Preparation method of sartan drug intermediate

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a sartan drug intermediate, which comprises the following steps: in an organic solvent, a compound shown in a formula IIIa generates a compound shown in a formula Ia under the action of resorcinol, sodium chlorite and acetic acid, and the synthesis route is shown in the specification. The preparation method of the sartan drug intermediate provided by the invention is simple and easy to operate, safe, environment-friendly, high in yield and purity, low in production cost and beneficial to industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an intermediate for a sartan drug. Background Art

[0002] Compound I and Compound III are important intermediates for preparing antihypertensive drug losartan carboxylic acid ester derivatives (such as alisartan ester), and their structural formulas are shown as follows:

[0003]

[0004] Currently, in the prior art, Compound I is mainly prepared by two-step oxidation of triphenylchlorosartan (Compound II), and the synthesis route is shown as follows:

[0005]

[0006] In CN103965171A, Compound II is oxidized with calcium hypochlorite in the presence of KBr, sodium bicarbonate and TEMPO to obtain Compound III, in which there is a certain content of unknown impurities, and the greater the amount of calcium hypochlorite used, the greater the content of this impurity; however, if the amount of calcium hypochlorite is insufficient, the conversion rate of triphenylchlorosartan is low, which affects the yield on the one hand, and on the other hand, the remaining raw materials will be carried into the subsequent processes to form impurities, increasing the purification pressure and resulting in unqualified related substances of the final API. Further, CN103965171A uses a hydrogen peroxide / sodium chlorite system to oxidize Compound III to generate Compound I, which requires 50% high-concentration hydrogen peroxide and is not conducive to industrial production. CN102558064B uses potassium permanganate to oxidize Compound III to generate Compound I, and the yield is 40%.

[0007] Therefore, it is necessary to provide a preparation method of sartan drug intermediate Compound I with high yield, high purity, few impurities and conducive to industrial production. Summary of the Invention

[0008] The first aspect of the present invention provides a preparation method of a compound shown in Formula Ia, comprising the following steps: in an organic solvent, the compound shown in Formula IIIa reacts under the action of resorcinol, sodium chlorite and acetic acid to generate the compound shown in Formula Ia, and the synthesis route is shown as follows:

[0009]

[0010] Among them, Ring A is a 5- to 10-membered heteroaromatic ring;

[0011] R 1 Each independently is halogen, -C 1-5 alkyl or -OC 1-5 alkyl, and n is 0, 1 or 2;

[0012] R2 is -H, a 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered heterocycle is optionally substituted by one or a plurality of =O, -Bn or -Trt within the range permitted by the valence, and the 5- or 6-membered heteroaryl ring is optionally substituted by one or a plurality of -Bn or -Trt within the range permitted by the valence.

[0013] In some embodiments, the preparation method further comprises the following steps: under basic conditions and in the presence of a catalyst, oxidizing the compound represented by formula IIa with an oxidizing agent in a polar organic solvent at an appropriate temperature to obtain the compound represented by formula IIIa, and the synthetic route is as follows:

[0014]

[0015] In some embodiments, ring A is a 5-membered heteroaryl ring. Preferably, the heteroatom of the 5-membered heteroaryl ring is N; and / or the number of heteroatoms of the 5-membered heteroaryl ring is 2; more preferably, ring A is

[0016] In some embodiments, R 1 are each independently a halogen or -C 1-5 alkyl; preferably, R 1 is -Cl or n-butyl.

[0017] In some embodiments, n is 2.

[0018] In some embodiments, R 2 is a 5- or 6-membered heteroaryl ring, preferably a 5-membered heteroaryl ring, more preferably

[0019]

[0020] In some embodiments, the 5- or 6-membered heterocycle is optionally substituted by one or a plurality of -Trt within the range permitted by the valence, preferably substituted by one -Trt.

[0021] In some embodiments, the compound represented by formula Ia is selected from compound I, and the preparation method comprises the following steps:

[0022] Step 2: In an organic solvent, compound III reacts with resorcinol, sodium chlorite and acetic acid to form compound I, and the synthetic route is as follows:

[0023]

[0024] In some embodiments, the molar ratio of resorcinol to compound III in step 2 is 2-8:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or any range therebetween, such as 4-6:1.

[0025] In some embodiments, the molar ratio of sodium chlorite to Compound III in Step 2 is 3 - 15:1, such as 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, or within any range therebetween, such as 4 - 8:1.

[0026] In some embodiments, the molar ratio of acetic acid to Compound III in Step 2 is 3 - 8:1, such as 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or within any range therebetween, such as 4 - 6:1.

[0027] In some embodiments, the sodium chlorite in Step 2 is added in the form of an aqueous sodium chlorite solution. Preferably, the concentration of the aqueous sodium chlorite solution is between 10% w / w and the saturation solution concentration, more preferably 30% - 35% w / w.

[0028] In some embodiments, the organic solvent in Step 2 is a polar organic solvent, including one or more of DMF, DMA, dimethyl sulfoxide, N - methylpyrrolidone, dichloromethane, tetrahydrofuran, or acetone.

[0029] In some embodiments, the amount of the organic solvent used in Step 2 is 7 - 15 mL relative to each gram of Compound III, such as 7 mL, 8 mL, 9 mL, 10 mL, 15 mL, or within any range therebetween, such as 8 - 10 mL.

[0030] In some embodiments, Step 2 includes the following process: Compound III, the organic solvent, resorcinol, and acetic acid are mixed and stirred evenly, and then an aqueous sodium chlorite solution is added dropwise to the above - mentioned mixture.

[0031] In some embodiments, the reaction temperature in Step 2 is 10 - 25 °C, preferably 10 - 20 °C.

[0032] In some embodiments, Step 2 further includes the following process: After the reaction is completed, a water - immiscible organic solvent and water are added to the reaction solution, and the mixture is stirred and separated; the organic layer is further purified to obtain Compound I.

[0033] In some embodiments, the water - immiscible organic solvent is a chlorinated hydrocarbon, such as dichloromethane.

[0034] In some embodiments, the method for further purifying the organic layer includes concentrating to remove part or all of the organic solvent, and preferably further recrystallizing the concentrate to obtain Compound I.

[0035] In some embodiments, the solvent for recrystallization is a mixed solvent of dichloromethane and acetonitrile; the volume ratio of dichloromethane to acetonitrile is 1:10 - 2:5, preferably the volume ratio is 1:5 - 2:5.

[0036] In some embodiments, the preparation method further comprises the following steps:

[0037] Under alkaline conditions and in the presence of a catalyst, compound II is oxidized with an oxidizing agent in a polar organic solvent at an appropriate temperature to obtain compound III. The synthetic route is as follows:

[0038]

[0039] The second aspect of the present invention provides a method for preparing compound III, which is characterized by comprising the following steps:

[0040] Step 1: Under alkaline conditions and in the presence of a catalyst, compound II is oxidized with an oxidizing agent in a polar organic solvent at an appropriate temperature to obtain compound III. The synthetic route is as follows:

[0041]

[0042] Wherein, the catalyst is TEMPO and KBr;

[0043] The oxidizing agent is calcium hypochlorite, wherein the amount of ClO - is 1.00 - 1.20 eq, preferably 1.06 - 1.16 eq, more preferably 1.12 eq.

[0044] In some embodiments, the concentration of ClO - in step 1 is 0.30 - 0.40 mol / L, preferably 0.30 - 0.35 mol / L, and more preferably, the concentration of ClO - is 0.34 mol / L.

[0045] In some embodiments, the appropriate temperature in step 1 is 5 - 25 °C, preferably 10 - 20 °C.

[0046] In some embodiments, the base used for the alkaline conditions in step 1 is sodium bicarbonate, and the amount of sodium bicarbonate is 1.0 - 3.0 eq, preferably 2.0 eq.

[0047] In some embodiments, the amount of TEMPO in step 1 is 0.05 - 0.15 eq, preferably 0.10 eq; and / or the amount of KBr is 0.20 - 0.30 eq, preferably 0.25 eq.

[0048] In some embodiments, the reaction time for the oxidation in step 1 is 14 - 16 h, preferably 15 h.

[0049] In some embodiments, the polar organic solvent in Step 1 is DMF, and the amount of the polar organic solvent is 3.0 - 7.0 mL / mol relative to Compound II, preferably 4.0 - 6.0 mL / mol, and more preferably 5.0 mL / mol.

[0050] In some embodiments, Compound III obtained by the preparation method contains Compound B The content of Compound B does not exceed 1.0%, preferably does not exceed 0.8%, and more preferably does not exceed 0.7%.

[0051] The third aspect of the present invention provides a preparation method of alisartan ester. Compound I is obtained by the preparation method of Compound I described in the first aspect of the present invention, and then further reacted to prepare alisartan ester.

[0052] In some embodiments, the method of the further reaction can refer to CN103965171A, including Step 3 and Step 4, and the synthetic route is as follows:

[0053] Step 3:

[0054] Step 4:

[0055] The fourth aspect of the present invention provides a compound represented by formula (III-1),

[0056]

[0057] wherein, X 1 and X 2 are each independently H or a halogen;

[0058] R 1 is H or trityl;

[0059] When R 1 is H, X 1 and X 2 are not both Cl at the same time.

[0060] In some embodiments, the compound represented by formula (III-1) is Compound A or Compound B:

[0061] Compound A Compound B

[0062] The fifth aspect of the present invention provides a preparation method of Compound B, including the following steps:

[0063] (1a) Oxidize Compound I with an oxidant in a polar organic solvent under alkaline conditions in the presence of a catalyst to obtain Compound B;

[0064]

[0065] (1b) Optionally, purify the compound B obtained in step (1a).

[0066] In some embodiments, the polar organic solvent in step (1a) is DMF, DMA, dichloromethane, acetonitrile, THF, or acetone.

[0067] In some embodiments, the oxidizing agent in step (1a) is sodium chlorite, calcium hypochlorite, or hydrogen peroxide.

[0068] In some embodiments, the catalyst in step (1a) includes potassium bromide.

[0069] In some embodiments, the catalyst in step (1a) is potassium bromide.

[0070] In some embodiments, the catalyst in step (1a) is potassium bromide and TEMPO.

[0071] In some embodiments, the base used under the basic conditions in step (1a) is sodium bicarbonate or disodium hydrogen phosphate.

[0072] In some embodiments, the volume-to-mass ratio of the polar organic solvent to compound I in step (1a) is 8 - 12 mL / g, preferably 10 mL / g.

[0073] In some embodiments, the base used under the basic conditions in step (1a) is disodium hydrogen phosphate, and the amount of the base is 1.0 - 3.0 eq, preferably 2.0 eq.

[0074] In some embodiments, the oxidizing agent in step (1a) is sodium chlorite, and the amount of the oxidizing agent is 5.0 - 7.0 eq, preferably 6.0 eq.

[0075] In some embodiments, the catalyst in step (1a) is potassium bromide, and the amount of the catalyst is 3.0 - 5.0 eq, preferably 4.0 eq.

[0076] In some embodiments, the oxidizing agent in step (1a) is hydrogen peroxide, with a concentration of 25 - 35%, preferably 30%; and the amount is 3.0 - 5.0 eq, preferably 4.0 eq.

[0077] In some embodiments, step (1a) is to react compound I with a certain amount of disodium hydrogen phosphate and sodium chlorite in DMF, and then add a certain amount of potassium bromide and hydrogen peroxide.

[0078] In some embodiments, step (1a) employs a segmented heating method, wherein the reaction temperature in the first period of time is lower than that in the second period of time.

[0079] In some embodiments, the first period of time is 20 - 40 min, preferably 30 min.

[0080] In some embodiments, the reaction temperature in the first period of time is 60 - 80 °C, preferably 70 °C.

[0081] In some embodiments, the second period of time is 70 - 110 min, preferably 80 - 100 min, and more preferably, the second period of time is 90 min.

[0082] In some embodiments, the reaction temperature in the second period of time is 85 - 95 °C, preferably 90 °C.

[0083] In some embodiments, the purification in step (1b) includes the following steps:

[0084] (1c) After cooling, add it to water, precipitate solids, and filter;

[0085] (1d) Pulverize the filter cake with an organic solvent to obtain Compound B.

[0086] In some embodiments, the volume - mass ratio of water to Compound I in step (1c) is 18.0 - 26.0 mL / g, preferably 20.0 - 24.0 mL / g, and more preferably, the volume - mass ratio of water to Compound I is 22.0 mL / g.

[0087] In some embodiments, the organic solvent in step (1d) is ethyl acetate.

[0088] In some embodiments, the volume - mass ratio of the organic solvent to Compound I in step (1d) is 4.0 - 8.0 mL / g, preferably 5.0 - 7.0 mL / g, and more preferably, the volume - mass ratio of the organic solvent to Compound I is 6.0 mL / g.

[0089] The sixth aspect of the present invention provides a method for preparing Compound A, comprising the following steps:

[0090] (2a) Add Compound B to an alcohol solvent, heat to reflux, and obtain Compound A;

[0091]

[0092] (2b) Optionally, purify the Compound A obtained in step (2a).

[0093] In some embodiments, the compound B described in step (2a) can be prepared by the preparation method described in the fourth aspect.

[0094] In some embodiments, the alcohol solvent described in step (2a) is methanol, ethanol or isopropanol. Preferably, the organic solvent is methanol.

[0095] In some embodiments, the volume-mass ratio of the alcohol solvent described in step (2a) to compound B is 8.0 - 12.0 mL / g, preferably 9.0 - 11.0 mL / g. More preferably, the volume-mass ratio of the alcohol solvent to compound B is 10.0 mL / g.

[0096] In some embodiments, the heating and refluxing time described in step (2a) is 5 - 9 h, preferably 6 - 8 h. More preferably, the heating and refluxing time is 7 h.

[0097] In some embodiments, the purification described in step (2b) includes the following steps:

[0098] (2c) Cooling, filtering, and concentrating the filtrate;

[0099] (2d) Adding an organic solvent and heating to reflux;

[0100] (2e) Dropwise adding another organic solvent. After addition, cooling and stirring;

[0101] (2f) Filtering and drying to obtain compound A.

[0102] In some embodiments, the organic solvent described in step (2d) is an alcohol solvent, preferably methanol, ethanol or isopropanol. More preferably, the organic solvent is ethanol.

[0103] In some embodiments, the volume-mass ratio of the organic solvent described in step (2d) to compound B is 1.00 - 2.00 mL / g, preferably 1.50 - 2.00 mL / g. More preferably, the volume-mass ratio of the organic solvent to compound B is 1.88 mL / g.

[0104] In some embodiments, the organic solvent described in step (2e) is a hydrocarbon solvent, preferably n-heptane, hexane, n-octane or petroleum ether. More preferably, the organic solvent is n-heptane.

[0105] In some embodiments, the volume-mass ratio of the organic solvent described in step (2e) to compound B is 2.00 - 3.00 mL / g, preferably 2.00 - 2.50 mL / g. More preferably, the volume-mass ratio of the organic solvent to compound B is 2.25 mL / g.

[0106] In some embodiments, the temperature reduction in step (2e) is to reduce the temperature to 0 - 10°C, preferably 3 - 7°C, and more preferably to 5°C.

[0107] The seventh aspect of the present invention provides the use of a compound represented by formula (Ⅲ-1) as a reference substance in the pharmaceutical production process.

[0108] In some embodiments, the drug is alisartan ester.

[0109] In some embodiments, the preparation method of the alisartan ester includes the following synthetic route:

[0110]

[0111] This route can refer to CN103965171A.

[0112] In some embodiments, the alisartan ester is prepared by the preparation method described in the third aspect of the present invention.

[0113] In some embodiments, compound B is contained in a certain amount in compound Ⅲ, compound Ⅰ or compound Ⅳ obtained according to the preparation method; compound A is contained in a certain amount in compound Ⅴ obtained according to the preparation method.

[0114] The eighth aspect of the present invention protects a detection method for alisartan ester and its intermediates. Using compound A or compound B as a reference substance and high performance liquid chromatography, the content of compound A or compound B in the sample to be tested is determined.

[0115] In some embodiments, the detection method has the following steps:

[0116] (1) Weigh compound A or compound B and prepare a reference substance solution; weigh the sample to be tested and prepare a test solution.

[0117] (2) Precisely measure the test solution and the reference substance solution, inject the sample, and perform detection under certain chromatographic conditions.

[0118] (3) Record the detection results and calculate the content of compound A or compound B in the sample to be tested by the external standard method.

[0119] In some embodiments, the chromatographic conditions for determining the content of compound B in the sample to be tested are:

[0120]

[0121]

[0122] In some embodiments, the chromatographic conditions for determining the content of compound A in the sample to be tested are:

[0123]

[0124]

[0125] The ninth aspect of the present invention provides a method for quality control of alisartan ester. According to the detection method described in the eighth aspect of the present invention, the content of compound A or compound B in the alisartan ester or alisartan ester intermediate obtained by the preparation method described in the third aspect of the present invention is determined. If the content exceeds the limit, the alisartan ester or alisartan ester intermediate is refined until the content of compound A or compound B therein is lower than the limit.

[0126] In some embodiments, the alisartan ester intermediate is compound III, compound I or compound IV.

[0127] In some embodiments, the content limit is that the content of compound A in the crude alisartan ester does not exceed 0.15%, the content of compound A in the finished alisartan ester does not exceed 0.10%, the content of compound B in compound I does not exceed 0.4%, and the content of compound B in compound IV does not exceed 0.4%.

[0128] In some embodiments, the refining is recrystallization.

[0129] In some embodiments, the solvent system for recrystallization is an alcohol solvent, and the alcohol solvent includes methanol, ethanol or isopropanol, preferably isopropanol.

[0130] In some embodiments, the steps of recrystallization include: dissolving the alisartan ester or alisartan ester intermediate in the alcohol solvent, heating to dissolve completely, optionally decolorizing or filtering, and cooling to crystallize.

[0131] The tenth aspect of the present invention provides a composition of compound III, which contains compound B, and the content of compound B does not exceed 1.0%, preferably does not exceed 0.8%, and more preferably does not exceed 0.7%;

[0132]

[0133] The eleventh aspect of the present invention provides an alisartan ester composition, which contains compound A, the content of alisartan ester is greater than 99.9%, and the content of compound A is less than or equal to 0.04%.

[0134] In some embodiments, the alisartan ester composition is prepared by the quality control method described in the ninth aspect of the present invention.

[0135] The preparation method of the sartan drug intermediate provided by the present invention, such as compound I, is simple and easy to operate, safe, environmentally friendly, with high yield and purity, and low production cost, which is conducive to industrial production. The preparation method of compound III provided by the present invention can effectively control the content of impurity compound B in the product, improve the properties of the product, enhance the purity of the product, and reduce the purification pressure in the subsequent steps. The cost of further synthesizing olmesartan medoxomil using the sartan drug intermediate prepared by the present invention is low, and the final product olmesartan medoxomil has few impurities and high purity. Description of the Drawings

[0136] Figure 1 : Typical spectrum of obtaining compound III by the original synthesis route;

[0137] Figure 2 : Chromatogram of compound III prepared in Example 3;

[0138] Figure 3 : Single crystal diagram of compound B;

[0139] Figure 4 : Typical chromatogram of the composition of compound III containing compound B;

[0140] Figure 5 : Typical chromatogram of the crude olmesartan medoxomil containing compound A. Detailed Description of the Invention

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless there is a contrary statement, the terms used in the specification and claims have the following meanings.

[0142] The terms "comprising", "including", "having", "containing" or "involving" and other variant forms thereof used herein are inclusive or open-ended and do not exclude other unenumerated elements or method steps.

[0143] The term "API" refers to the active pharmaceutical ingredient. In this article, the term "API" can also refer to "bulk drug", that is, the raw drug used for the production of various preparations, which is the effective ingredient (also known as the active ingredient) in the preparation, and is a substance in the form of powder, crystal, etc. prepared by chemical synthesis or biotechnology methods, but cannot be directly taken by the subject.

[0144] In the present invention, "optionally", "any" or "either" means that the subsequent described event or situation may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.

[0145] Unless otherwise specified, the term "halo" or "halogen", alone or as part of another substituent, means a fluorine, chlorine, bromine or iodine atom.

[0146] The term "alkyl", alone or as part of another substituent, refers to a saturated aliphatic hydrocarbon group having a specified number of carbon atoms (e.g., C 1-5 means one to five carbons), which is an uncyclized straight-chain or branched carbon chain (or carbon), or a combination thereof, preferably an alkyl group containing 1 to 4 carbon atoms, such as C 1-4 Alkyl includes ethyl, n-butyl.

[0147] The term "substituted" means that any one or more hydrogens on the specified atom or group are selectively replaced by the specified group, provided that the normal valence state of the specified atom is not exceeded. When the substituent is oxo or keto (i.e., =O), then 2 hydrogens on the said atom are replaced.

[0148] The term "heterocycle" or a group in which at least one ring atom on a cycloalkyl group is replaced by a heteroatom (e.g., a nitrogen atom, an oxygen atom or a sulfur atom). The heterocycle can be saturated or unsaturated. The 5-6 membered heterocycles described in the present invention include but are not limited to

[0149] The terms "heteroaromatic", "heteroaryl", "heterocyclic aromatic" or "heteroaryl group" have the same meaning and refer to a heterocyclic compound having aromatic characteristics, including monocyclic heteroaryl and fused heteroaryl. The 5-10 membered heteroaryl groups described in the present invention include but are not limited to

[0150] In the present invention, all the numbers disclosed herein are approximate values whether or not words such as "about" or "approximate" are used. Based on the disclosed numbers, the numerical value of each number may vary by less than ±10% or a reasonable difference considered by those skilled in the art, such as a difference of ±1%, ±2%, ±3%, ±4% or ±5%. Whether or not indicated, all values listed herein include the degree of expected experimental error, technical error and instrumental error of the given technique for measuring the value.

[0151] The preparation method of the valsartan ester described in the present invention refers to CN103965171A, and its steps are as follows: tritosartan is oxidized in two steps to obtain compound I, then compound I reacts with chloromethyl isopropyl carbonate under the action of a base to obtain compound IV, and finally compound IV is deprotected in methanol to obtain compound V. The synthesis route is as follows:

[0152]

[0153] Compound V described in the present invention is valsartan ester.

[0154] The "crude alisartan ester" in the present invention refers to the unpurified alisartan ester formed by the reaction.

[0155] The "finished alisartan ester" in the present invention refers to the alisartan ester purified after the reaction, and the purification includes recrystallization.

[0156] For the reaction steps in the present invention where specific reaction conditions are not mentioned, without special indication, they can all be carried out by conventional methods in the art.

[0157] For the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0158] In various embodiments of the present application, the magnitude of the serial numbers of the above processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.

[0159] For those in the embodiments herein where specific experimental steps or conditions are not indicated, the operations or conditions of the conventional experimental steps described in the literature in the art can be followed. For the reagents or instruments whose manufacturers are not indicated, they are all conventional reagent products that can be obtained through commercial purchase.

[0160] The abbreviations used in the present invention have their conventional meanings in the art. For example, the meanings of the following abbreviations are as follows:

[0161] HPLC High Performance Liquid Chromatography RRT Relative Retention Time DMF N,N-Dimethylformamide DMA N,N-Dimethylacetamide ACN Acetonitrile IPA Isopropanol TEMPO 2,2,6,6-Tetramethylpiperidine N-oxide Trt Triphenylmethyl Bn Benzyl eq. Molar Equivalent

[0162] Hereinafter, specific embodiments will be used to further elaborate and illustrate the technical solutions of the present invention.

[0163] The embodiments herein are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the protection scope of the present invention.

[0164] Example 1: Synthetic reference route of alisartan ester and determination of purity of related impurities

[0165] Synthesize alisartan ester with reference to the synthetic route of CN103965171A.

[0166]

[0167] Step 1: Compound Ⅲ was synthesized from compound Ⅱ, and the effective ClO of calcium chlorate as the oxidant was - 1.6eq of compound Ⅱ, and a reaction solution containing compound Ⅲ was obtained. HPLC monitoring found that there was a certain amount of unknown impurities in the obtained reaction solution. After analysis and preparation of the standard product, it was confirmed that the impurity was compound B (see Example 4). The purity of compound Ⅲ prepared by this process was 95.9%, and the content of compound B was 2.1%. The typical chromatogram is shown in Figure 1 ; Compound B remained in compound 4 obtained after two steps of step 2 and step 3, and the remaining compound B was deprotected to form compound A in step 4.

[0168] Example 2: Optimization of the synthesis process of compound Ⅲ

[0169] Referring to the synthesis method of CN103965171A, compound Ⅲ was synthesized from compound Ⅱ, and the dosage of calcium hypochlorite in the reaction conditions was optimized, as shown in Table 1. The available chlorine of calcium hypochlorite needs to be detected by titration, and the actual dosage is converted according to the available chlorine content: for example, in this example, the available chlorine content of calcium hypochlorite is 67%. Taking 0.86eq of calcium hypochlorite as an example, its actual dosage is 0.84 * 0.67% = 0.56eq, and the amount of ClO - is 2 * 0.56% = 1.12eq.

[0170]

[0171]

[0172]

[0173] Table 1

[0174] The greater the dosage of calcium hypochlorite, the greater the content of compound B; the lower the dosage of calcium hypochlorite, the lower the conversion rate of compound Ⅱ (RRT 17.8min), and about 5 - 10% remains.

[0175] As can be seen from the above table, when the equivalent of ClO - increased from 1.11eq to 1.15eq, the reaction of compound Ⅱ was more complete, but the compound B in the reaction solution gradually increased; when the equivalent of calcium hypochlorite was 1.12eq, both compound Ⅱ and compound B were at relatively low levels.

[0176] Example 3: Preparation method of compound Ⅲ

[0177]

[0178] Add DMF (600 mL) to the reaction kettle, start stirring, add Compound II (120 g), and stir until clear. Control the temperature at 11 °C, and successively add sodium bicarbonate (30.31 g), KBr (5.37 g), and TEMPO (2.82 g). Control the internal temperature at 11 °C, and add calcium hypochlorite (titration available chlorine content 67%, 21.55 g, actual dosage 0.56 eq) in five batches, with an interval of 15 min between each batch. Keep the reaction process away from light throughout. Stir at 15 °C for 16 h. When the HPLC detection shows that Compound II ≤ 1.5%, add diatomaceous earth (24 g), stir for 10 min, and filter. Rinse the reaction kettle with DMF (360 mL) and then wash the filter cake. Combine the washing solutions to obtain a light yellow solution containing Compound III. The external standard yield by HPLC is 98.7%, the purity is 95.56%, the content of Compound B is 0.61%, and the relevant spectra are as Figure 2 shown.

[0179] Example 4: Preparation and Structure Confirmation of Compound B

[0180]

[0181] Dissolve Compound I (20 g) in DMF (200 mL), add disodium hydrogen phosphate (7.08 g), sodium chlorite (20.0 g), stir evenly, then add potassium bromide (14 g) and water, and slowly add 30% hydrogen peroxide (13.36 g). After adding, raise the temperature to 70 °C and stir for 30 min. Continue to raise the temperature to 90 °C and stir for 1.5 h. When the HPLC detection shows the end of the reaction, cool the reaction solution and pour it into 1000 mL of water, precipitate, filter, pulp the filter cake with ethyl acetate for 0.5 h, filter, and dry to obtain Compound B. The yield is 31%, the purity is 97.5%, and the single crystal diagram is Figure 3 .

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H), 7.49 - 7.46 (m, 2H), 7.36 - 7.32 (m, 4H), 7.27 - 7.24 (m, 6H), 7.12 (d, 2H), 6.9 (m, 6H), 6.78 (d, 2H), 4.99 (s, 2H), 2.49 (t, 2H), 1.62 - 1.59 (m, 2H), 1.27 - 1.25 (m, 2H), 0.84 (t, 3H).

[0183] Example 5: Preparation and Structure Confirmation of Compound A

[0184]

[0185] Compound B (4 g) was dissolved in methanol (40 mL), heated to reflux for 7 h, cooled to 15 °C, filtered, and the filtrate was concentrated to dryness. Ethanol (7.5 mL) was added, heated to reflux until clear, and n-heptane (9 mL) was added dropwise. After addition, it was cooled to 5 °C, stirred for 30 min, filtered, and dried to obtain compound A with a yield of 75% and a purity of 96.7%.

[0186] LCMS (ESI-MS) m / z: 471 [M+H] + .

[0187] 1 1H NMR (400 MHz, DMSO-d6) δ 16.2 (s, 1H), 7.69 - 7.65 (m, 2H), 7.60 - 7.57 (m, 1H), 7.53 (d, 1H), 7.12 (d, 2H), 7.0 (d, 2H), 5.24 (s, 2H), 2.59 (t, 2H), 1.52 - 1.47 (m, 2H), 1.28 - 1.23 (m, 2H), 0.82 (t, 3H).

[0188] Example 6: Determination of the content of compound B in the intermediate compound III of alisartan

[0189] Solution preparation:

[0190] Diluent: N,N-dimethylformamide

[0191] Compound III reaction solution: Pipette 0.5 mL of the compound III reaction solution with a concentration of 20 mg / mL into a 20 mL volumetric flask, dissolve and dilute to the mark with the diluent, and mix well.

[0192] Chromatographic conditions:

[0193]

[0194] Experimental procedure:

[0195] Precisely pipette the compound III reaction solution, inject the sample, detect according to the above chromatographic conditions, record the chromatogram, and the representative chromatogram is as Figure 4 shown.

[0196] Example 7: Determination of the content of compound A in the crude product of alisartan or API

[0197] Solution preparation:

[0198] Diluent: Acetonitrile

[0199] Blank solution: Diluent

[0200] Test solution: Weigh 100 mg of alisartan API or crude product accurately, transfer it to a 100 mL volumetric flask, dissolve it with the diluent and make up the volume to the mark, then mix well.

[0201] Reference solution of Compound A: Prepare a solution with a certain concentration using the diluent and Compound A.

[0202] Chromatographic conditions:

[0203]

[0204] Precisely measure the test solution of the compound and the reference solution of Compound A, inject the samples, detect according to the above chromatographic conditions, record the chromatogram, and calculate the content of Compound A in the test sample by the external standard method. The representative chromatogram is as Figure 5 shown.

[0205] Example 8: Preparation of Compound I

[0206] Add the solution of Compound III prepared in Example 3 (equivalent to 100 g of Compound III, 1.0 eq) to a reaction flask, add DMF (300 mL, 3.0 V), resorcinol (83 g, 5.0 eq), and glacial acetic acid (45 g, 5.0 eq). After stirring evenly, control the temperature at 10 - 20 °C, and add an aqueous solution of sodium chlorite (30% - 35%) (containing 68 g of sodium chlorite, 5.0 eq) dropwise to the above mixture within 3 h. Keep the temperature for reaction for 0.5 h, and monitor the reaction by HPLC. After the reaction is completed, add dichloromethane and water to the reaction solution, stir and separate the layers. Wash the organic phase with water three times and then concentrate it until there is no obvious distillate. Add dichloromethane (100 mL, 1.0 V) to the concentrate, and raise the temperature to 35 - 40 °C. Control the temperature at 30 - 40 °C, and add acetonitrile (500 mL, 5 V) to crystallize. After cooling and filtering, Compound I is obtained (93.2 g, yield 91%, purity 98.1%, and the residue of Compound III is 0.33%).

[0207] Example 9: Purification of Crude Alisartan

[0208] Synthesize alisartan (Compound V) according to the synthesis method of CN103965171A to obtain a crude alisartan control, and purify it according to the following recrystallization method to obtain a finished alisartan control.

[0209] Using the product compound III of Example 3 as a reference, the crude valsartan was continuously prepared according to the synthesis method of CN103965171A to obtain crude valsartan 1. 4.0 g of crude valsartan 2 and isopropanol (32 mL) were successively added to a reaction flask, and the temperature was controlled at 65 °C and stirred until dissolved. The temperature was lowered to 40 °C, and the mixture was stirred at a constant temperature for 0.5 h. Then the temperature was lowered to 20 °C (cooling rate: 20 °C / h), and the mixture was stirred at a constant temperature for 1 h. The mixture was filtered, and the filter cake was washed with isopropanol (8 mL). After drying, the finished product of valsartan 1 was obtained. Another batch of samples, crude valsartan 2 and finished product of valsartan 2, were prepared in the same way.

[0210] The impurity content and purity of the above products and the reference tablets were detected by the analysis method of Example 7, and the specific values are shown in the following table:

[0211]

[0212] Comparative Example 1

[0213] A solution of compound III prepared in Example 3 (equivalent to 8 g of compound III) was added to a reaction flask, DMF (48 mL) was added, sodium dihydrogen phosphate (2.89 g) was added, and 30% hydrogen peroxide (2.19 g) was added dropwise at 25 °C. Then a solution prepared by dissolving 1.75 g of sodium chlorite in 3 mL of water was added dropwise. The reaction was carried out for 5 h, and the reaction solution was poured into water to precipitate a solid. The solid was filtered (HPLC detection showed that the filtrate contained no compound I and compound III), and the solid was dried to obtain compound I (6.7 g, purity 88.4%, and 3.3% of compound III remained).

[0214] Comparative Example 2

[0215] A solution of compound III prepared in Example 3 (equivalent to 3.70 g of compound III) was added to a reaction flask, DMF (45 mL) was added, resorcinol (2.5 g) was added, and a mixture of sodium chlorite (0.96 g) dissolved in 4.5 mL of water and sodium dihydrogen phosphate (1.7 g) was added dropwise at 20 °C. The reaction was carried out overnight, and the reaction was poured into water to precipitate a solid. The solid was filtered (HPLC detection showed that the filtrate contained no compound I and compound III), and the solid was dried to obtain compound I (3.3 g, purity 87.7%, and 5.8% of compound III remained).

Claims

1. A method for preparing a compound represented by formula Ⅰa, characterized in that: The method comprises the following steps: in an organic solvent, the compound represented by formula IIIa is reacted with resorcinol, sodium chlorite and acetic acid to generate the compound represented by formula Ia. The synthesis route is as follows: wherein ring A is a 5-10 membered heteroaromatic ring; R 1 are independently halogen, -C 1-5 Alkyl or -OC 1-5 Alkyl, n is 0, 1 or 2; R 2 It is -H, a 5-6 membered heterocycle or a 5-6 membered aromatic heterocycle, wherein the 5-6 membered heterocycle is optionally substituted by one or more =O, -Bn or -Trt within the range allowed by the valence, and the 5-6 membered aromatic heterocycle is optionally substituted by one or more -Bn or -Trt within the range allowed by the valence.

2. The preparation method according to claim 1, characterized in that: The following steps are also included: Under alkaline conditions and in the presence of a catalyst, the compound represented by formula IIa is oxidized with an oxidant under appropriate temperature conditions in a polar organic solvent to obtain the compound represented by formula IIIa. The synthetic route is as follows:

3. The preparation method according to claim 1 or 2, characterized in that: Ring A is a 5-membered aromatic heterocyclic ring, preferably, the heteroatom of the 5-membered aromatic heterocyclic ring is N; and / or the number of heteroatoms of the 5-membered aromatic heterocyclic ring is 2; more preferably, Ring A is and / or R 1 are independently halogen or -C 1-5 Alkyl; preferably, R 1 is -Cl or n-butyl; and / or n is 2.

4. The preparation method according to any one of claims 1 to 3, characterized in that: R 2 is a 5-6 membered aromatic heterocycle, preferably a 5 membered aromatic heterocycle, more preferably and / or The 5-6 membered heterocyclic ring is optionally substituted with one or more -Trt groups within the range allowed by the valence, and is preferably substituted with one -Trt group.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The compound represented by formula Ia is selected from compound I, and the preparation method comprises the following steps: Step 2: In an organic solvent, compound III is reacted with resorcinol, sodium chlorite and acetic acid to generate compound I. The synthesis route is as follows: Preferably, the molar ratio of resorcinol to compound III in step 2 is 2-8:1, more preferably 4-6:1; and / or Preferably, the molar ratio of sodium chlorite to compound III in step 2 is 3-15:1, more preferably 4-8:1; and / or Preferably, the molar ratio of acetic acid to compound III in step 2 is 3-8:1, more preferably 4-6:1; and / or Preferably, the sodium chlorite in step 2 is added in the form of an aqueous sodium chlorite solution, more preferably the concentration of the aqueous sodium chlorite solution is between 10% w / w and a saturated solution concentration, further preferably 30%-35% w / w; and / or Preferably, the organic solvent in step 2 is a polar organic solvent, including one or more of DMF, DMA, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, tetrahydrofuran or acetone; and / or Preferably, the amount of the organic solvent in step 2 is 7-15 mL, more preferably 8-10 mL, per gram of compound III.

6. The preparation method according to claim 5, characterized in that: Step 2 comprises the following process: mixing compound III, an organic solvent, resorcinol and acetic acid, stirring them evenly, and then dropping a sodium chlorite aqueous solution into the mixture; Preferably, the reaction temperature of step 2 is 10-25°C, more preferably 10-20°C.

7. The preparation method according to claim 5 or 6, characterized in that: Step 2 comprises the following process: after the reaction is completed, adding a water-insoluble organic solvent and water to the reaction solution, stirring and separating the liquids; further purifying the organic layer to obtain compound I; Preferably, the water-insoluble organic solvent is dichloromethane; and / or Preferably, the organic layer is further purified by concentrating to remove part or all of the water-insoluble organic solvent, and preferably the concentrate is further recrystallized to obtain compound I; More preferably, the recrystallization solvent is a mixed solvent of dichloromethane and acetonitrile; the volume ratio of dichloromethane to acetonitrile is 1:10-2:5, preferably 1:5-2:

5.

8. The preparation method according to any one of claims 5 to 7, characterized in that: The preparation method further comprises the following steps: Under alkaline conditions and in the presence of a catalyst, compound II is oxidized with an oxidant in a polar organic solvent at an appropriate temperature to obtain compound III. The synthetic route is as follows:

9. A method for preparing compound III, characterized in that: The following steps are involved: Step 1: Under alkaline conditions and in the presence of a catalyst, compound II is oxidized with an oxidant in a polar organic solvent at an appropriate temperature to obtain compound III. The synthetic route is as follows: Wherein, the catalyst is TEMPO and KBr; The oxidant is calcium hypochlorite, wherein ClO - The amount is 1.00-1.20 eq, preferably 1.06-1.16 eq, and more preferably 1.12 eq.

10. The preparation method according to claim 9, characterized in that: Step 1 ClO - The concentration of ClO is 0.30-0.40 mol / L, preferably 0.30-0.35 mol / L, more preferably, ClO - The concentration is 0.34 mol / L; and / or The appropriate temperature in step 1 is 5-25°C, preferably 10-20°C; and / or The base used in the alkaline condition of step 1 is sodium bicarbonate, and the amount of sodium bicarbonate is 1.0-3.0eq, preferably 2.0eq; and / or The amount of TEMPO in step 1 is 0.05-0.15 eq, preferably 0.10 eq; and / or the amount of KBr is 0.20-0.30 eq, preferably 0.25 eq; and / or The reaction time of the oxidation in step 1 is 14-16 hours, preferably 15 hours; and / or The polar organic solvent in step 1 is DMF, and the amount of the polar organic solvent used is 3.0-7.0 mL / mol, preferably 4.0-6.0 mL / mol, and more preferably 5.0 mL / mol relative to compound II.

11. The preparation method according to claim 9 or 10, characterized in that: The compound III obtained by the preparation method contains compound B The content of compound B is no more than 1.0%, preferably no more than 0.8%, and more preferably no more than 0.7%.

12. A method for preparing alisartan medoxomil, characterized in that: Compound I is obtained according to the preparation method of claims 1-8, and further reacted to prepare allisartan medoxomil.

13. A compound represented by formula (III-1), It is characterized in that X 1 and X 2 are each independently H or halogen; R 1 is H or trityl; When R 1 When H, X 1 and X 2 Not at the same time Cl; Preferably, the compound represented by formula (III-1) is compound A or compound B: Compound A Compound B 14. A method for preparing compound B, comprising the following steps: (1a) oxidizing compound I with an oxidant in a polar organic solvent under alkaline conditions and in the presence of a catalyst to obtain compound B; (1b) Optionally, purifying the compound B obtained in step (1a); Preferably, the polar organic solvent in step (1a) is DMF, DMA, dichloromethane, acetonitrile, THF or acetone; and / or Preferably, the oxidant in step (1a) is sodium chlorite, calcium hypochlorite or hydrogen peroxide; and / or Preferably, the catalyst in step (1a) comprises potassium bromide, preferably, the catalyst in step (1a) is potassium bromide and TEMPO; and / or Preferably, the base used in the alkaline condition of step (1a) is sodium bicarbonate or disodium hydrogen phosphate, preferably disodium hydrogen phosphate.

15. The preparation method according to claim 14, characterized in that: The volume mass ratio of the polar organic solvent to compound I in step (1a) is 8-12 mL / g, preferably 10 mL / g; and / or The base used in the alkaline condition of step (1a) is disodium hydrogen phosphate, and the amount of the base is 1.0-3.0 eq, preferably 2.0 eq; and / or The oxidant in step (1a) is sodium chlorite, and the amount of the oxidant is 5.0-7.0 eq, preferably 6.0 eq; and / or The catalyst in step (1a) is potassium bromide, and the amount of the catalyst is 3.0-5.0 eq, preferably 4.0 eq; and / or The oxidant in step (1a) is hydrogen peroxide, with a concentration of 25-35%, preferably 30%; the amount is 3.0-5.0eq, preferably 4.0eq; and / or Step (1a) is to add a certain amount of disodium hydrogen phosphate and sodium chlorite to DMF, and then add a certain amount of potassium bromide and hydrogen peroxide to react with compound I.

16. The preparation method according to claim 14 or 15, characterized in that: The step (1a) adopts a staged heating method, wherein the reaction temperature in the first period is lower than the reaction temperature in the second period; Preferably, the first period of time is 20-40 min, preferably 30 min; and / or Preferably, the reaction temperature in the first period is 60-80°C, preferably 70°C; and / or Preferably, the second period of time is 70-110 min, more preferably 80-100 min, and even more preferably, the second period of time is 90 min; and / or Preferably, the reaction temperature during the second period is 85-95°C, preferably 90°C.

17. The preparation method according to any one of claims 14 to 16, characterized in that: The purification in step (1b) comprises the following steps: (1c) After cooling, put it into water, precipitate solid, and filter; (1d) beating the filter cake with an organic solvent to obtain compound B; Preferably, the volume mass ratio of water to compound I in step (1c) is 18.0-26.0 mL / g, more preferably 20.0-24.0 mL / g, and further preferably, the volume mass ratio of water to compound I is 22.0 mL / g; and / or Preferably, the organic solvent in step (1d) is ethyl acetate; and / or Preferably, the volume mass ratio of the organic solvent to compound I in step (1d) is 4.0-8.0 mL / g, more preferably 5.0-7.0 mL / g, and further preferably, the volume mass ratio of the organic solvent to compound I is 6.0 mL / g.

18. A method for preparing compound A, characterized in that: The following steps are involved: (2a) Compound B is added to an alcohol solvent and heated to reflux to obtain Compound A; (2b) Optionally, purifying the compound A obtained in step (2a); Preferably, the compound B in step (2a) is prepared according to the preparation method according to any one of claims 14 to 17; and / or Preferably, the alcohol solvent in step (2a) is methanol, ethanol or isopropanol, more preferably, the organic solvent is methanol; and / or Preferably, the volume mass ratio of the alcohol solvent to compound B in step (2a) is 8.0-12.0 mL / g, more preferably 9.0-11.0 mL / g, and further preferably, the volume mass ratio of the alcohol solvent to compound B is 10.0 mL / g; and / or Preferably, the heating reflux time in step (2a) is 5-9 hours, more preferably 6-8 hours, and even more preferably, the heating reflux time is 7 hours.

19. The preparation method according to claim 18, characterized in that: The purification in step (2b) comprises the following steps: (2c) cooling, filtering, and concentrating the filtrate; (2d) adding an organic solvent and heating to reflux; (2e) adding another organic solvent dropwise, cooling and stirring after the addition is complete; (2f) filtering and drying to obtain compound A; Preferably, the organic solvent in step (2d) is an alcohol solvent, more preferably methanol, ethanol or isopropanol, and further preferably, the organic solvent is ethanol; and / or Preferably, the volume mass ratio of the organic solvent to compound B in step (2d) is 1.00-2.00 mL / g, more preferably 1.50-2.00 mL / g, and further preferably, the volume mass ratio of the organic solvent to compound B is 1.88 mL / g; and / or Preferably, the organic solvent in step (2e) is a hydrocarbon solvent, more preferably n-heptane, hexane, n-octane or petroleum ether, and further preferably, the organic solvent is n-heptane; and / or Preferably, the volume mass ratio of the organic solvent to compound B in step (2e) is 2.00-3.00 mL / g, more preferably 2.00-2.50 mL / g, and further preferably, the volume mass ratio of the organic solvent to compound B is 2.25 mL / g; and / or Preferably, the cooling in step (2e) is to 0-10°C, more preferably to 3-7°C, and even more preferably to 5°C.

20. A compound III composition, characterized in that The composition contains compound B, and the content of compound B is no more than 1.0%, preferably no more than 0.8%, and more preferably no more than 0.7%; 21. An allisartan medoxomil composition, comprising compound A, wherein the content of allisartan medoxomil is greater than 99.9%, and the content of compound A is less than or equal to 0.04%.

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