Potassium ion competitive blocker intermediate and preparation method thereof

Abstract

The invention relates to a potassium ion competitive blocker intermediate and a preparation method thereof. The first aspect of the invention provides a preparation method of a potassium ion competitive blocker compound in a formula 1, and the reaction route is shown as follows: # imgabs0 # R1 is H or F; r < 2 > is F, H,-O (CH2) 3OCH3; r3 and R5 are independently selected from H and OCH3; r4 is C or N; the method comprises the following steps: step 4, obtaining a compound shown in a formula 1 from a compound shown in a formula 2 under the action of a borane-amine complex and titanium tetrachloride. According to the method for preparing the potassium ion competitive blocker, one step of oxidation can be reduced, material loss is reduced, cost is reduced, aftertreatment is simplified, the yield of each step reaches 88% or above, and the purity reaches 99% or above. The process for preparing the potassium ion competitive blocker compound in the formula 1 is simpler and more convenient, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a potassium ion competitive blocker intermediate and a preparation method thereof, belonging to the technical field of medicine and chemistry. Background Art

[0002] The potassium ion competitive blocker compound of formula 1 has the following molecular structure:

[0003]

[0004] Wherein, R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N;

[0005] The compound of formula 1 has excellent anti-ulcer activity (ie, proton pump inhibitory activity, etc.) and eradication activity against Helicobacter pylori (H. pylori), and can therefore be used to prevent and treat gastrointestinal ulcers, gastritis, reflux esophagitis or gastrointestinal damage caused by Helicobacter pylori.

[0006] In the prior art, most of the compounds of formula 1 are reduced from compound A to compound B and then oxidized to compound C, and finally reductively aminated to obtain compound 1. The preparation route is shown in the following formula. The preparation steps of this method are long and the general oxidants are expensive, difficult to handle, difficult to scale up, the process operation is relatively cumbersome, the production cost is high, and dimethylamine impurities are easily generated when the existing method is used for preparation. Therefore, it is urgent to develop a method for synthesizing potassium ion competitive blockers that is easy to operate, simple in route, short in time, and high in atomic utilization, so as to improve efficiency and promote industrial production.

[0007]

[0008] Wherein, R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H, OCH3; R4 is C or N.

[0009] The present invention provides a new potassium ion competitive retarder intermediate for preparing a key intermediate 2 and then preparing a potassium ion competitive retarder, avoiding the use of a reducing agent and an oxidizing agent twice, making the process for preparing the potassium ion competitive retarder easier and simpler; the new potassium ion competitive retarder intermediate provided by the present invention and the preparation method thereof are suitable for industrial production, and therefore have good market value and far-reaching practical significance. Summary of the invention

[0010] In view of the above technical background, the present invention discloses a potassium ion competitive blocker intermediate and a preparation method thereof.

[0011] The first aspect of the present invention provides a method for preparing a potassium ion competitive blocker compound of formula 1, and the reaction scheme is as follows:

[0012]

[0013] R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N;

[0014] The following steps are included:

[0015] Step 4: The compound of formula 2 is reacted with a borane-amine complex and titanium tetrachloride to obtain a compound of formula 1;

[0016] Preferably, the borane-amine complex in step 4 is selected from a combination of one or more of borane ammonia complex, borane dimethylamine complex, borane-triethylamine complex, borane tert-butylamine complex, borane diethylamine complex and borane N,N-diisopropylethylamine complex, preferably a combination of one or more of borane ammonia complex, borane dimethylamine complex, borane-triethylamine complex and borane diethylamine complex;

[0017] Preferably, the molar equivalent ratio of the compound of formula 2 and the borane-amine complex in step 4 is 1:(1-3), preferably 1:(1.1-2);

[0018] Preferably, the molar equivalent ratio of the compound of formula 2 in step 4 to titanium tetrachloride is 1:(0.05-0.5), preferably 1:(0.08-0.3);

[0019] Preferably, the reaction temperature in step 4 may be 60 to 80°C, preferably 70 to 75°C;

[0020] Preferably, the reaction time of step 4 is 8 to 15 hours, preferably 10 to 15 hours;

[0021] Preferably, the reaction solvent in step 4 is one or more of benzene, toluene, xylene, trimethylbenzene, acetonitrile, dioxane, cyclopentane, and cyclohexane, preferably benzene, toluene, xylene, and trimethylbenzene;

[0022] Preferably, the post-treatment method of step 4 comprises adding a saturated sodium chloride solution, stirring for 0.5 to 2 hours, standing and separating the liquids, concentrating the organic phase, adding n-heptane, stirring at 15 to 30° C. for 1 to 4 hours, crystallizing, filtering and drying to obtain the compound of formula 1.

[0023] The post-treatment method provided by the invention does not require column chromatography, is simple to operate and is highly efficient, and can obtain a product with a molar yield of more than 94% and a product HPLC purity of more than 99%.

[0024] The second aspect of the present invention provides a method for preparing the compound of formula 2, wherein the compound of formula 2 is as follows:

[0025]

[0026] Scenario 1:

[0027] The reaction route is as follows:

[0028]

[0029] R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N;

[0030] The following steps are included:

[0031] Step 3: The compound of formula 3 is reacted with phenyltrimethylammonium bromide to obtain the compound of formula 2;

[0032] Preferably, the molar feed ratio of the compound of formula 3 to phenyltrimethylammonium bromide in step 3 is selected from 1:(1-3), preferably 1:(1.2-2);

[0033] Preferably, the reaction solvent in step 3 is one or more of benzene, toluene, xylene, trimethylbenzene, acetonitrile, dioxane, cyclopentane, and cyclohexane, preferably benzene, toluene, xylene, and trimethylbenzene;

[0034] Preferably, the reaction temperature in step 3 is selected from 70 to 100°C;

[0035] Preferably, the reaction time of step 3 is 15 to 25 hours, preferably 18 to 22 hours;

[0036] Preferably, the post-treatment method of step 3 comprises adding a saturated sodium bicarbonate aqueous solution, stirring for 0.5 to 2 hours, and then standing to separate the liquids, concentrating the organic phase, adding n-heptane, stirring at 15 to 30° C. for 1 to 4 hours, and then filtering to obtain compound 2.

[0037] The post-treatment method provided by the present invention does not require column chromatography, is simple to operate and is highly efficient, and can obtain a biological product with a molar yield of more than 94% and a product HPLC purity of more than 99%.

[0038] Scenario 2:

[0039] The reaction route is as follows:

[0040]

[0041] R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N;

[0042] The following steps are included:

[0043] Step A: the compound of formula 8 reacts with methylamine hydrochloride in the presence of a condensing agent to obtain a compound of formula 7;

[0044] Step B: The compound of formula 7 and the compound of formula 4 are reacted with an organic base and DMAP to obtain the compound of formula 2.

[0045] Preferably, the condensing agent in step A is selected from 1,1'-carbonyldiimidazole (CDI), O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), propylphosphonic anhydride (T3P) or any combination thereof; preferably CDI, HATU, T3P or any combination thereof.

[0046] Preferably, in step A, the molar ratio of the compound of formula 8, the condensing agent and methylamine hydrochloride is 1:(1-3):(1-3), preferably 1:(1-2):(1-2);

[0047] Preferably, the reaction temperature of step A is 50-70°C;

[0048] Preferably, the reaction time of step A is 15 to 24 hours, preferably 18 to 22 hours.

[0049] Preferably, the solvent used in step A is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N'-dimethylformamide (DMF), ethyl acetate, and acetonitrile, preferably DMF and acetonitrile.

[0050] Preferably, the organic base in step B is selected from one or more of N,N-diisopropylethylamine (DIPEA), triethylamine, diisopropylamine, diisopropylethylamine, pyridine, preferably one or more of DIPEA, triethylamine, diisopropylamine, pyridine.

[0051] Preferably, in step B, the molar ratio of the compound of formula 7, the compound of formula 4, the organic base and DMAP is 1:(1-2):(1-3):(0.1-0.5), preferably 1:(1-1.5):(1-2.5):(0.1-0.4);

[0052] Preferably, the solvent used in step B is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, preferably one or more of dichloromethane, THF, dichloroethane, and chloroform;

[0053] Preferably, the reaction temperature of step B is -10 to 30°C;

[0054] Preferably, the reaction time of step B is 0.5 to 8 h, preferably 1 to 4 h.

[0055] In certain embodiments, the compound of formula 8 is prepared with the corresponding lipid (for example, when R1=F; R2=F; R3=OCH3; R4=C; R5=H, the corresponding lipid is 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester) as a raw material, and sodium hydroxide aqueous solution and acetonitrile are added and refluxed for 2 hours to obtain the compound of formula 8 in a relatively high yield (prepared by referring to the method of CN108368121A).

[0056] The third aspect of the present invention provides a method for preparing a compound of formula 3, the reaction is as follows:

[0057]

[0058] R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N;

[0059] The following steps are included:

[0060] Step 1: Compound 6 is reacted with hydrogen peroxide in the presence of a base to obtain compound 5;

[0061] Step 2: Compound 5 and compound 4 are reacted with an organic base and DMAP to obtain compound 3;

[0062] Preferably, the base in step 1 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably potassium carbonate, sodium carbonate, and cesium carbonate;

[0063] Preferably, in step 1, the molar ratio of the compound of formula 6, hydrogen peroxide and base is 1:(1-4):(1-4), preferably 1:(2-3):(2-3);

[0064] Preferably, the solvent used in step 1 is selected from DMSO, tetrahydrofuran, acetonitrile, and dichloromethane;

[0065] Preferably, the reaction temperature of step 1 is 20°C to 40°C, preferably 20°C to 35°C;

[0066] Preferably, the reaction time of step 1 is 12 to 25 hours, preferably 15 to 20 hours;

[0067] Preferably, the organic base in step 2 is selected from one or more of N,N-diisopropylethylamine (DIPEA), triethylamine, diisopropylamine, diisopropylethylamine, pyridine, preferably one or more of DIPEA, triethylamine, diisopropylamine, pyridine.

[0068] Preferably, in step 2, the molar ratio of the compound of formula 5, the compound of formula 4, the organic base and DMAP is 1:(1-2):(1-3):(0.1-0.5), preferably 1:(1-1.5):(1-2.5):(0.1-0.4);

[0069] Preferably, the solvent used in step 2 is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, preferably one or more of dichloromethane, THF, dichloroethane, and chloroform;

[0070] Preferably, the reaction temperature of step 2 is -10 to 30°C, preferably -10 to 25°C;

[0071] Preferably, the reaction time of step 2 is 0.5 to 8 h, preferably 1 to 4 h.

[0072] In certain embodiments, the compound of formula 6 is prepared according to the following general formula:

[0073]

[0074] For example, when R1 = F; R3 = OCH3, 2,4-difluoro-1-(isocyanato(tosyl)methyl)benzene and 2-cyano-3-methoxyethyl acrylate are used as raw materials, and reacted at room temperature for 3 hours under the conditions of NaH and MeCN to obtain the compound of formula 6 in a high yield (reference Letters in Organic Chemistry (2012), 9(4), 305-308).

[0075] As described above, the potassium ion competitive blocker intermediate and the preparation method thereof of the present invention have the advantages of using only a reducing agent once, not using an oxidizing agent, and shortening the reaction step by one step, thereby greatly reducing the cost.

[0076] The fourth aspect of the present invention also provides a potassium ion competitive blocker intermediate, the structural formula of which is shown below:

[0077]

[0078] Wherein, R1 is H, F; R2 is F, -O(CH2)3OCH3; R3 and R5 are independently selected from H, OCH3; R4 is C, N;

[0079] And in the compound of formula 2, R1 and R2 are not F at the same time;

[0080] In the compounds of formula 5, 6, 7 and 8, R1 and R3 are not H at the same time.

[0081] The fifth aspect of the present invention provides a process for synthesizing a potassium ion competitive blocker, which includes the preparation method of the compound of formula 2 provided in the second aspect above or the preparation method of the compound of formula 3 provided in the third aspect above or the use of the potassium ion competitive blocker intermediate described in the fourth method above.

[0082] Beneficial technical effects of the present invention:

[0083] 1. The inventors have found through multiple experiments that when the compound of formula 2 is used to prepare the compound of formula 1, the yield is less than 13% when 1,1,3,3-tetramethyldisiloxane, aluminum trichloride system or triethylsilane, aluminum trichloride system is used to reduce the amide bond; during the process of lithium tetrahydrogen aluminum reducing the amide bond, the m-fluorobenzenesulfonyl group is easy to leave, resulting in the failure to obtain the target product; and when the borane-amine complex, titanium tetrachloride system, and dichloroethane are used as the solvent, the yield is reduced by 44% relative to toluene as the solvent; the inventors have also found that when the compound of formula 3 is used to prepare the compound of formula 2, the use of phenyltrimethyl iodide When the present inventors used different conditions to obtain the compound of formula 7 from the compound of formula 8, they found that the product was not obtained when oxalyl chloride and methylamine hydrochloride were used, a yield of 50% was obtained when oxalyl chloride and methylamine tetrahydrofuran solution were used, and a yield of 90.7% was obtained when CDI and methylamine hydrochloride were used, which was more than 40% higher than other conditions.

[0084] The applicant found that the compound of formula 3A reacted with methylamine tetrahydrofuran solution for methylation, reacted at 80-85°C for 20h, and a small amount of raw materials remained under TLC monitoring, resulting in impurity points. The impurities increased after adding methylamine tetrahydrofuran solution, the reaction system was completely converted, the impurity points were obvious, and the yield of the separated and purified product was only 58%. In the existing method, due to the strong reducing property of the reducing agent sodium borohydride, potassium borohydride or lithium borohydride, while reducing the imine, part of the pyridine structure was also reduced, forming a variety of pyridine partial reduction products or pyridine full reduction products, such as: genotoxic impurities 3-pyridine sulfonic acid methyl ester, 3-pyridine sulfonic acid ethyl ester, 3-pyridine sulfonic acid isopropyl ester, making subsequent purification very difficult. The applicant also found that the reduction of the compound of formula 2B using sodium borohydride in ethanol solvent and boron trifluoride and sodium borohydride system in THF solvent could not obtain a satisfactory compound of formula 1B.

[0085] 2. The method of the present invention not only avoids the dimethylamine impurity generated by reductive amination, but also avoids the impurities of pyridine ring reduction generated by sodium borohydride reduction. Such impurities are difficult to remove due to their similar polarity to the final product. Therefore, the method of the present invention simplifies the post-treatment and improves the purity.

[0086] 3. The method of the present invention can be used to prepare a potassium ion competitive retarder, which can reduce one oxidation step, reduce material loss, reduce costs, simplify post-processing, and achieve a yield of more than 85% and a purity of more than 99% in each step.

[0087] 4. Patent WO2016175555A1 uses compound A as raw material to prepare compound 3 in three steps, and the total yield of the three steps is 56.5%. Patent WO2020060213A1 is an improvement on WO2016175555A1, and the total yield of the three steps is 70%. The present invention only needs two steps from compound 3 to compound 1, and the total yield of the two steps is 83.5%, which increases the total yield by 13.5%. Therefore, the method of the present invention not only shortens the steps, but also achieves a higher yield, can effectively solve the problems of high production cost, long route, low product purity, etc., and is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 This is the HPLC spectrum of Example 6. DETAILED DESCRIPTION

[0089] The present invention will be further described below in conjunction with specific examples. It should be understood that the following detailed description of the technical solution of the present invention with examples will help to further understand the advantages and effects of the technical solution of the present invention, and the examples do not limit the protection scope of the present invention, which is determined by the claims.

[0090] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0091] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0092] Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used directly without further treatment.

[0093] Embodiment 1:

[0094]

[0095] Preparation of the compound of formula 6A: 2,4-difluoro-1-(isocyanato(tosyl)methyl)benzene and ethyl 2-cyano-3-methoxyacrylate are used as raw materials, and reacted at room temperature for 3 hours under the conditions of NaH and MeCN to obtain the compound of formula 6A in a high yield (reference Letters in Organic Chemistry (2012), 9(4), 305-308);

[0096] The NMR data of the compound of formula 6A are as follows:

[0097] 1 H NMR (400MHz, DMSO) δ11.79(s,1H),7.67–7.52(m,2H),7.43-7.34(m,1H),7.20(td,J=8.4,2.4Hz,1H),3.83(s,3H).

[0098] Embodiment 2:

[0099]

[0100] 5-(2,4-Difluorophenyl)-4-methoxy-1H-pyrrole-3-carbonitrile (100 g, 1.0 eq) compound 6A was dissolved in DMSO (400 mL), and K2CO3 (177 g, 3.0 eq) and 30 wt% H2O2 (145.5 g, 3.0 eq) were added to react at 30-35°C for 20 h. After the reaction was completed by HPLC control, water (1 L) was added at 20-30°C for crystallization. The mixture was stirred for 0.5 h and filtered. The filter cake was rinsed with water (300 mL) and dried at 60°C to obtain compound 5A (105.7 g, yield 98.2%) as an off-white solid.

[0101] 1H NMR(400MHz,d6-DMSO)δ11.23(s,1H),7.67(td,J=8.7,6.7Hz,1H),7.43–7.2 8(m,1H),7.23(s,1H),7.19(td,J=8.5,2.2Hz,1H),6.96(s,2H),3.64(s,3H).

[0102] Embodiment 3:

[0103]

[0104] The compound of formula 5A (100 g, 1 eq) was dissolved in DCM (500 mL), stirred for 30 min at 20-30 ° C, cooled to -10--5 ° C, DIPEA (61.5 g, 1.2 eq) and DMAP (9.7 g, 0.2 eq) were added, and 3-fluorobenzenesulfonyl chloride (92.6 g, 1.2 eq) was added dropwise at -10--5 ° C, and the temperature was raised to 20-25 ° C, stirred for 30 min, and the raw material was ≤1.0% by HPLC control detection. It was concentrated to dryness under reduced pressure at 45 ° C, ethyl acetate (500 mL) was added, and 1M HCl aqueous solution (600 mL) was added, stirred for 5 min, allowed to stand, separated, extracted, and dried to obtain a yellow solid. The solid was washed with ethyl acetate, filtered, and the filter cake was dried at 60 ° C to obtain the compound of formula 3A (149.7 g, yield 92%) as an off-white solid.

[0105] 1 H NMR(400MHz, CDCl3)δ8.13(s,1H),7.50(td,J=8.1,5.2Hz,1H),7.38(td,J=8.2,2.4Hz,1H),7.34–7.21(m, 2H),7.14(dt,J=7.8,2.1Hz,1H),7.04–6.92(m,2H),6.86(td,J=8.9,2.5Hz,1H),6.00(s,1H),3.56(s,3H).

[0106] Embodiment 4:

[0107]

[0108] The compound of formula 3A (100 g, 1.0 eq) was dissolved in toluene (500 mL), and phenyltrimethylammonium bromide (79.0 g, 1.5 eq) was added. The temperature was raised to 80-85° C. and the reaction was carried out for 20 h. Samples were taken and the reaction was completed by TLC monitoring. The temperature was lowered to 15-25° C., saturated aqueous sodium chloride solution (500 mL) was added, and the mixture was stirred for 0.5 h and then allowed to stand for separation. The organic phase was concentrated to 300 mL, and n-heptane (500 mL) was added. The mixture was stirred at 20-30° C. for 3 h and then filtered after crystallization. The filter cake was rinsed with n-heptane and dried at 60° C. for 12 h to obtain the compound of formula 2A (92.1 g, yield 88%, purity 99.2%) as an off-white solid.

[0109] 1 H NMR (400MHz, Acetone) δ7.90(s,1H),7.70(td,J=8.1,5.4Hz,1H),7.59(td,J=8.5,2.5Hz,1H),7.44( d,J=7.9Hz,1H),7.32(dt,J=11.7,7.0Hz,3H),7.15–7.06(m,2H),3.54(s,3H),2.88(d,J=4.8Hz,3H).

[0110] Embodiment 5:

[0111]

[0112] The compound of formula 3A (1 g, 1.0 eq) was dissolved in a solvent (5 mL), and phenyltrimethylammonium bromide (0.79 g, 1.5 eq) was added. The temperature was raised to temperature A and the reaction was continued for 20 h. Samples were taken and HPLC was performed. The HPLC results are shown in Table 1:

[0113] Table 1

[0114]

[0115] Embodiment 6:

[0116]

[0117] The compound of formula 2A (50 g, 1.0 eq) was dissolved in toluene (250 mL), and titanium tetrachloride (2.2 g, 0.1 eq) and borane ammonia complex (5.5 g, 1.5 eq) were added, and the temperature was raised to 70-75°C for reaction for 12 h. After HPLC detection, the reaction was complete, and saturated sodium bicarbonate aqueous solution (250 mL) was added. After stirring for 0.5 h, the mixture was allowed to stand for separation, and vacuum distillation was performed to concentrate the mixture to 50 mL. n-heptane (250 mL) was added, and the mixture was stirred at 20-30°C for 3 h for crystallization, and then filtered. The filter cake was dried at 60°C for 12 h to obtain the compound of formula 1A (45.9 g, yield 94.9%, purity 99.8%). The HPLC spectrum is shown in the attached figure. Figure 1 shown.

[0118] 1 H NMR (400MHz, d6-DMSO) δ7.70–7.60(m,3H),7.37–7.24(m,3H),7.23–7.10(m,2H),3.73(s,2H),3.44(s,3H),2.43(s,3H).

[0119] Embodiment 7:

[0120]

[0121] The compound is prepared by using 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester as a raw material, adding sodium hydroxide aqueous solution and acetonitrile, and refluxing for 2 hours to obtain the compound of formula 8A in a relatively high yield (prepared by referring to the method of CN108368121A);

[0122] The NMR data of the compound of formula 8A are as follows:

[0123] 1 H NMR (400MHz, DMSO) δ11.48(s,1H),7.64(td,J=8.7,6.7Hz,1H),7.35(ddd,J=9.2,8.3,3.2Hz,2H),7.21–7.14(m,1H),3.72(d,J=3.2Hz,6H).

[0124] Embodiment 8:

[0125]

[0126] 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid compound 8A (50 g, 1.0 eq) was dissolved in acetonitrile (100 mL) and DMF (100 mL), and CDI (35.2 g, 1.1 eq) and methylamine hydrochloride (14.7 g, 1.1 eq) were added. The temperature was raised to 60-65° C. and the reaction was carried out for 20 h. The raw material was ≤1.0% by HPLC control. Saturated sodium chloride aqueous solution (250 mL) and ethyl acetate (250 mL) were added at a temperature of 20-30° C., and the mixture was stirred for 0.5 h and then allowed to stand for separation. The organic phase was concentrated to 150 mL, and n-heptane (250 mL) was added. The mixture was stirred at 20-30° C. for 3 h and then filtered after crystallization. The filter cake was rinsed with n-heptane and dried at 60° C. for 12 h to obtain compound 7A (47.7 g, yield 90.7%) as an off-white solid.

[0127] 1 H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 7.84 (td, J = 8.8, 6.5Hz, 1H), 7.30 (d, J = 3.7Hz, 1H), 7.04–6.84 (m, 3H), 3.70 (s, 3H), 2.96 (d, J = 4.9Hz, 3H).

[0128] Embodiment 9:

[0129]

[0130] 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (5 g, 1.0 eq) was dissolved in acetonitrile (10 mL) and DMF (10 mL), and then a condensing agent (1.1 eq) and methylamine hydrochloride (1.47 g, 1.1 eq) were added. The temperature was raised to 60-65° C. and the reaction was carried out for 20 h. The reactor was sampled and tested by HPLC. The HPLC data are shown in Table 4. The post-treatment was the same as in Example 8.

[0131] Table 4

[0132]

[0133]

[0134] Embodiment 10:

[0135]

[0136] The compound of formula 7A (100 g, 1 eq) was dissolved in DCM (200 mL), the temperature was controlled at 20 to 30 ° C, stirred for 30 min, then cooled to -10 to -5 ° C, DIPEA (58.2 g, 1.2 eq) was added, the temperature was controlled at -10 to -5 ° C, DMAP (9.2 g, 0.2 eq) was added, the temperature was controlled at -10 to -5 ° C, the compound of formula 4A (87.7 g, 1.2 eq) was added dropwise, the temperature was increased to 20 to 25 ° C, stirred for 30 min, and the raw material was detected by HPLC. ≤1.0%, concentrated to dryness under reduced pressure at 45 ° C, ethyl acetate (500 mL) was added, 1M HCl aqueous solution (600 mL) was added, stirred for 5 min, allowed to stand for 10 min, separated, extracted, concentrated to obtain a yellow solid, washed with ethyl acetate, filtered, and the filter cake was dried at 60 ° C to obtain the compound of formula 2A (144.3 g, yield 90.5%, purity 98.2%) as an off-white solid.

[0137] 1 H NMR (400MHz, Acetone) δ7.90(s,1H),7.70(td,J=8.1,5.4Hz,1H),7.59(td,J=8.5,2.5Hz,1H),7.44( d,J=7.9Hz,1H),7.32(dt,J=11.7,7.0Hz,3H),7.15–7.06(m,2H),3.54(s,3H),2.88(d,J=4.8Hz,3H).

[0138] Embodiment 11:

[0139]

[0140] The compound of formula 2B (10 g, 1.0 eq) was dissolved in toluene (50 mL), the temperature was controlled at 15-20° C., titanium tetrachloride (0.53 g, 2.78 mmol) was added, borane ammonia complex (1.29 g, 41.7 mmol) was added, the temperature was raised to 70-75° C. and the reaction was carried out for 12-13 h. The system was monitored by TLC and converted. The temperature was lowered to 30-35° C. and fumaric acid was added. The mixture was stirred and crystallized at 30-35° C. for 1 h. The temperature was lowered to 15-20° C. and stirred and crystallized for 1 h. The mixture was filtered to obtain vonoprazan fumarate with a yield of 92.7%.

[0141] 1 H NMR(400MHz,DMSO)δppm 2.42(s,3H),3.83(s,2H),6.24-6.72(m,3H),

[0142] 7.16-7.29(m,2H),7.41-7.57(m,2H),7.62(dd,J=8.25,4.88Hz,2H),7.67-7.77( m,1H),7.80-7.95(m,1H),8.56(d,J=2.38Hz,1H),8.88(dd,J=4.75,1.38Hz,1H).

[0143] Comparative Example 1:

[0144]

[0145] The compound of formula 3A (10.0 g, 1.0 eq) was dissolved in toluene (50 mL), and tetramethylammonium fluoride (5.67 g, 2.5 eq) was added. The temperature was raised to 100-110° C. and the reaction was carried out for 16 h. A small amount of raw materials remained in the reaction after TLC monitoring. The temperature was lowered to 15-25° C., a saturated sodium chloride solution (500 mL) was added, and the mixture was stirred for 0.5 h and then allowed to stand for separation. The organic phase was concentrated to 30 mL, and n-heptane (50 mL) was added. The mixture was stirred at 20-30° C. for 3 h and then filtered after crystallization. The filter cake was rinsed with n-heptane and dried at 60° C. for 12 h to obtain the compound of formula 2A (5.7 g, molar yield 55.1%, purity 96.4%) as an off-white solid.

[0146] The experimental parameters were adjusted, and the reaction conditions were shown in Table 5 below:

[0147] Table 5

[0148]

[0149] Comparative Example 2:

[0150] Comparative Example 2.1:

[0151]

[0152] Compound 2A (5 g, 1.0 eq), dichloroethane (25 mL), titanium tetrachloride (0.22 g, 0.1 eq), borane ammonia complex (0.55 g, 1.5 eq), heated to 70-75 ° C for 16 h, TLC detected that the reaction was complete, added saturated sodium bicarbonate aqueous solution (25 mL), stirred for 0.5 h and then allowed to stand for separation, the organic phase was distilled under reduced pressure at 45-50 ° C, concentrated to 15 mL, added n-heptane (25 mL), stirred at 20-30 ° C for 3 h, crystallized and filtered, the filter cake was rinsed with n-heptane and dried at 60 ° C for 12 h to obtain compound 1A (2.44 g, yield 50.5%, purity 99.4%).

[0153] Comparative Example 2.2:

[0154]

[0155] The compound of formula 2B (10 g, 1.0 eq) was dissolved in ethanol (50 mL), the temperature was controlled at 15-20 ° C, sodium borohydride (1.05 g, 27.8 mmol) was added, and the temperature was raised to 30-35 ° C for reaction for 2-3 h. According to TLC monitoring, the system was not completely converted and new impurity points were generated. There was no obvious conversion when the reaction time was extended. The temperature was increased gradually. As the temperature increased, the impurity points of the system became larger. When the temperature was raised to 70-75 ° C, the system showed obvious degradation and no purification treatment was performed.

[0156] The experimental parameters were adjusted, referring to the comparative example 2.1 or 2.2 method, and the reaction conditions were shown in Table 6 below:

[0157] Table 6

[0158]

[0159]

[0160] Comparative Example 3:

[0161]

[0162] Method 1:

[0163] 5-(2,4-Difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (5 g, 1.0 eq) was dissolved in dichloromethane (10 mL) and DMF (1 mL), and oxalyl chloride (2.76 g, 1.1 eq) was added dropwise at 0-5°C, and the temperature was controlled to 0-5°C for 2 h. The conversion was complete when detected by TLC. Methylamine hydrochloride (1.47 g, 1.1 eq) was added, and the temperature was raised to 20-25°C for 2 h. Sampling was performed, and the system became impure and was not purified.

[0164] Method 2:

[0165] 5-(2,4-Difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (5 g, 1.0 eq) was dissolved in dichloromethane (10 mL) and DMF (1 mL). Oxalyl chloride (2.76 g, 1.1 eq) was added dropwise at 0-5°C. The temperature was kept at 0-5°C for 2 h. After TLC detection, the conversion was complete. 2N methylamine tetrahydrofuran solution (11 mL, 1.1 eq) was added. The temperature was raised to 20-25°C for 2 h. Sampling was performed and the conversion was complete after TLC control. Saturated sodium chloride solution (25 mL) was added at 20-30 ° C. The mixture was stirred for 0.5 h and then allowed to stand for separation. The organic phase was concentrated to 25 mL, and n-heptane (25 mL) was added. The mixture was stirred at 20-30 ° C. for 3 h to crystallize and then filtered. The filter cake was rinsed with n-heptane and dried at 60 ° C. to obtain the compound of formula 7A (2.7 g, yield 50.9%, purity 95.4%) as an off-white solid.

Claims

1. A method for preparing a potassium ion competitive blocker compound of formula 1, the reaction route is as follows: R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N; The following steps are included: Step 4: The compound of formula 2 is treated with borane-amine complex and titanium tetrachloride to obtain the compound of formula 1.

2. The preparation method according to claim 1, characterized in that The preparation method of the compound of formula 2 is as follows: Scenario 1: The reaction route is as follows: R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N; The following steps are included: Step 3: The compound of formula 3 is reacted with phenyltrimethylammonium bromide to obtain the compound of formula 2; Scenario 2: The reaction route is as follows: R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N; The following steps are included: Step A: reacting the compound of formula 8 with methylamine hydrochloride in the presence of a condensing agent to obtain a compound of formula 7; Step B: The compound of formula 7 and the compound of formula 4 are reacted with an organic base and DMAP to obtain the compound of formula 2.

3. The preparation method according to claim 2, characterized in that The preparation of the compound of formula 3 comprises the following steps, and the reaction is as follows: R1 is H, F; R2 is F, H, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N; Step 1: Compound 6 is reacted with hydrogen peroxide in the presence of a base to obtain compound 5; Step 2: The compound of formula 5 and the compound of formula 4 are reacted with an organic base and DMAP to obtain the compound of formula 3.

4. The preparation method according to claim 1, characterized in that: The borane-amine complex is selected from a combination of one or more of a borane ammonia complex, a borane dimethylamine complex, a borane-triethylamine complex, a borane tert-butylamine complex, a borane diethylamine complex and a borane N,N-diisopropylethylamine complex, preferably a combination of one or more of a borane ammonia complex, a borane dimethylamine complex, a borane-triethylamine complex and a borane diethylamine complex.

5. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The molar equivalent ratio of the compound of formula 2 and the borane-amine complex in step 4 is 1:(1-3), preferably 1:(1.1-2); (2) The molar equivalent ratio of the compound of formula 2 in step 4 to titanium tetrachloride is 1:(0.05-0.5), preferably 1:(0.08-0.3); (3) The reaction temperature of step 4 is 60 to 80° C., preferably 70 to 75° C.; (4) The reaction time of step 4 is 8 to 15 hours, preferably 10 to 15 hours; (5) The reaction solvent in step 4 is one or more of toluene, xylene, trimethylbenzene, acetonitrile, dioxane, cyclopentane, and cyclohexane, preferably toluene, xylene, or trimethylbenzene.

6. The preparation method according to claim 2 or 3, characterized in that: The preparation method satisfies one or more of the following conditions: (1) In step 3, the molar feed ratio of the compound of formula 3 to phenyltrimethylammonium bromide is selected from 1: (1 to 3), preferably 1: (1.2～2)； (2) The reaction solvent of step 3 is one or more of benzene, toluene, xylene, trimethylbenzene, acetonitrile, dioxane, cyclopentane, and cyclohexane, preferably benzene, toluene, xylene, and trimethylbenzene; (3) The reaction temperature of step 3 is selected from 70 to 100° C.; (4) The reaction time of step 3 is 15 to 25 hours, preferably 18 to 22 hours.

7. The preparation method according to claim 2, characterized in that: The preparation method satisfies one or more of the following conditions: (1) The condensing agent in step A is selected from 1,1'-carbonyldiimidazole CDI, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TBTU, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate HBTU, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU, O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate HOTU, propylphosphonic anhydride T3P or any combination thereof; preferably CDI, HATU, T3P or any combination thereof; (2) In step A, the molar ratio of the compound of formula 8, the condensing agent and methylamine hydrochloride is 1:(1-3):(1-3), preferably 1: (1～2):(1～2)； (3) The reaction temperature of step A is 50-70°C; (4) The reaction time of step A is 15 to 24 hours, preferably 18 to 22 hours; (5) The solvent used in step A is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N'-dimethylformamide (DMF), ethyl acetate, and acetonitrile, preferably DMF and acetonitrile; (6) The organic base in step B is selected from one or more of N,N-diisopropylethylamine DIPEA, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, preferably one or more of DIPEA, triethylamine, diisopropylamine, pyridine; (7) In step B, the molar ratio of the compound of formula 7, the compound of formula 4, the organic base and DMAP is 1:(1-2):(1-3): (0.1~0.5), preferably 1:(1~1.5):(1~2.5):(0.1~0.4); (8) The solvent used in step B is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, preferably one or more of dichloromethane, THF, dichloroethane, and chloroform; (9) The reaction temperature of step B is -10 to 30°C; (10) The reaction time of step B is 0.5 to 8 h, preferably 1 to 4 h.

8. The method according to claim 3, characterized in that The preparation method satisfies one or more of the following conditions: (1) The base in step 1 is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide, preferably potassium carbonate, sodium carbonate, and cesium carbonate; (2) In step 1, the molar ratio of the compound of formula 6, hydrogen peroxide and base is 1:(1-4):(1-4), preferably 1:(2-3):(2-3); (3) The solvent used in step 1 is selected from DMSO, tetrahydrofuran, acetonitrile, and dichloromethane; (4) The reaction temperature of step 1 is 20°C to 40°C, preferably 20°C to 35°C; (5) The reaction time of step 1 is 12 to 25 hours, preferably 15 to 20 hours; (6) The organic base in step 2 is selected from one or more of N,N-diisopropylethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, preferably one or more of DIPEA, triethylamine, diisopropylamine, pyridine; (7) In step 2, the molar ratio of the compound of formula 5, the compound of formula 4, the organic base and DMAP is 1:(1-2):(1-3): (0.1~0.5), preferably 1:(1~1.5):(1~2.5):(0.1~0.4); (8) The solvent used in step 2 is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, preferably one or more of dichloromethane, THF, dichloroethane, and chloroform; (9) The reaction temperature of step 2 is -10 to 30°C, preferably -10 to 25°C; (10) The reaction time of step 2 is 0.5 to 8 h, preferably 1 to 4 h.

9. A potassium ion competitive blocker intermediate, the structural formula of which is as follows: R1 is H, F; R2 is F, -O(CH2)3OCH3; R3 and R5 are independently selected from H and OCH3; R4 is C, N; And in the compound of formula 2, R1 and R2 are not F at the same time; In the compounds of formula 5, 6, 7 and 8, R1 and R3 are not H at the same time.

10. A method for preparing a compound of formula 1 which is a potassium ion competitive blocker, comprising using the method for preparing the compound of formula 2 as claimed in claim 2 or using the potassium ion competitive blocker intermediate compound as claimed in claim 9 to prepare the compound of formula 1.

Images