

[0099] Comparative Example 8

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

[0101] Comparative Example 2 is basically the same as Example 1, except that:

[0102] In step (2), DBU is replaced by triethylamine.

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

Claims

1. A process for preparing high-purity Azilsartan Medoxomil, characterized in that: The following steps are involved: Step S1: adding compound I and compound II into a solvent, adding a base and a catalyst, and obtaining compound III after reaction; Step S2: adding compound III and compound IV into a solvent, adding a catalyst and a base, and obtaining compound V after reaction; Step S3: subjecting compound V to oximation reaction with hydroxylamine hydrochloride to obtain VI; Step S4: performing ring closure on compound VI under the action of CDI to finally obtain azilsartan medoxomil; 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: The solvent in step S1 is acetonitrile and N,N-dimethylacetamide in a volume ratio of 10 to 20:1; the base in step S1 is potassium carbonate and triethylamine in a mass ratio of 100 to 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 to 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, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium acetate, bis(dibenzylideneacetone)dipalladium, and bistriphenylphosphinepalladium dichloride; Catalyst 2 is one or more of bidentate phosphine ligands or biaryl phosphine ligands.

6. The preparation process of high-purity Azilsartan Medoxomil according to claim 5, characterized in that: Catalyst 2 is a biaryl phosphine ligand and a bidentate phosphine ligand 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 ligand is one or more of BrettPhos, RuPhos, XPhos, SPhos and BippyPhos.

7. The process for preparing 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 1, characterized in that: The reaction temperature in step S1 is 20-120° C.; 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: adding hydroxylamine hydrochloride to NMP, adding sodium bicarbonate in batches, controlling the temperature below 40°C, stirring the reaction after the addition is completed, then heating to 60±5°C, adding compound V, and keeping the temperature for reaction. After the reaction is completed, cooling to 30-40°C, adding purified water, adjusting the pH to neutral with hydrochloric acid, and precipitating a large amount of white solid, filtering to obtain a wet sample, adding isopropanol to the wet sample, slurrying at 30-40°C, then filtering, and drying under reduced pressure at 40-50°C to obtain compound VI.

10. The process for preparing high-purity Azilsartan Medoxomil according to claim 1, characterized in that: Step S4 is: adding compound VI, triethylamine, and carbonyldiimidazole to dichloromethane, heating to reflux reaction, adding purified water to quench the reaction after completion, separating the liquids, collecting the organic phase, concentrating under reduced pressure, adding acetonitrile, hot slurrying at 40 to 50° C., then cooling to 0 to 5° C. for crystallization, filtering, and drying to obtain the compound azilsartan medoxomil.

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