A method for recovering a tegoprazan key intermediate mother liquor

Abstract

The application discloses a recovery method of tegoprazan key intermediate mother liquor material, and belongs to the field of resource recycling. The recovery method comprises the following steps: (1) dissolving the tegoprazan key intermediate mother liquor material with an organic solvent; (2) performing oxidation under the condition of an oxidizing agent to obtain an oxide; and (3) performing purification treatment on the oxide to obtain a recovery product. The recovery method provided by the application realizes resource recycling of the tegoprazan key intermediate production process, and reduces economic losses caused by low crystallization yield. The recovery method of the tegoprazan key intermediate mother liquor material provided by the application is simple, has high purification purity, and has high product yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of resource recycling, and in particular to a recovery method of a Tegoprazan key intermediate mother liquor. BACKGROUND

[0002] Tegoprazan (also known as Tezepelum) is mainly used for the treatment of gastroesophageal reflux disease and erosive esophagitis. Its structural formula is as follows:

[0003]

[0004] Pfizer discloses a route for synthesizing Tegoprazan using a key intermediate (4R)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-ol, which is shown as formula I:

[0005]

[0006] Chinese patent CN107849003A discloses a preparation method of formula I compound, i.e. using 5,7-difluoro-chroman-4-one as raw material and adopting chiral ruthenium catalyst for reduction. The yield of the obtained formula I compound is 91%, and the chiral purity is 100% ee. In this method, the ruthenium reagent involved is difficult to purchase and expensive.

[0007] Chinese patent CN115029397A discloses the preparation of formula I compound using ketoreductase, but does not disclose the sequence number of the enzyme. Chinese patent CN101341149B discloses a preparation method of formula I compound, i.e. adding a tetrahydrofuran solution of 5,7-difluoro-chroman-4-one to a mixed solution composed of chiral reagent (S)-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole, borane-dimethyl sulfide complex and tetrahydrofuran at 0℃. After the reaction is completed, column chromatography is used for purification, and then recrystallization with hexane is performed to obtain formula I compound with optical purity >99% ee and yield of 58%. This method has low yield and low economic benefit.

[0008] Chinese patent CN112851646A optimizes the preparation process of formula I compound, adopts the method of slowly dropping the tetrahydrofuran solution of 5,7-difluoro-chroman-4-one to control the chiral purity, and does not need column chromatography purification in post-treatment. Formula I compound with optical purity >99% ee is obtained by direct recrystallization with ethyl acetate / n-hexane, and the yield is 66%. Although the yield of this method is improved to a certain extent, the yield is still low and the crystallization loss is large.

[0009] In view of the prior art, after crystallization and purification of the compound of formula I, the yield is low, and the mother liquor material still contains more than 90wt% of 5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-ol, and the chiral purity is low, the mother liquor material cannot be recycled, and the overall cost is high. Therefore, it is of great significance to develop a method for recycling the mother liquor material for the synthesis of tegoprazan. SUMMARY

[0010] The present application provides a method for recycling the mother liquor material of a key intermediate of tegoprazan to solve the problems in the prior art, and the recovered product has high purity and high yield, effectively reducing the synthesis cost of tegoprazan.

[0011] To solve the above technical problems, the present application adopts the following technical solutions:

[0012] A method for recycling the mother liquor material of a key intermediate of tegoprazan, the mother liquor material of the key intermediate of tegoprazan contains a compound of formula II, and the recovered product has a structure of formula III,

[0013]

[0014] The recycling method is to oxidize the mother liquor material of the key intermediate of tegoprazan with an oxidizing agent to obtain an oxidation product, and then purify the oxidation product to obtain a recovered product.

[0015] Preferably, the reaction formula of the oxidation reaction is as follows:

[0016]

[0017] Preferably, the recycling method comprises the following steps:

[0018] (1) Dissolving the mother liquor material of the key intermediate of tegoprazan with an organic solvent to obtain a mother liquor material solution;

[0019] (2) Adding an oxidizing agent to the mother liquor material solution to perform an oxidation reaction to obtain an oxidation product;

[0020] (3) Purifying the oxidation product to obtain a recovered product.

[0021] Further preferably, in step (1), the organic solvent is selected from at least one of dichloromethane, chloroform, and acetonitrile;

[0022] More preferably, the organic solvent is dichloromethane.

[0023] Further preferably, in step (1), the ratio of the organic solvent to the mother liquor material is 5-10mL:1g.

[0024] Further preferably, in step (2), the oxidizing agent is selected from at least one of sodium hypochlorite, calcium hypochlorite, PDC (pyridinium dichromate), PCC (pyridinium chlorochromate).

[0025] Still further preferably, the oxidizing agent is sodium hypochlorite.

[0026] Further preferably, in step (2), the molar ratio of the oxidizing agent to the compound of formula II in the mother liquor is 1.2-3.0:1.0.

[0027] Further preferably, in step (2), the temperature of the oxidation reaction is 0-30℃, and the reaction time is 1-4h.

[0028] Further preferably, in step (2), the purification method of the oxidation product is recrystallization.

[0029] Still further preferably, the recrystallization requires a solvent, and the recrystallization solvent is a mixed solvent of a good solvent and a poor solvent, selected from at least one of methanol / water, ethanol / water, isopropanol / water, ethyl acetate / petroleum ether, isopropyl acetate / petroleum ether, dichloromethane / petroleum ether, toluene / petroleum ether.

[0030] Still further preferably, in the recrystallization solvent, the volume ratio of the good solvent to the poor solvent is 1:5-20.

[0031] Further preferably, the tegoprazan key intermediate mother liquor is a mother liquor produced in the preparation of the tegoprazan key intermediate compound of formula I,

[0032]

[0033] Still further preferably, the preparation route of the compound of formula I is as follows:

[0034]

[0035] Still further preferably, the preparation process of the tegoprazan key intermediate mother liquor comprises the following steps:

[0036] The reaction of 5,7-difluoro-chroman-4-one with S-Me-CBS, borane dimethyl sulfide complex is carried out, and the obtained reaction product is purified by recrystallization to obtain the compound of formula I. The residual liquid after recrystallization is the mother liquor of the compound of formula I. The solvent in the mother liquor of the compound of formula I is removed under reduced pressure to obtain the tegoprazan key intermediate mother liquor.

[0037] Preferably, the tegoprazan key intermediate mother liquor contains 90wt% or more of 5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-ol, wherein the R configuration accounts for 60-70%, and the S configuration accounts for 30-40%.

[0038] Compared with the prior art, the present application has the following beneficial effects:

[0039] The method provided by the present application realizes the resource recycling of mother liquor in the production process of the key intermediate of tegoprazan, reduces the economic loss caused by low crystallization yield. The recovery method of the present application is simple to operate, the reagents used are common reagents, the purification purity is high, the product yield is high, and the production cost of the key intermediate of tegoprazan is greatly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 Chiral purity spectrum of the compound of formula I prepared in Example 1.

[0041] Figure 2 Chiral purity spectrum of the mother liquor of the compound of formula I prepared in Example 2.

[0042] Figure 3 Liquid phase purity spectrum of the mother liquor of the compound of formula I prepared in Example 2.

[0043] Figure 4 Liquid phase purity spectrum of the compound of formula III prepared in Example 6.

[0044] Figure 5 Liquid phase purity spectrum of the compound of formula III prepared in Comparative Example 1. DETAILED DESCRIPTION

[0045] The following non-limiting examples can enable those of ordinary skill in the art to more fully understand the present application, but in no way limit the present application. The following content is only an exemplary description of the scope of the present application, and those skilled in the art can make various changes and modifications to the present application according to the disclosed content, and it should also belong to the scope of the present application.

[0046] When the examples give numerical ranges, it should be understood that, unless otherwise specified by the present application, each numerical range has two endpoints and any number between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as generally understood by those skilled in the art to which the present application belongs.

[0047] The present application will be further described in the following specific examples. Unless otherwise specified, the experimental methods in the following examples are all conventional methods. Unless otherwise specified, the various chemical reagents used in the examples of the present application are obtained through conventional commercial channels. Among them, 3,5-difluorophenol, sulfuric acid, dichloromethane, sodium hypochlorite, sodium bicarbonate, TEMPO used in the specific examples of the present application are all self-owned products of the company; acrylonitrile, copper hydroxide are purchased from An'ailing reagent.

[0048] In the following examples, the stirring, refluxing reaction, temperature control and other operations are carried out using the instruments commonly used in the art: the manufacturers of the instruments are Taizhou Xindeli Instrument Co., Ltd.; the manufacturers of the instruments for detecting the purity of the products are Agilent Technologies.

[0049] In the following examples, the yield = actual weight / theoretical weight x 100%;

[0050] The purity is detected by high performance liquid chromatography (HPLC).

[0051] Example 1

[0052] Preparation of the compound of formula I

[0053] The preparation route of the compound of formula I is as follows:

[0054]

[0055] Synthesis of formula I-1:

[0056] Into the reaction bottle, add (130 g, 1.00 mol) compound 3,5-difluorophenol, (210 g, 3.95 mol) acrylonitrile, stir and dissolve, add (100 g, 1.03 mol) copper hydroxide, heat to 80°C, reflux for 48 h, after the reaction is complete, cool to room temperature, concentrate under reduced pressure, add 500 mL dichloromethane and 1 L purified water, stir and separate the layers, wash the organic layer with 500 mL purified water, separate the layers, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the organic layer under reduced pressure to remove the organic solvent to obtain formula I-1 (110 g, 60%).

[0057] Synthesis of formula III:

[0058] Into the glass reaction bottle containing 300 g of concentrated sulfuric acid, add (110 g) formula I-1 obtained in the previous step, heat to 50°C, and keep the reaction, after the reaction is complete, add 1 L of pre-cooled purified water dropwise, add 1.1 L of dichloromethane, stir and dissolve, adjust the pH to 7 with 5% sodium bicarbonate solution, separate the layers, remove the organic solvent from the organic phase under reduced pressure, add 550 mL of n-heptane, stir, filter, and dry the filter cake at 40°C to obtain the compound of formula III (90 g, 80%).

[0059] Synthesis of formula I:

[0060]

[0061] Into a 3 L three-necked flask, anhydrous THF (660 mL) and S-Me-CBS (1 mol / L in toluene, 90 mL, 90 mmol) were added, and the mixture was protected by argon. Borane dimethyl sulfide complex (10 mol / L, 99 mL, 990 mmol) was added dropwise into the above mixture at room temperature. The dropwise addition was completed in 5.5 hours. After the dropwise addition was completed, the mixture was allowed to stand overnight. The reaction mixture was slowly poured into methanol cooled in an ice water bath, and a large amount of bubbles were generated. The mixture was stirred until no obvious bubbles were generated. The solvent was removed by concentration. 1000 mL of ethyl acetate was added to dissolve the mixture. The organic phase was washed with water (500 mL, 300 mL) and 10% brine (200 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oil. The oil was allowed to stand at room temperature to obtain a yellow solid. The chiral purity of the solid was determined by chiral HPLC (OZ-H column, n-hexane / isopropyl alcohol = 95 / 5, flow rate = 1 mL / min, detection wavelength = 220 nm), and the chiral purity was 93.6% ee. The solid was dissolved in a mixed solvent of n-hexane and ethyl acetate (n-hexane / ethyl acetate = 17:1) by heating, and recrystallization was performed to obtain 111 g of needle-shaped crystals at a yield of 66.5%. The chiral purity of the crystals was determined by chiral HPLC, and the chiral purity was >99.9% ee. The chiral purity spectrum of the crystals is shown in FIG. 1, and the liquid phase purity spectrum is shown in FIG. 2. Figure 1 The remaining liquid was a mother liquor of compound I (formula I).

[0062] Example 2

[0063]

[0064] The mother liquor of compound I (formula I) (Example 1) was subjected to solvent removal under reduced pressure to obtain a mother liquor of compound I (a mother liquor of a key intermediate of tegoprazan). The purity of the mother liquor was 94% by HPLC detection, and the chiral purity was <40% ee. The chiral purity spectrum of the mother liquor of compound I is shown in FIG. 3, and the liquid phase purity spectrum is shown in FIG. 4. Figure 2 Figure 3

[0065] ​​Take compound I mother liquor (10 g, 50 mmol), 100 g DCM, 4.2 g of 50 mmol sodium bicarbonate, 78 mg of 0.5 mmol TEMPO, 1.1 g of 10 mmol sodium bromide, 10 g of drinking water, cooling to 0 ℃, drop 48 g of sodium hypochlorite solution (10% concentration, 64.8 mmol), incubation reaction, after the reaction is complete, drop into 10% sodium thiosulfate solution (128 g) to quench the reaction, separate the layers, the aqueous phase is extracted with 50 g of dichloromethane, the two organic phases are combined, the organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, the residue is dissolved in 60 g of methanol aqueous solution (10 g of methanol + 50 g of water), cooled to 10 ℃, filtered, and dried at 40 ℃ to obtain compound III (compound of formula III) 8.5 g, yield 85.9%, purity 99.5%.

[0066] Example 3-8

[0067] Referring to Example 2, sodium hypochlorite is used as the oxidizing agent, and the difference is that the solvent system for recrystallization in the purification process is different, and the volume ratio of good solvent and poor solvent is 1:5, and the purification results are as follows:

[0068] Example Purification recrystallization solvent Purity Yield Example 3 Ethanol / water 99.0％ 87.8％ Example 4 Isopropanol / water 99.1％ 87.5％ Example 5 Ethyl acetate / petroleum ether 99.5％ 90.5％ Example 6 Isopropyl acetate / petroleum ether 99.9％ 92.5％ Example 7 Toluene / petroleum ether 98.5％ 91.5％ Example 8 Dichloromethane / petroleum ether 98.8％ 90.5％

[0069] Conclusion: the use of isopropyl acetate / petroleum ether system for crystallization has the highest yield and the best impurity removal effect. The liquid phase purity spectrum of compound III (compound of formula III) prepared in Example 6 is shown in Figure 1. Figure 4

[0070] Example 9

[0071]

[0072] Take compound I mother liquor (10 g, 50 mmol), 100 g DCM, (4.2 g, 50 mmol) sodium bicarbonate, (78 mg, 0.5 mmol) TEMPO, (1.1 g, 10 mmol) sodium bromide, 10 g of drinking water, cooling to 0 ℃, drop 46 g of calcium hypochlorite solution (10% concentration, 32.4 mmol), incubation reaction, after the reaction is complete, drop into 10% sodium thiosulfate solution (128 g) to quench the reaction, separate the layers, the aqueous phase is extracted with 50 g of dichloromethane, the two organic phases are combined, the organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, the residue is recrystallized with 10 g of isopropyl acetate and 50 g of petroleum ether, filtered, and dried at 40 ℃ to obtain compound III (compound of formula III) 9.0 g, yield 89.0%, purity 99.7%.

[0073] Example 10

[0074] ​

[0075] Into a 250 mL three-necked flask, compound I mother liquor (10 g, 50 mmol), 100 g dichloromethane, 10 g 3A molecular sieve, PCC (17.5 g, 81 mmol) were added in turn under nitrogen protection, stirred, reacted at room temperature for 3 hours, the reaction was complete, filtered, 50 g dichloromethane was used to wash the filter cake, concentrated under reduced pressure to obtain a residue, the residue was recrystallized with 10 g isopropyl acetate and 50 g petroleum ether, filtered, dried at 40°C to obtain compound III (compound of formula III) 8.4 g, yield 84.9%, purity 98.5%.

[0076] Example 11

[0077]

[0078] Into a 250 mL three-necked flask, compound I mother liquor (10 g, 50 mmol), 100 g dichloromethane, 10 g 3A molecular sieve, PCC (17.5 g, 81 mmol) were added in turn under nitrogen protection, stirred, reacted at room temperature for 3 hours, the reaction was complete, filtered, 50 g dichloromethane was used to wash the filter cake, concentrated under reduced pressure to obtain a residue, the residue was recrystallized with 10 g isopropyl acetate and 50 g petroleum ether, filtered, dried at 40°C to obtain compound III (compound of formula III) 8.4 g, yield 84.9%, purity 98.5%.

[0079] Comparative Example 1

[0080] Into a 250 mL three-necked flask, compound I mother liquor (10 g, 50 mmol), 100 g dichloromethane, 10 g 3A molecular sieve, PCC (17.5 g, 81 mmol) were added in turn under nitrogen protection, stirred, reacted at room temperature for 3 hours, the reaction was complete, filtered, 50 g dichloromethane was used to wash the filter cake, concentrated under reduced pressure to obtain a residue, the residue was recrystallized with 10 g isopropyl acetate and 50 g petroleum ether, filtered, dried at 40°C to obtain compound III (compound of formula III) 8.4 g, yield 84.9%, purity 98.5%. Figure 5 The liquid chromatography purity spectrum of compound III (compound of formula III) prepared in Comparative Example 1 is shown in FIG. 1.

[0081] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A process for recovery of a mother liquor stream of a key intermediate of tegoprazan characterized in that, The tiglycerazan key intermediate mother liquor is subjected to oxidation reaction with an oxidizing agent sodium hypochlorite, and the oxidation product is subjected to recrystallization purification, and the recrystallization solvent is a mixed solvent of a good solvent and a poor solvent, to obtain a recovered product; The recrystallization solvent is at least one selected from ethyl acetate / petroleum ether, isopropyl acetate / petroleum ether, dichloromethane / petroleum ether, and toluene / petroleum ether; The tiglycerazan key intermediate mother liquor contains a compound of formula II, and the recovered product has a structure of formula III, ， ； The tiglycerazan key intermediate mother liquor is a mother liquor produced in the preparation of a tiglycerazan key intermediate compound of formula I, and the compound of formula I has the following structure: ； The preparation process of the tiglycerazan key intermediate mother liquor comprises the following steps: ； The 5,7-difluoro-chroman-4-one is reacted with S-Me-CBS and borane dimethyl sulfide complex, and the obtained reaction product is subjected to recrystallization purification to obtain a compound of formula I, and the residual liquid after recrystallization is a compound I mother liquor, and the compound I mother liquor is subjected to solvent removal under reduced pressure to obtain the tiglycerazan key intermediate mother liquor.

2. The recycling method according to claim 1, characterized in that, The method comprises the following steps: (1) The tiglycerazan key intermediate mother liquor is dissolved with an organic solvent to obtain a mother liquor solution; (2) An oxidizing agent is added to the mother liquor solution to perform oxidation reaction, and an oxidation product is obtained; (3) The oxidation product is purified to obtain a recovered product.

3. The recycling method according to claim 2, characterized in that, In step (1), the organic solvent is at least one selected from dichloromethane, chloroform, and acetonitrile, and the ratio of the organic solvent to the mother liquor is 5-10 mL:1 g.

4. The recycling method according to claim 3, characterized in that, In step (1), the organic solvent is dichloromethane.

5. The recycling method of claim 1, wherein, The molar ratio of the oxidizing agent to the compound of formula II in the mother liquor is 1.2-3.0:1.

0.

6. The recycling method of claim 1, wherein, The oxidation reaction is performed at a temperature of 0-30℃ for 1-4 h.

7. The recycling method of claim 1, wherein, In the recrystallization solvent, the volume ratio of the good solvent to the poor solvent is 1:5-20.

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